Medical Physiology

A Systems Approach

Hershel Raff, PhD

Professor
Departments of Medicine and Physiology
Medical College of Wisconsin
Endocrine Research Laboratory
Aurora St. Luke’s Medical Center
Milwaukee, Wisconsin

Michael Levitzky, PhD

Professor of Physiology and Anesthesiology
Louisiana State University Health Sciences Center
New Orleans, Louisiana

Medical
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To our students, mentors, colleagues, and families.
iv
KEY FEATURES v
About the Authors
Hershel Raff
Hershel Raff received his
Ph.D. in Environmental
Physiology from the Johns
Hopkins University in 1981
and did postdoctoral training
in Endocrinology at the
University of California at
San Francisco. He joined the
faculty at the Medical College
of Wisconsin in 1983, and rose
to the rank of Professor of Medicine (Endocrinology,
Metabolism, and Clinical Nutrition) and Physiology
in 1991. He is also Director of the Endocrine Research
Laboratory at Aurora St. Luke’s Medical Center. At the
Medical College of Wisconsin, he teaches physiology
and pharmacology to medical and graduate students.
He was an inaugural inductee into the Society of
Teaching Scholars, received the Beckman Basic
Science Teaching Award and the Outstanding Teacher
Award, and has been one of the MCW’s Outstanding
Medical Student Teachers each year the award has
been given. Dr Raff was elected to Alpha Omega
Alpha (AOA) Honor Medical Society as a faculty
teacher in 2005. He is also an Adjunct Professor of
Biomedical Sciences at Marquette University. He is
Associate Editor of Advances in Physiology Education.
He was Secretary-Treasurer of the Endocrine Society
and is currently Chair of the Publications Committee
of the American Physiological Society. He was
elected a Fellow of the American Association for the
Advancement of Science in 2005. Dr. Raff ’s basic
research focuses on the adaptation to low oxygen
(hypoxia). His clinical interest focuses on pituitary and
adrenal diseases, with a special focus on the diagnosis
of Cushing’s syndrome. Dr. Raff is also a co-author of
Vander’s Human Physiology (McGraw-Hill) currently
in its 12th Edition, and Physiology Secrets, currently in
its 2nd Edition.
vi
Michael Levitzky
Michael Levitzky is Professor of
Physiology and Anesthesiology
at the Louisiana State University
Health Sciences Center and
is Director of Basic Science
Curriculum at the LSU School
of Medicine in New Orleans.
He received a B.A. from the
University of Pennsylvania in
1969 and a Ph.D. in Physiology
from Albany Medical College in 1975. He joined
the faculty of the LSU School of Medicine in 1975,
rising to the rank of Professor in 1985. He has also
been Adjunct Professor of Physiology at Tulane
University School of Medicine since 1991. Dr.
Levitzky teaches physiology to medical students,
residents, fellows, and graduate students. He has
received numerous teaching awards from student
organizations at both LSU and Tulane. He received
the inaugural LSUHSC Allen A. Copping Award for
Excellence in Teaching in the Basic Sciences in 1997
and the American Physiological Society’s Arthur C.
Guyton Teacher of the Year Award in 1998. He was
elected to the Alpha Omega Alpha (AOA) Honor
Medical Society as a faculty teacher in 2006. Dr.
Levitzky has served the American Physiological
Society as a member of the Education Committee
and as a member of the Steering Committee of the
Teaching Section. He served as a member of the
National Board of Medical Examiners United States
Medical Licensing Examination (USMLE) Step 1
Physiology Test Material Development Committee
from 2007-2011. He is the author or co-author of
several other textbooks, one of which, Pulmonary
Physiology (Lange/McGraw-Hill), is currently in its
7th edition.
Contents
Contributors xi
Preface xiii

S E C T I O N I 10. Cardiac Muscle Structure and Function 93

INTRODUCTION 1 Kathleen H. McDonough
11. Smooth Muscle Structure and Function 99
1. General Physiological Concepts 1 Kathleen H. McDonough
Hershel Raff and Michael Levitzky

S E C T I O N II
S E C T I O N IV
CNS/NEURAL PHYSIOLOGY 105
CELL PHYSIOLOGY 9
12. Introduction to the Nervous System 105
2. Cells and Cellular Processes 9 Susan M. Barman
David Landowne
13. General Sensory Systems: Touch, Pain,
3. Cell Membranes and Transport and Temperature 115
Processes 15 Susan M. Barman
David Landowne
14. Spinal Reflexes 125
4. Channels and the Control of Membrane Susan M. Barman
Potential 33
David Landowne 15. Special Senses I: Vision 133
Susan M. Barman
5. Sensory Generator Potentials 43
David Landowne 16. Special Senses II: Hearing and
Equilibrium 147
6. Action Potentials 47 Susan M. Barman
David Landowne
17. Special Senses III: Smell and Taste 159
7. Synapses 59 Susan M. Barman
David Landowne
18. Control of Posture and Movement 167
Susan M. Barman
S E C T I O N III 19. Autonomic Nervous System 177
MUSCLE PHYSIOLOGY 79 Susan M. Barman
8. Overview of Muscle Function 79 20. Electrical Activity of the Brain, Sleep–Wake
Kathleen H. McDonough States, and Circadian Rhythms 185
Susan M. Barman
9. Skeletal Muscle Structure and Function 83
Kathleen H. McDonough 21. Learning, Memory, Language,
and Speech 191
Susan M. Barman

vii
viii CONTENTS
S E C T I O N V and Causes of Hypoxia 375
CARDIOVASCULAR
PHYSIOLOGY 199
22. Overview of the Cardiovascular
System 199
Lois Jane Heller and David E. Mohrman
23. Cardiac Muscle Cells 211
Lois Jane Heller and David E. Mohrman
24. The Heart Pump 223
Lois Jane Heller and David E. Mohrman
25. Cardiac Function Assessments 235
Lois Jane Heller and David E. Mohrman
26. Peripheral Vascular System 251
David E. Mohrman and Lois Jane Heller
27. Vascular Control 263
David E. Mohrman and Lois Jane Heller
28. Venous Return and Cardiac Output 275
David E. Mohrman and Lois Jane Heller
29. Arterial Pressure Regulation 285
David E. Mohrman and Lois Jane Heller
30. Cardiovascular Responses to
Physiological Stress 295
Lois Jane Heller and David E. Mohrman
S E C T I O N VI
PULMONARY PHYSIOLOGY 305
31. Function and Structure of the
Respiratory System 305
Michael Levitzky
32. Mechanics of the Respiratory System 313
Michael Levitzky
33. Alveolar Ventilation 331
Michael Levitzky
34. Pulmonary Perfusion 341
Michael Levitzky
35. Ventilation–Perfusion Relationships
and Respiratory Gas Exchange 353
Michael Levitzky
36. Transport of Oxygen and
Carbon Dioxide 363
Michael Levitzky
37. Acid–Base Regulation
Michael Levitzky
38. Control of Breathing 385
Michael Levitzky
S E C T I O N VII
RENAL PHYSIOLOGY 397
39. Renal Functions, Basic Processes,
and Anatomy 397
Douglas C. Eaton and John P. Pooler
40. Renal Blood Flow and
Glomerular Filtration 409
Douglas C. Eaton and John P. Pooler
41. Clearance 417
Douglas C. Eaton and John P. Pooler
42. Tubular Transport Mechanisms 423
Douglas C. Eaton and John P. Pooler
43. Renal Handling of Organic Substances 429
Douglas C. Eaton and John P. Pooler
44. Basic Renal Processes for Sodium,
Chloride, and Water 437
Douglas C. Eaton and John P. Pooler
45. Regulation of Sodium and
Water Excretion 449
Douglas C. Eaton and John P. Pooler
46. Regulation of Potassium Balance 463
Douglas C. Eaton and John P. Pooler
47. Regulation of Acid–Base Balance 471
Douglas C. Eaton and John P. Pooler
48. Regulation of Calcium and
Phosphate Balance 485
Douglas C. Eaton and John P. Pooler
S E C T I O N VIII
GI PHYSIOLOGY 491
49. Overview of the GI System—Functional
Anatomy and Regulation 491
Kim E. Barrett
50. Gastric Secretion 507
Kim E. Barrett
 CONTENTS ix

51. Pancreatic and Salivary Secretion 517 62. Anterior Pituitary Gland 623
Kim E. Barrett Patricia E. Molina
52. Water and Electrolyte Absorption 63. Thyroid Gland 633
and Secretion 527 Patricia E. Molina
Kim E. Barrett
64. Parathyroid Gland and Calcium
53. Intestinal Mucosal Immunology and Phosphate Regulation 643
and Ecology 535 Patricia E. Molina
Kim E. Barrett
65. Adrenal Gland 655
54. Intestinal Motility 543 Patricia E. Molina
Kim E. Barrett
66. Endocrine Pancreas 671
55. Functional Anatomy of the Liver Patricia E. Molina
and Biliary System 559
67. Male Reproductive System 683
Kim E. Barrett
Patricia E. Molina
56. Bile Formation, Secretion, 68. Female Reproductive System 695
and Storage 565
Patricia E. Molina
Kim E. Barrett
69. Endocrine Integration of Energy
57. Handling of Bilirubin and Ammonia and Electrolyte Balance 715
by the Liver 575
Patricia E. Molina
Kim E. Barrett
58. Digestion and Absorption of
Carbohydrates, Proteins, S E C T I O N X
and Water-soluble Vitamins 583 INTEGRATIVE PHYSIOLOGY 729
Kim E. Barrett
59. Lipid Assimilation 593 70. Control of Body Temperature 729
Kim E. Barrett Hershel Raff and Michael Levitzky
71. Hypoxia and Hyperbaria 735
S E C T I O N IX Michael Levitzky and Hershel Raff
ENDOCRINE AND METABOLIC 72. Exercise 745
PHYSIOLOGY 601 Michael Levitzky and Kathleen H. McDonough
73. Aging 753
60. General Principles of Endocrine Hershel Raff
Physiology 601
Patricia E. Molina
61. The Hypothalamus and Posterior Answers to Study Questions 757
Pituitary Gland 613 Index 761
Patricia E. Molina
This page intentionally left blank
Contributors

Susan M. Barman, PhD Kathleen H. McDonough, PhD

Professor Professor
Department of Pharmacology & Toxicology and Department of Physiology
Neuroscience Program Associate Dean, School of Graduate Studies
Michigan State University Louisiana State University Health Sciences Center
East Lansing, Michigan New Orleans, Louisiana
Kim E. Barrett, PhD Patricia E. Molina, MD, PhD
Professor of Medicine and Dean of Graduate Studies Richard Ashman, PhD Professor and Head of Physiology
University of California, San Diego Department of Physiology
La Jolla, California Louisiana State University Health Sciences Center
New Orleans, Louisiana
Douglas C. Eaton, PhD
Distinguished Professor and Chair of Physiology and David E. Mohrman, PhD
Professor of Pediatrics Associate Professor, Emeritus
Department of Physiology and Department of Physiology and Pharmacology
Center for Cell & Molecular Signaling University of Minnesota Medical School
Emory University School of Medicine Duluth, Minnesota
Atlanta, Georgia
John P. Pooler, PhD
Lois Jane Heller, PhD Professor of Physiology Emeritus
Professor Emory University School of Medicine
Department of Physiology and Pharmacology Atlanta, Georgia
University of Minnesota Medical School
Hershel Raff, PhD
Duluth, Minnesota
Professor
David Landowne, PhD Departments of Medicine and Physiology
Professor Medical College of Wisconsin
Department of Physiology and Biophysics Endocrine Research Laboratory
University of Miami, Miller School of Medicine Aurora St. Luke’s Medical Center
Miami, Florida Milwaukee, Wisconsin
Michael Levitzky, PhD
Professor of Physiology and Anesthesiology
Louisiana State University Health Sciences Center
New Orleans, Louisiana

xi
This page intentionally left blank
Preface
Medical Physiology: A Systems Approach is intended to pro-
vide first-year medical and graduate students and advanced
undergraduate students with the basis of the major physiolog-
ical processes necessary for understanding both health and
disease. The curriculum of many medical schools is changing;
most medical schools have undergone, or are in the midst of,
a transition from the block approach, with each discipline
having its own course, to a vertically integrated structure. One
of the goals of an integrated curriculum is the presentation of
much more clinical material during the first two years of med-
ical school as well as the reinforcement of basic concepts in the
two primarily clinical years. As a result, there is an increasing
focus on the essential concepts necessary to understand
pathophysiology.
Therefore, this book is considerably shorter than the full-
length, standard physiology textbook. It focuses on major
physiological concepts and clinical correlates, and leaves the
minute details to larger books. Most of this book evolved from
the Lange Physiology Series of monographs. The section on the
central nervous system arose from the 23rd edition of Ganong’s
Review of Medical Physiology. Finally, the Introduction, Muscle
Physiology, and Integrative Physiology sections are new.
Each chapter begins with a list of objectives and concludes
with a chapter summary. Most chapters also end with a clinical
correlation that reinforces the major physiological principles
just learned, and illustrates their importance to understanding
disease states. Each chapter ends with multiple-choice ques-
tions designed to test the knowledge of some of the major con-
cepts covered in the chapter.
The authors are indebted to our mentors who provided us
with a foundation for advances in physiological education in
the 21st century. We also thank our students for providing a
sounding board for the pedagogical approaches exploited in
this book. The authors are thankful to Michael Weitz, Karen
Davis, and Brian Kearns at McGraw-Hill for their outstanding
editorial help. Finally, we give special thanks to our families:
Judy and Jonathan; and Elizabeth, Edward, and Sarah.
Hershel Raff
Michael Levitzky
xiii
This page intentionally left blank
 SECTION I INTRODUCTION

1
C H A P T E R

General Physiological
Concepts
Hershel Raff and Michael Levitzky

O B J E C T I V E S

■ Understand the general properties of a eukaryotic cell.

■ Explain the general organization of the internal organs of
the body.
■ Compare and contrast the composition of extracellular versus
intracellular fluid.
■ Describe the different types of membrane transport.
■ Understand the general concepts of pressure, flow, resistance,
and compliance.
■ Explain mass balance.
■ Define negative and positive feedback.

INTRODUCTION caused by disease or injury. Therefore, physiology is one of

Physiology is the science of the function of organisms. The
object of physiology is to explain how the organ systems, cells,
and even molecules interact to maintain normal function.
The hallmark of physiology is the concept of homeostasis,
which is the maintenance of a normal internal environment
in the face of external and internal perturbations so that the
functions of the cells and organ systems of the body are main-
tained. This is accomplished primarily by feedback systems
such that when a system is disturbed, a variety of local
responses, systemic reflexes (automatic, rapid reactions
to stimuli), and long-term adjustments are activated to
return the system to its normal set point. By understanding
how things work under normal conditions, one can appreci-
ate when and why there is a malfunction. This is called
pathophysiology—a lasting disturbance in normal function
the foundations of the health sciences.
THE CELL
The basic building block of the organs of the body is the
cell. The details of cell physiology are covered in Section 2.
Figure 1–1 shows the general structure of a nucleated
(eukaryotic) cell. It is surrounded by a cell membrane that is
composed of a lipid bilayer, membrane proteins, and car-
bohydrates in association with lipids (glycolipids) or pro-
teins (glycoproteins). The cell membrane is the gatekeeper
for anything that enters or leaves the cell and is a barrier that
helps to maintain the internal composition of the cell. Some
membrane proteins and glycoproteins function as sensors,
or receptors, which sense the external environment and

Ch01_001-008.indd 1 11/26/10 9:50:25 AM

2 SECTION I Introduction

Secretory granules

Golgi
apparatus

Centrioles

Rough
endoplasmic Smooth
reticulum endoplasmic
reticulum

Lysosomes
Nuclear envelope Lipid
droplets

Mitochondrion

Globular heads
Nucleolus

FIGURE 1–1 Diagram showing a hypothetical cell in the center seen with a light microscope. (Adapted with permission from Fawcett DW, et al.
The ultrastructure of endocrine glands, Recent Prog Horm Res. 1969;25:315–380.)

chemical signals, and then signal the interior of the cell, usu- response to stimuli. Some cells contain numerous lipid drop-
ally through chemical second messengers or changes in elec- lets, because fat is hydrophobic and does not dissolve readily
trical activity of the membrane. Other membrane proteins in the aqueous environment of the cytosol. Mitochondria have
function as transporters that regulate the entry or exit of two lipid bilayer membranes in apposition, and are the energy-
substances into or out of the cell. The lipid bilayer structure
and associated proteins of the cell membrane are shown in
Figure 1–2.
The inside of the cell is composed of cytosol, which is a liq- Extracellular fluid
uid consisting primarily of water in which proteins, metabo- Transmembrane
Carbohydrate proteins Phospholipids
lites, fuel, and inorganic ions (called electrolytes) are dissolved. portion of
Also dispersed in the cytosol are a variety of subcellular parti- glycoprotein
cles and organelles. Altogether, the combination of cytosol
and the intracellular structures is called the cytoplasm. The Channel
organelles include the endoplasmic reticulum, which is an
extensive network of membranes inside of which are proteins Integral
proteins
and other important chemicals. The endoplasmic reticulum is
important in many metabolic functions and the packaging of
secretory products. The ribosomes are involved in translation,
Peripheral
which is the synthesis of proteins from messenger protein
RNA (mRNA). These ribosomes are associated with endoplas-
mic reticulum in a combined structure called the rough endo- Polar regions
plasmic reticulum (RER). The Golgi apparatus is associated
with endoplasmic reticulum; the Golgi apparatus packages Nonpolar regions Intracellular fluid
material synthesized in the RER. Lysosomes are intracellu-
lar, membrane-surrounded structures that contain digestive FIGURE 1–2 Organization of the phospholipid bilayer and
enzymes located in granules that are involved in intracellular associated proteins in a biological cell membrane. (Reproduced with
metabolism. Secretory granules contain molecules that the permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed.
cell will release into the extracellular fluid by exocytosis, in McGraw-Hill, 2008.)
 CHAPTER 1 General Physiological Concepts 3

generating organelles. The cytoplasmic organelles are held in
position by filaments and microtubules, arising from the cen-
trosomes, which are also important in the movement of chro-
mosomes during cell division. Finally, the nucleus, also
surrounded by a lipid bilayer membrane called the nuclear
envelope, contains chromatin that is composed of DNA con-
taining the nucleic acid code for cellular differentiation, func-
tion, and replication. DNA contains the genes that encode
mRNAs that are produced from DNA by transcription. Also
contained within the nucleus is the nucleolus, which is the site
of ribosome synthesis.
As you will learn in many chapters in this book, the cell
membrane contains many different types of receptors that
sense extracellular signals that are transduced into intracellu-
lar signals. In addition, there are receptors within the cyto-
plasm and nucleus that respond to signals that enter the cell.
Examples of such signals are steroid hormones such as estro-
gen and testosterone that are lipophilic (“fat-loving”) and, as a
result, can readily diffuse through the cell membrane to exert
an intracellular action.
GENERAL STRUCTURE
OF THE BODY
Figure 1–3 is a diagrammatic representation of the human
body. The organs (e.g., brain and heart) receive nutrients and
eliminate waste products via the circulatory system. The heart
is illustrated as two parts—right and left—as a functional

Central nervous system

Afferent and efferent nerves

O2 CO2 Atmosphere

Right O2 CO2 Lung Left

Heart Heart
Venous Arterial
blood blood
Tissues
Nutrients

Waste products

Endocrine glands

Hormones

Liver GI tract Food &

Synthesis water
Nutrients intake

Metabolism Bile Waste

Kidney Reabsorption

FIGURE 1–3 General

organization of the major organs
Filtration Waste
of the body. Arrows show the
direction of blood flow and flux
Feces
Urine of gases, nutrients, hormones, and
waste products.
4 SECTION I Introduction
depiction even though it is actually one organ. The right side
of the heart receives partially deoxygenated blood returning
from the tissues and pumps blood to the lungs. In the lungs,
oxygen diffuses into the blood from the gas phase for use in
cellular respiration in the body, and carbon dioxide, a waste
product of cellular respiration, is eliminated by diffusion from
the blood into the gas phase. The left side of the heart receives
oxygenated blood from the lung and pumps the blood into the
arterial tree to perfuse the organs of the body. Nutrients, min-
erals, vitamins, and water are taken in by the ingestion of food
and liquids and absorption in the gastrointestinal (GI) tract.
The liver, usually considered part of the GI system, processes
substances absorbed into the blood from the GI tract, and also
synthesizes new molecules such as glucose from precursors.
Metabolic waste products are eliminated by the GI system in
the feces and by the kidney in the urine. The two main integra-
tive controllers of the internal environment are the nervous
and endocrine systems. The nervous system is composed of
the brain, spinal cord, sensory systems, and nerves. The endo-
crine system is composed of ductless glands and scattered
secretory cells distributed throughout the body that release
hormones into the blood in response to metabolic, hormonal,
and neural signals. It is the function of the nervous and endo-
crine systems to coordinate the behavior and interactions of
the organ systems described throughout this book.
Water is the most abundant molecule in the body, constitut-
ing about 50–60% of the total body weight. All cells and organs
exist in an aqueous environment. The intracellular water is the
main component of the cytosol. Water is also the main compo-
nent of the extracellular fluid. The extracellular fluid includes
the interstitial fluid, which bathes the cells of the body, the
blood plasma, which is the liquid component of the blood,
cerebrospinal fluid, which is found only in the central ner-
vous system, synovial fluid, which is found in joints such as
the knee, and lymph, which is a liquid formed from interstitial
fluid that flows back to the circulatory system via the lym-
phatic system. There are significant differences in the compo-
sition of intracellular and extracellular fluids that are very
important in many aspects of cellular function (Table 1–1).
GENERAL PHYSICAL
FACTORS AND CONCEPTS
It is not an accident that physiology and physics come from the
same Greek word physis (nature). It is important that students
of physiology understand the physical forces and factors that
govern body function.
MEMBRANE TRANSPORT
There are several different mechanisms by which molecules
cross the cell membrane either coming into or going out of
the cell. These are all described in detail in Section 2. The sim-
plest is diffusion in which the rate at which a molecule crosses
TABLE 1–1 Composition of extracellular and
intracellular fluids.
Extracellular Intracellular
Concentration (mM) Concentration (mM)
Na+ 140 12
+
K 5 150
2+
Ca 1 0.0001
Mg 2+
1.5 12
−
Cl 100 7
−
HCO3 24 10
Amino acids 2 8
Glucose 4.7 1
Protein 0.2 4
The intracellular concentrations are slightly different for different tissues. The Ca2+
concentrations shown are the free, biologically active ions not bound to proteins.
Total Ca2+ (bound plus free) are considerably higher in extracellular (2.5 mM) and
intracellular (1.5 mM) fluids.
Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human
Physiology, 11th ed. McGraw-Hill, 2008.
the cell membrane is governed by the concentration gradient
and the ease with which each molecule can go through the
cell membrane (permeability); energy expenditure is not
directly required for diffusion, which is why it is sometimes
called passive diffusion. There are also protein transporters
located in the cell membrane that mediate facilitated diffu-
sion of molecules that are too large or hydrophilic to perme-
ate the membrane by simple diffusion. Facilitated diffusion
does not require energy and moves molecules down a concen-
tration gradient. By contrast, active transport is a process of
moving molecules across a cell membrane against a concen-
tration gradient; it can be thought of as a pump that uses
energy to do work.
The movement of water molecules across the cell membrane
also occurs by diffusion from a higher to a lower water “con-
centration.” This is termed osmosis; water moves from a com-
partment with fewer osmotically active particles (higher water
concentration) to a compartment with more osmotically active
particles (lower water concentration). Examples of osmotically
active particles are ions such as sodium, potassium, and chlo-
ride, and organic molecules such as glucose and amino acids.
BUFFERING AND pH
One of the most tightly controlled variables in the body is the
hydrogen ion concentration of the intracellular and extracellu-
lar fluids. This is because most proteins have optimal function
within a very narrow range of pH. Remember that the pH is the
negative logarithm (base 10) of the hydrogen ion concentration
in molar units—when pH is low, the fluid is acidic; when pH is
high, the fluid is alkaline. The body has several mechanisms for

maintaining a normal pH. These are extensively covered in
Sections 6 and 7. The body can rid itself of acid by increasing
the elimination of carbon dioxide from the lungs. This is
because carbon dioxide and hydrogen ion are linked through
chemical reactions to bicarbonate, one of the main buffers in
the body. A buffer is an ionic compound that attenuates changes
in pH by combining with or releasing hydrogen ions. The kid-
neys can also remove hydrogen ion from the body via the com-
plex processes involved in producing urine. Finally, changes in
intracellular and extracellular pH can be prevented by a variety
of buffers in addition to bicarbonate.
HYDROSTATIC FORCES AND
PRESSURE, RESISTANCE, AND
COMPLIANCE
Pressure is defined as force per unit of area. The pressure at the
bottom of a column of liquid increases with the height of the
column and is also dependent on the density of the liquid and
on gravity. The pressure at any point in a column of liquid is
called the hydrostatic pressure, and is the pressure difference
between that point and the top of the column. Hydrostatic pres-
sure differences have many important physiologic consequences,
particularly in blood vessels, as will be seen in Section 5.
The flow of a fluid (a liquid or a gas) is quantified as the
volume of the fluid moving through a vessel per unit of time.
The relationships among pressure, flow, and the resistance
offered by the vessels through which a fluid flows can be com-
plex, but are simplified as follows. The rate of flow of liquid
through a tube is proportional to the difference in pressure
between the two ends of the tube and inversely proportional to
the resistance to flow through the tube. Resistance cannot be
determined directly, but is calculated from the pressure and
flow. If the resistance does not change, increasing the pressure
difference through a tube will increase the flow. If the pressure
difference from one end of the tube to the other does not
NET GAIN TO BODY
Food GI tract
Air Lungs
Synthesis in body
FIGURE 1–4 Concept of mass balance. The central compartment is usually extracellular fluid (which includes blood plasma). It receives
substances from intake, synthesis, and release from cells. It loses substances by excretion, metabolism, and uptake into cells. In the steady state,
when a substance is said to be “in balance,” intake and excretion are nearly equal. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s
Human Physiology, 11th ed. McGraw-Hill, 2008.)
CHAPTER 1 General Physiological Concepts 5
change, increasing the resistance will decrease the flow. If the
flow through the tube does not change, increasing the resis-
tance will increase the pressure difference between the ends
of the tube. The pressure difference between the two ends of
the tube represents energy conversion to heat by the internal
friction of the fluid with itself and with the wall of the vessel.
You will notice that the relationship between pressure, flow,
and resistance for liquid flowing through a tube is analogous
to Ohm’s law for electricity in which the voltage drop across a
circuit (analogous to a pressure drop in a tube with liquid
flowing through it) is proportional to the product of current
(analogous to flow) and resistance.
Most of the vessels or chambers in the body will stretch pas-
sively if the pressure difference across their walls increases.
This results in an increased volume of the vessel. This ability to
stretch in response to an increased transmural (across the
wall) pressure difference is called compliance. A less specific
term for compliance is distensibility.
The inverse of compliance is elastance. Elastance can there-
fore be thought of as the resistance to stretch when the trans-
mural pressure difference increases or as the ability of a vessel
to return to its original volume after the increased transmural
pressure difference is removed. It is directly related to Hooke’s
law of elasticity for mechanical springs.
MASS BALANCE AND
METABOLISM
In order to achieve the steady state that defines homeostasis,
any substance taken in by the body must be nearly equal to
the amount of the substance leaving the body plus that
removed by metabolism (Figure 1–4). The influx of a sub-
stance is the sum of uptake in the lung, absorption in the
GI tract, synthesis in the body (e.g., liver synthesis of glucose
from molecular precursors), and release from cells (e.g., fatty
acid release from adipose tissue). The efflux of a substance is
DISTRIBUTION WITHIN NET LOSS FROM
BODY BODY
Storage depots Metabolism
POOL
Excretion from body
Reversible via lungs, GI tract,
incorporation kidneys, skin,
into other menstrual flow
molecules
6 SECTION I Introduction
the sum of metabolism, uptake into cells, losses via the GI
tract, respiratory system, sweat, and urinary excretion. In the
steady state, the difference between total influx and efflux
should be very close to zero. From minute to minute, there are
obviously large differences between influx and efflux, but over
days to weeks when the substance is usually in balance, the
difference should be close to zero. Examples of this are sodium
balance described in Section 7 and calcium and phosphate
balance described in Section 9.
EXCITABILITY
As you will learn in Sections 2–4, living cells have an electrical
charge difference across the cell membrane created primarily
by differences in ion concentration and movement between
the outside and inside of the cell (see Table 1–1). As a result,
the membranes have a resting electrical potential that can be
changed by a variety of inputs. Dramatic changes in ion flux
across the cell membrane lead to large changes in electrical
potential that can result in major cellular responses. For exam-
ple, muscular contraction described in Section 3 results from
the depolarization of the muscle cell membrane that is trans-
duced into a chemical signal within the cell that leads to the
generation of force and movement.
CELL–CELL INTERACTIONS
As you will learn in Sections 2–4, 8, and 9, cells interact with
each other locally. One mechanism is by direct contact between
cells via tight junctions and gap junctions. Another is the
synapse, in which neurons can release chemicals called neu-
rotransmitters to alter the function of a neighboring cell.
Finally, there are a variety of chemical signals by which cells
can communicate with neighboring cells by diffusion. An
example of this is paracrine signaling by which humoral fac-
tors are released by one cell, diffuse through the interstitial
fluid, and bind to a receptor on a neighboring cell within the
same tissue.
Set
point 100
95
75
Nadir
blood pressure (mm Hg)
Mean arterial
FIGURE 1–5 Moderate hemorrhage as
an example of the gain of a feedback control
system. The higher the gain of a system, the
better able it is to restore a controlled variable
to its set point in response to a perturbation.
CONTROL SYSTEMS
The main focus of physiology is the understanding of the
mechanisms by which cells, organs, and organ systems main-
tain homeostasis. This is accomplished primarily by negative
feedback. The general concept is that the body tries to increase
a variable when it is below its optimum (termed the set
point), and decrease a variable when it is above its optimum.
This is analogous to the thermostat that controls room
temperature by adjusting the heating and/or cooling of the
room. For example, if you open a window on a cold day, the
room temperature decreases from the set point of the thermo-
stat. This is called perturbation. The thermostat contains a
sensor that detects the difference between the room tempera-
ture and the set point. The thermostat signals the furnace to
generate heat, and the room temperature is returned toward
normal. The difference between the low point in room tem-
perature and the final room temperature at steady state is called
the correction. Because the window is left open in this exam-
ple, room temperature does not quite return to the set point;
the remaining difference between the final room temperature
and its thermostatic set point is called the error. The ability of
the control system to restore the system to its set point is called
gain, which is represented by the following equation:
Correction
Gain = ____________
Remaining error
(1)
A classic example of this is shown in Figure 1–5 that shows
the response of the cardiovascular system to rapid blood loss
(hemorrhage). In this example, the rapid loss of 1 L of blood
leads to a decrease in mean blood pressure from the set point
of 100 to 75 mm Hg. As you will learn in Chapter 29, there are
sensors in the cardiovascular system called baroreceptors that
detect blood pressure. These sensors change their neural input
to the brain to activate systemic reflexes to restore blood pres-
sure to normal. In this example, these reflexes restore blood
pressure to 95 mm Hg. The correction, therefore, is 20 mm Hg
and the remaining error is 5 mm Hg. Using equation (1), this
gives a gain of about 4. Although clinicians do not usually cal-
culate gain when taking care of patients, it is a convenient way
Rapid blood loss Final blood pressure
100-95=5 Remaining error
Original
95-75=20 Correction due perturbation
to reflexes
Correction 20
Gain= = =4
Remaining error 5
Time (min)

to think of the ability of reflexes to restore a perturbed system
to normal via negative feedback. The higher the gain, the
higher the ratio of correction to remaining error and the better
the control system is at restoring the system to its set point. For
example, as you will learn in Chapter 70, the control of body
temperature has a very high gain.
Included in many feedback systems is a change in behavior.
For example, drinking extra water when blood volume is
decreased helps to restore plasma volume. Putting on warm
clothes and curling up helps to minimize heat loss in a cold
environment. Finally, set points of control systems can change.
Examples of this are resetting of the baroreceptor set point
during chronic increases in blood pressure (hypertension) that
you will learn about in Chapter 29, and during the acclimatiza-
tion to the low ambient oxygen of high altitude (hypoxia) that
you will learn about in Chapter 71.
Although most control systems of the body are negative
feedback, there are a few examples of positive feedback, which
are feedback loops that amplify themselves. You will learn
about several examples of this in Chapter 68. One is the stimu-
lation of the anterior pituitary hormone LH by estrogen just
before ovulation that causes a large increase in LH, which then
stimulates more estrogen release, and so on. Another example
is the birth of a baby during which stretch of the cervix stimu-
lates the release of oxytocin from the posterior pituitary gland
that, in turn, stimulates stronger uterine contractions. This
causes additional cervical stretch, more oxytocin release, and
greater uterine contractions. Positive feedback is also respon-
sible for detrimental effects in the body. One example is heart
failure during which the pumping of the heart decreases due
to, for example, an infection of the heart muscle. The resultant
decrease in blood pressure leads to reflexes that stimulate the
heart to pump harder in an effort to raise blood pressure. This
additional stress on the heart actually makes it work less well,
and the heart failure feeds on itself.
Another important concept in homeostatic control is poten-
tiation. This is when one substance augments the response to
another substance, even though the first substance does not
exert a significant response on its own. An example of this that
you will learn in Chapters 49 and 66 is the release of the GI
hormones from the intestine in response to a meal. These hor-
mones can potentiate the pancreatic insulin response to
absorbed glucose. This is an example of feedforward potentia-
tion, because these GI hormones “announce” the impending
increase in blood glucose before glucose absorption actually
occurs in the small intestine. When glucose finally arrives via
the bloodstream at the pancreas, there is a potentiated insulin
response such that hyperglycemia is prevented.
CHAPTER SUMMARY
■ The cell is surrounded by a membrane that regulates the
intracellular composition and the flux of molecules in and
out of the cell.
■ Water is the most abundant molecule in the body, and its
concentration and balance is highly regulated.
CHAPTER 1 General Physiological Concepts 7
■ There are significant concentration gradients between
intracellular and extracellular fluid for sodium, potassium,
calcium, magnesium, chloride, and bicarbonate, as well as
organic compounds.
■ Molecules can enter the cell by passive diffusion, and through
transporters that do not (facilitated transport) and do directly
use cellular energy (active transport).
■ The rate of flow of a liquid through a tube is determined by the
pressure difference between the inflow and outflow, and the
resistance to flow of the tube.
■ Most important substances in the body are in balance, with
the influx and efflux being approximately the same over time.
■ Most systems are controlled by negative feedback with the
controlled variable being able to shut off its own release much
like a thermostat controls room temperature.
STUDY QUESTIONS
1. Which of the following organelles is primarily response for
generation of energy?
A) Golgi apparatus
B) mitochondria
C) lysosomes
D) ribosomes
2. Which of the following has an intracellular fluid concentration
much higher than its extracellular fluid concentration?
A) sodium ion
B) chloride ion
C) glucose
D) potassium ion
3. Which of the following would result in an increase in flow of
a liquid through a tube?
A) increase in resistance
B) increase in pressure at the downstream end of the tube
C) increase in pressure at the inflow end of the tube
D) increase in length of the tube
4. Which of the following has the highest feedback gain?
A) starting blood pressure = 100; low point in blood
pressure = 70; final blood pressure after feedback
correction = 90
B) starting body temperature = 37.2°C; high point in body
temperature = 38.9°C; final body temperature after
feedback correction = 37.4°C
C) starting blood glucose = 80 mg/dL; high point in blood
glucose = 110 mg/dL; final blood glucose after feedback
correction = 85 mg/dL
D) starting plasma osmolality = 280 mOsm/kg; low point in
plasma osmolality = 270 mOsm/kg; final osmolality after
feedback correction = 278 mOsm/kg
This page intentionally left blank
 SECTION II CELL PHYSIOLOGY
Cells and Cellular
Processes
David Landowne
O B J E C T I V E S
■ Recognize and describe the types of electrophysiological events.
■ Describe the types of membrane channels and their roles.
■ Describe physiological control systems.
INTRODUCTION
Life is cellular, and cells are the fundamental units of life.
Without cells, there would be no living beings. All the cells of
a given individual are ultimately derived from a single fertil-
ized ovum. Most of the cells of multicellular organisms reside
within their tissues and organs. This chapter concentrates on
the cellular processes and leaves the discussion of their higher
organization to chapters concerned with the various organ
systems. Drugs, toxins, and diseases are introduced to illus-
trate the cellular processes.
COMMUNICATION
Dynamic cell processes support sensory perception of the en-
vironment, communication, and the integration of informa-
tion within and between cells, as well as their expression, or
actions on the environment. These are the processes that
enable the cell to contribute to the functioning of tissues, or-
gans, and individuals. These processes make up one of the
phenomena of cells—excitability. The others, reproduction
and metabolism, are not covered in depth here. Perception,
integration, and expression can be best considered as physio-
Ch02_009-014.indd 9
2
C H A P T E R
logical events in terms of inputs, processes, and outputs
(Figure 2–1). Complex processes can be broken down into
simpler ones, with the outputs of one or more processes be-
coming the inputs to the next one.
In order to survey the processes discussed here, it is useful
to consider a three-cell model of the body. Figure 2–2 shows
a sensory neuron or nerve cell, a motor neuron, and a skel-
etal muscle cell. These cells represent the hardware the body
uses to carry out the dynamic cell processes described in the
previous paragraph. The cells have specialized portions for
the different processes. Starting from the left, the sensory
cell has one end that is specialized for the transduction of a
stimulus into a cellular signal. The various senses have dif-
ferent specializations to accomplish this transduction.
Besides the classic five senses (touch, hearing, vision, taste,
and smell), there are sensors or proprioceptors inside the
body that sense internal parameters—for example, body
temperature, blood pressure, blood oxygen levels, or the
lengths of various muscles.
If it is sufficiently large, the initial signal causes another
signal to propagate over the axon (the long cylindrical portion
of the nerve cell) until it reaches the other end, where the sen-
sory neuron makes a synaptic connection with dendrites of
the motor neuron, located in the central nervous system
(CNS). The message is transmitted from the presynaptic cell
11/26/10 9:40:02 AM
10 SECTION II Cell Physiology

branes. Every living cell has a surface membrane that separates

Input Output
Process
FIGURE 2–1 The input–process–output structural framework
is a specification of causal relationships in a system. Complex
systems can be considered as composed of simple units. (Modified with
permission from Landowne D: Cell Physiology. New York: Lange Medical
Books/McGraw-Hill, 2006.)
to the postsynaptic cell, where it is integrated or evaluated
along with messages from other neurons that synapse on the
same motor neuron. In the complete organism, this integra-
tion and comparison occurs in many cells and at different lev-
els within the CNS, so the decision to move or not move can
be made considering more than one input and also anything
the organism has learned from the past.
If the motor neuron is sufficiently excited, it will send an-
other message along the axon that leads to a synapse on a
muscle cell. In healthy people, this neuromuscular synapse
leads to a signal that propagates over the length of the mus-
cle cell and activates contraction, which can act on the envi-
ronment. Other actions on the environment are effected by
the secretions of various glands; these too may be controlled
by synaptic connections. These muscles and glands may act
internally (e.g., to control heart rate or blood pressure) or
externally (for locomotion or communication with other
people).
These signals are all electrical; they all represent changes in
the electrical potential difference across the various cell mem-
its intracellular and extracellular spaces. All cells, not just
those of nerve and muscle, are electrically negative inside the
cell with respect to outside. This is called the membrane
potential. When the cells are “resting”—that is, not signal-
ing—their membrane potential is called the resting potential.
Chapter 4 is about the origins of the resting potential.
Even though the signals described above are changes in
potential, they are generally referred to as named poten-
tials. On the left in Figure 2–2, there is the sensory genera-
tor potential, which has two properties to distinguish it
from the next signal, the action potential. The sensory
generator potential is local; it occurs only within a few mil-
limeters of the sensory ending. The action potential is prop-
agated; it travels from the sensory ending to the presynaptic
terminal, perhaps more than a meter away. The sensory gen-
erator potential is also graded; a larger-amplitude stimulus
produces a larger-amplitude sensory generator potential. In
contrast, the action potential has a stereotyped amplitude
and duration; it is all-or-none. The information about the
stimulus is encoded in the number of action potentials, or
the number per second. A larger-amplitude stimulus will
result in a higher frequency of action potentials, each with
the same stereotyped amplitude. Because the all-or-none
character of neurons is similar to the true-or-false character
of logical propositions, cyberneticists (people who study
control and communication in the animal and the machine)
have considered that neural events and the relations among
them can be treated by means of propositional logic.
Chapters 5 and 6 are about sensory generator potentials and
action potentials, respectively.
The presynaptic terminals contain a mechanism to re-
lease the contents of vesicles containing chemical transmit-

Hardware Sensory ending Axon Synapse Axon Muscle

Signals Sensory Action Synaptic Action Endplate

(potentials) generator
Local Propagated Local Propagated Local

Graded All-or-none Graded All-or-none Graded

Channels Mechano Voltage Chemo Voltage Chemo

sensitive sensitive sensitive sensitive sensitive

Cybernetics Input Transmission Process Transmission Output

FIGURE 2–2 The cellular processes of a hypothetical three-celled organism. Different types of channels underlie different physiological
processes that support the input–process–output functions of animals, including humans. (Modified with permission from Landowne D: Cell Physiology.
New York: Lange Medical Books/McGraw-Hill, 2006.)

ters that diffuse across the narrow synaptic cleft and react
with the postsynaptic cell to produce a postsynaptic poten-
tial. The postsynaptic potential is also local and graded. It is
only seen within a few millimeters of the site of the presynap-
tic ending and its amplitude depends on how much transmit-
ter is released. There are excitatory postsynaptic potentials
(EPSPs) and inhibitory postsynaptic potentials (IPSPs), de-
pending on whether the postsynaptic potential makes the cell
more or less likely to initiate an action potential. If there is
sufficient excitation to overwhelm any inhibition that may be
occurring, an action potential will be initiated in the postsyn-
aptic cell. There are many presynaptic cells ending on each
postsynaptic neuron as well as various different transmitters
in different synapses. These transmitters, the release mecha-
nism, and the resulting postsynaptic potentials are discussed
in Chapter 7.
The action potential in the motor neuron and the synapse
with the muscle cell are very similar to the neuron to neuron
synapse discussed above. In the light microscope, the neuro-
muscular junction looks like a small plate; hence, the junction
is often called an endplate and the postsynaptic potential an
endplate potential. The neuromuscular junction differs from
most other synapses because there is only one presynaptic cell,
its effect is always excitatory, and—in healthy people—the
endplate potential is always large enough to initiate an action
potential in the muscle cell.
The muscle action potential propagates along the length
of the cell and into the interior by small transverse tubules,
whose membranes are continuous with the surface mem-
brane. The action potential excitation is coupled to the mus-
cular contraction by processes described in Chapter 10. That
chapter also discusses the control of cardiac and smooth
muscle cells.
The resting potential, the sensory generator potentials, the
action potentials, and the synaptic potentials all occur by
the opening and closing of channels in the cell membranes.
These channels are made of proteins that are embedded in and
span the membrane connecting the intracellular and extracel-
lular spaces. Each has a small pore through the middle, which
may be opened or closed and is large enough to allow specific
ions to flow through and small enough to keep metabolites and
proteins from flowing out of the cell. There are many channels,
and a good part of Chapter 3 is devoted to their description.
They are generally named either for the ion that passes through
them or for the agent that causes them to open.
There are three classes of channels that act to produce the
changes in potential described in Figure 2–2. All these chan-
nels will be discussed individually in Chapter 3 and then again
in the context of the various potentials in subsequent chapters.
Mechanosensitive channels subserve the sensations of
touch and hearing and the many proprioceptors that provide
information on muscle length, muscle tension, joint position,
the orientation and angular acceleration of the head, and blood
pressure. These channels open when the membrane of the sen-
sory ending is stretched, sodium ions flow through the chan-
nels, and the membrane potential changes.
CHAPTER 2 Cells and Cellular Processes 11
Voltage-sensitive channels underlie action potentials. They
open in response to a change in membrane potential. When
they are open, ions flow through them, and this changes the
membrane potential as well. The generator potential or the
synaptic potentials activate these channels, and then they open
the remaining adjacent voltage-sensitive channels. This ac-
counts for the propagation and all-or-none, stereotyped qual-
ity of the action potentials. Nerve and skeletal muscle action
potentials are produced by the successive activation of volt-
age-sensitive sodium channels, followed by voltage-sensitive
potassium channels. There are also voltage-sensitive calcium
channels in the presynaptic nerve endings. When the action
potential reaches the presynaptic terminal, these calcium
channels open and permit calcium to enter the cell. The calci-
um binds to intracellular components and initiates the release
of synaptic transmitters.
Chemosensitive channels are responsible for the synaptic
potentials. The transmitters bind to these channels, causing
them to open. There are different channels for different trans-
mitters and also different channels for EPSPs and IPSPs.
Chemosensitive channels also subserve the chemical senses of
smell and taste. There are also channels that open or close in
response to intracellular chemicals such as adenosine triphos-
phate (ATP) or the cyclic nucleotides, cyclic adenosine mono-
phosphate (cAMP) or cyclic guanosine monophosphate
(cGMP). Vision is supported by a reaction series whereby light
absorption leads to a decrease in cGMP, which produces a clo-
sure of cyclic nucleotide–gated (chemosensitive) channels.
When sodium ions stop flowing through these channels, the
membrane potential changes.
From a cybernetic viewpoint, Figure 2–2 indicates that the
body has mechanisms to input information, to transmit it
within the body, to process the information, and to provide
output. This type of analysis appears frequently in physiolo-
gy. Much of what you will learn can be broken into various
steps where the output of one process becomes the input for
the next. For example, the sensory generator potentials are
an input to the action potential–generation process and the
action potential is the input to the voltage-sensitive calcium
channel, which permits calcium to enter the presynaptic ter-
minal. This calcium is the input for the transmitter release
process, and so on.
CONTROL
Although most of this book focuses on isolating the different
processes so as to analyze them more easily, an understanding of
the value and true significance of each physiological quality must
refer to the whole organism. A recurring theme throughout all of
physiology is the maintenance of a stable internal environment
through homeostasis. Many internal properties (e.g., body tem-
perature or blood glucose levels) are homeostatically controlled
within narrow limits by feedback control systems.
Homeostasis is a property of many complex open systems.
Feedback control is the central feature of organized activity.
12 SECTION II Cell Physiology
Desired value
Comparator
A
From higher centers
Motoneuron
Sensory neuron
FIGURE 2–3 Homeostasis and feedback control. A and B) By having inputs that sense the output and feed information back to the
controller, machines and humans can gain control of their operating conditions. (Modified with permission from Landowne D: Cell Physiology. New York:
Lange Medical Books/McGraw-Hill, 2006.)
A homeostatic system (e.g., a cell, the body, an ecosystem) is an
open system that maintains itself by controlling many dynamic
equilibria. The system maintains its internal balance by reacting
to changes in the environment with responses of opposite direc-
tion to those that created the disturbance. The balance is main-
tained by negative feedback. Perhaps the most familiar negative
feedback control system is the thermostat that controls the tem-
perature of a room, which was described in Chapter 1.
The basic steps (Figure 2–3A) in negative feedback control
of any measurable parameter are the measurement by a sen-
sor, communication of that measurement to a comparator,
making the comparison, and communicating the compari-
son to an effector that changes the parameter of interest. The
feedback is called negative because the signal to the effector
is in the opposite direction to any disturbance and reduces
the difference between the measured value and the desired
value.
The three cells in Figure 2–2, arranged as a negative feed-
back loop (Figure 2–3B), represent the process used to control
the length of muscles both to maintain posture and to achieve
movement in response to signals from the brain. This feedback
loop can be easily demonstrated by the stretch reflex—that is,
the knee-jerk reflex (see Chapter 14). When a muscle is
Effector
Controlled parameter
Sensor
Muscle
Muscle spindle
stretched, mechanosensitive channels in sensory organs open,
changing membrane potentials in the sensory endings that in-
duce action potentials to propagate to the spinal cord. Trans-
mitter is released, which excites the nerve leading back to the
muscle, where the synaptic process is repeated and the muscle
shortens to compensate for the initial stretch.
There are a few positive feedback systems that are physio-
logically important. A positive feedback system is unstable;
the signal from the sensor increases the effect, which increas-
es the signal from the sensor in a “vicious cycle,” which is lim-
ited only by the availability of resources. The all-or-none
property of action potentials is due to a positive feedback
loop. Some other examples of positive feedback were de-
scribed in Chapter 1.
CHAPTER SUMMARY
■ Communication in excitable cells occurs via electrical signals
within the cells and via chemical signals at synapses between
the cells.
■ There are two classes of electrical signals: those that are local
and graded and those that are propagated and stereotyped, or
all-or-none.
 CHAPTER 2 Cells and Cellular Processes 13

■ The chemical transmitters are released presynaptically and
produce an electrical signal in the postsynaptic cell.
■ Three classes of ion channels produce the electrical signals:
mechanosensitive, chemosensitive, and voltage-sensitive
channels.
■ Homeostasis by negative feedback control is an important
feature of living systems.
■ There are three basic elements of a negative feedback loop: a
sensor, a comparator, an effector, and two communication links
connecting them.
2. Negative feedback control systems do not
A) improve the reliability of control.
B) require the sensing or measurement of the controlled
process.
C) require communication between separate parts of the
system.
D) regulate blood pressure and body temperature.
E) cause the all-or-none property of the action potential.

STUDY QUESTIONS
1. Which of the following changes in electrical potential require
voltage-sensitive channels?
A) excitatory synaptic potentials
B) mechanical sensory generator potentials
C) propagated action potentials
D) light sensory generator potentials
E) inhibitory synaptic potentials
This page intentionally left blank
 3
C H A P T E R

Cell Membranes and

Transport Processes
David Landowne

O B J E C T I V E S

■ Describe the molecular composition of biological membranes.

■ Describe the functional biophysical properties of biological membranes.
■ Describe classes of ion channels, their molecular structure, and their
biophysical properties.
■ Describe the molecular organization, properties, control, and functional roles
of cell–cell channels.
■ Describe the movement and transport of substances across biological
membranes by passive processes.
■ Describe the movement and transport of substances across biological
membranes by active processes.
■ Describe the physiological importance of two examples of active transport
and two examples of passive transport.
■ Define osmotic pressure.
■ Calculate the osmolarity of simple solutions.
■ Calculate the changes in osmolarity in body compartments caused by
drinking various simple solutions.
■ Describe physiological mechanisms to regulate osmolarity.

Every living cell has a surface membrane that defines its limits
and the connectivity of the intracellular and extracellular com-
partments. Cell membranes are about 10-nm thick and consist
of a 3–4-nm-thick lipid bilayer with various embedded proteins
that may protrude into either compartment (see Figure 1–2).
Membranes also delimit intracellular organelles, including the
nuclear envelope, Golgi apparatus, endoplasmic reticulum (ER),
mitochondria, and various vesicles (see Figure 1–1). The lipid
bilayer is impermeable to charged or polar substances. The pro-
teins handle the transport of specific ions or molecules across
the membranes and thus control the composition of different
solutions on either side. They support communication across
the membranes and along the surface of the cell and provide
mechanical coupling between cells.
LIPIDS
Most of the membrane lipids are glycerophospholipids, which
have a glycerol backbone with two of its three –OH groups
esterified by fatty acids and the third esterified to a phosphate
group, which is in turn esterified to a small molecule that gives
its name to the whole molecule (Figure 3–1). The most com-
mon glycerophospholipids are phosphatidylcholine (PC),
phosphatidylethanolamine (PE), and phosphatidylserine
(PS). Membranes also contain phosphatidylinositol (PI),
which plays an important role in signaling within the cyto-
plasm. Notice that PS and PI have a net negative charge.
Animal cell membranes may also contain sphingolipids, in-
cluding the phosphosphingolipid, sphingomyelin, which has

15

Ch03_015-032.indd 15 11/26/10 9:40:20 AM

16 SECTION II Cell Physiology

R
O +
N(CH3)3
O P O–
HCH
O Phosphatidylcholine (PC)
HCH
O O

C=O C=O +
NH3
HCH Phosphatidylethanolamine (PE)
HCH

+
NH3

COO– Phosphatidylserine (PS)

HCH

OH
OH
OH Phosphatidylinositol (PI)
OH HO

FIGURE 3–1 Glycerophospholipids. Along with cholesterol, these form the bilayer that separates the inside of cells and supports the
embedded membrane proteins. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

two acyl chains and a phosphate-linked choline head linked to
a serine backbone, and glycosphingolipids, which have sugars
in the head group. Membranes also contain cholesterol, which
has a steroid ring structure.
All of these lipids are amphipathic because they have
hydrophilic, or “water-loving,” head groups and hydropho-
bic, or “water-fearing,” acyl tails. The –OH group of
cholesterol is hydrophilic and the rest is hydrophobic. A hy-
drophobic effect arises from the lack of interactions of
hydrocarbons with water and the strong attraction of water
for itself. Thus, when placed in an aqueous environment,
these lipids spontaneously assemble into closed bilayer
membrane vesicles.
The lipids are relatively free to diffuse laterally within the
plane of the membranes, but—with the exception of
cholesterol—they are unlikely to flip-flop from one half of
the bilayer to the other owing to the hydrophilicity of the head
groups. The bilayer is asymmetrical, with the choline-
containing phospholipids, PC and sphingomyelin, in the out-
er half and the amino-containing phospholipids, PE and PS,
in the inner half. In addition, the glycosphingolipids are in
the noncytoplasmic half and PI is facing the cytoplasm. The
asymmetrical arrangement is produced as the membranes are
assembled in the ER. The phospholipids are synthesized and
inserted on the cytoplasmic side of the membrane; then a
phospholipid translocator or “flippase” transfers PC to the
noncytoplasmic side. Sphingomyelin and the glycosphingo-
lipids are produced in the Golgi apparatus on the noncyto-
plasmic side.
The ease of lateral diffusion, or membrane fluidity, is in-
creased by the presence of unsaturation or double bonds in the
hydrocarbon tails. This forms a kink in the tail and therefore
looser packing. At the concentrations generally found in bio-
logical membranes, cholesterol reduces the fluidity because of
its rigid ring structure. Glycosphingolipid head groups tend to
associate with each other and reduce fluidity. Lipid protein
interactions may also reduce fluidity. There are cholesterol–
sphingolipid microdomains, or “lipid rafts,” involved in intra-
cellular trafficking of proteins and lipids.
PROTEINS
The intrinsic proteins of the membrane support the selec-
tive movement of ions and small molecules from one side of
the membrane to the other, sense a ligand on one side of the
membrane and transmit a signal to the other side, and pro-
vide mechanical linkage for other proteins on either side of
the membrane. The proteins that move materials across the
membrane can be functionally divided into channels,
pumps, and transporters. Channels may be specific and
may open and close, but, when open, they facilitate the
movement of materials only with their electrochemical
gradients. Ion channels control the flow of electrical cur-
rent through the membrane. Pumps move ions against their
electrochemical gradient at the expense of consuming ATP.
The pumps maintain the gradients that allow the channels
and transporters to do their jobs. Transporters can link the
 CHAPTER 3 Cell Membranes and Transport Processes
movement of two (or more) substances and can move one of
them against its gradient at the expense of moving the other
one with its gradient.
A protein is the product of translating a gene; it is a folded,
linked sequence of alpha amino acids chosen from a palette
with 20 possible different side chains. The peptide link between
amino acids –CO–NH– has a planar transconformation; the
folding occurs according to the torsion angles between the
amino group and the alpha carbon (Φ) and between the alpha
carbon and the carboxyl group (ψ). The alpha helix axis and
the beta sheet are secondary structures, with particular torsion
angles, that are found in proteins.
The conformation or tertiary structure of the entire pro-
tein is the three-dimensional relationship of all its atoms.
Proteins have regions of various secondary structures con-
nected by linkers with less easily characterized structure.
Most of the proteins discussed in this book have more than
one conformation. For example, a channel may be open or
closed. The local secondary structures do not change very
much during these conformational changes; rather, change
occurs in the relationship between larger portions of the
molecule.
There is also a supermolecular or quaternary level of organi-
zation. Some channels are made of a single polypeptide chain,
while others are made of four to six chains. Many channels
also have accessory proteins that modulate their function. In
addition, the lipid matrix imposes structural restrictions on
the embedded proteins.
In general, proteins are amphipathic and have regions that
are more hydrophobic or hydrophilic, depending on the na-
ture of the side chains. The membrane proteins discussed here
have one or more transmembrane (TM) alpha-helical seg-
ments with hydrophobic side chains in contact with the hy-
drocarbon of the lipid. If more than one helix is involved, it is
possible to have hydrophobic residues facing the lipid and
other groups facing each other in the more interior parts of the
protein. The general pattern is for the protein to cross the
membrane several times, with intracellular and extracellular
loops between TM segments. There is also an N-terminal re-
gion before the first segment and a C-terminal region after the
last; an example is shown in Figure 3–3. The N-terminal re-
gion can be on either side, but the C-terminal region is usually
cytoplasmic. Either or both terminal regions can be quite large
compared to the TM regions.
The TM folding occurs as the protein is synthesized in the
ER. The noncytoplasmic portions of the protein may be glyco-
sylated in the Golgi apparatus before being inserted in the sur-
face membrane. Subunit assembly may also occur in the ER or
Golgi apparatus.
For most membrane proteins, only the primary sequence is
known. Secondary structure can be predicted by sequence
analysis. The presence of putative hydrophobic helices of suf-
ficient length is taken as a suggestion of a TM segment. A to-
pology or pattern of loops and TM segments can be predicted;
such a prediction has been tested for many proteins by prepar-
ing antibodies for the putative extracellular portions. Sequence
17
analysis of entire genomes suggests that about 20% of the pro-
teins contain one or more TM segments and are thus mem-
brane proteins.
Only a few membrane proteins have been crystallized and
subjected to x-ray diffraction analysis. These crystals must
include lipid or detergent molecules to satisfy the hydrophobic
needs of the TM segments. Most of the solved structures are of
bacterial proteins that have been genetically modified to en-
hance crystallization. A strong sequence homology between
the crystallized molecule and part of the human protein is
taken to indicate that they have similar structures.
Channels, pumps, transporters, receptors, and cell adhesion
molecules come in many varieties to serve many roles. The
following five sections will describe a taxonomy and the anat-
omy of examples of each functional class. It may be useful to
return to this section while reading the later part of this chap-
ter and those parts of the rest of the book that describe the role
of these molecules in physiological processes.
CHANNELS
In the previous chapter, channels were distinguished by the
mechanism by which they open. There are mechanosensitive
channels involved in sensory processes, voltage-sensitive
channels involved in action potential propagation, and
chemosensitive channels involved in synaptic transmission.
There are also channels that are usually open, such as chan-
nels that maintain resting potential, water channels, and spe-
cialized cell–cell channels that connect the cytoplasm of one
cell with the cytoplasm of another. This section describes
some channels that support various cell processes discussed
later in the book. It is not exhaustive; many channels and
many classes of channels are not mentioned. This is a “golden
age” for ion channels. Electrophysiology and molecular and
structural biology are revealing some amazing membrane
proteins.
Many ion channels are selective and are named according to
the ion that passes through them. The first channel to be crys-
tallized is the resting potential potassium channel, also known
as the inward rectifier or Kir. The reason for this name is
discussed in the next chapter, along with its function. Kir is a
tetramer with four identical subunits arranged with radial
symmetry and a pore that permits ion flow at the axis (Figure
3–2A). Each monomer has two TM segments with an extracel-
lular P loop in between (Figure 3–2B; see also Figure 3–4,
segments 5 and 6). The four P loops dip back into the mem-
brane and together form the lining of a pore that goes about
one third of the way through the membrane. This pore emp-
ties into a larger intramembranous cavity that communicates
with the cytoplasmic space. The eight helices form a wall for
the cavity and also surround the inserted P loops. The TM
helices form a conical structure with the point toward the
cytoplasm.
The selectivity of the pore for potassium ions depends on the
specific amino acids forming the lining. VGYGD is the
18 SECTION II Cell Physiology

A B

C
FIGURE 3–2 The crystal structure of an inward rectifier K channel (Kir). A) Top view of a ribbon-structure representation
with stick-and-ball for the GYG sequences. B) Side view with two monomers removed; the GYG sequence is a space-filling representation.
C) Close-up view of two VGYGD sequences and an ion. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical
Books/McGraw-Hill, 2006.)

K-channel signature sequence (Figure 3–2C); it has been
found in K channels from more than 200 organisms. This por-
tion of the molecule is the selectivity filter because it accepts
K+ ions and excludes other ions. The pore is lined with the
carbonyl oxygen groups; these are in the same relation to each
other as the oxygen of the water molecules that coordinate
around K+ ions in solution because of its positive charge and
the oxygen’s electronegativity. Two of the coordinating oxy-
gens from glycines just below the tyrosines can be seen in
Figure 3–2C. Ions with different charges or radii will coordi-
nate water differently and thus will be less likely than K+ ions
to leave the water and enter the K channel.
It is thought that Figure 3–2 represents a closed Kir channel.
The structure of another prokaryotic 2-TM channel has been
solved; its inner helices are bent and splayed open, creating a
wide entryway. This second Kir channel responds to Ca2+ on
its intracellular side by increasing its open probability. The
Ca2+ binds to the regulator of K conductance (RCK) domain
in the C-terminal part of the protein, not shown in Figure
3–2, inducing a conformational change that splays the inter-
nal helices. Ca2+ and cyclic nucleotides increase the open
probability of some other 2- and 6-TM channels by a similar
mechanism.
There are eight subfamilies of 2-TM Kir channels in the hu-
man genome. Several are important in cardiac electrophysiol-
ogy. Kir2 (or IK1) is the original inward rectifier discovered in
cardiac muscle; it is responsible for maintaining the resting
potential. Kir3 channels open via G protein–coupled receptors
(GPCRs); in the heart, they are referred to as KACh. Kir6 chan-
nels open when the ADP/ATP ratio rises. In the heart, they are
referred to as KATP.
MECHANOSENSITIVE CHANNELS
Mechanosensitive channels are a diverse class of structur-
ally unrelated channels that subserve many different func-
tions in different cells. Mechanosensation is important for
touch and hearing and also for sensing blood pressure and
for proprioception, providing information about position,
 CHAPTER 3 Cell Membranes and Transport Processes 19

G
Y
P G
+
+
S1 S2 S3 S4 S5 S6
+
+

C
N
FIGURE 3–3 The topology of one monomer of voltage-dependent K channels (KV). The six transmembrane helices (S1–S6)
are characteristic of all voltage-dependent ion channels. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/
McGraw-Hill, 2006.)

orientation, velocity, and acceleration of the body and its
parts. The channels are associated with accessory molecules
and cellular structures that enhance their particular func-
tions. Somatic nonsensory cells also respond to mechanical
stress without informing the nervous system—for instance,
to compensate for osmotic swelling or modulate secretion
or contraction.
Many mechanosensitive channels are relatively nonselective
cation channels. Some are very large and permit electrolytes
and small metabolites, but not proteins, to cross the mem-
brane. The two structures that have been solved are bacterial.
One is a homopentamer, with each subunit containing two
TM helices. The other is a heptamer, with each subunit con-
taining three TM helices. These are beautiful structures, but
they do not shed much light on the many other forms of
mechanosensitive channels.
VOLTAGE-SENSITIVE CHANNELS
Voltage-sensitive K channels (KV) are responsible for the
return to the resting state, which ends an action potential. KV
has a core structure similar to that of Kir and an additional
four TM helices on each subunit (see Figure 3–3). The fourth
TM segment (S4) is distinguished because it has between
four and eight positively charged side chains (Arg or Lys). S4
is a signature feature of voltage-sensitive channels. It is
thought to be the voltage sensor that moves toward the extra-
cellular surface when the membrane potential changes and
causes the conformational changes that lead to channel open-
ing. There are nine subfamilies of KV channels and several
more 6-TM-channel subfamilies, including the Ca-activated
K channels, the hyperpolarization-activated channels im-
portant for pacemaker activity in the heart, and cyclic nucle-
otide–gated channels. The last two families are nonselective
cation channels.
Voltage-sensitive Na channels (NaV) are responsible for
the upstroke of the action potential and support its propaga-
tion. Voltage-sensitive Ca2+ channels (CaV) couple mem-
brane potential changes with an increase in intracellular Ca2+
concentration, which acts as a second messenger to control a
variety of intracellular processes. NaV and CaV channels have
a structure similar to the KV channels except that they are
single larger molecules incorporating four domains, each
with slightly different 6-TM segments (Figure 3–4). The se-
lectivity filters have four different walls. The CaV channel has
four characteristic glutamates (EEEE) in its pore lining, one
on each domain. The NaV channel has a DEKA pattern on
the four walls of its pore. These side chains must be exposed
to the lumen of the pore. The charges they expose to the
lumen and the size of the pore determine the selectivity of
the channel.

P P P P
+ + +
+ + +
S1 S2 S3 S4 S5 S6 S1 S2 S3 S4 S5 S6 S1 S2 S3 S4 S5 S6 S1 S2 S3 S4 S5 S6
+ + +
+ + +

C
N

FIGURE 3–4 The topology of voltage-dependent Na channels (NaV). Four slightly different domains are linked together in one protein.
(Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)
20 SECTION II Cell Physiology
CHEMOSENSITIVE CHANNELS
There are many different chemosensitive or ligand-gated
channels. These control the flow of ions and thus generate elec-
trical signals in response to specific chemicals, such as acetyl-
choline (ACh), glutamate, or ATP. They can be grouped into
three different superfamilies according to the stoichiometry
and membrane topology of their subunits. Many of these were
first discovered pharmacologically by noticing that certain
compounds, called agonists, produced membrane currents or
altered the electrical activity of cells and other compounds;
antagonists could block these effects. For some agonist-induced
currents, the ligand binds the same molecule that contains the
pore. These are the ligand-gated channels, which are sometimes
called ionotropic ligand receptors to distinguish them from
metabotropic ligand receptors, where the ligand binds a GPCR
and triggers a biochemical cascade that may include opening of
other channels, for example, KACh, described above.
The ACh receptor channels (AChRs) are referred to as
nicotinic AChRs, or nAChRs. The term nicotinic indicates
these receptor bind nicotine, which also opens the channels.
nAChRs are distinguished from muscarinic AChRs, which
are not channels but rather GPCRs. nAChRs are found on the
postsynaptic membranes at skeletal neuromuscular junctions
and in the autonomic and central nervous systems.
The best-studied nAChRs are heteromeric pentamers
(Figure 3–5). The monomers have four TM segments each and
N
Out
In
α β
γ α
δ
FIGURE 3–5 The topology of one monomer of nicotinic
acetylcholine receptor channels (nAChR), with a top view showing
the arrangement of the five monomers. (Modified with permission from
Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)
a large extracellular N-terminal region. At the neuromuscular
junction, the nAChR has two alpha subunits, with Ach-binding
sites at the interface between subunits and far from the lipid
membrane. ACh binding induces a conformational change
that opens the pore formed at the level of the lipid membrane
and lined by the second TM segment of each of the monomer’s
five subunits. The open channels are highly permeable to both
Na+ and K+, slightly permeable to Ca2+, and not permeable to
anions. They are not as selective as the Kir or voltage-sensitive
channels. Functionally, the Na permeability is most important,
as discussed in Chapter 7.
The CNS postsynaptic receptors for glycine (glyR), gamma-
aminobutyric acid (GABAAR), and serotonin (5HT3R) have
similar pentameric architecture, although some are homomer-
ic, as are some nAChRs. glyRs and GABAARs are selectively
permeable to anions and produce inhibitory postsynaptic po-
tentials (IPSPs.) 5HT3Rs are cation-selective, similar to nACh-
Rs, and produce excitatory postsynaptic potentials (EPSPs).
The most common CNS EPSP channels are glutamate re-
ceptors (gluR), which have an architecture (Figure 3–6) remi-
niscent of an inverted Kir molecule with extra TM segments.
gluRs are heteromeric tetramers with three TMs per subunit.
They have a large extracellular region with four glutamate-
binding sites and a cytoplasmic-facing P loop. Several func-
tionally different gluRs are discussed in more detail in
Chapter 7. They are all cation-selective; some allow Ca2+ entry
and others do not.
N
Out
In
FIGURE 3–6 The topology of one monomer of glutamate
receptor channels (gluR), with a top view showing the arrangement
of the four monomers. (Modified with permission from Landowne D: Cell
Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)
 CHAPTER 3 Cell Membranes and Transport Processes 21

The ATP-sensitive channels or P2X receptors (P2XRs) CELL–CELL CHANNELS

have two TMs per subunit and three subunits per channel. “P”
refers to the purine sensitivity; adenine is a purine. P2 distin- In most tissues, there are channels that connect the cytoplasm
guishes them from P1 receptors, which are sensitive to of one cell to the cytoplasm of its neighbor. The exceptions are
adenosine and act through adenylyl cyclase (AC). The P1 re- free-floating cells in the blood and skeletal muscle cells.
ceptors are often referred to as A receptors (A for adenosine); These channels are mostly between cells of the same type, but
they are GPCRs. Caffeine is an antagonist of some of the A there are some cells of different type with junctions between
receptors. P2 receptors prefer ADP or ATP to adenosine. them. These channels were originally detected electrically by
P2XRs are channels and P2YRs are GPCRs. Purinergic recep- showing that current could pass from one cell to another
tors are best known as regulators of blood flow in tissues; they through an electrical synapse. Later they were associated with
have also been implicated in several sensory processes. an anatomic structure called the gap junction, named for its
Two additional channel families have chemosensitive mem- appearance in electron micrographs. Actually this gap is
bers but also have important members without known ligands. spanned by matching arrays of proteins from each cell, with up
These are the epithelial sodium channel (ENaC) and the to thousands of cell–cell channels per gap junction.
inositol triphosphate (IP3) receptor (IP3R) family. Each cell–cell channel is made of two hemichannels, one
ENaCs are important in the reabsorption of sodium from from each cell (Figure 3–7). They are also called connexons. A
the nascent urine in the tubules of the nephron. They are hemichannel is a homomeric or heteromeric hexamer of pro-
thought to be heteromeric tetramers each with two TM seg- teins called connexins. There are more than 15 different con-
ments; they are not voltage-dependent. It is known that they nexins with molecular weights between 25 and 50 kDa. They
are regulated by control of their insertion and removal from all have four TM segments and two extracellular loops and
the membrane, and there may be an unknown ligand for this their N- and C-terminals are in the cytoplasm. Some but not
channel. There are structurally related channels in inverte- all connexins can form hybrid channels joining different he-
brates that have known ligands. michannels on the two cells.
IP3Rs and the related ryanodine receptors (RyR) are found
in the membrane of the ER. When open, they permit the re-
lease of Ca2+ from the ER. IP3 is a second messenger produced
by the action of phospholipase C (PLC) on the membrane
lipid phosphotidylinositol, which has been previously phos-
phorylated to be PIP2. RyRs also control the release of calcium, Out
primarily in muscle, from the sarcoplasmic reticulum. Ryano-
dine refers to a toxin that partially opens these channels. RyRs
are opened by direct interaction with a modified CaV channel
In
in skeletal muscle and by intracellular Ca2+ in cardiac muscle.
The functions of IP3Rs and RyRs are discussed in further detail
in Chapters 9 and 10.
RyRs are homotetramers with an enormous 20-nm-diameter
cytoplasmic N-terminal region. The total molecular weight
for the tetramer is above 2,000 kDa, about 10 times larger than
N C
NaV or KV channels. IP3R channels are also homotetramers
about half the size of RyRs. It has been predicted that IP3Rs
have 6 TM segments per monomer and RyRs have 4–12.
In
WATER CHANNELS
Some cells require more permeability to water than is provided
by the lipid bilayer. Red blood cells, which must quickly change Out
shape to pass through narrow capillaries, and many epithelial
cells, most notably those in the kidney, have specialized water
channels or aquaporins (AQPs), which permit the passage of
water but exclude ions. The AQPs are found as tetramers with In
four functional pores, one in each subunit. The subunits have
FIGURE 3–7 The topology of connexin, a monomer
six TM segments and two regions similar to the P loop of KV of cell–cell channels, top view showing the arrangement of
channels. One of the loops faces the extracellular surface and six monomers in a hemichannel and side view showing two
the other faces the cytoplasm, and they meet in the middle of cell membranes with aligned hemichannels. (Modified with
the membrane. The functions of AQPs and ENaCs are dis- permission from Landowne D: Cell Physiology, New York: Lange Medical Books/
cussed toward the end of this chapter. McGraw-Hill, 2006.)
22 SECTION II Cell Physiology

The pore is much larger than the ion channels described

above. It is about 1.2 nm and is permeable to anions, cations, Out
2Ko 3Nao
and small metabolites as well as second messengers such as
ATP, cAMP, or IP3 but not proteins. Experimentally, the pore E2
3Na 2K
is permeable to molecules with molecular weights below
1 kDa. Cell–cell channels allow cells in a tissue to work in a In
coordinated manner.
If a cell is damaged, it can close its cell–cell channels leading P P
to its neighbors and thus prevent the loss of small molecules
from the whole tissue. This gating is controlled by intracellular
Ca2+, H+, or transjunctional voltage. Different connexons have P
relatively different sensitivity to these three changes. Gating
can also be induced by octanol and anesthetics such as halo-
thane. Out
In some situations unpaired connexons, or the related
pannexons, can open and allow small molecules to move from Occluded
the cytoplasm to the extracellular space. Pannexons have been
suggested to have a role in inflammation and the response to 3Na 2K
In
ischemia by allowing the release of ATP to signal to cells near
a site of tissue insult.
P

ADP ATP
PUMPS
Ions move across cell membranes via channels, pumps, and
Out
transporters. These are three fundamentally distinct mecha-
nisms and the student should be careful not to confuse them.
Pumps create and maintain ionic gradients, moving ions against E1
the gradient at the expense of ATP. Channels use these gradi-
3Na 2Ki 3Nai 2K
ents to produce the various electrical signals. Transporters use In
one or more gradients; the with-gradient movement of an ion
(often Na+) is coupled to the against-gradient movement of an- ATP ATP
other substance. Because they consume ATP, pumps are often
referred to as ATPases. Five pumps will be described in detail: FIGURE 3–8 The Na/K pump cycle. Operating in the clockwise
the Na/K pump, the Ca pump, and three types of proton pump. direction the pump moves three Na+ out and then moves two K+
in at the expense of converting one ATP to ADP. (Modified with
The first three of these are called P-type pumps, because they
permission from Landowne D: Cell Physiology, New York: Lange Medical Books/
are autophosphorylated during the reaction cycle, or E1–E2
McGraw-Hill, 2006.)
pumps, because they have two major conformational states.

Na/K PUMP
The Na/K pump, often referred to more simply as the Na
pump, moves three Na+ ions out of the cell and two K+ ions
into the cell in a cycle that converts one ATP molecule to
ADP + Pi. At maximum speed, the pump completes about
100 cycles per second (cps), which means the movement of
ions per molecule is much less than a NaV channel, which may
allow 1,000 ions/ms to flow into the cell. The NaV channels are
open only briefly when the cell is active; the pump runs con-
tinuously to recover from the activity. Pump activity increases
when intracellular Na+ or extracellular K+ increase and the
pump acts homeostatically to restore the original levels.
The Na pump is a heterodimer with an alpha subunit that has
the Na+, K+, and ATP-binding sites and a beta subunit thought
to be important for membrane insertion. The beta subunit has
1 TM segment; the alpha subunit probably has 10. Intracellular
Na+ and ATP bind to the E1 form of the alpha subunit, which is
then phosphorylated and converts to the E2 form (Figure 3–8,
lower left, proceeding clockwise). The E2 form releases the Na+
into the extracellular space and binds extracellular K+. The crys-
tal structure of the E2-2K+–Pi form has recently been solved.
The overall structure of domains and helices is similar to the Ca
pump described below but there are differences related to the
specific functions of each pump. The cycle continues when the
phosphate is hydrolyzed off the protein; the protein changes
back to the E1 form, releases the K+ inside the cell, and then
binds the next Na load. As the Na+ and K+ alternately move
through the membrane, the pump passes through an occluded
state where the ions are not accessible to either solution.
Digitalis and ouabain, a related cardiac glycoside, stop the
action of the pump by binding extracellularly to the E2 form
near the K+-binding location. Digitalis is used to treat a variety
of cardiac conditions. It is a relatively dangerous drug and must
 CHAPTER 3 Cell Membranes and Transport Processes
be used cautiously so as to block only some of the pump mole-
cules and leave others functional. The danger is complicated
because extracellular K+ antagonizes the binding of digitalis by
driving the pump toward the E1 form; the prudent clinician will
monitor blood potassium levels during digitalis treatment.
The Na pump is electrogenic, because each cycle moves one
net charge out of the cell. This current has only a small effect on
the membrane potential compared to ion flow through channels,
which is discussed in the next chapter. The net movement of Na+
out of the cell prevents NaCl from accumulating in the cell. If the
pump is blocked with cardiac glycosides, the cell will swell be-
cause of the osmotic influx of water following the NaCl.
Ca PUMP
There are two important Ca pumps, one that pumps Ca2+ from
the cytoplasm into the extracellular space and another, the
SERCA pump, that pumps Ca2+ from the cytoplasm into
the lumen of the sarcoplasmic or ER. They are thought to have
similar mechanisms; both are P-type E1–E2 pumps that move
two Ca2+ ions out of the cytoplasm and two or three H+ ions
into the cytoplasm for each ATP consumed.
The SERCA pump structure has been solved in several differ-
ent states. It is a tall molecule, about 15-nm high and 8-nm thick,
mostly extending out of the membrane on the cytoplasmic side.
There are 10 TM segments. The cytoplasmic headpiece consists
of the actuator (A), nucleotide binding (N), and phosphorylation
(P) domains. The three cytoplasmic domains are widely split in
the E1 • 2Ca state but gather to form a compact headpiece in the
other states. This motion is transmitted to the membrane por-
tion through helices 1–3, attached to the A domain, and 4 and 5,
attached to the P domain, to allow the Ca2+ to be released on the
noncytoplasmic side. The distance between the Ca2+-binding
sites and the phosphorylation site is greater than 5 nm.
H/K PUMP
The H/K pump secretes acid into the stomach by pumping two
H+ ions out of the parietal cells of the gastric glands and two K+
ions into the cell while splitting one ATP molecule. Similar
pumps also operate in epithelial cells in the intestine and kidney.
This is an E1–E2 P-type pump and has a beta subunit, similar to
the Na/K pump. The H/K pump is inhibited by omeprazole
(Prilosec) and other similar drugs used in the treatment of fre-
quent heartburn.
F-TYPE H PUMPS
The most significant F-type H pump usually runs in reverse as
the F0–F1 ATP synthase found in mitochondria. This protein
complex allows protons to flow with their electrochemical
gradient and converts the flow of 10 protons to form three
ATPs from ADP. The hydrogen gradients are produced by
oxidative metabolism in mitochondria.
23
TABLE 3–1 Localization of membrane pumps.
Pump Cell Type Membrane Inhibitor
Na/K All Surface Digitalis
Ca All Surface and ER Thapsigargin
H/K Gut, kidney Surface Omeprazol
F-type H All Mitochondria Oligomycin
V-type H All Surface and Bafilomycin
vesicles
The pump has 8 different subunits and more than 20 poly-
peptide chains. The F0 portion spans the membrane and car-
ries the H ions; the F1 extends into the mitochondrial matrix.
Part of the complex rotates about an axis perpendicular to the
plane of the membrane, similar to a turbine, as the H ions flow
through. Another portion, the stator, stays fixed in position,
and the interaction between the rotator and the stator produc-
es a sequence of conformational states that favor the synthesis
of ATP. In the presence of high ATP, low ADP, and no proton
gradient, the process can be reversed to pump H+.
V-TYPE H PUMPS
V-type H pumps are also protein complexes of up to 14 sub-
units with rotors and stators. They move protons into vacuoles
and other intracellular organelles such as lysosomes, the Golgi
apparatus, and secretory vesicles. The H+ gradient produced
across synaptic vesicle membranes is used to drive the packag-
ing of neurotransmitters (see Figures 7–3 to 7–5). These
pumps are responsible for the H+ that is secreted by osteoclasts
to dissolve bones and also for H+ secretion in the kidney and
epididymus (Table 3–1).
TRANSPORTERS
Transporters move ions and other small molecules across the
membrane and are not channels or pumps. Sometimes the
word transporter is used in the general sense to include all
transport mechanisms and secondary transporter is used to
distinguish this group. Transporters undergo a conformational
change as they transport; in this aspect they are similar to
pumps and different from an open channel. Unlike a pump,
they do not consume ATP. Most transporters are thought to
have 12 TM segments in two groups of 6 with a larger cyto-
plasmic loop between them. Some have a 2-fold pseudosym-
metry and P loops facing both surfaces. There are three gen-
eral categories of transporters: uniporters, symporters or
cotransporters, and antiporters or exchangers (Figure 3–9).
The glucose transporter (GLUT) is a uniporter that fa-
cilitates the diffusion of glucose with its concentration gra-
dient into many cells that are consuming glucose. It also
facilitates movement of glucose from cells that are releasing
24 SECTION II Cell Physiology
Uniporter Symporter Antiporter
FIGURE 3–9 Three types of transporters. (Modified with
permission from Landowne D: Cell Physiology, New York: Lange Medical Books/
McGraw-Hill, 2006.)
glucose by breaking down glycogen and from basal surfaces
of epithelial cells that line the intestines and kidney tubules
(see Figure 3–14).
The Na–glucose cotransporter (SGLT) is a symport that
carries glucose into intestinal and kidney epithelial cells across
their apical surfaces against the glucose concentration gradi-
ent. The energy required for this transport comes from the
movement of one or two sodium ions with their electrochemi-
cal gradient for each transported glucose molecule.
A Na/glutamate cotransporter recovers glutamate that is
used as a neurotransmitter at CNS synapses (see Figure
7–4). It couples the downhill movement of three Na+ ions
and one K+ ion to the uphill transport of one glutamate. The
structure of a bacterial glutamate transporter, which is
thought to be similar to that of humans, has recently been
solved. It has eight TM segments and two P loops, one fac-
ing the cytoplasm and one facing the outside. It is thought
that relatively small movements of the protein can transfer
the glutamate from one P loop to the other and thus across
the membrane.
There is an H/glutamate antiporter that uses the H+ gradi-
ent, established by a V-type pump, across the membrane en-
closing synaptic vesicles to concentrate glutamate inside the
vesicle (see Figure 7–4).
There are many other Na-driven cotransporters to move
other small molecules into cells and H-driven transporters to
move some material into vesicles. Some of these transporters
are targets for pharmacologic intervention. For example,
fluoxetine (Prozac) acts on a Na/serotonin cotransporter.
Others are discussed further in Chapter 7. Some anions are
cotransported with sodium; for example, the Na/I symporter
concentrates iodine into thyroid follicle cells.
The Na/Ca exchanger (NCX) is an important regulator of
intracellular Ca2+ concentration. Three sodium ions moving
with their electrochemical gradient into the cell can move one
calcium ion out, or vice versa; all of the exchangers can run
either way depending on the relative gradients. The effect of
digitalis on cardiac muscle is to raise intracellular Na by inhib-
iting the Na/K pump. Elevated Nai+ means that there is less
inward gradient for Na+ and therefore less Ca2+ efflux via NCX.
This increases Cai2+ and produces a stronger contraction (see
also Chapter 23).
The Cl/HCO3 exchanger, also known as the anion
exchanger (AE), is important for moving CO2 from the tissues
to the lungs. CO2, produced by metabolism in the cells, is con-
verted to bicarbonate by carbonic anhydrase in the red blood
cells, and the HCO3– moves into the plasma exchanging for
chloride via AE. The process is reversed as the blood passes
through the lungs and the CO2 moves into the air to be ex-
haled. This process will be covered in Chapter 37.
ABC TRANSPORTERS
This mixed group of 12 TM transport proteins contains a
characteristic ATP-binding cassette (ABC) amino acid se-
quence and, in the absence of more specific information, is
assumed to consume ATP while transporting some material
across the membrane. Two ABC transporters deserve men-
tion here, the multidrug resistance (MDR) transporter,
which is a pump, and the cystic fibrosis transmembrane
regulator (CFTR), which is a channel.
MDR1 extrudes hydrophobic drugs across the cell mem-
brane. It is thought to act somewhat like the flippase and ex-
trudes the drugs without much specificity. A wide variety of
cells in the GI tract, liver, and kidney express MDR proteins.
These can frustrate the physician who is attempting to provide
drugs to treat cancer among these cells.
CFTR is a protein that, when mutated, leads to cystic fibrosis.
The wild-type protein is a chloride channel that requires phos-
phorylation by protein kinase A (PKA) and additional ATP
hydrolysis by the activated CFTR protein in order to open.
The Cl− moves with its electrochemical gradient. Cystic fibrosis
occurs because of the lack of Cl− transport in the pancreatic
duct (hence cystic). The decreased Cl− leads to decreased wa-
ter and the protein-rich secretion thickens and can block the
ducts that then become fibrotic. Before the development of
oral replacement therapy for the missing pancreatic enzymes,
many CF patients died of complications of malnutrition. Now
the major problem is the thickening of mucus in the lungs be-
cause of insufficient fluid secretion.
MEMBRANE RECEPTORS
The word receptor comes from pharmacologic studies, where
it designates the site of action or the molecule that a small
molecule of interest, perhaps a hormone or neurotransmitter,
acts on. Here it is used in a more restrictive sense to mean
molecules that span the membrane, are acted on the external
surface by the small molecule, and trigger some action inside
the cell when the small molecule is present. There are also
intracellular receptors, for example, the steroid hormone
receptor. Steroid hormones and related drugs can cross the
lipid bilayer and bind these intracellular proteins. Chemosen-
sitive channels are excluded as well, although some pharma-
cologists like to call them ionotropic receptors. There are two
major categories of these membrane receptors: the GPCRs and
the enzyme-linked or catalytic receptors.

Agonist
GPCR
β/γ
G protein
FIGURE 3–10 The Gαs signaling pathway. Binding of agonist to the G protein–coupled receptor causes the dissociation of the α subunit,
which causes adenylyl cyclase to raise cAMP levels. This, in turn, causes protein kinase A to phosphorylate an effector protein (in this case a
channel). (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)
G PROTEIN–COUPLED RECEPTORS
GPCRs have seven TM segments with an extracellular N termi-
nus. They are coupled to a trimeric GTP-binding protein com-
plex. When a hormone or neurotransmitter interacts with a
GPCR, it induces a conformation in the receptor that activates
a heterotrimeric G protein on the inner membrane surface of
the cell (Figure 3–10). In the inactive heterotrimeric state, GDP
is bound to the Gα subunit. On activation, GDP is released,
GTP binds to Gα, and subsequently Gα–GTP dissociates from
Gβγ and from the receptor. Both Gα–GTP and Gβγ are then
free to activate other membrane proteins. Most Gα and Gγ are
lipidated; they have a covalently attached lipid anchor into the
membrane bilayer. The duration of the G-protein signal is de-
termined by the intrinsic GTP hydrolysis rate of the Gα subunit
and the subsequent reassociation of Gα–GDP with Gβγ.
There are more than 2,000 predicted GPCRs in the human
genome, more than 5% of all the genes. More than 800 are
olfactory receptors; others detect almost all neurotransmit-
ters and many hormones. Light also is detected by GPCRs in
the eye (Figure 5–2). Different cells have different palettes of
GPCRs coupled to different G proteins controlling different
sets of intracellular reactions.
There are only about 16 different Gα subunits and even
fewer Gβγ. Three classes of Gα subunits initiate most of the
subsequent events described in this book. Gαs stimulates ad-
enylyl cyclase (AC), Gαi inhibits AC and its associated βγ
directly activates KAch channels, and Gαq stimulates a phos-
pholipase (PLCβ). AC produces cAMP that can directly in-
fluence some channels. cAMP also activates protein kinase A
(PKA) by dissociating the regulatory subunits from the cata-
lytic subunits. The PKA phosphorylates many proteins, thus
altering the activity of the cells. PLCβ splits the membrane
CHAPTER 3 Cell Membranes and Transport Processes 25
AC Effector
P
α
ATP cAMP
PKA
phospholipid PI to produce IP3 and diacylglycerol (DAG). As
described above, IP3 binds the IP3R channels, which increases
Cai, which in turn triggers various reactions. Several exam-
ples of GPCR-initiated cascades are described more fully in
later chapters.
The toxins that underlie two infectious diseases, cholera
and pertussis, ADP-ribosylate Gα subunits leading to consti-
tutive activation. In cholera, activated Gα in intestinal epithe-
lial tissue stimulates AC, cAMP levels increase, and CFTR
chloride channels open, leading to a watery diarrhea. People
with cystic fibrosis can be resistant to cholera because they
have fewer functional chloride channels. The cellular patho-
genesis of pertussis is not clear.
ENZYME-LINKED RECEPTORS
Most enzyme-linked receptors are receptor tyrosine kinases
(RTK) and act by phosphorylating tyrosine side chains on
other proteins, which may in turn phosphorylate other
proteins. Some enzyme-linked receptors are not kinases
themselves but are coupled to an associated protein that phos-
phorylates other proteins. Some enzyme-linked receptors are
guanylyl cyclases, tyrosine phosphatases, or serine kinases.
Most growth and differentiation factors act by binding spe-
cific RTKs.
The insulin receptor is an RTK that phosphorylates a fam-
ily of substrates known as insulin-receptor substrates; these
stimulate changes in glucose, protein, and lipid metabolism
and also trigger the Ras signaling pathway, activating tran-
scription factors that promote growth. Interferon receptors
and the CD4 and CD8 molecules on the surface of T lympho-
cytes are examples of receptors that are coupled to cytoplas-
mic tyrosine kinases.
26 SECTION II Cell Physiology
CELL ADHESION MOLECULES
Most cells except red blood cells have integral membrane pro-
teins that attach to the extracellular matrix or with adhesion
molecules on neighboring cells. These molecules hold the
tissue together and can allow the transmission of mechanical
forces from one cell to another. They can act as signals during
development, so one cell can recognize another. Many also act
as receptors, informing the inside of the cell that they have
bound something. Some are controlled from the inside, bind-
ing only when some signal has been received.
The integrins are examples of cell-matrix adhesion mole-
cules. They have a single TM segment and link cells to
fibronectin or laminin in the extracellular matrix.
Cadherins are Ca-dependent cell–cell adhesion molecules;
they are glycoproteins with a single TM segment and are
thought to bind homophilically (to another copy of the same
molecule) to cadherins on the other cell. Cadherins have been
found at many neuron–neuron synapses. There is a large fam-
ily of cell adhesion molecules, of which the N-CAMs are the
best understood. N-CAMs are found on a variety of cell types
and most nerve cells. Like cadherins, N-CAMs have a single
TM segment and bind homophilically, but they differ in that
they do not require Ca2+ for binding. Intercellular adhesion
molecules (ICAMs) are a related class expressed on the surface
of capillary endothelial cells that have been activated by an in-
fection in the surrounding tissue. They bind heterophilically
(to a different molecule) to integrins on white blood cells and
help them move to the site of infection. Selectins are carbohy-
drate-binding proteins on the endothelial cell membrane that
recognize sugars on the surface of the white blood cell and
form the initial binding, which is strengthened by the ICAMs.
TRANSPORT ACROSS
CELL MEMBRANES
From a functional point of view, discussion of the transport of
materials across cell membranes can be divided into passive
transport, where the materials move with their concentration
Flux
Concentration
FIGURE 3–11 The concentration dependence of simple diffusion (left) and facilitated diffusion (right). (Reproduced with permission from
Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)
gradient, and active transport, which creates or maintains
these gradients.
PASSIVE TRANSPORT
Simple Diffusion
Some materials can move with their concentration gradient by
simple diffusion though the lipid bilayer. Small, uncharged
molecules such as O2, CO2, NH3, NO, H2O, steroids, and lipo-
philic drugs can enter or leave cells by simple diffusion. The
net flux of these compounds through the membrane is pro-
portional to difference in their concentrations on the two
sides, or as expressed in the following equation:
J1→2 = –P(C2 – C1) = –PΔC (1)
Using the centimeter–gram–second (CGS) system of units,
J1→2 is the number of moles that move through a square centi-
meter of membrane from side 1 into side 2 each second and C1
and C2 are the numbers of moles of the material per cubic cen-
timeter of solution on the two sides. P, the proportionality
constant, is called the permeability of the membrane to this
material in centimeters per second. The equation is written
with the leading minus sign as an aid to remembering that the
flux is moving with the concentration gradient. This relation-
ship is shown graphically in Figure 3–11.
Equation (1) is Fick’s first law. It can be used to describe the
flux by simple uncharged substances through any membrane.
For example, it is useful to describe the movement of oxygen
from the air into the alveoli of the lungs and into the blood,
across the cells of the alveolar epithelium and the capillary en-
dothelium. A charged species will also be influenced by the
electrical potential difference across the membrane in a man-
ner to be discussed in the next chapter. If there is no potential
difference across the membrane, Fick’s law is also applicable to
charged substances.
Permeability describes a property of a particular mem-
brane in relation to a particular substance. The membrane is
considered permeable, while the substances are said to be
permeant or to permeate. The permeability will be propor-
tional to the ability of the substance to partition into the
Flux
Vmax
Km Concentration
 CHAPTER 3 Cell Membranes and Transport Processes
membrane and to diffuse within the membrane. The perme-
ability will be inversely proportional to the thickness of the
membrane. It is usually not easy or necessary to know these
three factors separately, but one should appreciate that thick-
ening of the complex membrane between the alveolus and the
pulmonary capillary blood will reduce the movement of oxy-
gen into blood.
It is sometimes convenient to think of Fick’s law as saying that
the net influx of a substance is equal to the unidirectional in-
flux (PC0) minus the unidirectional efflux (PCi).
The permeability is a measure of the ease with which a sol-
ute crosses through a membrane. Plain lipid bilayers are rela-
tively permeable to small, uncharged molecules; the perme-
ability to water is about 10−3 cm/s. Thus, water equilibrates
across a cell membrane in a few seconds. Urea is moderately
permeable (P = 10−6 cm/s), and its equilibration time is a few
minutes. Hydrophilic small organic molecules such as
glucose or uncharged amino acids are less permeable, with
P = 10−7 and equilibration times of hours; ions are essentially
impermeable, with P = 10−12 cm/s and equilibration times of
many years.
Facilitated Diffusion
Many substances, such as glucose or urea, easily enter cells in
spite of the fact that the lipid bilayer is relatively impermeable
to them. The flux of these materials is described by Fick’s law
only for low concentrations. At higher concentrations, the flux
saturates at a maximum value (see Figure 3–11). This behavior
can be described by the Michaelis–Menten equation, which is
also used to describe enzyme kinetics. The unidirectional flux
is given by the following equation:
J C
J = _____
max
(2)
C+K m
where Jmax is the maximum flux and Km the affinity or the con-
centration at which the flux is half its maximum value. This
saturable property of the flux suggests that there are a fixed
number of sites at which the flux can take place. Also, as in the
case of enzymes, it may be possible to demonstrate the compe-
tition of different substances for the same site or noncompeti-
tive inhibition of the transport sites. The sites are selective for
a particular substance or group of substances that they will
transport or that allow competition for transport. Selectivity,
affinity, and Jmax are three independent qualities of the sites;
they will be found with different values in different systems.
Facilitated diffusion is now understood in terms of channels
or transporters.
Most channels have low affinity or high Km values; they are
not saturated under normal physiological conditions. Three
glucose uniporters, GLUT1, GLUT3, and GLUT4 (which is
regulated by insulin), are found in many tissues and have
a high affinity for glucose; they are saturated at all physiologi-
cal concentrations. GLUT2, which is found in tissues carrying
large glucose fluxes (such as intestine, kidney, and liver), has a
low affinity for glucose, and the influx through GLUT2 trans-
porters increases as the glucose concentration increases.
27
ACTIVE TRANSPORT
Pumps provide primary active transport, moving materials
against their electrochemical gradients at the expense of ATP.
The Na/K pump moves Na+ out of the cell and K+ into the cell;
both ions are moving against their respective gradients. The
SERCA pump moves Ca2+ against its gradient from the cyto-
plasm into the lumen of the ER.
Cotransporters and exchangers can provide secondary
active transport, using a gradient produced by primary active
transport to move another material against its gradient. Many
transporters couple the movement of Na+ or H+ with its elec-
trochemical gradient with the movement of another substance
against its gradient. The Na-GLUT and the H/glutamate anti-
porter are two examples of secondary transport mechanisms.
The flux by pumps and transporters can be described by
equations similar to equation (2), modified to include the affin-
ity for each substance and for ATP. When more than one ion at
a time is involved in the reactions at one pump or transporter
molecule, the equation must also be modified to reflect this co-
operativity. Thus, the efflux of sodium through the Na/K pump
has a sigmoidal relationship to the internal Na+ concentration.
OSMOSIS
Life is intimately associated with the movement of water. Our
bodies are mostly water and are vitally dependent on its sup-
ply. Water is a small but abundant molecule. It is not much
larger than an oxygen atom, about 0.2 nm across—small
enough to intercalate between other molecules, even in some
crystals. A mole of water is 18 mL; thus, pure water is 55 mol/L.
This concentration is several hundred-fold higher than the
Na+, K+, or Cl− concentrations in the body that are the next
highest. More than 99% of the molecules in the body are H2O.
Because the molecules are small, they move easily; because
they are so abundant, their movements are important to our
health. There are two or three distinct mechanisms for water
movement: bulk flow, molecular diffusion, and, perhaps, mo-
lecular pumping. When you pull the plug in a bathtub or your
heart beats, there is bulk flow of fluid in response to an exter-
nal mechanical force—a push or a pull. The driving force for
bulk flow is the mechanical pressure commonly produced by
pushing or by gravity.
Molecular diffusion or osmosis is a passive process by which
water diffuses from areas of high water concentration to those
of low. There is a high water concentration where there is low
solute concentration, and vice versa. Water can diffuse across
most cell membranes directly through the lipid bilayer or by
traveling through AQPs. Many cells produce AQPs, because
simple diffusion does not permit adequate water flux. Some
kidney cells insert AQPs in response to antidiuretic hormone
(ADH), so as to increase water flow from the forming urine
back into the blood, thereby conserving water. This passive
type of water movement is called osmotic flow, and the associ-
ated driving force is the concentration gradient of the water.
28 SECTION II Cell Physiology
Water may also be transported across membranes at the ex-
pense of energy by the Na–glucose cotransporter (SGLT). The
TM transport of two Na+ ions and one sugar molecule has
been associated with the influx of 210 water molecules, inde-
pendent of the osmotic gradient. The energy could come from
allowing Na+ to move with its concentration gradient. This
molecular pumping would be a secondary active transport
mechanism and might account for almost half the daily uptake
of water from the small intestine.
Osmotic pressure is the mechanical pressure needed to
produce a flow of water equal and opposite to the osmotic flow
produced by a water concentration gradient. In animal cells,
this pressure does not develop across the cell membrane be-
cause the cells will change their volume in response to osmotic
flow. The concept of osmotic pressure is similar to (and his-
torically preceded) the Nernst equilibrium potential, an elec-
trical potential that produces a flow of ions equal and opposite
to a flow produced by a concentration gradient. The Nernst
potential is discussed in Chapter 4.
If two different solutions are in contact, the osmotic pres-
sure, π, between them is:
π = RTΔc
where R is the molar gas constant (Avogadro’s number times
Boltzmann’s constant), T the absolute temperature, and Δc the
concentration difference of all of the impermeable solutes. The
concentration difference refers to the summated molar con-
centration of all the particles created when the solute is dis-
solved in water. It is measured as the osmolarity, that is, the
sum of the moles of each component of the solution. A 2-mM
solution of MgCl2 contains 6 milliosmoles (mOsm) per liter
of solution, 2 for the Mg2+ and 2 for each Cl−. The osmolarity
of this solution is 6 mOsm. A 3-mM NaCl solution and a
6-mM urea solution have the same osmolarity because they
have the same number of particles per liter of solution. They
are said to be isosmotic.
The osmolality of a solution can be measured by the change
it produces in the freezing point or vapor pressure. Osmolality
refers to moles of solute per kilogram of solvent, whereas os-
molarity refers to moles of solute per liter of solution. Because
1 L of any body fluid contains very close to 1 kg of water,
the distinction is moot in clinical situations, and you may hear
150 mM 300 mM
NaCl NaCl
Cell volume
FIGURE 3–12 Cells shrink in hypertonic solutions and swell in hypotonic solutions. (Modified with permission from Landowne D: Cell Physiology,
New York: Lange Medical Books/McGraw-Hill, 2006.)
the terms used interchangeably. Also, the actual pressures are
rarely discussed; rather, the osmoles are mentioned directly.
Tonicity is a concept that is related to osmolarity but is a
special case for cells. A solution is said to be isotonic if it
causes neither shrinking nor swelling of cells. A 150-mM NaCl
solution (9 g/L or 0.9%) is isotonic for mammalian cells and
also isosmotic to the cell contents. A 300-mM urea solution is
also isosmotic to the cell contents, but a cell placed in this so-
lution will swell and eventually lyse or burst (Figure 3–12).
The urea solution is hypotonic; it has insufficient tonicity to
keep the cell from swelling. It differs from the NaCl solution
because the urea can cross the cell membrane. The addition of
a permeable material to a solution increases its osmolarity but
not its tonicity. The addition of more impermeable solutes
makes a hypertonic solution; a 300-mM NaCl solution is hy-
pertonic and will cause cells to shrink.
If a moderately permeable solute is added to an isotonic solu-
tion (e.g., 300-mM urea + 150-mM NaCl), the cells will tran-
siently shrink and then return to their original volume
(Figure 3–13). The rate at which they shrink is proportional to
the water permeability of the membrane; the rate at which the
volume recovers is proportional to the urea permeability. If the
(3)
original 150-mM NaCl solution is replaced, the opposite effects
will occur. The cells will swell as water rushes in and then return
to their original volume as the urea (and water) leaves the cell.
In some cases, it is convenient to consider a reflection coef-
ficient as a description of the permeability of solutes. Water
movement across capillary walls depends on the mechanical
or hydrostatic pressure difference and on the difference in col-
loid osmotic pressure due to differences in protein concentra-
tion in the plasma and the interstitial fluid. If the capillary wall
is completely impermeable to the proteins, it is said to have a
reflection coefficient of 1.0. If the walls become leaky, the re-
flection coefficient decreases, proteins enter the interstitial
space, and water follows.
Water movement in the whole body is concerned with two
compartments, intracellular and extracellular. The extracellu-
lar compartment has two subcompartments: the plasma fluid
in the blood vessels and the interstitial fluid that bathes the
rest of the cells. The plasma and the interstitial fluid are sepa-
rated by the capillary walls, which are freely permeable to all
the small molecules and ions but normally prevent the plasma
150 mM 300 mM
NaCl urea
Time

150 mM
NaCl
Cell volume
FIGURE 3–13 The addition of urea causes transient shrinking but does not change the steady-state tonicity. (Modified with permission
from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)
proteins from entering the interstitial fluid. The proteins have
an overall net negative charge at blood pH. The equilibrium
that arises with impermeable proteins and freely permeable
ions is called the Gibbs–Donnan equilibrium. This effect
produces small ion concentration gradients (<3%) and a small
potential (a few millivolts, lumen-negative) across the capil-
lary walls. For most clinical purposes, these can be ignored
and the ionic concentrations in the plasma, which are easily
measured, can be considered to represent the extracellular
fluid in general.
The plasma proteins are osmotically important; they tend to
keep water in the blood vessels. The balance between the hy-
drostatic pressure and this “colloid” osmotic pressure is
described by the Starling hypothesis discussed in detail in
Chapter 26. It regulates the flow of water across capillary en-
dothelia. Edema represents the loss of this balance.
Intracellular proteins promote the entry of water into cells
that is counteracted by the extrusion of sodium ions by Na/K
pumps. Cell membranes are not freely permeable to ions and
the intracellular compartment is not in Gibbs–Donnan equi-
librium with the extracellular space.
Short-term changes in the volumes and osmolarity of body
compartments can be calculated using the following four
principles: in every compartment, the volume times the
osmolarity is the total number of osmoles. Water will move
between the compartments to make the osmolarity equal in
all compartments. The total amount of water and the total
number of osmoles is the sum of the amounts in the compart-
ments. Any added impermeant osmotically active substances
will remain extracellular; added water will distribute among
the compartments according to the first three principles.
These calculations do not include the effects of the renal sys-
tem (Chapter 45) that will act to restore the original volumes
and osmolarities.
For example, consider a 70-kg medical student with 16 L of
extracellular fluid and 24 L of intracellular fluid for a total of
40 L. If the osmolarity of these compartments is 300 mosm,
the extracellular compartment contains 16 × 0.3 = 4.8 osm and
the intracellular compartment contains 7.2 osm, for a total of
12 osm. If this student should happen to swallow 1 L of seawa-
ter containing 1 osm of salts, mostly NaCl, the total water in-
creases to 41 L and the total number of osmoles increases to
CHAPTER 3 Cell Membranes and Transport Processes 29
150 mM NaCl + 150 mM
300 mM urea NaCl
Time
13, so the new osmolarity is 13/41 = 317 mosm. The extracel-
lular compartment will have 5.8 osm, so its new volume will be
5.8/0.317 = 18.3 L. The new intracellular volume will be
7.2/0.317 = 22.7 L. Notice that water moved out of the cells to
dilute the seawater.
TRANSPORT ACROSS
EPITHELIAL CELLS
Many epithelial cell layers functionally separate two solutions
with different compositions and act in a coordinated way to
selectively transport solutes and water across the layer. This is
achieved by having tight junctions between the sides of the
epithelial cells so that the sheet of cells is impermeable to sub-
stances that cannot pass through the cell membranes and by
incorporating selective pumps and channels appropriately on
the two surfaces of the sheet. The two sides may be called by
different names in different epithelia. The apical membrane
faces the lumen or outside of the body; it can be known as the
luminal or mucosal membrane or the brush border after the
appearance of its microvilli. The basolateral membrane that
faces the inside of the body can be known as the serosal or
peritubular membrane.
Figure 3–14 shows pathways for Na+ and glucose trans-
port across epithelial cell layers. Na/K pumps in the basolat-
eral membrane keep the intracellular Na+ low by moving it
into the extracellular fluid. Na+ can enter the cell by moving
with its concentration gradient through ENaC channels on
the apical membrane and leave via the pump on the other
side. Glucose may be brought into the cell through the api-
cal membrane, against its concentration gradient by the
SGLT, and then move with its concentration gradient
through the glucose uniporter (GLUT) on the basolateral
surface.
When solutes are moved across epithelial membranes, water
may flow osmotically, “following” the solute. This effect is im-
portant for rehydration therapy to combat the water loss of
diarrhea. Adding glucose and salt to the drinking water will
stimulate SGLT to move Na+, glucose, and water into the cell.
The Na/K pump and GLUT transporter will then move the
solutes into the body and the water will follow.
30 SECTION II Cell Physiology
Tight junction
ENaC
Na
Lumenal
apical
mucosal
Na
Glucose
SGLT
FIGURE 3–14 Sodium and glucose are transported through epithelial cell layers by a combination of pumps, channels, and
transporters. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)
Water and water-soluble material may move across epithelia
by transcytosis or by receptor-mediated endocytosis. The
substance is taken up into vesicles by endocytosis on one sur-
face and either released unchanged by exocytosis on the other
surface or broken down in endosomes and the products
released by transporters. Transcytosis occurs across capillary
endothelia; receptor-mediated endocytosis is important in the
kidney and liver.
CLINICAL CORRELATION
As she passed her coach and friends at the 15-mile mark
of the Boston Marathon, the 28-year-old runner smiled
and waved cheerily. She looked good as she passed
Heartbreak Hill, about 6 miles from the finish. Two
miles later, she stopped to drink a cup of fluid. Another
runner remembers her saying she felt dizzy and disori-
ented. She began to falter and told a friend running next
to her that she felt rubber-legged, and then tumbled to
the pavement.
When she reached the hospital, she was unresponsive
with stable vital signs. After endotracheal intubation, a
blood serum sodium value was found to be very low at
113 mmol/L. Computed tomography of the brain and
chest radiography showed diffuse cerebral and pulmo-
nary edema. She was given intravenous isotonic saline
(150 mmol/L) but never regained consciousness. Diffuse
cerebral edema was found at postmortem examination. A
few days later, the newspapers reported she died from a
condition called hyponatremic encephalopathy.
Na/K pump
Na
K
Basal
ATP
serosal
ADP
Glucose
GLUT
Hyponatremia, defined by a blood sodium concentra-
tion less than 135 mmol/L, may lead to hypotonic enceph-
alopathy with fatal cerebral edema. Of 488 runners in the
2002 Boston Marathon providing a usable blood sample at
the finish line, 13% were hyponatremic and 0.6% had crit-
ical hyponatremia (120 mmol/L or less). The study con-
cluded that hyponatremia occurs in a substantial fraction
of nonelite marathon runners and can be severe. It is usu-
ally caused by drinking excessive amounts of fluid that ex-
ceed the kidney’s capacity to excrete water during exercise.
Considerable weight gain during the race, a long racing
time, and body mass index extremes were associated with
hyponatremia, whereas female sex, composition of fluids
ingested, and use of nonsteroidal anti-inflammatory
drugs were not. Mild cases can be managed by restricting
fluids until the onset of urination. Manifestations of hy-
ponatremic encephalopathy indicate the need for emer-
gent treatment with hypertonic solutions such as 3% saline
(513 mmol/L).
Na+ and Cl− account for most of the osmotic strength
of the serum. If Na+ levels are low, the serum will be hy-
potonic and water will move into all the cells of the body
causing them to swell (edema). This can have serious ef-
fects in the brain because it is in the closed space of the
cranium and the swollen tissue will restrict blood flow
and therefore oxygen supply. Swelling may cause hernia-
tion of the brain through the tentorium and foramen
magnum, compressing the brainstem and causing respi-
ratory arrest. Blood sodium level is influenced by salt
and water intake, sweating, and urinary secretion and is
regulated by the endocrine system. The recommenda-
tion for marathon runners is to drink only when thirsty.
 CHAPTER 3 Cell Membranes and Transport Processes 31

CHAPTER SUMMARY 2. In an intestinal epithelial cell, glucose transport from the

intestinal lumen to the blood involves which of the following
■ A lipid bilayer surface membrane with embedded proteins processes?
separates and connects cells with the surrounding extracellular
A) secondary active transport
environment.
B) facilitated diffusion
■ Cell membrane lipid molecules are amphipathic, with C) active transport
hydrophobic groups facing the interior of the membrane and D) secondary active transport and facilitated diffusion
hydrophilic groups facing both aqueous interfaces. E) Active transport and secondary active transport
■ Cell membrane proteins carry out specific functions by acting 3. A solution is prepared by adding 10 g of NaCl (formula
as channels, pumps, transporters, receptors, or cell adhesion weight = 58.5) to 1 L of distilled water. An isotonic solution
molecules. is 300 mOsm. The prepared solution is
■ Cell membrane proteins are amphipathic, generally with one or A) very hypotonic (with less than 50% normal tonicity).
more hydrophobic TM helices. B) slightly hypotonic (about 10% low).
■ Ion channels are membrane proteins with a pore that selects for C) isotonic (within 1%).
the type of ion(s) that passes through the channel with their D) slightly hypertonic (about 10% high).
electrochemical gradient. E) very hypertonic (more than twice normal tonicity).
■ Mechanosensitive channels are generally cation-selective and 4. Drinking isotonic saline solution will decrease
have diverse structures. A) extracellular volume.
■ Voltage-sensitive channels have a 4-fold symmetry. Each of B) extracellular osmolarity.
the parts has six transmembrane helices, one of which carries C) intracellular volume.
multiple positively charged amino acids. D) intracellular osmolarity.
■ There are many different families of chemosensitive or E) none of the above.
ligand-gated channels corresponding to the different chemical
ligands.
■ Cell–cell channels connect the interior of one cell to the
interior of an adjacent cell by an aqueous path that permits
the passage of ions and other small molecules.
Rate of transport

■ Pumps move ions or other molecules against their gradients

at the expense of ATP.
■ Transporters move some ions or other molecules against their
gradients at the expense of having other ions move with their
gradients.
■ GPCRs initiate intracellular G-protein cascades under the
control of extracellular activators.
■ Some materials can simply diffuse with their concentration
gradients through the membrane lipids.
■ Many substances have specific facilitated diffusion mechanisms Concentration gradient
characterized by an affinity and a maximum transport velocity.
■ Osmotic pressure is proportional to the osmolarity or the total 5. The above diagram is typical for the concentration gradient
concentration of all solutes. dependence of
■ Tonicity describes a solution’s ability to prevent the shrinking A) the rate of secondary active transport.
or swelling of cells. B) the rate of primary active transport.
■ Substances may be transported through epithelial cell layers by C) the rate of transport by passive diffusion.
combinations of pumps and transporters arranged on opposite D) the rate of transport by facilitated diffusion.
sides of the cells. 6. Which one of the following is least likely to affect Na/K pump
activity?
A) cardiac glycosides
STUDY QUESTIONS B) second messengers (e.g., cAMP and diacylglycerol)
1. Cell membranes C) intracellular Na+ concentration
D) extracellular Mg2+ concentration
A) consist almost entirely of protein molecules.
E) extracellular K+ concentration
B) are impermeable to fat-soluble substances.
C) contain amphipathic phospholipid molecules.
D) are freely permeable to electrolytes but not to proteins.
E) have a stable composition throughout the life of the cell.
This page intentionally left blank
 4
C H A P T E R

Channels and the Control

of Membrane Potential
David Landowne

O B J E C T I V E S

■ Describe how membrane potentials are measured and provide typical values
for different cells.
■ Discuss the relationship between the separation of charge across the
membrane and the membrane potential.
■ List the approximate concentrations of the major ions in the intracellular and
extracellular compartments.
■ Describe the three factors that control the movement of ions through
membranes.
■ Determine whether an ion will move into or out of cells given the membrane
potential and the concentration gradient of the ion.
■ Discuss how the membrane potential changes when ions flow across cell
membranes.
■ Explain the steps that occur during the generation of a Nernst potential.
■ Explain the steps that occur during the generation of a resting membrane
potential.
■ Discuss why the net flux of charge is 0 in the resting state even though ions are
moving through the membrane.
■ Discuss the role of the Na/K pump in the generation of the membrane potential.
■ Define single-channel recording and describe currents through single K channels.
■ Describe the two types of the spread of electrical information in nerve and
muscle cells.
■ Discuss why the cell membrane acts as a capacitor and what properties this
confers on nerve and muscle cells.
■ Discuss the difference between length (space) and time constants and the
relationship of these constants to nerve conduction.
■ Explain the steady-state and transient cable properties of nerve and muscle cells.

INTRODUCTION 10–100 mV. Concentration gradients of ions across the mem-

All living cells have an electrical potential difference across
their surface membranes. Cells act as miniature batteries; the
battery cell is named after the biological cell. At rest, the inside
of cells is negative to the outside by about 0.01–0.1 V or
brane are the immediate supplier of the energy to create and
maintain the resting potential. The resting potential is neces-
sary for electrical excitability of nerve and muscle cells, sensory
reception, CNS computation, and to help regulate transfer of
ions across the membrane.

33

Ch04_033-042.indd 33 11/26/10 9:41:01 AM

34 SECTION II Cell Physiology
Microelectrode
FIGURE 4–1 Membrane potentials are
measured with microelectrodes filled with
electrolyte solutions. (Modified with permission
from Landowne D: Cell Physiology. New York: Lange
Medical Books/McGraw-Hill, 2006.) Muscle
MEASURING MEMBRANE
POTENTIALS
Figure 4–1 shows how resting potentials are measured. A mus-
cle is secured to the bottom of a dish that is filled with an iso-
tonic salt solution with an ionic composition similar to that of
blood. A microelectrode with a fine tip pulled out of glass and
filled with 3-M KCl is positioned over one of the muscle cells.
A chlorided silver wire in the microelectrode is attached to
one terminal of a voltage-measuring device that displays a
trace of voltage versus time. The other terminal is attached to
another chlorided silver wire placed in the dish; this is called
the ground wire. When the microelectrode is in the solution, it
is at the same potential as the ground wire and the oscilloscope
reads 0 mV. When the microelectrode is advanced a few mi-
crometers into the muscle cell, the trace on the oscilloscope
abruptly jumps to about −90 mV and stays there as long as the
microelectrode remains in place. When the electrode is with-
drawn, the trace returns to 0 mV. The experiment can be re-
peated. If a second microelectrode is inserted, it measures the
same potential, showing that the electrodes are not somehow
creating the potential.
When the microelectrode is inside the cell, the KCl is in
contact with the cytoplasm that is in contact with the mem-
brane. The ground wire is in contact with the external solu-
tion, which is in contact with the outside of the membrane.
The potential difference is across the membrane; it is called the
membrane potential. The particular membrane potential
measured when the cell is at rest—that is, not active—is also
called the resting potential. Different cells have different
resting potentials. Skeletal and cardiac muscle cells have a rest-
ing potential of about −90 mV. Sensory and motor neurons
have a resting potential of about −70 mV; smooth muscle cells,
about −60 mV; and red blood cells, about −10 mV.
SEPARATION OF CHARGE
The resting membrane potential is a reflection of the separa-
tion of charges across the membrane. There are a few excess
negative charges (about 1 pmol/cm2) on the inner surface and
the same number of excess positive charges on the outer sur-
face (Figure 4–2). The solutions on the two sides contain about
0 mV
−90 mV
In Out In Out
Oscilloscope
150 mmol/L of cations and anions (Table 4–1) with exactly
balanced positive and negative charges except for the layer
within about 1 nm from the surface of the membrane. The
bulk solutions on both sides are electrically neutral.
The excess charges of opposite sign experience an attractive
force for each other but are prevented from reaching each oth-
er because they cannot easily leave the aqueous solutions and
enter the oily lipid membrane. Any charge within the mem-
brane also experiences this force, tending to pull positive
charges inward and push negative charges outward. The volt-
age across the membrane is the electrical measurement of this
electromotive force or this potential for movement of charges
if they happen to be within the membrane.
The voltage is directly proportional to the amount of charge
(Q) that is separated. The ratio of separated charge to the volt-
age is called the membrane capacitance:
C = __
Q
(1)
V
Electrical charge is measured in terms of coulomb (C); there
are 96,484 C/mol of charge (this is Faraday’s constant). The
unit of capacitance is the farad (F); 1 C/1 V is 1 F. Capacitance
is the ability to store separated charges. Many small computers
use a capacitor to store enough charge to allow some minimal
function to remain for a short time while the battery is being
FIGURE 4–2 The separation of charge. Left: A single layer of
charges separated by the membrane. Right: Adding a representation
of the mobile charges in the bulk solutions. (Modified with permission from
Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
 CHAPTER 4 Channels and the Control of Membrane Potential 35

TABLE 4–1 Concentrations of some ions of ent muscles for Na+, K+, and Cl− values. External Ca2+ is nor-
importance across a muscle cell membrane.a mally about 2.5 mM, but internal Ca2+ can change dramati-
cally with activity, increasing above 1 μM when the muscle is
Extracellular Intracellular contracting.
Ion concentration (mM) concentration Eion (mV) The cell membrane is permeable to all of the ions listed in
Cations Table 4–1 except A−; they can move through the membrane via
various channels. The active transport of Na+, K+, and Ca2+
Na+ 145 12 mM +65
maintains the gradients. If the cell membrane is damaged or
K +
4 155 mM −95 there is not an adequate supply of ATP, the cell will gain Na+
Ca 2+
2.5 100 nM +132 and Ca2+ and lose K+. The membrane is not very permeable to
ions; compared with water, their permeability is insignificant.
Anions
However, it is the control of this ionic permeability that regu-
Cl− 132 4 mM −90 lates the membrane potential and small (by chemical standards)
A− ~0 155 mM
movements of ions that change the membrane potential.

HCO3− 22 8 mM
a −
A represents impermeant anions inside the cell. Many are polyvalent; all together,
they contribute less than 155 mOsm to the osmotic pressure. There are also other
uncharged osmolytes in the cell.
changed. The membrane stores the opposite charges by keep-
ing them separated.
The membrane capacitance is about 1 μF/cm2. One pico-
mole of univalent ions carries about 100 nC of charge. Putting
these values into equation (1) means separating 1 pmol/cm2 of
univalent ions will produce a 100-mV membrane potential.
GENERATION OF THE
RESTING POTENTIAL
The membrane separates two solutions with quite different
ionic compositions. The extracellular concentrations are
thought to represent the concentration of these ions in seawa-
ter at the time the ancient ancestor left the sea. They are about
one third the concentration in seawater today. The generation
of the resting potential and all of the changes in potential (such
as the action potential and the synaptic potentials) depend on
the concentration gradients of ions across the cell membrane.
Table 4–1 presents some typical values for a skeletal muscle.
Both sides are electrically neutral; the sums of positive and
negative charges are equal. The external solution has relatively
high Na+ and Cl− concentrations and modest K+ and Ca2+ con-
centrations, whereas the internal solution is high in K+ and
low in Na+ and Cl− and very low in Ca2+; it has a high concen-
tration of other anions (A−), such as phosphate groups on pro-
teins or nucleic acids and negatively charged amino acids on
proteins.
There is an inward concentration gradient for Na+ and Cl−
and an outward concentration gradient for K+. The sodium
gradient is about 10-fold; Cl−, about 30-fold; and K+, about
40-fold. Table 4–1 indicates a 25,000-fold inward concentra-
tion gradient for Ca2+. Exact numbers are given in this table to
facilitate the calculation of examples later in this chapter. There
is a normal variation of about 10% in different people or differ-
−26
FACTORS THAT CONTROL
ION MOVEMENTS
The movement of ions through the membrane is proportional
to the net driving force on them. The net driving force is the
electrochemical gradient or the difference between the driv-
ing force due to the concentration gradient and the force due
to the voltage gradient or membrane potential. Movement of
charged particles is an electrical current. The current, I, car-
ried by a particular ion, x, is related to the driving force by the
following expression:
Ix = gx (V − Ex) (2)
where Ex is the chemical driving force for ion x expressed as an
electrical potential; this is described more fully below. V is the
membrane potential and (V − Ex) is the driving force on ion x.
The membrane conductance for ion x is gx. The overall mem-
brane conductance for ion x is proportional to the number of
channels for that ion, N; the probability that a channel is open,
Po; and the conductance of a single open channel, γ; or:
gx = NPoγ (3)
The conductance is proportional to the permeability of the
membrane (the ease with which ions move through it). The
conductance is also proportional to the concentration of the
conducting ion(s). In the absence of sodium ions, a sodium
channel may be permeable (if it is open), but it will not con-
duct any current.
The voltage gradient pushes or pulls an ion because the ion
is charged. The concentration gradient is a conjugate force;
ions tend to move from a high concentration to a low concen-
tration. More ions will hit an open channel from the side with
higher concentration than the side with lower concentration,
so there will be a flow with the concentration gradient in pro-
portion to the gradient.
To determine the net flux of an ion through the membrane
it is necessary to know the concentration gradient, the voltage
gradient (the membrane potential), and the conductance for
the ion. Unless all three factors are known, it is not possible to
predict the flux of the ion. The two forces on the ion from the
36 SECTION II Cell Physiology

Cl− Na+ K+
C C C
V V V

Cl− Na+ K+
−90 mV −90 mV −90 mV

60 mV 132 60 mV 145 60 mV 4
ECI = log ENa = log EK = log
−1 4 +1 12 +1 155

ECI = −90 mV ENa = +65 mV EK = −95 mV

FIGURE 4–3 The driving force on ions crossing through the membrane, voltage gradients (V), and concentration gradients (C) for
the three most common ions in the solutions in the intracellular and extracellular fluids. (Modified with permission from Landowne D: Cell Physiology.
New York: Lange Medical Books/McGraw-Hill, 2006.)

voltage and concentration gradients may act in the same direc- For chloride, the concentration gradient is inward; Cl− would
tion or in opposite directions. like to move into the cell because there is a higher concentra-
tion outside. The –90-mV resting potential exerts an outward
force on the negatively charged chloride ions. These two are
THE NERNST EQUILIBRIUM equal and opposite, that is, (V – ECl) = –90 – (–90) = 0 mV, and
chloride ions are in electrochemical equilibrium.
POTENTIAL For sodium, the concentration gradient is also inward, but
For any particular concentration gradient, it is possible to pick the negative membrane potential exerts an inward force on the
a voltage gradient that is equal and opposite, so that the term positively charged Na+. Both forces are inward and sodium
in parentheses in Eq. (2) is zero and there is no net current. ions are far from equilibrium, that is, (V – ENa) = –90 – (+65) =
This is called the electrochemical equilibrium potential or –155 mV. If the membrane were permeable to Na+, it would
the Nernst potential and is given by: readily enter.
For potassium, the concentration gradient is outward while
RT __o C
Ex = ___ln
Fz e
(4) the force from the voltage gradient is inward. The magnitude
Ci
of the concentration gradient is slightly larger than that of the
where Ex is the Nernst potential (or the equilibrium potential voltage gradient, that is, (V – EK) = –90 – (–95) = + 5 mV.
or diffusion potential) for the ion, Co and Ci the concentra- Potassium ions are not at equilibrium; they have a tendency to
tions on the outside and inside of the cell, z the charge of the leave the cell.
ion or the valence, R the molar gas constant, T the absolute Chloride is the only ion in Table 4–1 that is at equilibrium.
temperature, and F the Faraday’s constant. RT is the thermal Cl− are distributed at or very near equilibrium in skeletal mus-
energy of the material at temperature T and RT/F is this ener- cle cells but not in most nerve cells.
gy expressed in electrical units. At room temperature, RT/F is
about 25 mV. At body temperature, 37°C, the equation can be
simplified to:
GENERATION OF THE
60mV Co
Ex = _____ __
z log10 C (5) NERNST POTENTIAL
i

with z = +1 for Na+ or K+, +2 for Ca2+, –1 for Cl−, and so on.
The equilibrium potential for an ion is the potential at which
the net flux is zero. It can be calculated theoretically using the
formula of equation (5) without knowledge of the actual mem-
brane potential. It is a way to express the concentration
gradient in electrical terms, so that the concentration gradient
can be compared to the voltage gradient.
The Nernst potentials for the various ions in Table 4–1 are
listed in the last column. Figure 4–3 compares three of these
equilibrium potentials with a resting potential of –90 mV.
The resting potential has its particular value because of the K+
and Na+ gradients and because the resting membrane is much
more permeable to K+ than to Na+. This is more easily under-
stood by first considering a membrane separating the same
gradient that is permeable only to K+. Such a membrane could
be constructed by reconstituting biological K channels into an
artificial lipid bilayer (Figure 4–4).
When the solutions are first added to the compartments,
there is zero membrane potential. K+ will start to move with its
concentration gradient and thereby move positive charge from
 CHAPTER 4 Channels and the Control of Membrane Potential
A B
4 mM 155 mM
K+ Cl−
K+ Cl−
FIGURE 4–4 K+ flowing with its concentration gradient
through an artificial bilayer that is permeable only to K+. Cl− is
impermeant and a separation of charge develops. (Modified with
permission from Landowne D: Cell Physiology. New York: Lange Medical Books/
McGraw-Hill, 2006.)
compartment B to compartment A, leaving an excess negative
charge on side B and producing an excess positive charge on
side A. This separation of charge means that there is now a
membrane potential with side B negative to side A (or, equiva-
lently, side A positive with respect to side B). As side B becomes
more negative, the further net flow of K from B to A will be
reduced, until eventually sufficient charge will have been sepa-
rated so that the flux due to the increasing electrical attraction
is equal and opposite to the flux due to the concentration gra-
dient. At this point electrochemical equilibrium will have been
reached and the membrane potential will be equal to the Nernst
potential—in this example, –95 mV with side B negative to
side A. This could also be expressed by saying that the Nernst
potential is +95 mV, with side A positive to side B. This is a
property of equation (5), because log A/B = –log B/A.
Notice that less than 1 pmol/cm2 flux of positive charge is
required to establish the membrane potential. The bulk con-
centrations of K+ on the two sides of the membrane have not
changed significantly. The change in concentrations is unde-
tectable by ordinary chemical experiments.
THE RESTING POTENTIAL
The example above can be extended to explain the resting po-
tential in a muscle cell by considering the situation that would
occur if the membrane potential were artificially held at zero
Na K 3 Na 2 K
ATP
37
electronically and then released. Such a condition can be ar-
ranged with the voltage-clamp apparatus in described Chapter
6. In order to understand the process, it is necessary to know
the concentration gradients listed in Table 4–1 and also that
the permeability of the membrane to K+ is 50–100 times great-
er than its permeability to Na+.
Starting at 0-mV membrane potential, K+ will start to move
out of the cell while Na+ will start to move in, both moving
with their concentration gradients. However, more K+ will
move than Na+ because the permeability to K+ is much greater
than the permeability to Na+, so a net positive charge will move
out of the cell, making the inside of the cell negative with re-
spect to the outside.
The developing negative membrane potential opposes the
further efflux of K+ and acts to increase the influx of Na+. This
trend will continue, with the membrane potential becoming
more and more negative until three Na+ are entering through
the Na channels for every two K+ that are leaving through the
K channels. At this point a steady state will be reached because
the Na/K pump is extruding three Na+ and taking up two K+
on each ATP-consuming cycle. There is no net flux in this
steady state, so the membrane potential will not change as
long as the ATP supply is adequate (Figure 4–5).
It is important to realize that the major role of the pump is
indirect; the pump is very important for maintaining the gra-
dients but contributes only a few millivolts directly to the
membrane potential. If the “starting at 0 mV” experiment were
repeated with the pump blocked by ouabain (a cardiac glyco-
side similar to digitalis) or the absence of ATP, the initial pro-
cesses would be the same and the process would continue until
the influx of sodium were equal to the efflux of potassium. At
this point the membrane potential would stop becoming more
negative and then, very slowly, start to move back toward 0
mV as the concentrations on the two sides of the membrane
changed over several hours.
Using the figures in Table 4–1, it is possible to estimate the
immediate difference in membrane potential that can be at-
tributed to the running pump. When the membrane potential
is –90 mV, there is a 5-mV net driving force on K+. If the mem-
brane potential became 2.5 mV less negative to –87.5 mV, the
driving force on K+ would be increased by 50%, so that three
K+ would leave for every two that left at –90 mV. There would
FIGURE 4–5 Ions flowing with their
concentration gradient through channels
and actively transported against their
concentration gradient by pumps. (Modified with
permission from Landowne D: Cell Physiology. New York:
ADP Lange Medical Books/McGraw-Hill, 2006.)
38 SECTION II Cell Physiology
be a 2.5-mV decrease in the driving force on Na+, but this is
less than 2% of the 155-mV driving force, so it would make a
negligible change in the Na+ influx, and three Na+ would enter
for every three K+ leaving. Thus, about 87.5 mV of the resting
potential comes from the gradients and an additional 2.5 mV
comes directly from the pump.
If the concentrations and the ionic conductances are known,
the membrane potential can be calculated using equation (4) to
find the Nernst potentials and equation (2) to find the currents.
When the membrane potential is not changing, there is no net
current. If the pump is not running and the membrane only
conducts Na+ and K+, INa = –IK or gNa(V – ENa) = –gK(V – EK),
which can be rearranged to solve for V:
g E +g E
V = _________
Na Na
g +g
K K
Na
The membrane potential is the weighted average of the
equilibrium potentials; the weighting is by their respective
conductances. If gK >> gNa, the membrane potential will be
near EK; if gNa >> gK, it will be near ENa, and if they are equal,
it will be halfway between. If the membrane is permeable
only to these two ions and there is no external source of
electrical current, the membrane potential will always be
between EK and ENa. These concepts will become more use-
ful when the conductances change, as seen in the next three
chapters.
Because the resting membrane is preferentially permeable
to potassium, the resting potential is sensitive to the external
potassium concentration (Figure 4–6). Increasing external K
will bring the membrane potential closer to zero or depolarize
the membrane. The resting membrane in its normal ionic en-
vironment is considered polarized. A change of potential in
the positive direction, toward 0 mV, is a depolarization. A
change in the other direction, making the membrane potential
more negative, is a hyperpolarization.
Membrane potential (mV)
FIGURE 4–6 The observed membrane potential as a function of the external K+ concentration. The solid line is the theoretical
prediction for a membrane that is permeable only to K+. Notice the logarithmic concentration scale. (Modified with permission from Landowne
D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
Increased Ko depolarizes membranes because it reduces the
K+ gradient across the membrane and makes EK closer to zero.
This reduces the tendency for K+ to leave the cell, so the bal-
ance is reached at a less negative potential. Increased Ko+ is a
dangerous, potentially lethal condition because excitable cells
require the normal resting potential to remain excitable.
Doubling the blood K+ level (hyperkalemia) is likely to com-
promise cardiac muscle function.
Kir CHANNELS SUPPORT
THE RESTING POTENTIAL
Some cells, notably cardiac and skeletal muscle cells, have Kir
channels that are open, thus conducting, at the resting poten-
(6)
K
tial and are thought to be the major contributor to the resting
K conductance. These were named inward rectifiers when ex-
periments demonstrated that the inward current through
them, when the membrane potential was hyperpolarized be-
yond EK, was larger than the outward current seen when the
membrane was depolarized. It is perhaps an unfortunate name
because, in normal life, the membranes never experience such
a large hyperpolarization. The important aspects of this chan-
nel’s function are to be open for outward movement of potas-
sium near the resting potential and then to become noncon-
ducting when the cell is depolarized. This blocking in the
depolarized state will be seen to be important for cardiac mus-
cle action potentials, as described in Chapter 6.
Kir is not a voltage-sensitive channel. The blocking comes
about because Mg2+ or other polyvalent cations in the cyto-
plasm attempt to go through the channel when they are depo-
larized and get stuck, thus preventing K+ from using the chan-
nel. If the channels are studied under conditions without
polyvalent cations, they conduct K+ equally well in both
directions.
−20
−40
−60
−80
−100
EK = 60 mV log [K]o/155
−120
−140
−160
1 10 100
[K]o mM (note log scale)
 CHAPTER 4 Channels and the Control of Membrane Potential
GOLDMAN–HODGKIN–KATZ
EQUATION
If permeabilities are known, rather than conductances, a mem-
brane potential can be calculated using the theoretical
Goldman–Hodgkin–Katz (GHK) or constant field equation:
P Na + + P K + + P Cl −
V = 60mV log10_________________
Na o
+
K o
+
Cl i
−
(7)
PNaNai + PKKi + PClClo
As in equation (6), the GHK equation simplifies to the Nernst
equation if only one permeability is greater than zero. The
GHK equation has been useful to describe experimental re-
sults when some of the concentrations are set to zero, which
makes the Nernst potentials in equation (6) meaningless.
The relationship between permeability and conductance can
be set on a quantitative basis by considering the condition
when the membrane potential is zero and then, after multiply-
ing the chemical flux by Faraday’s constant, equating equations
(3–1) and (4–2) to obtain the electrical current. Thus, we have:
gxEx = PxF ΔCx (8)
CHANGES IN MEMBRANE
POTENTIAL
The membrane potential will change if current is injected into
the cell by opening channels that allow ions to flow with their
electrochemical gradients. It takes time to change the mem-
brane potential; it will not jump instantaneously to a new value.
Many nerve and muscle cells are quite long, more than 1 m for
some nerve cells. The effect of a localized current will spread
passively from the site of injection but may not change the po-
tential of the entire cell. These temporal and spatial effects are
shared by electrical cables and are referred to as the cable prop-
erties. They can be understood by considering the membrane
capacitance, the membrane resistance, and the longitudinal cy-
toplasmic resistance between different parts of the cell.
The passive spread by cable properties must be distin-
guished from the active spread by action potentials. The pas-
sive effects occur without any change in the number of open
channels. If sufficient current enters a nerve axon and depolar-
izes it above threshold, an action potential will be elicited and
will propagate without loss of amplitude over the entire length
of the cell. The action potential is regenerated as it propagates.
As the wave of opening sodium channels moves, energy is sup-
plied to the process from the Na+ gradient all along the axon.
In contrast, a smaller depolarization or a hyperpolarization
that does not open Na channels will spread only a few millime-
ters, becoming progressively smaller when measured at a
greater distance from the stimulus.
The membrane capacitance is the ratio of the charge sepa-
rated to the membrane potential—equation (1). The capaci-
tance is related to the membrane geometry by the following
equation:
K × area
C = ________ (9)
Thickness
39
where K is a constant describing the material composition of
the membrane. If the area is larger, it will take a greater amount
of charge to change the potential. The thinner the membrane,
the closer the charges are to each other and the more charges
will have to be moved to change the potential. The capaci-
tance of a typical membrane is about 1 μF/cm2; this value is
often used to estimate the size of a cell by measuring its
capacitance.
The membrane resistance is the reciprocal of the membrane
conductance:
1
Rm = __
g (10)
m
The longitudinal resistance is proportional to the length and
inversely proportional to the cross-sectional area:
ρ × length
Rl = ________
Area
(11)
where ρ is the resistivity of the cell contents.
PASSIVE PROPERTIES OF
A SMALL ROUND CELL
When pulse of current is injected into a small round cell (which
can be assumed to have the same membrane potential over its
entire surface), the membrane potential does not change in-
stantaneously. Instead, it changes with an exponential time
course with a characteristic time constant (τ), the time it takes
to discharge the change in voltage to 1/e = 37 percent of its
value (or the time it takes to charge to 63 percent of its final
value) (Figure 4–7). Initially the injected charges are adding to
the stored charges that were causing the original membrane
potential. Later, when the membrane potential has reached a
new steady state, current equal to the injected current is leaking
back out through membrane channels. When the pulse is ter-
minated, the excess stored charge leaks out through the chan-
nels and the membrane potential decays exponentially to its
original value.
The time constant of these exponential changes is the prod-
uct of the cell’s membrane resistance and capacitance. Many
cells have time constants in the range of 1–20 milliseconds.
These time constants limit how rapidly the membrane poten-
tial can change and permit temporal summation of synaptic
events in the central nervous system (see Chapter 7).
PASSIVE PROPERTIES OF
A LONG CYLINDRICAL CELL
An extended cell or a tissue with cells that are electrically
connected by gap junctions may have different membrane
potentials at different locations. If there is a local change in per-
meability, current will flow into or out of the cell and the mem-
brane potential will change at that location and, to a lesser extent,
at nearby locations. With a prolonged steady current, which lasts
much longer than the time constant described in the previous
40 SECTION II Cell Physiology

I V
value at the site of injection (Figure 4–8). Typical length con-
stants for nerve and muscle cells are 0.1–2.0 mm. A 10-μm cell is
approximately isopotential, but a 150-cm-long nerve cell re-
In quires an active propagation mechanism to be able to communi-
cate electrical activity from end to end.
C R
I V The voltage change declines because some of the injected
current leaks out of the cell and is not available to depolarize
the adjacent regions. The amount that leaks out is proportion-
Out
al to the voltage change, so the decline is exponential. The
A B length constant depends on the ratio of the membrane resis-
tance to the longitudinal axoplasmic resistance.
As the distance from the injection increases, the amplitude of
I
the transient response decreases and the rise time becomes lon-
ger and more sigmoidal (Figure 4–9). Initially most of the charge
entering the cell goes to the membrane immediately adjacent to
ΔV = IR[1 −exp(−t/τ)] the source; only later it is enough available to charge the distal
ΔV = IR exp(−t /τ)
V 63% 37% membrane. When the pulse is terminated, all responses decay at
τ τ the same rate. Synapses are distributed on the dendritic tree at
C
different distances from the cell body. The more distant syn-
apses will have less effect on the cell’s activity; the amplitude of
FIGURE 4–7 A spherical cell (A), its equivalent circuit (B), the effect will be lower and its time course will be slower.
and the voltage response to an injected pulse of current (C).
Passive spread is important for action potential propaga-
(Modified with permission from Landowne D: Cell Physiology. New York:
Lange Medical Books/McGraw-Hill, 2006.)
tion; it is the mechanism of connection between the active re-
gion and the adjacent resting region. Action potentials propa-
gate more rapidly in larger-diameter axons because they have
section, there will be a steady change in potential that is largest lower longitudinal resistance and longer length constants.
at the point of current entry and falls off exponentially with dis- The passive properties, membrane capacitance, membrane
tance with a characteristic length constant (λ) or space constant, resistance, and longitudinal resistance, are referred to as cable
the distance it takes for the potential to drop to 37 percent of its properties because they also determine the ability of under-

I V1 V2 V3

RI RI RI RI
In

I C Rm Rm Rm Rm

Out
B

1 ΔV(x) = ΔVo exp(−x/λ)

2
37% 3

λ Distance x

C
FIGURE 4–8 A long cell (A), its equivalent circuit (B), and the steady-state distribution of its membrane potential in response
to a steady injection of current (C). (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
 CHAPTER 4 Channels and the Control of Membrane Potential
I V1
1
2
V
FIGURE 4–9 The transient voltage responses at three distances from the site of an injected pulse of current. (Modified with permission
from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
water cables to transmit signals. The length constant for
undersea cables is several kilometers; for nerve axons it rang-
es from about 0.1 to 20.0 mm depending on the diameter.
Undersea cables rely on repeater amplifiers for longer distanc-
es; nerves use voltage-dependent sodium channels, as de-
scribed in Chapter 6.
When cell–cell junctions join cells, they can operate electri-
cally as if they were all one cell. Many of the cells in the heart
are coupled and action potentials propagate from one cell to
another supported by the passive spread of depolarization via
the cell–cell junctions. There are also cell–cell junctions be-
tween some neurons in the CNS.
For some it is helpful to visualize a hydraulic analogy of
these electrical phenomena. Electrical voltage is analogous to
water pressure and electrical current to solution flow. The
long cell is similar to a leaky hose, with lower membrane resis-
tance corresponding to more leaks and lower longitudinal
resistance corresponding to larger hose diameter.
CHAPTER SUMMARY
■ An electrical membrane potential is directly proportional to
the separation of positive and negative charges across the cell
membrane. The ratio of separated charge to voltage is the
membrane capacitance.
■ Cell membranes separate solutions with quite different ionic
compositions.
■ The movement of ions is directly proportional to the net
driving force on the ions. The net driving force is the electro-
chemical gradient or the difference between the effect of the
membrane potential and the effect of chemical gradient.
■ The effect of the chemical gradient can be expressed by the
Nernst equilibrium potential.
41
V2 V3
3
■ Only a very small number of ions must be separated to produce
the membrane potential. This is negligible compared with the
concentrations available on both sides.
■ The resting membrane potential is a steady state with ions
moving with their electrochemical gradient through channels
and an equal number being pumped against their electrochem-
ical gradient at the expense of ATP.
■ The GHK equation can be used to calculate the membrane
potential if the permeabilities to the various ions and their
concentrations are known.
■ When current flows through the membrane, the membrane
potential changes in time and in space, governed by the “cable
properties.”
■ When a pulse of current is injected into a cell, there is a
characteristic time required for the membrane potential to
change.
■ When a steady current is injected into a long cell, the potential
change is largest at the injection site and decreases characteris-
tically away from the site.
STUDY QUESTIONS
1. If all the Na–K pumps in the membrane of a muscle cell were
stopped, all of the following changes would be expected for the
muscle cell except
A) immediate loss of the ability of the cell to carry action
potentials
B) gradual decrease in internal K+ concentration
C) gradual increase in internal Na+ concentration
D) gradual decrease in resting membrane potential (the
potential would become less negative)
E) gradual increase in internal Cl− concentration.
42 SECTION II Cell Physiology

2. If the potassium ion concentration on the outside of a resting
skeletal muscle cell is doubled to twice of the normal value by
adding K+ and Cl− in equal amounts, what would be the best
estimate of the effect on the resting membrane potential?
A) hyperpolarize about 100 mV
B) depolarize about 5 mV
C) hyperpolarize about 15 mV
D) depolarize about 20 mV
E) no measurable effect
3. The following cell in an organism called the Europa louse
was recovered from a moon of Jupiter with a space probe.
The intracellular and extracellular concentrations of all the
ions are given as follows:
4. A scientist is recording from the soma of a neuron with an
intracellular microelectrode to study synaptic inputs on the
dendrites. The letters a, b, and c below indicate the synaptic
potentials recorded from three different synaptic inputs. For
identical synaptic inputs to the dendrites, which synaptic
potential was generated by the synapse at a location on the
dendrites closest to the soma?
A) B) C)

Extracellular Intracellular
+
Rb = 100 mM Rb+ = 1 mM

SO42− = 50 mM SO42− = 0.5 mM

The cell membrane is permeable to Rb+ and not to SO42− or water.

What is the resting membrane potential? (The sign refers to the
potential inside of the cell.)
A) +30 mV
B) +60 mV
C) +120 mV
D) −30 mV
E) −60 mV

Sensory Generator
Potentials
David Landowne
O B J E C T I V E S
■ List eight sensations and the names of the specialized sensory receptor cells
responsible for generating these sensations.
■ Describe sensory adaptation in these receptors.
■ Draw a schematic cartoon of (a) a Pacinian corpuscle and its sensory ganglion
cell (including cell body and central process); (b) a cochlear hair cell and its
synapses; and (c) a photoreceptor and its synapses.
■ List three or more differences between ion channels that underlie action
potentials, resting potentials, and receptor potentials.
Animals have developed a wide variety of sensory organs ca-
pable of monitoring chemicals, light, sound, and other me-
chanical events in the external and internal environments. In
all of these organs there are mechanisms to convert informa-
tion about the environment into electrical signals within the
nervous system. This chapter is concerned about the conver-
sion process and some general properties of all receptors. More
details about the sensory organs and the systems that process
the nerve signals are provided in Section 4: Chapters 13, 15,
16, and 17.
Transducers can convert one type of energy to another.
The cells or portions of cells that perform the initial step of
sensory transduction convert light or mechanical energy or
the presence of specific chemical conditions into a change in
the membrane potential called the receptor potential or sen-
sory generator potential. In small sensory cells, this genera-
tor potential directly controls the synaptic release process to
be described in Chapter 7. In longer cells, the generator
potential will initiate an action potential that propagates to a
distant presynaptic ending and then trigger the release pro-
cess. The information about the stimulus energy that was
transduced into a generator potential is then encoded in the
frequency of action potentials.
Each sensory cell has an appropriate stimulus, called its
adequate stimulus. The CNS interprets signals coming from
this cell in terms of its adequate stimulus. The adequate stimu-
lus for photoreceptors in the eye is visible light. If an electric
Ch05_043-046.indd 43
5
C H A P T E R
shock or sufficient pressure is applied to the eye, a person will
report flashes of light, even if the room is dark.
Each cell also has a receptive field that is the region in stim-
ulus space that evokes a response in that cell. The receptive
field of a photoreceptor in the retina is a particular location in
the visual space in front of the eye and a range of colors to
which that receptor is sensitive. The receptive field for a
somatosensory nerve in the skin is the area of skin that elicits
a response. The receptive field for an olfactory neuron is the
range of chemicals it can detect. Cells in the CNS concerned
with sensory information also have receptive fields. Different
cells handle sensory information from the feet than that from
the hands. The incoming information arrives on “labeled
lines”; the CNS processors know from whence it comes. There
are several locations in the brain that have receptive fields in-
cluding the same location in visual space. The receptive fields
of these higher-order cells are more complex, as signal pro-
cessing has occurred comparing the output from one lower-
order cell with that of others.
Mechanosensory transduction is direct, by mechanosensi-
tive channels in the membrane. The sensory cell often has mol-
ecules or structures to focus the mechanical energy or filter out
undesired mechanical disturbances, and there may be an elab-
orate organ—such as that comprising the outer, middle, and
inner ear—to deliver the desired mechanical energy to the ap-
propriate cell. In the end, a relatively nonspecific cation chan-
nel opens and both Na+ and K+ move with their concentration
43
11/26/10 9:41:42 AM
44 SECTION II Cell Physiology
FIGURE 5–1 The changes in membrane potential of a
mechanosensory nerve ending to stimuli of three different
amplitudes. (Modified with permission from Landowne D: Cell Physiology, New
York: Lange Medical Books/McGraw-Hill, 2006.)
gradients. In skin mechanoreceptors, such as the Pacinian
corpuscle discussed below, there is a greater driving force on
Na+, so more Na+ than K+ moves and the cell depolarizes. The
number of mechanosensitive channels that open is propor-
tional to the amount the membrane is stretched by the stimu-
lus. A larger stimulus will open more channels and produce a
larger depolarization (Figure 5–1). If the depolarization is large
enough, action potentials will be initiated and will propagate
toward the CNS.
The situation is more complex in the ear, because the sensory
cells (called sensory hair cells, for the hairlike appearance of the
modified cilia on their apical surface) are part of an epithelium
that separates two different solutions. However, mechanical
Disk membrane
Rhodopsin
(GPCR)
β/γ
α
Transducin
(G protein)
hν
FIGURE 5–2 The processes linking light absorption by rhodopsin and the closing of cyclic nucleotide–gated channels. Light induces
a conformational change in rhodopsin that causes the subunits of transducin to dissociate. The alpha subunit stimulates a phosphodiesterase
that degrades cGMP. In the absence of cGMP a channel that was allowing the entry of Na+ closes and the cell hyperpolarizes. (Modified with
permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)
disturbance of these cells by the appropriate sound also leads to
inward current carried by K+ through mechanosensitive chan-
nels on the cilia and depolarizes the cell. The sensory hair cells
are short and synapse with auditory nerve cells in the ear. The
hair cells do not have action potentials; they are short compared
to their length constant, so they can rely on passive spread to
open CaV channels to release transmitters.
Some taste chemosensation is supported directly by chemo-
sensitive channels, as in the glutamate receptors for the umami
taste (the distinctive savory taste of glutamate); these are rela-
tively nonselective cation channels that depolarize the cells.
Others use channels even more directly; Na+ moving through
epithelial sodium channels (ENaCs) depolarizes cells to pro-
vide the salty taste sensation. Odors are detected by G protein–
coupled receptors (GPCRs) whose G proteins activate adenylyl
cyclase, thus elevating levels of cyclic adenosine monophos-
phate (cAMP). The cAMP opens a cyclic nucleotide–gated
(CNG) nonspecific cation channel that depolarizes the cell.
CNG channels are tetramers with six TM segments and are
structurally similar to KV channels but lack the latter’s exquisite
selectivity for K ions and the voltage sensitivity.
Light transduction also involves GPCRs with seven TM seg-
ments: rhodopsin in the rods and three other opsins in the cones
tuned for short, medium, and long (or blue, green, and red)
wavelengths. The chromophore that absorbs the light is 11-cis
retinal (MW 284). Absorption of a photon triggers conversion
of the retinal to the all-trans isomer, which causes a conforma-
tional change in the opsin protein informing the G protein that
Phosphodiesterase
cGMP GMP
cGMP
Na
 CHAPTER 5 Sensory Generator Potentials 45

an event has taken place (Figure 5–2). The G protein is called

transducin; it was the first G protein to be identified and was
named before the family was well known. Transducin activates
a phosphodiesterase that hydrolyzes cyclic guanosine mono-
phosphate (cGMP). In the dark, there is a CNG channel that is FIGURE 5–3 Fast and slow sensory adaptation. The colored
open and carrying inward current. The channel closes when the bars indicate a steady level of stimulation. The rapidly adapting
cGMP level drops; when the light is on, the dark current de- receptor on the left adapts completely after two impulses have
creases and the cell hyperpolarizes. There is amplification along occurred. In the slowly adapting receptor on the right, the rate of
this chemical pathway, so one photon leads to the closure of firing declines less rapidly. (Modified with permission from Landowne D: Cell
many CNG channels. The hyperpolarization reduces a steady Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)
output of synaptic vesicles to pass the message on to the next cell
in the pathway to the brain.
The sensation of uncomfortably hot skin temperature has
cells that surrounds the nerve ending. When one side of the
been linked to the direct activation of a channel called VR1,
capsule is distorted by the stimulus, at first the distortion is
for vanilloid receptor. It is also known as the capsaicin recep-
transmitted to the nerve ending and the nerve depolarizes.
tor because it can be activated by the vanilloid capsaicin, the
Then the capsule balloons out to the sides, the forces on the
major piquant ingredient in hot peppers. VR1 is a member of
nerve are relieved, and the nerve stops firing. When the stimu-
the transient receptor potential (TRP) channel family; it has
lus is removed, the capsule rebounds to its original shape,
a six-TM architecture and is permeable to cations. Raising the
transiently pushing the sides of the nerve in the process. The
temperature into the range of 42°C (107.6°F), which many hu-
Pacinian corpuscle is tuned to provide maximum information
man observers identify as painfully hot, opens this channel,
about vibratory stimuli and to ignore steady pressure.
depolarizes the sensory ending, and initiates a train of action
Muscle spindle organs are sensory structures embedded in
potentials. Other members of the TRP family have been asso-
skeletal muscles, which provide information about the length
ciated with temperature sensation and other functions, though
of the muscle to the CNS (see Figure 2–3 and Chapter 14).
not all with pain.
Muscle spindles adapt rapidly to changes in length but also
Our everyday experience of our sense is not a direct repre-
continue to fire during a sustained stimulus. The firing rate
sentation of the stimuli but rather the result of processing
decreases slowly during the stimulus; muscle spindles are said
that occurs in the nervous system. We do not see the world as
to be slowly adapting (Figure 5–3).
flashes of light at different positions in our visual fields but
The nervous system responds to changes in the environ-
rather as objects and surroundings. Pain is an experience
ment, and by reducing the messages indicating that a stimulus
that can arise from a wide variety of stimuli without neces-
is still present, more attention can be given to any changes.
sarily telling us anything definite about the stimulus. A few
Adaptation takes place at many levels—accessory tissue before
specific nociceptors have been identified, but there are also
the receptor potential, the receptor potential itself, the encod-
many other receptors that may be associated with pain.
ing mechanism that initiates action potentials, and at many
Elevated K+ from damaged cells or the direct cutting of a
higher synapses where the incoming message is integrated
nerve cell can induce action potentials that may be interpret-
with other signals. Adaptation to light occurs by constricting
ed as pain. Acid-sensing ion channels (ASICs) in the ENaC
the pupils, by photobleaching the pigments, and by feedback
family respond to lactic acid released in the heart and depo-
regulation of the steps in the biochemical cascade.
larize nerves that provide the sensory pathway for the pain-
Many senses have some form of efferent control. The sympa-
ful experience of angina. P2X3 receptor channels, which can
thetic nervous system can release norepinephrine onto the Pa-
be activated by adenosine triphosphate (ATP) released by
cinian corpuscle, which will increase its sensitivity to mechani-
damaged cells, have been associated with pain from over-
cal stimuli. Muscle spindle organs (see Chapter 14) have efferent
stretched bladders, and P2X4 receptors have been associated
nerves (γ motor nerves) that set the range of lengths to which
with a neuropathic pain generated within the nervous system
the sensory nerve is most sensitive. There are also motor hair
without obvious outside stimuli.
cells in the ear that can selectively enhance the sensitivity of sen-
sory hair cells to particular sounds (see Chapter 16). There are
many controls on the eye to assure that the object of interest is
SENSORY ADAPTATION suitably focused on an appropriate portion of the retina even as
the head changes its position in space (see Chapter 15).
All senses except pain adapt; if they are presented with a
maintained stimulus, the response will diminish in time. The
Pacinian corpuscle adapts rapidly and responds to a sustained
stimulus with only one or two action potentials at the start CHAPTER SUMMARY
(Figure 5–3). When the stimulus is released, there is an off- ■ Each sensory cell has an adequate stimulus.
response and another action potential is initiated. Most of this ■ Touch, hearing, and other mechanosensation occur via
adaptation takes place in the onionlike capsule of accessory mechanosensitive channels.
46 SECTION II Cell Physiology

■ Taste is mediated by chemosensitive channels and odor by 2. Which of the following sensory cells has a hyperpolarizing
GPCRs and CNG channels. generator potential in response to its adequate stimulus?
■ Vision is also mediated by GPCRs—for example, A) Pacinian corpuscle nerve ending
rhodopsin—and CNG channels. B) muscle spindle nerve
■ Pain is mediated by ASICs and purine-activated channels. C) taste bud cell
■ All senses except pain adapt. D) retinal cone cell
E) olfactory nerve ending
3. Hair cells are the sensory receptor cells in the cochlea. They are
excited by the vibration of the hair bundle. Vibration of the hair
STUDY QUESTIONS bundle causes which one of the following events?
A) influx of K+ through mechanosensitive cation channels
10 10 in the tips of the cilia
Response

Response
impulse/s

impulse/s

B) influx of Ca2+ through cyclic nucleotide–gated (CNG)

5 5 channels in the tips of the cilia
C) long-lasting hyperpolarization of the hair cell
D) a train of action potentials propagated from the cilia to
10 30 50 10 30 50 the cell body of the hair cell
Seconds Seconds
A) B)
10 10
Response

Response
impulse/s

impulse/s

5 5

10 30 50 10 30 50
Seconds Seconds
C) D)

1. The graphs above show the frequency of action potentials (y-axis)

recorded from a primary sensory afferent fiber during sensory
stimulation. Which one of these graphs shows the response from
a typical sensory fiber (excluding pain fibers) to a constant
maintained stimulus applied beginning at 10 seconds and lasting
throughout the recording (i.e., until 50 seconds)?
 6
C H A P T E R

Action Potentials
David Landowne

O B J E C T I V E S

■ Describe the activation of action potentials.

■ Explain the propagation of action potentials.
■ Describe the membrane currents underlying action potentials.
■ Describe the activity of channels producing action potentials.
■ Explain the membrane basis of the action potential threshold and
refractory period.
■ Explain actions of calcium, local anesthetics, and neurotoxins on
action potentials.
■ Describe the relationship between channel activity and cardiac muscle
contraction.
■ Describe the membrane basis of intrinsic cardiac pacemakers.
■ Describe the effects of acetylcholine and NE on cardiac action potentials.

ROLE OF VOLTAGE-SENSITIVE in nerve and skeletal muscles is on the order of 1 millisecond;

in cardiac ventricular muscle cells, their duration is several
SODIUM CHANNELS hundred milliseconds. In nerve and skeletal muscles, the un-
derlying permeability changes are a transient increase in so-
Action potentials are changes in membrane potential that dium permeability followed, after a delay, by an increase in
propagate along the surface of excitable cells. They are best potassium permeability due, respectively, to the activation of
known in nerve and muscle cells but also occur in some other sodium and potassium channels (Figure 6–1). Cardiac action
cells, including egg cells associated with fertilization. Unlike
some other changes in membrane potential, action potentials
are characterized as being “all-or-none”; they have a threshold
for excitation and a stereotyped duration. Immediately follow- 25 mV
ing an action potential, the excitable cell has a refractory pe- 10 mS/cm2
riod when it is more difficult or impossible to elicit a second
1 ms
action potential.
Like most changes in membrane potential, action potentials
are the result of changes in membrane permeability due to the
activity of channels, or proteins embedded in the membrane
lipid bilayer that facilitate the passive movement of specific
ions with their electrochemical gradients. An action potential FIGURE 6–1 An action potential (red trace) and the
is a change in membrane potential from a resting potential underlying changes in membrane conductance for Na+ (blue
of about –70 mV (the inside of the cell is negative) to about trace) and K+ (beige trace). (Modified with permission from Landowne D:
+30 mV and then back to the resting potential. Their duration Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

47

Ch06_047-058.indd 47 11/26/10 9:42:20 AM

48 SECTION II Cell Physiology

potentials are more complex and also involve the activation of Change of
calcium channels. channel
conformation
Action potentials are all-or-none and propagate because the
sodium channels are voltage-sensitive. Depolarization, the
reduction of the membrane potential, from –70 to 0 mV,
induces a conformational change within a few hundred micro-
seconds in the sodium channel protein, which leads to in in- Depolarization Increase of
crease in permeability to sodium ions. Sodium ions rush into of membrane sodium
potential permeability
the cell through these open voltage-dependent Na (NaV)
channels and bring positive charge with them, which further
depolarizes the cell, opening more NaV channels (Figure 6–2).
This positive feedback loop persists until all of the sodium
channels have opened. Once the loop is started, it continues to Entry of
completion. The depolarization spreads passively to adjacent sodium
into cell
regions of the membrane and activates nearby sodium chan-
nels. This wave of molecular conformational change and elec- FIGURE 6–2 The action potential’s positive feedback cycle.
trical activity propagates over the length or surface of the cell The cycle is started by a depolarization and continues until all of the
at velocities up to 120 m/s. Potential energy that is stored in sodium channels have been activated. (Modified with permission from
the sodium concentration gradient is sequentially used along Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

the propagation path. The propagation velocity is determined

by the rate of molecular change and the electrical properties of
the cell that control the spread of potential changes (cable
properties).
About 1 millisecond later, the sodium channels undergo a
second conformational change and inactivate. In this third
conformation, they are closed and sodium no longer passes
through. In addition, the NaV channels are unable to open
again until the membrane is repolarized to the resting po-
tential for a few milliseconds to allow recovery from inacti-
vation (Figure 6–3). This automatic closing of the sodium
channels limits the duration of nerve and skeletal muscle

Open

Activated

Resting Inactivated
closed closed

FIGURE 6–3 Sodium channels can be in different functional states. A depolarization first causes the channel to change from the resting
state to the activated and open states and later to the inactivated state. Repolarization is required to go from the inactivated state back to the
resting state. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
 CHAPTER 6 Action Potentials 49

Vi
Vm Axon

Axial
wire

Vo

Vc I

FIGURE 6–4 A simplified voltage-clamp circuit for a squid giant axon. The membrane potential, Vm, is sensed as the difference
between the inside potential, Vi, and the outside potential, Vo. Vm is compared to the command potential, Vc, and, if they are different a current
flows through the axial wire and the cell membrane to make Vm equal to Vc. (Modified with permission from Landowne D: Cell Physiology. New York:
Lange Medical Books/McGraw-Hill, 2006.)

action potentials. Loss of the ability to open again produces
the refractory period.
The outward movement of K+ carrying positive charge out of
the cell produces the repolarization (the falling phase of the
action potential). In some cells, voltage-dependent K channels
(KV) channels—whose activation is slower than that of sodium
channels—facilitate repolarization. In mammalian myelinated
axons, the repolarizing current passes through the (nonvoltage-
sensitive) potassium channels that produce the resting potential.
The axons seem to be an exception; the presynaptic nerve termi-
nals and the cell bodies of most neurons have KV channels.
VOLTAGE CLAMPING
This understanding of the action potential mechanism comes
from the work of Alan Hodgkin and Andrew Huxley about
50 years ago. Working with giant nerve axons isolated from
squid, they were able to break the positive feedback loop and
measure the effect of a change in membrane potential in the
ionic permeabilities without any change to the membrane poten-
tial due to the movement of ions. Their technique was to include
the nerve membrane in a negative feedback circuit (Figure 6–4).
A pair of electrodes measures the membrane potential;
this is then compared with a desired command potential. If
the membrane potential is different from the command po-
tential, a current is made to flow through the membrane in
a direction that reduces the difference. Thus, the voltage
across the membrane is clamped at a desired value. When
the controlled voltage is a pulse from the resting potential to
0 mV, four different kinds of current can be identified
(Figure 6–5).
The first is the charge movement necessary to change the
potential or change the charge on the membrane capacitance.
Second, there is a small outward current called the gating
current. Then there is an inward current that is replaced in a
few milliseconds by an outward current, which lasts as long as
the pulse.

0 mV
“Voltage clamped”
membrane potential
−70 mV

Ic
IK
Ig Outward
INa Current with both
potassium and
sodium ions
Inward

FIGURE 6–5 The membrane currents (lower trace) in response to a voltage-clamp pulse (upper trace). Ic, capacity current; Ig, gating
current; INa, sodium current; IK, potassium current. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
50 SECTION II Cell Physiology

0 mV
“Voltage clamped”
membrane potential
−70 mV
IK

Outward
Current without
sodium ions
Inward

INa Current without

potassium ions

1 ms
Ig

Current without
either ions

FIGURE 6–6 The separation of the currents by changing the solutions. The labels have the same significance as Figure 6–5.
(Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

One can replace the contents of a segment of squid axon
with a simple salt solution and maintain functioning channels.
By changing the solutions bathing both sides of the membrane,
one can separate the currents carried by Na+ (INa) and K+ (IK)
and also see the gating current (Ig) still present in the absence
of either ion (Figure 6–6).
Notice that at 0 mV, the Na current is inward and the
K current outward. The Na current activates or increases more
rapidly than the K current. It inactivates or decreases during
the pulse, even though the membrane potential is kept at 0 mV,
whereas the K current remains for the duration of the pulse.
If the potential is pulsed to other depolarized potentials, all
four components of the current are present, although their am-
plitude and time course and, in the case of INa, direction may
change (Figure 6–7). The Na current becomes more inward
between the resting potential and about 0 mV. Larger pulses
produce less inward Na current until, at about +60 mV, no net
current passes through the Na channels. Still larger pulses can
drive outward Na current through the Na channels. The rever-
sal of the current occurs at the sodium equilibrium potential,
ENa. If the ratio of the sodium concentrations bathing both sides
of the membrane is changed, this reversal potential also chang-
es. With modest depolarizations, the inward current increases
because larger pulses open more sodium channels. However,
the less negative potential decreases the inward driving force
on the sodium ions; after most of the NaV channels have been
opened, still larger depolarizations decrease the Na current.
When the membrane potential exceeds the sodium equilibri-
um potential, Na is forced out of the cell through the open NaV
channels. In a free-running action potential, the membrane po-
tential never exceeds the sodium equilibrium potential and
there is always a net entry of Na into the cell.

+80 mV

1 mA/cm2 +60

1 ms +40

−20

+80 mV
+60
+40
0
−20
−70

FIGURE 6–7 The current’s responses (upper traces) to voltage steps of varying amplitude (lower traces). Capacity current transients
not shown. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

1 mA/cm2
10 ms
0 mV
−70
FIGURE 6–8 The recovery from inactivation shown by a
two-pulse experiment with different amounts of time at the
resting potential between pulses. Capacity current transients
not shown. (Modified with permission from Landowne D: Cell Physiology.
New York: Lange Medical Books/McGraw-Hill, 2006.)
The Na current activates and inactivates more rapidly as the
size of the pulse is increased. If a second pulse is given imme-
diately after the first, the gating current and the sodium cur-
rent during the second pulse are smaller than during the first
pulse (Figure 6–8). They both recover in parallel as the dura-
tion between pulses is increased. The rate of recovery from
inactivation is also voltage-dependent, as the channels recover
more rapidly at more hyperpolarized potentials.
The K current increases and becomes more rapid as the
membrane potential is increased. Above about +20 mV, the
increase in amplitude becomes proportional to the change in
potential, indicating that all of the channels are open and that
only the driving force continues to increase.
The gating current is a direct sign of the conformational
changes in the NaV channel proteins. These molecules con-
tain charged groups and dipoles that move or reorient when
the electrical field changes, specifically the S4 TM helices
shown in Figures 3–3 and 3–4. This movement can be mea-
sured as the gating current. As the pulse is made progressive-
ly more positive and more sodium channels open, the ampli-
tude of the gating current grows and the currents become
more rapid. Above about +20 mV, these two changes are com-
plementary and the area under the gating current trace is
constant, indicating that all of the channels are undergoing
conformational changes and are doing so more rapidly at
more positive potentials.
The capacitance current increases linearly with the size of
the pulse because it requires more charge to change the voltage
by larger amounts.
Hodgkin and Huxley separated the currents and showed
how the ionic currents were proportional to the driving
force on the ions. They created mathematical equations that
emulated the amplitude and time course of the permeability
changes and showed that these equations could predict the
amplitude and time course of action potentials as well as their
threshold, conduction velocity, refractory period, and several
other features. Their concept of describing ionic current as the
product of conductance times driving force is used to describe
most of the remaining electrophysiological phenomena in all
cells and tissues.
CHAPTER 6 Action Potentials 51
The Hodgkin–Huxley equations are available in a com-
mercial computer program called Neuron. The Web site
(http://nerve.bsd.uchicago.edu/nerve1.html) has a JavaScript
rendition that will allow you to manipulate the equations
with most modern Web browsers.
THRESHOLD
The threshold arises because there are two different effects
of small depolarizations. On the one hand, depolarization
will increase the probability that NaV channels open and
permit inward current, which will lead to further depolar-
ization. On the other hand, depolarization moves the
membrane potential further away from the potassium equi-
librium potential, increasing the net driving force on potas-
sium ions and thus producing an outward current through
the resting potential potassium channels, which will lead to
repolarization.
If a sufficient number of sodium channels are opened so that
the inward sodium current exceeds the outward potassium cur-
rent, the cell has exceeded threshold and will continue to depo-
larize until all of the available sodium channels have opened.
Treatments that reduce the sodium current—for example, re-
ducing extracellular sodium concentration or reducing the
number of NaV channels—will elevate the threshold.
REFRACTORY PERIODS
During an action potential, most of the NaV channels activate
or open and then inactivate and close into a state that differs
from their condition before the action potential. In order to
recover from inactivation and be available to open again, the
NaV channels must spend some time with the membrane po-
tential near the resting potential. They will not recover if the
membrane remains depolarized.
During this recovery, the axon is said to be refractory be-
cause it is resistant to stimulation. The refractory period is di-
vided into two segments: an absolute refractory period when
no stimulus, however large, can elicit a second action potential,
followed by a relative refractory period when the axon can be
stimulated again but requires a larger stimulus to elicit the sec-
ond response than was needed for the first (Figure 6–9).
During the absolute refractory period, so few NaV channels
have recovered that even if all of the recovered channels were
opened, there would be insufficient sodium current to exceed
the outward potassium current, which tends to restore and
maintain the resting potential. During the relative refractory
period, a larger depolarization is required because a larger
fraction of the available NaV channels must be opened to ob-
tain the same number of channels opened in the first stimulus.
In addition, in many nerve and muscle cells, there are more
open potassium channels immediately following an action
potential, which also makes the cell more difficult to excite a
second time.
52 SECTION II Cell Physiology

3
Absolute Relative

Relative threshold
2

0
0 2 4 ms 6
FIGURE 6–9 The absolute and relative refractory periods. The time axis begins with the occurrence of an action potential. During the
absolute refractory period no stimulus, however large, can elicit a second action potential. During the relative refractory period a second action
potential can be elicited but it requires a larger stimulus than that in the resting state. (Modified with permission from Landowne D: Cell Physiology. New York:
Lange Medical Books/McGraw-Hill, 2006.)

MYELINATION
Vertebrate nervous systems present a specialization of ner-
vous function not seen in invertebrates, namely myelination
(Figure 6–10). Accessory cells wrap nerve axons with many
layers of their own membrane, electrically insulating most of
the cell. NaV channels cluster in the regions between these
wraps, in the nodes of Ranvier. The Na current enters the
cell only at these nodes; excitation “jumps” from node to
node in what is called saltatory conduction. The spread be-
tween nodes is the same passive spread seen in unmyelinated
nerve cells, but it is more effective, that is, it produces a more
rapid conduction velocity. The myelin wraps increase the re-
sistance between the axoplasm and the surrounding media,
which, in turn, increases the length constant for passive
spread. The myelin also increases the effective thickness,
which decreases the effective capacitance and reduces
the amount of charge required to change the potential. Both
effects speed conduction.
DISEASES
There are many diseases or conditions of reduced or excessive
excitation of cells. Perhaps the most familiar is the conduction
of acute pain information, which is frequently treated with
local anesthetics; these act by blocking the NaV channels. Some
forms of epilepsy and some cardiac arrhythmias are also treat-
ed with NaV channel blockers. One type of long-QT (LQT)
syndrome, a cardiac arrhythmia, has been linked to a mutation
in one of the Na+ channel genes, and a hyperkalemic periodic
paralysis (HyperKPP) has been linked to another. Other LQT
syndromes have been associated with KV channels.
Hypocalcemia is associated with increased excitability of
nerves and skeletal muscle and may produce uncontrollable
muscle contraction (tetany). Hypercalcemia renders nerves and
muscles less excitable. Calcium binds to the membrane near the
S4 voltage sensor (Figure 3–4) of the NaV channel and has an
effect similar to hyperpolarization. The positive charge on the
calcium ion repels the positively charged S4 helix, making it

FIGURE 6–10 The effect of myelination on the longitudinal spread of current. In the upper diagram Na+ is shown entering
(colored arrow) at a node of Ranvier and the associated current loops are shown in black. In an unmyelinated nerve (lower diagram) the
same current loops occur but over a shorter distance; hence, the action potential propagates more slowly. (Modified with permission from
Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
 CHAPTER 6 Action Potentials 53

more difficult for the S4 to move outward and open the channel.
The result is that, in low calcium conditions, the sodium chan-
nel opens in response to a smaller stimulus or even spontane-
ously at the resting potential. The calcium binding does not
change the resting potential as measured with electrodes in the
bulk compartments on both sides of the membrane.
There are demyelinating diseases, such as multiple sclero-
sis (MS), where myelin is lost and conduction can become
slower or fail altogether. MS is an autoimmune disease and is
generally treated with synthetic corticosteroids such as pred-
nisone. The symptoms can be eased by providing air condi-
tioning or moving to a cooler climate. Cooling helps, some-
what paradoxically, because although it slows the opening of
sodium channels and thereby slows the propagation velocity,
it also slows the inactivation of NaV channels and increases
the duration of the action potentials; thus, the greater Na+
influx makes the propagation more reliable.
Reliability is often discussed in terms of the safety factor for
propagation. In healthy individuals, the 100-mV action poten-
tial that arrives at the next node of Ranvier is about five times
larger than the 20-mV depolarization required for initiating a
new impulse at that node. In patients with MS, the action po-
tential reaching the next node may be diminished to near or
below the size needed to reinitiate the impulse. One effect of
cooling nerves is to increase the safety factor for propagation.
DRUGS AND TOXINS
After the identification of these specific Na+ and K+ conduc-
tances, they were shown to be molecularly separate because
they differ in pharmacology and respond differently to various
drugs. Tetrodotoxin (TTX), a poison found in the internal
organs of puffer fish, selectively blocks nerve NaV channels at
nanomolar concentrations. Local anesthetics such as lido-
caine or benzocaine also block NaV channels. There is a great-
er diversity among KV channels and also among the drugs
that block them. Tetraethyl ammonium (TEA) ions and
4-aminopyridine are among the KV channel blockers. There
are also compounds that chronically activate NaV channels,
such as veratridine, pyrethroid insecticides, and brevetoxin,
one of the red-tide toxins.
EXTRACELLULAR RECORDINGS—
COMPOUND ACTION POTENTIALS
Action potentials can be recorded with a pair of wires placed
on the surface of a nerve bundle, typically about 1 cm apart.
When a nerve impulse passes these wires, a biphasic action
potential is seen on the display (Figure 6–11). This is a
differential recording of the same nerve impulse that would

++++−−−−+++++++++++++++ ++++−−−−++++
−−−−++++−−−−−−−−−−−−−−− −−−−++++−−−−
1 1

++++++++++−−−−+++++++++ ++++ ++++−−−−

−−−−−−−−−−++++−−−−−−−−− −−−− −−−−++++
2 2

+++++++++++−−−−++++++++ +++++++++++++
−−−−−−−−−−−++++−−−−−−−− −−−−−−−−−−−−−
3 3

++++++++++++++−−−−+++++
−−−−−−−−−−−−−−++++−−−−−
4

+++++++++++++++−−−−++++
−−−−−−−−−−−−−−−++++−−−−
5 FIGURE 6–11 Externally recorded
action potentials. Left: Biphasic action
2 2 potential recorded from an intact axon.
Right: Monophasic action potential recorded
near the site of a crush injury. The potential is
measured between the two circles above each
1 3 5 1 3 diagram. The numbers on the traces indicate
the timing of the associated diagram above.
The colored region inside the nerve cell is
propagating from left to right. (Modified with
permission from Landowne D: Cell Physiology. New York:
4 Lange Medical Books/McGraw-Hill, 2006.)
54 SECTION II Cell Physiology
1 mV
β 10 ms
γ
δ
FIGURE 6–12 A compound action potential. Left: High sweep speed. Right: Lower sweep speed, higher vertical gain. The letters refer to
specific groups of axons within the nerve. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
appear as in Figure 6–1 if the recording were made with an
intracellular microelectrode. One deflection occurs as the im-
pulse passes the first wire and the second occurs as it passes
the second wire. They are in opposite directions because the
two wires lead to opposing inputs for the display. If the nerve
is crushed between the electrodes so that the impulse does
not reach the second electrode, the response becomes mono-
phasic.
This type of recording with external electrodes is used
clinically to test nerve integrity. A nerve bundle can also be
stimulated with another pair of wires on a remote stretch of
the same bundle. With appropriate equipment, stimulation
and recording can be made through the skin without
dissecting out the nerve bundle. When a nerve bundle is
stimulated, more than one axon may be excited. The electri-
cal recording of the combination of the action potentials
produced is called a compound action potential. The com-
pound action potential is also biphasic if the nerve is intact
between the recording wires.
Besides being biphasic, there are many differences between
compound action potentials recorded with external electrodes
and the single-cell action potential recorded with an electrode
inside the cell and a reference electrode outside the cell. The
compound action potentials are much smaller, on the order of
1 mV, and there is no sign of the resting potential because both
wires are outside the nerve. The compound action potential is
not all-or-none because a larger stimulus will bring more indi-
vidual axons above threshold and the compound action
potential’s amplitude is proportional to the number of axons
firing. The compound action potential becomes smaller and
longer at greater distances from the stimulating electrodes be-
cause the conduction velocity of the various axons is not
exactly the same and the action potentials disperse as they
travel away from the stimulation site.
The threshold and conduction velocity of the various ax-
ons within a nerve bundle vary with the diameter of the
axons. Large axons have a lower threshold to stimulation by
external electrodes. (Of course, in life they are usually stimu-
lated more selectively by a specific receptor or synaptic
input.) The larger-diameter fibers have a lower threshold;
more of the stimulating current flows through them because
they have a lower internal resistance. Larger axons also have
a more rapid conduction velocity, again because of their low-
er internal resistance.
B
δ
1 μV
50 ms
C
Vertebrate peripheral axons are classified by their diameter
(or conduction velocity or threshold to external stimulation).
There are groups of nerve fibers with similar diameters. The
groups of different diameters can be distinguished as separate
elevations in the compound action potential (Figure 6–12).
There is some correlation of function with diameter. For exam-
ple, large myelinated motoneurons leading to skeletal muscles
are Aα fibers and small unmyelinated fibers carrying pain in-
formation are C fibers. The larger fibers have faster conduction
velocities and lower thresholds to external electrical stimuli.
CARDIAC ACTION POTENTIALS
The heart is a pump made up of excitable muscle cells. The
electrical activity of these cells controls their contraction. The
function of these cells will be discussed further in the context
of function of the heart in Chapter 23. The overall control of
the heart’s pattern of contraction is by the spread of action po-
tentials through a special conducting system of modified heart
muscle cells (Purkinje fibers) and through the atrial and ven-
tricular muscle cells themselves (see Figure 23–3).
There are two types of action potentials in the heart distin-
guished by their rate of depolarization and their conduction
velocity. The fast action potentials, with a rapid rate of depo-
larization and a rapid propagation velocity, are found in atrial
and ventricular muscle cells and Purkinje fibers. The slow ac-
tion potentials are normally found in the sinoatrial (SA) node
and the atrioventricular (AV) node.
CARDIAC MUSCLE
ACTION POTENTIALS
In cardiac muscle action potentials, current from adjacent cells
depolarizes the cell to a level where fast, voltage-dependent NaV
channels open and rapidly depolarize the membrane toward
the sodium equilibrium potential (phase 0 in Figure 6–13).
These channels are similar to the sodium channels of nerve and
skeletal muscle; they open in response to depolarization. They
are also blocked by local anesthetics. After opening, they inac-
tivate quickly and the membrane potential starts to return.
However, the depolarization also opens voltage-activated
L-type CaV channels that do not inactivate. This maintains the

1 The description above is a simplified view of cardiac muscle
2 action potentials. The complete story has several more K chan-
Vm
50 mV
0 changes. There are two KV channels that open transiently just
3 50 ms
4 at least two different slow voltage-dependent K channels with
IK
ICa
1 mA/cm2
INa
FIGURE 6–13 A ventricular muscle cell action potential
(upper trace) and its underlying ionic currents. The INa and ICa
currents are inward and the IK current is outward. (Modified with
permission from Landowne D: Cell Physiology. New York: Lange Medical Books/
McGraw-Hill, 2006.)
action potential in the plateau phase (phase 2). Reducing
external Ca2+ concentration or adding drugs that block calcium
channels will reduce the plateau phase and also reduce the
strength of muscle contraction. Cardiac muscle, unlike skeletal
muscle, requires external Ca2+ for contraction (Figure 6–13).
Cardiac muscle cells also differ from nerve and skeletal
muscle by lacking the fast KV channel for quick repolarization.
The potassium conductance system of the heart is rather com-
plex; at least five different components have been identified on
the basis of their kinetics and voltage dependence. Two of
these are important to understand the plateau phase. During
the plateau phase, the conductance is less than that during
diastole, the period between action potentials. This is because
of the inward rectifier channel (Kir), which is responsible for
maintaining the resting potential and has a high conductance
near and below the resting potential (at more negative poten-
tials); it does not conduct during the plateau phase when the
membrane is depolarized.
The Kir channel rectifies, allowing current to flow and main-
tain the resting potential, but it does not allow much current to
flow out during depolarization. The rectification is caused by
Mg2+ or other polyvalent cations from the internal solution
moving into the channel and plugging it when the cell is depo-
larized. The low conductance to K+ during the plateau phase
means that the modest conductance to Ca2+ through the CaV
channels maintains the membrane potential at depolarized
levels during the plateau.
Slow KV channels open very slowly during the action po-
tential and are responsible for the downward slope during
the plateau phase. When the membrane potential falls below
a certain level, the CaV channels close and the repolarization
toward the potassium equilibrium potential accelerates
(phase 3). Since the membrane is no longer depolarized, the
KV channels close.
CHAPTER 6 Action Potentials 55
nels and must account for differences among muscle action
potentials in different regions of the heart as well as age-related
after the NaV channels and produce the initial partial repolar-
ization (phase 1) from the peak to the plateau (IKto). There are
similar kinetics but distinct pharmacology (IKR and IKS). Some
cardiac muscle cells have T-type calcium channels. In all car-
diac cells, some current is carried by the sodium–calcium
exchanger and by the Na/K pump.
The regional and age-related differences in the action po-
tentials are functionally and clinically important. The ventric-
ular muscle’s action potentials near the endocardial (inner)
surface have a longer duration than those near the epicardial
(outer) surface. More work is done by the inner fibers, and
they are more likely to be damaged in a heart attack. These
differences must arise because of a different balance of Na, Ca,
and K channel activities. The interactions between the effects
of different channels are complex and are best explored with
computer models. Clearly more research is necessary to un-
derstand the details.
SA AND AV NODE ACTION POTENTIALS
The overall control of the heart’s pattern of contraction is nor-
mally initiated by action potentials that spontaneously arise
60–80 times/min from modified muscle cells in the SA node.
Similar action potentials are also seen in the AV node, where
they regulate the activation of the ventricles. In the absence of
stimulation from the atria, the AV node’s cells spontaneously
produce about 40 action potentials/min; in healthy hearts, how-
ever, the atrial cells drive them at the rate set by the SA node.
The action potentials in the nodes lack the rapid upstroke
and do not have as pronounced a plateau phase as the cardiac
muscle action potentials. They are further characterized by the
slow depolarization between action potentials: the pacemaker
potential. These cells fire rhythmically; they are never at rest
and have no true resting potential.
The upstroke of the action potential is produced by a slow
inward current carried primarily by Ca2+ (Figure 6–14). There
is an initial phase through T-type CaV channels and a major
phase through L-type CaV channels. The T-type channels are
transient and have a low threshold for opening, near –60 mV.
The L-type channels are long-lasting and have a higher thresh-
old, near –30 mV. The L-type channels are similar to the CaV
channels that maintain the plateau of the cardiac muscle ac-
tion potentials; they are blocked by dihydropyridines. T-type
channels have a different pharmacology. Reducing external
Ca2+ concentration or adding Ca2+ channel blockers reduces
the amplitude of the node’s action potentials. Outward K+ cur-
rent gradually replaces the slow inward current and the cells
repolarize toward EK. As the potential passes –50 mV, an
inward hyperpolarization-activated current, If , appears,
56 SECTION II Cell Physiology
Vm
IK
If
ICa
FIGURE 6–14 The SA node’s action potentials (upper trace) and their underlying currents. The If and ICa currents are inward and
the IK current is outward. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
competes with IK, and eventually begins to depolarize the cell
again. If is carried mainly by sodium ions. When the potential
again passes –60 mV, the CaV channels are again activated and
the cycle is repeated.
EFFECTS OF SYMPATHETIC
AND PARASYMPATHETIC
INNERVATIONS
The heart can beat spontaneously without neural input. In
healthy individuals, however, the autonomic nervous system
and circulating hormone levels regulate the heart rate and its
strength of contraction. The autonomic nervous system
controls many internal organs through its two divisions, the
sympathetic and the parasympathetic nervous systems. These
release norepinephrine (NE) and acetylcholine (ACh), re-
spectively, into the heart. The autonomic nervous system can
also cause the adrenal medulla to release epinephrine into the
blood. Epinephrine has effects on the heart similar to those of
NE. Some of the details about the autonomic synapses and
their pharmacology are described in the next chapter.
The cells in the SA and AV node cells have GPCRs that pro-
duce a stimulation (via Gαs) or inhibition (via Gαi) of adenylyl
cyclase, which, in turn, raises or lowers cAMP levels in re-
sponse to NE and ACh, respectively. The cAMP enhances the
activity of the If channels. The end result is that NE increases If
and thus depolarizes the cells more rapidly and increases the
heart rate. ACh reduces If , slows the rate of depolarization, and
reduces the heart rate (see Figure 23–4). Changing If also leads
to a speeding or slowing of conduction through the AV node.
These effects are discussed further in terms of heart function
in Chapter 23.
High ACh levels lead to the opening of another potassium
channel (KACh). (It is a G protein–activated inward rectifier
GIRK channel.) This channel further reduces the tendency to
50 mV
50 ms
1 mA/cm2
depolarize between action potentials and can temporarily stop
the heart.
NOREPINEPHRINE ALSO
INCREASES CONTRACTILITY
In the presence of NE, the plateau of the muscle action po-
tentials is elevated and has a shorter duration (Figure 6–15).
This shortening of the action potential shortens the duration
of the muscle contraction, which is functionally important
for the heart. At high heart rates, the time required to refill
the heart limits its performance. By reducing the time that
muscle force is being generated (systole), more time is left
for filling (diastole). The shortening of the ventricular ac-
tion potentials can be seen in the ECG as a shortening of the
QT interval.
NE increases the amplitude of the plateau by causing the ac-
tion potential to open more L-type Ca2+ channels. This drives
the membrane closer to the Ca equilibrium potential. The
increased Ca influx leads to a greater strength of contraction
by a mechanism described in Chapter 10. NE shortens the
NE elevates plateau
NE shortens duration
50 mV
50 ms
FIGURE 6–15 The effects of norepinephrine on ventricular
muscle cells’ action potentials. (Modified with permission from Landowne
D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

duration by making the KV channels open more rapidly. The
effects on the K and Ca2+ channels are mediated via cAMP
acting as a second messenger, stimulating protein kinase A
(PKA) and phosphorylating the channels. This pathway also
enhances the calcium reuptake mechanism by phosphorylat-
ing phospholamban. This speeds up muscle relaxation.
ACETYLCHOLINE REDUCES
ATRIAL CONTRACTILITY
The ACh-activated K channel (KACh) remains open during
the action potentials; in atrial muscle and Purkinje fibers, it
makes the plateau phase shorter and lower. The atrial contrac-
tions are weaker. ACh receptors are relatively sparse on ven-
tricular muscle cells.
CLINICAL CORRELATION
Since early childhood, a 42-year-old woman experienced
stiffness of her muscles, particularly when loosening a
tight handgrip or starting to walk. Cold exposure exacer-
bated these symptoms. Outdoors on a cold and windy
day, her face stiffened in a grimace and she could not open
her eyes or move them from side to side. These symptoms
disappeared within a few minutes after she had entered a
warm room. When she ate ice cream, her throat stiffened
and she could not swallow. From age 16, she also had at-
tacks of generalized weakness unrelated to cold. Some-
times she woke up at night severely paralyzed. She was
more liable to have an attack when hungry. During preg-
nancy she had daily attacks of weakness; within a few days
after delivery she improved.
A neurologist performed diagnostic testing. The pa-
tient was given 60 mEq of potassium orally with a mixture
of anions. Forty-five minutes later, she was so stiff that she
could make no quick movements. About an hour later,
she noticed increasing weakness and had to lie down. The
paralytic attack reached its peak roughly half an hour lat-
er. At that time, she could not lift her head, arms, or legs,
nor could she move her limbs on the examination table.
Myotonia (difficulty of relaxing muscles) of her facial and
extraocular muscles was intense. Respiration was mildly
impaired. Reflexes were unchanged and sensation was
normal. Improvement started half an hour later and was
complete 3.5 hours from the start. Before, during, and af-
ter, her serum potassium values were: 4.5, 7.3, and 3.9
mEq/L (normal is 3.5–4.5 mEq/L).
This disease also affected her son, sister, mother, mater-
nal aunt, and maternal grandfather. The inheritance was
due to a single autosomal, dominant gene with probably
complete penetrance.
This patient was suffering from familial HyperKPP,
which occurs in approximately 1 in every 200,000 people.
CHAPTER 6 Action Potentials 57
It is caused by mutations of the NaV channel of skeletal
muscle that make them slowly inactivating; the myotonia
results from abnormal reopenings of the NaV channels.
Moderate elevation of extracellular potassium favors ab-
errant gating with persistent and prolonged reopenings.
The Na current through these channels may cause skeletal
muscle weakness by depolarizing the cells, thereby inacti-
vating normal NaV channels, which are then unable to
generate action potentials. Patients with HyperKPP are at
increased risk for malignant hyperthermia induced by
anesthesia during surgery. Other NaV channel mutations
in heart muscle are linked to sudden death syndromes.
Attacks can be stopped by ingesting a high sugar load
or by thiazide diuretics, both of which reduce extracellu-
lar potassium. They can be prevented by a diet low in po-
tassium and high in carbohydrates, and also with thiaz-
ides. The disease is a lifelong condition.
CHAPTER SUMMARY
■ Depolarization opens NaV channels, which allows Na+ to rush
in and produce further depolarization. This positive feedback
loop produces the all-or-none quality and the propagation of
action potentials.
■ K+ leaving the cell repolarizes the membrane potential and
terminates action potentials.
■ Voltage clamping, or negative feedback control of the
membrane potential, facilitates understanding of the
currents underlying the action potential.
■ The amplitude and direction of the sodium current vary with
the amplitude of voltage-clamp steps in membrane potential.
■ Depolarizing steps first activate and then inactivate Na+
current. They also activate K+ current after a delay.
■ The gating current is a direct sign of the conformational
changes in the sodium channel proteins.
■ There is a threshold for action potential initiation.
■ Following an action potential, excitable cells have an absolute
refractory period when they will not produce a second action
potential and then a relative refractory period when a larger
stimulus is required to produce a second action potential.
■ Myelination increases conduction velocity by increasing the
length constant.
■ Hypocalcemia (low extracellular calcium) makes excitable cells
more excitable.
■ Demyelinating diseases slow the conduction velocity and may
block the propagation of action potentials.
■ Action potentials appear differently when they are recorded
with a pair of wires placed on the outside of a nerve bundle.
Compound action potentials, the sum of many externally
recorded action potentials, have properties that differ from
those of single action potentials recorded with intracellular
electrodes.
■ In the heart, action potentials arise automatically in the SA
node and then spread from cell to cell over the heart via gap
junctions.
58 SECTION II Cell Physiology
■ Cardiac muscle cells have KIR channels to maintain the resting
potential, NaV channels for the upstroke of the action potential,
CaV channels for the plateau phase, and slow KV channels for
the repolarization.
■ SA node cells use CaV channels for the upstroke of the
action potential, KV channels for the repolarization, and
a hyperpolarization-activated If channel to produce the slow
“pacemaker” depolarization between action potentials.
■ ACh and NE slow or speed the heart rate, respectively,
via G protein–coupled receptors, which leads to a decrease
or increase in If.
■ NE increases the amplitude of the plateau and decreases the
duration of ventricular muscle action potentials.
STUDY QUESTIONS
1. Hyperkalemia (high extracellular potassium concentration) can
stop the heart because
A) potassium ions bind to sodium channels, preventing their
activity.
B) potassium ions stimulate the sodium–potassium pump and
thereby prevent cardiac action potentials.
C) the membrane potential of heart cells depolarizes and its
sodium channels inactivate.
D) potassium ions rush out through the inward rectifier.
E) potassium ions block the actin–myosin interaction
in the heart.
2. Myelination of axons
A) reduces conduction velocity to provide more reliable
transmission.
B) forces the nerve impulse to jump from node to node.
C) occurs in excess in multiple sclerosis (MS).
D) leads to an increase in effective membrane capacitance.
E) decreases the length constant for the passive spread of
membrane potential.
3. Consider the following three channels in ventricular muscle
cells: sodium channel (NaV), inward rectifier potassium channel
(Kir), and calcium channel (CaV). Choose the answer that best
describes which of these channels is open during the plateau
phase of the ventricular action potential.
A) all three
B) NaV and Kir only
C) CaV and Kir only
D) Kir only
E) CaV only
4. There is an inward current (If ) associated with pacemaker
activity in cells of the sinoatrial node. Stimulation of sympathetic
nerves leading to the heart or application of norepinephrine
produces
A) a decrease of If , a decrease in heart rate, and an increase in
strength of contraction.
B) a decrease of If , an increase in heart rate, and an increase
in strength of contraction.
C) an increase of If , an increase in heart rate, and an increase
in strength of contraction.
D) an increase of If , a decrease in heart rate, and a decrease in
strength of contraction.
E) an increase of If , an increase in heart rate, and a decrease
in strength of contraction.
5. Propagation of a nerve impulse does not require
A) closure of potassium channels that maintain the
resting potential.
B) a conformational change in membrane proteins.
C) a membrane depolarization that opens Na+ channels.
D) current to enter the axon and flow within the axon.
E) entry of sodium ions into the axon.
6. The compound action potential recorded with a pair
extracellular electrodes from an intact bundle of nerve fibers
A) propagates without change in size or shape.
B) is all-or-none. If a threshold is exceeded, further increase
in stimulus does not increase the response.
C) has an amplitude of about 100 mV.
D) is biphasic, showing both upward and downward
deflections from the baseline.
E) is not blocked by tetrodotoxin (TTX).
 7
C H A P T E R

Synapses
David Landowne

O B J E C T I V E S

■ Describe the steps in chemical synaptic transmission.

■ Describe the biosynthesis and actions of acetylcholine, catecholamines
(dopamine, norepinephrine, epinephrine), serotonin, histamine, and
excitatory and inhibitory amino acids.
■ Describe the biosynthesis and actions of neuropeptides.
■ Describe the structure of the neuromuscular junction and the functions
of the various substructures.
■ Describe and explain the steps involved in neuromuscular transmission.
■ Describe the actions and explain the mechanisms for the effects of Ca2+
and Mg2+ on transmitter release.
■ Describe how acetylcholine interacts with receptors on the postsynaptic
membrane and the fate of the acetylcholine.
■ Describe the generation of the endplate potential and the effects and
mechanisms of action of acetylcholine esterase inhibitors and blockers
of acetylcholine receptors.
■ Describe facilitation and posttetanic potentiation of transmitter release and
how these processes can be used to explain certain features of myasthenia
gravis and recovery from receptor blockade.
■ Describe the structures and explain the functions of the various parts
of neurons.
■ Describe transport of materials up and down axons (orthograde and
retrograde axonal transport) including mechanisms and materials.
■ Calculate the time required for the regeneration of peripheral nerves.
■ Describe the differences and similarities between synaptic transmission
at a central synapse and at neuromuscular junctions.
■ Describe the generation of IPSPs and EPSPs by ionotropic and metabotropic
receptors.
■ Describe the integration of information and repetitive firing in neurons
and the concept of presynaptic inhibition.

INTRODUCTION synaptic cleft and binds to a receptor on the postsynaptic

A synapse is a specialized region where a neuron communi-
cates with a target cell: another neuron, a muscle cell, or a
gland cell. Most synapses are chemical; the presynaptic neu-
ron releases a transmitter substance that diffuses across the
cell. The postsynaptic receptor may be ionotropic, in
which case it will open a selective pore and allow ions to flow
to produce a postsynaptic potential (PSP), or it may be
metabotropic and inform a G protein to initiate a chemi-
cal cascade, which may include the opening or closing of

59

Ch07_059-078.indd 59 11/26/10 9:41:14 AM

60 SECTION II Cell Physiology
channels. A few synapses are electrical; current passes through
cell–cell channels directly into the postsynaptic cell. Chemical
synapses offer the possibility of amplification, signal inversion,
and persistent effects; electrical synapses are faster and seem
to be used when synchronization is more important than com-
putation (information processing).
Chemical synapses may be excitatory or inhibitory, depend-
ing on their effect on the postsynaptic cell. In the CNS, neu-
rons receive both types of synapses and integrate the
information coming into them before sending the processed
message on to another cell. Chemical synapses are major phar-
maceutical targets.
PRESYNAPTIC PROCESSES
The presynaptic terminal must provide for the synthesis, pack-
aging, and release of the various transmitters (Figure 7–1).
The nonpeptide transmitters are concentrated inside vesicles
by specific H/transmitter cotransporters. A V-type H+ pump,
which consumes ATP, produces the H+ gradient. The trans-
mitter concentration inside the vesicle can be quite high, on
the order of 20,000 molecules in a 20-nm radius sphere, or
about 30 mM.
After release, transmitters are degraded or transported back
into the presynaptic terminal for reuse. The vesicular mem-
branes are also recycled. Some transmitters are small polypep-
tides that are synthesized on rough endoplasmic reticulum
near the nucleus, packaged by the Golgi apparatus, and then
transported in vesicles the length of the axon by an active
process called axoplasmic transport. This process also brings
other proteins to the presynaptic terminals.
FIGURE 7–1 Synaptic vesicle docking, releasing of
contents, and recycling. (Modified with permission from Landowne
D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
Neurotransmitters can be chemically classified into five
groups (Figure 7–2). They are all hydrophilic and contain
groups that are charged at physiologic pH. Thus, they do not
readily pass through lipid membranes and can be compart-
mentalized as needed.
ACETYLCHOLINE
Acetylcholine (ACh) was the first recognized transmitter. It is
used by spinal motoneurons to excite skeletal muscles; by the
parasympathetic nerves to communicate with various end or-
gans, including the vagus nerve slowing pacemaker regions of
the heart; in sympathetic and parasympathetic ganglia; and in
various locations in the CNS. There are two classes of postsyn-
aptic ACh receptors (AChRs), which are named for other ag-
onists that can also bind to them. Nicotinic AChRs are at
neuromuscular junctions, sympathetic and parasympathetic
ganglia, and in the CNS. Nicotinic AChRs are ionotropic re-
ceptors or heteromeric pentamers (see Figure 3–5). They are
chemosensitive channels that are opened by nicotine and
blocked by curare. Muscarinic AChRs occur in the heart,
smooth muscles, gland cells, and CNS. They are metabotropic
7-TM GPCRs that are activated by muscarine and blocked by
atropine. nAChRs tend to excite the postsynaptic cell;
mAChRs may be excitatory or inhibitory.
ACh is synthesized from acetyl-CoA and choline by the en-
zyme choline acetyl transferase (CAT), found in the presyn-
aptic cytoplasm. ACh is concentrated into vesicles by an H/
ACh cotransporter (Figure 7–3). A Ca2+-activated process re-
leases the vesicles. It is described below, after all of the trans-
mitters have been discussed.
Fill
Dock
Fuse and release
Recycle
 CHAPTER 7 Synapses 61

Cholinergic Biogenic Amines Amino Acids

O COOH
+ HO
N(CH3)3 NH2
O
HO HOOC NH2

Acetylcholine Dopamine Glutamic acid

HO
NH2
Peptidergic HO HOOC NH2
OH

Endorphin Norepinephrine γ-aminobutyric acid

Enkephalin (GABA)
Dynorphin
HO
Calcitonin gene N(CH3)
related peptide (CGRP) HO
Substance Y HOOC NH2
Substance P OH
Vasopressin (ADH) Epinephrine Glycine
Oxytocin
Cholecystokinin (CCK)
Vasoactive intestinal
peptide (VIP) HO NH2 Purinergic

ATP
NH

Serotonin Adenosine

NH2
HN
N
FIGURE 7–2 The neurotransmitters.
NH
N (Modified with permission from Landowne D: Cell Physiology.
Histamine New York: Lange Medical Books/McGraw-Hill, 2006.)

Poisoning by botulinum toxin (Botox) blocks ACh release
and results in a failure of neuromuscular transmission.
Recently Botox injections have been used to treat dystonia, a
movement disorder characterized by involuntary muscle con-
tractions, and cosmetically to locally block facial muscles that
wrinkle the skin. Excessive doses or systemic toxin delivery
from contamination during food canning can lead to death.
Black (or brown) widow spider venom (BWSV) also blocks
neuromuscular transmission. It makes the presynaptic mem-
branes permeable to Ca2+ and causes a massive release of vesi-
cles, followed by a failure of transmission due to the lack of
stored ACh.
After release, ACh may be broken down into acetate and
choline by acetylcholinesterase (AChE) in the extracellu-
lar space. A Na/choline cotransporter recaptures most of
the choline; then ACh is resynthesized by CAT and repack-
aged. AChE inhibitors or anticholinesterases are used for
medical purposes, as insecticides, and as nerve gases in
chemical warfare. Their effect is to increase the amount and
duration of ACh interaction with the postsynaptic recep-
tors. The battlefield countermeasures are to block the post-
synaptic receptors on the heart with atropine. The nerve
gases are organofluorophosphates that irreversibly bind
AChE but can be displaced by pyridine aldoxime methyl
iodide (PAM).
AMINO ACIDS
GLUTAMATE
Glutamate is the major excitatory neurotransmitter of the
CNS. It is a nonessential amino acid, but, because it cannot
pass the blood–brain barrier, it must be synthesized in the
CNS. There are several synthetic pathways but none specific
for neurons. Ionotropic glutamate receptors, gluRs, are classi-
fied as NMDA-type if the synthetic agonist N-methyl-d-
aspartate activates them or non-NMDA-type if it does not.
Both types are heteromeric tetramers (see Figure 3–6) and
permit the passage of Na+ and K+, but the NMDA gluRs also
allow Ca2+ to enter the cell and have a special role in synaptic
plasticity, described later. There are also metabotropic gluRs
(mgluRs). All of these are normally activated by glutamate
(Figure 7–4).
62 SECTION II Cell Physiology

Glia

Cholinesterase

H+ Muscarinic
GPCR
ATP
ACh
Nicotinic
Presynaptic channel

Choline
ACh Cholinesterase
Na
ATP
Postsynaptic

K Na
FIGURE 7–3 A generalized schematic acetylcholine synapse. The presynaptic terminal has transporters for choline reuptake and ACh
packaging. The postsynaptic membrane has ACh receptors and cholinesterase. The nearby glial cell membrane also has cholinesterase. ACh is
hydrolyzed by the esterases and the choline part is taken back by the presynaptic terminal. (Modified with permission from Landowne D: Cell Physiology.
New York: Lange Medical Books/McGraw-Hill, 2006.)

Glutamate is removed from the extracellular space by a Na/ membrane and nearby glial cell membranes. Inside the glia,
glu cotransporter, the excitatory amino acid transporter glutamate can be converted to glutamine, released, and taken
(EAAT), which also countertransports K+. EAATs are in the up by the presynaptic terminal by a Na/Cl-coupled cotrans-
presynaptic terminal membrane and also in the postsynaptic porter and finally reconverted into glutamate.

Na glu K
gln
Na gln
Glia

mgluR
H+ GPCR

ATP
Ionotropic
channel
Presynaptic

K
glu glu
ATP Na
Postsynaptic

K Na
FIGURE 7–4 A generalized schematic glutamate synapse. In addition to the reuptake and packaging transporters, glutamate synapses
have uptake transporters in the postsynaptic and glia cell membranes. There is also a glutamine (gln) pathway to move glutamate in the glial cell
back to the presynaptic terminal. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

H+
ATP
Presynaptic
GABA
ATP
K Na
FIGURE 7–5 A generalized schematic GABA synapse. This is similar to the glutamate scheme but has GABA receptors and transporters.
(Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
Excess extracellular glutamate kills neurons by allowing
excess Ca2+ into the cells, which can lead to necrosis (cell
death). This neurotoxicity is postulated to play a role in
ischemic stroke, amyotrophic lateral sclerosis (ALS),
Huntington’s disease, Alzheimer’s disease, and possibly
some forms of epilepsy. Ischemia can raise extracellular
glutamate by limiting oxidative metabolism, ATP, and so-
dium gradients, thus the movement of glutamate away from
the receptors.
GABA AND GLYCINE
Gamma-aminobutyric acid (GABA) and glycine are the
major inhibitory neurotransmitters in the CNS. Glutamate
decarboxylase (GAD) converts glutamate into GABA in the
presynaptic terminal cytoplasm. GABA is packaged and
released as other transmitters (Figure 7–5). There is a Na/
GABA cotransporter that removes GABA from the synaptic
cleft. GABAA receptors and glycine receptors are pentam-
eric heteromers in the nAChR superfamily; they are perme-
able to Cl– ions. GABAB receptors are GPCRs that activate
Kir (or GIRK) channels.
The CNS operates with a tonic level of inhibition that can be
shifted with various drugs. Muscimol, from the mushroom
Amanita muscaria, is a potent GABAAR agonist. Common
tranquilizers such as diazepam (Valium) and barbiturates
such as phenobarbital enhance the opening of GABAARs.
Picrotoxin, a potent convulsant, blocks GABAAR. Strychnine,
also a convulsant, blocks glyRs. Tetanus toxin produces a
spastic paralysis by blocking the release mechanism for GABA
and glycine.
CHAPTER 7 Synapses 63
Na GABA Cl
Glia
GABAB
GPCR
GABAA
channel
Cl
GABA
Na
Postsynaptic
BIOGENIC AMINES
The catecholamines, serotonin, and histamine are all biogenic
amines. The catecholamines are dopamine, norepinephrine
(NE), and epinephrine (EPI). Most of the effects produced by
these biogenic amines are via GPCRs, often without producing
PSPs. All are concentrated into vesicles and released by similar
mechanisms, but some are released by nerve swellings, which
are in the vicinity of the receptors but not as closely apposed (see
Figure 7–19). Non-nerve cells also release EPI and histamine.
CATECHOLAMINES
Dopamine and NE are found in the CNS. NE is the principal
final transmitter of the sympathetic nervous system and EPI is
made and released by the adrenal medulla. All three are syn-
thesized by the same pathway, starting with the hydroxylation
of tyrosine to dihydroxyphenylalanine (DOPA), which is then
decarboxylated to form dopamine. Adding a beta-hydroxyl
group forms NE and, in the adrenal medullary cells, a subse-
quent transfer of an N-methyl group forms EPI. Tyrosine hy-
droxylase (TH) is the rate-limiting enzyme. TH and DOPA
decarboxylase are in the presynaptic terminal cytoplasm.
Dopamine is concentrated into vesicles, where dopamine
beta-hydroxylase (DBH) converts it to NE. NE is taken back
into the presynaptic terminal by a Na/Cl-coupled cotrans-
porter; there, it is broken down by monoamine oxidase
(MAO) in mitochondria and by catecholamine-O-methyl
transferase (COMT) in the cytoplasm.
Catecholamine receptors are GPCRs and are found in the
CNS, smooth muscle, and heart. Adrenergic receptors respond
64 SECTION II Cell Physiology
to NE and/or EPI. There are two categories of adrenergic recep-
tors: alpha-adrenergic receptors have a higher affinity for NE
and beta-adrenergic receptors have a higher affinity for EPI.
However, there is cross-reactivity, and both receptors will re-
spond to higher concentrations of both agonists. In the cardio-
vascular system, the alpha receptors are primarily found on the
smooth muscle cells that control the diameter of small blood
vessels; NE acts to constrict these vessels. The beta receptors are
primarily in the heart and can make it beat faster and harder.
Muscle relaxation via adrenergic receptor activation occurs in
smooth muscle cells in the gut and the lungs. Some of these
functions are discussed at greater length in the next section.
Parkinson’s disease is characterized by the loss of dopamin-
ergic neurons; its treatment often includes DOPA, which can
partially relieve the symptoms. Drugs that block dopamine re-
ceptors have been used to treat schizophrenia; sometimes they
induce Parkinson-like tremors. Reserpine, an early tranquil-
izer, inhibits dopamine transport into vesicles. Cocaine blocks
the reuptake of catecholamines, prolonging their actions.
Many over-the-counter remedies for nasal congestion, such as
neosynephrine, activate catecholamine receptors.
SEROTONIN
Serotonin, or 5-hydroxytryptamine (5-HT), is made from
tryptophan by hydroxylation and decarboxylation. 5-HT re-
ceptors function in the gut in secretion and peristalsis, medi-
ate platelet aggregation and smooth muscle contraction, and
are distributed throughout the limbic system of the brain. Se-
rotonin was initially identified as a substance in blood serum
that constricted blood vessels, hence the name.
Tryptophan hydroxylase is the rate-limiting step of 5-HT
synthesis; in the CNS tryptophan hydroxylase is present only
in serotonergic neurons. 5-HT is deactivated by reuptake and
then broken down by MAO in mitochondria. Most 5-HT re-
ceptors are GPCRs; 5-HT3 receptors are ion channels.
Selective serotonin reuptake inhibitors such as fluoxetine
hydrochloride (Prozac) are commonly prescribed as antide-
pressants. Lysergic acid diethylamide (LSD) and psilocin,
the active metabolite of psilocybin, are hallucinogens that
activate 5-HT receptors.
HISTAMINE
Most histamine in the body is released from mast cells (part of
the immune system) in response to antigens or tissue injury.
Histamine also is a regulator of acid secretion in the gut and
acts as a neurotransmitter in the central nervous system. His-
tamine release is associated with allergic reactions; it initiates
inflammatory responses, dilates blood vessels and increases
capillary permeability, decreases heart rate, and contracts
smooth muscles in the lung. Enterochromaffin-like cells in the
gastric mucosa also release histamine, which promotes acid
production. Histamine is made from histidine, stored in
vesicles, and released; it is then broken down by histamine
N-methyl transferase. There are four different histamine re-
ceptors, which are all GPCRs.
PURINES
ATP is contained in synaptic vesicles and released with NE in
sympathetic vasoconstrictor neurons. It induces constriction
when applied directly to the smooth muscles. P2X ATP recep-
tors are ion channels that permit the entry of Ca2+, and the
cells also have P2Y GPCRs. These receptors are also in the
brain, as well as P1 receptors for adenosine.
PEPTIDES
Neuropeptides are small polypeptides that are synthesized as
larger inactive precursors (propeptides) and then cleaved out
by specific endopeptidases. As they are proteins, they are
synthesized in the cell body and transported in vesicles to the
terminals. There is no reuptake mechanism. Peptides are less
concentrated than other neurotransmitters in vesicles but have
higher affinity for their receptors, which are GPCRs. Neuro-
peptides are released from large dense-core vesicles, while
other neurotransmitters are secreted from smaller, clearer ves-
icles. Neuropeptides often act in concert with classic neu-
rotransmitters.
Not much is known about the function of most neuropeptides
in the CNS except the opiate peptides, endorphin, enkephalin,
and dynorphin, which are involved in the regulation of pain
perception. Three opiate receptors have been identified, initially
as the sites that bind synthetic opiates such as morphine.
There are many nonopiod peptides released from neurons.
The calcitonin gene–related peptide (CGRP) and sub-
stance Y are involved in maintaining blood pressure. Antidi-
uretic hormone (ADH, also called vasopressin) helps control
water reuptake in the kidney. Oxytocin, luteinizing hormone
(LH), and follicle-stimulating hormone (FSH) are involved
in reproduction. Cholecystokinin (CCK), gastrin, and vaso-
active intestinal peptide (VIP) facilitate digestion. All of these
and many more have been identified as potential neurotrans-
mitters in the CNS.
SYNAPTIC RELEASE
The details of the synaptic release process are currently under
active investigation. It is clear that the process is triggered by
an increase in cytoplasmic Ca2+ levels. At many synapses, when
a presynaptic action potential arrives, the Ca2+ enters the ter-
minal through CaV channels. In some small sensory cells there
is no action potential and the sensory generator potential
opens the CaV channels.
Synaptic vesicles cycle through loading with transmitters,
docking at an active zone or release site, fusion with the sur-
face membrane and release of contents, endocytotic recovery,
 CHAPTER 7 Synapses 65

Na
Dock

Ca

Fuse and release

Recycle

FIGURE 7–6 The channels involved in synaptic release. NaV channels depolarize the ending and CaV channels permit Ca2+ influx to trigger
release. There are also KV channels that repolarize the membrane and thereby limit Ca2+ influx. (Modified with permission from Landowne D: Cell Physiology.
New York: Lange Medical Books/McGraw-Hill, 2006.)

and then loading again. In Figure 7–6, each step in the vesicu-
lar cycle is illustrated by a shift in the position of the vesicle. In
reality, however, there is little movement in the attached states.
In many synapses, the release site is across from a postsynaptic
area containing the channels that are sensitive to the transmit-
ter. In the neuromuscular junction (see Figure 7–9), CaV chan-
nels are adjacent to the release site, so that internal Ca2+ need
only be elevated locally to cause release.
Docking and fusion involves the SNARE or soluble N-
ethylmaleimide-sensitive factor attachment protein (SNAP)—
receptor proteins that are present on both membranes before
fusion and associate into tight core complexes during fusion.
Figure 7–7 shows the vesicular v-SNARE synaptobrevin bind-
ing the target t-SNARE syntaxin and SNAP-25. Synaptobrevin
is the substrate of the endopeptidases contained in botulinum
and tetanus toxins.

Synaptotagmin

Synaptobrevin
v-SNARE
Ca

Syntaxin
t-SNARE
FIGURE 7–7 A possible mechanism of vesicle fusion. SNARE proteins dock the vesicle and Ca2+ binds to synaptotagmin to cause fusion.
(Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
66 SECTION II Cell Physiology
Ca-stimulated fusion requires the Ca2+-binding protein syn-
aptotagmin, which is in the vesicular membrane and binds
Ca2+. A proposed model suggests that Ca2+ allows the synap-
totagmin to bind the surface membrane and pull the two lipid
layers together.
The recycling process returns the lipids and proteins to the
vesicle pool. The vesicle is reformed as a clathrin-coated pit.
The clathrin molecules have the shape of a triskelion, or three
bent legs. The clathrin forms a closed surface covered with
pentagons and pinches the recovered vesicle off the surface.
AXOPLASMIC TRANSPORT
All of the proteins in the presynaptic terminal are synthesized in
the cell body and transported perhaps 1 m before they are use-
ful. In addition, the neuron has mechanisms that transport some
materials in the reverse or retrograde direction back to the cell
body. Some of the mechanisms used for this transport are used
in other cells to deliver material to the periphery of the cell and
also for the movement of chromosomes during mitosis.
Axoplasmic transport is distinguished by the direction into
orthograde and retrograde. Orthograde transport can be fur-
ther divided into fast (100–400 mm per day or 1–5 μm/s) and
slow (0.5–4 mm per day). Fast transport is for vesicles and mi-
tochondria; slow transport is for soluble enzymes and those
that make up the cytoskeleton. Retrograde transport is only of
the fast type.
Fast axoplasmic transport involves molecular motors that
hydrolyze ATP and walk along microtubules, long hollow cyl-
inders 25 nm in diameter. Two different classes of motors are
used, kinesins for orthograde transport and dyneins for retro-
grade. Microtubules are polarized, and these motors can sense
the polarity and move by 8-nm steps in the appropriate direc-
tion. The motors have two “feet,” or sites of interaction with
the microtubules, and exhibit processivity, or the ability to
function repetitively without dissociating from their substrate,
the microtubule. Accessory molecules are used to attach the
payload to the motor (Figure 7–8).
Fast orthograde transport delivers the membrane proteins
needed in the terminal for both the vesicles and the terminal
Orthograde
Kinesin
Microtubule
Dynein
Retrograde
FIGURE 7–8 Axoplasmic transport. Kinesin motors carry
vesicles toward the nerve terminals. Dynein motors carry different
vesicles toward the cell body. (Modified with permission from Landowne
D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
membrane. During development, it can also deliver cell adhe-
sion molecules that recognize or induce targets. Retrograde
transport can return damaged proteins for the endolytic path-
way and bring information about signaling events back to the
cell body.
Retrograde transport is part of the pathophysiology of several
diseases including polio, rabies, tetanus, and herpes simplex.
The herpesvirus enters peripheral nerve terminals and then trav-
els back to the cell body, where it replicates or enters latency. It
can later return to the nerve ending by orthograde transport and
make itself available for contact transmission to another person.
The tetanus toxin is transported retrogradely in motoneurons to
the dendrites and then transsynaptically to GABA- and glycine-
releasing terminals, where it inhibits synaptic release.
Axoplasmic transport is important for the regeneration of
nerves following injury in the peripheral nervous system. Un-
der usual circumstances, nerves in the CNS do not regenerate,
although current researchers are hopeful that this will change
in the future. If a peripheral nerve axon is cut or crushed, the
distal portion will die and go through a characteristic Walle-
rian degeneration as the axon is resorbed over a few weeks.
Within a few days, the cell body undergoes the axon reaction,
often called chromatolysis, because of a change in staining
when it is studied histologically. The nucleolus enlarges, the
rough endoplasmic reticulum, or ER (Nissl substance), dis-
perses, and the nucleus is displaced. Genes have been activat-
ed, RNA transcribed, and proteins synthesized. The longer the
distance from the injury to the cell body, the greater the la-
tency, indicating that retrograde transport is involved in the
signaling to initiate the axonal reaction.
At the site of injury, the end that is coupled to the cell body
will reseal in hours and buds or sprouts will appear in a day or
two. The cut tip swells with mitochondria and smooth ER. The
sprouts grow out as thin fibers. If the regeneration is success-
ful, one of the new fibers finds its way down the sheath of the
distal degenerating nerve and reinnervates a postsynaptic tar-
get. The fiber will then increase in diameter and become remy-
elinated. The rate of fiber growth is about 1 mm per day, in the
range of slow axonal transport. This is the number to use in
estimating recovery times.
In addition to the microtubule-based systems, intracellular
transport can also occur via myosin motors traveling along ac-
tin filaments. The interaction is similar to that described in the
section Chapters 8 and 9 except that the actin stays fixed and
individual myosin molecules process along it. There are adapt-
er molecules that attach the payload to the myosin.
POSTSYNAPTIC PROCESSES
There are several different postsynaptic receptors for each
transmitter; they are distinguished by their amino acid se-
quences and, in some cases, pharmacology. Different regions
of the nervous system have characteristic receptors; sometimes
an individual postsynaptic cell will have multiple receptor
types. The ionotropic receptors are excitatory or inhibitory ac-

cording to their ionic selectivity. The metabotropic receptors
may indirectly cause channels to open or close and may also
modulate the activity of the cells in other ways.
The PSPs are called excitatory postsynaptic potentials
(EPSPs), if their effect is to make the postsynaptic cell more
likely to respond with an action potential, or inhibitory post-
synaptic potentials (IPSPs), if they make the postsynaptic cell
less likely to fire an action potential. Each channel has a selec-
tivity pattern and allows different ions to flow through with dif-
fering ease. This means that each channel will have a reversal
potential: a potential at which there will be no net flow of ions
through the channel. If the membrane potential is more posi-
tive than the reversal potential, net current will flow out of the
cell, tending to hyperpolarize it. If the membrane is less positive
or more negative, current will flow in and tend to depolarize the
cell. The current that flows through channels drives the mem-
brane potential toward the reversal potential for that channel.
Most neurons in the CNS receive a constantly fluctuating in-
put from a variety of synapses and their membrane potential is
always changing. If a synapse opens channels having a reversal
potential more positive than the threshold for action potentials,
they will produce an EPSP. If the reversal potential is more nega-
tive than the threshold, an IPSP will result. If a channel is perme-
able to a single ion, its reversal potential is the Nernst potential
Myelin
Axon
Mitochondria
Synaptic
vesicles
Synaptic
cleft
Synaptic
fold
Myofibrils
FIGURE 7–9 The neuromuscular junction. A myelinated nerve (gray) ends on a specialized region of a skeletal muscle (colored). (Modified
with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
CHAPTER 7 Synapses 67
for that ion (equation (4) in Chapter 4). If the channel is perme-
able to multiple ions, its reversal potential is the weighted average
of the Nernst potentials for its ions (equation (6) in Chapter 4).
nAChR channels and GluR channels are approximately
equally permeable to Na+ and K+, and their reversal potential is
about –10 mV; when activated, they make EPSPs. GABAAR
and glyR are Cl channels; their reversal potential is about –80
mV. The cardiac mAChR, through a G protein, activates a Kir
channel (KACh) that has a reversal potential about –90 mV. Both
Cl− channels and K+ channels make IPSPs. If for some reason
the cell happens to be more negative than –80 mV, opening Cl
channels will depolarize the cell but still work to keep other
channels from further depolarizing the cell to threshold.
THE NEUROMUSCULAR
JUNCTION—A SPECIALIZED
SYNAPSE
Because of its easy accessibility, the neuromuscular (or myo-
neural) junction (Figure 7–9) is the best-studied synapse; it is
the source of much of what is known about synapses. This sec-
tion describes the functioning of this synapse, bringing together
Schwann cell
Presynaptic
membrane
Postsynaptic
membrane
Muscle
nucleus
68 SECTION II Cell Physiology
and illustrating many of the ideas introduced more abstractly
above. The neuromuscular junction is of considerable clinical
interest. Myasthenia gravis is a disease that incapacitates the
neuromuscular junction; there are other diseases and several
drugs and toxins that target the junction. The neuromuscular
junction provides a convenient assay for the anesthesiologist
gauging recovery from muscle immobilization after surgery.
A single motoneuron controls between 3 and 1,000 muscle
cells. Each muscle cell receives input from one motoneuron.
The motoneuron and all of its muscle cells function together as
a motor unit. In healthy people, an action potential in the mo-
toneuron will produce a large EPSP in all of its muscle cells,
large enough to greatly exceed the threshold of the muscle
cells and produce action potentials and contraction. The CNS
regulates movement by choosing which motor units to acti-
vate. Smaller motor units produce finer movements.
At the nerve ending, the axon loses its myelin and spreads
out to form the motor endplate, named for its anatomic ap-
pearance. The nerve terminals contain many mitochondria
and many 40-nm-diameter synaptic vesicles that contain ACh.
The nerve terminal is separated from the muscle by a 50-nm
gap, the synaptic cleft, which contains a basal lamina. The
muscle membrane contains AChRs and also AChE. In trans-
mission electron micrographs, both presynaptic and postsyn-
aptic membranes appear thickened, indicating the presence of
channels and other proteins.
Neuromuscular transmission can be described as a 10-step
process: (1) an action potential enters the presynaptic termi-
nal; (2) the nerve terminal is depolarized; (3) depolarization
opens CaV channels; (4) Ca2+ enters the cell, moving with its
electrochemical gradient; (5) Ca2+ acts on a release site, prob-
ably synaptotagmin, causing synaptic vesicles to fuse with the
presynaptic membrane; (6) about 200 vesicles release their
ACh into the synaptic cleft; (7) the ACh in the cleft either (a)
diffuses away out of the cleft, (b) is hydrolyzed by AChE into
acetate and choline, or (c) interacts with AChRs on the post-
synaptic membrane; (8) the activated AChRs are very perme-
able to Na+ and K+ and slightly permeable to Ca2+; hence, a net
influx of positive charge into the muscle cell depolarizes the
muscle membrane in the endplate region; (9) when the muscle
membrane is depolarized to threshold, an action potential is
elicited, which propagates in both directions to the ends of the
muscle cell (the link between muscle excitation and contrac-
tion is discussed in the next section); and finally (10) choline
is recycled into the nerve terminal, Ca2+ is pumped out of the
nerve terminal, and vesicles are recycled and refilled.
RECORDING THE ENDPLATE POTENTIAL
If a microelectrode is inserted into a muscle fiber near the neu-
romuscular junction, a resting potential of about –90 mV will
be measured. If the nerve is stimulated and the muscle is pre-
vented from contracting by extreme stretching the membrane
potential will be seen to change, as shown in the solid trace on
the left in Figure 7–10. If, instead, the electrode is placed sev-
FIGURE 7–10 An endplate potential and action potential
at the neuromuscular junction (left) and 2 cm away (right).
Dashed lines indicate responses in low Ca2+ (see text). (Modified with
permission from Landowne D: Cell Physiology. New York: Lange Medical Books/
McGraw-Hill, 2006.)
eral centimeters away from the neuromuscular junction, the
potential shown in the right trace will be seen. If the concen-
tration of Ca2+ in the bath is decreased or the concentration of
Mg2+ is increased and the nerve is stimulated again, the poten-
tial at the neuromuscular junction will change as shown in the
dashed trace. Under these conditions there will be no change
in the membrane potential several centimeters away from the
junction.
The solid trace on the left shows an action potential super-
imposed on an endplate potential (EPP). There is an initial
depolarization due to a net entry of positive charge through
AChRs that were activated by the released ACh. When the po-
tential reached about –50 mV, an action potential was initiat-
ed. In normal Ca2+ the EPP is two or three times larger than
necessary to depolarize the muscle membrane to threshold.
The pure action potential is seen in the trace on the right; it
can be recorded by stimulating one end of the muscle electri-
cally or by placing the recording electrode a few centimeters
away from the endplate. The dashed trace on the left shows an
EPP with reduced amplitude. The EPP is not visible a few cen-
timeters away from the endplate (right). A reduction in extra-
cellular Ca2+ reduces the release of ACh and thus reduces the
EPP. An increase in Mg2+ reduces transmitter release by reduc-
ing Ca2+ entry through CaV channels. These opposing effects of
Ca2+ and Mg2+ have been seen on all chemical synapses that
have been examined; this is now considered one of the tests for
identifying a chemical synapse.
Ca2+ and Mg2+ concentrations have different effects on the
excitability or the threshold for action potentials on the nerve
and muscle cells. The reduction of Ca2+ makes the cells more
excitable or have a more negative threshold, or requires a small-
er depolarization to reach threshold for an action potential.
This is an effect on the NaV channels; in low Ca2+, NaV channels
will open at more negative potentials. Ca2+ and Mg2+ have a
synergistic action on NaV channels; they have opposing actions
on neuromuscular transmission. Clinically, the effects of hy-
pocalcemia are hyperexcitability and spontaneous action po-
tentials in nerve and muscle. These effects are seen when there
is still enough Ca2+ to support sufficient ACh release, so that
every nerve action potential leads to a muscle action potential.

1 mV
10 ms
FIGURE 7–11 Some miniature endplate potentials (MEPPs)
seen by stimulating a neuromuscular junction bathed in low
Ca2+ four times. The second MEPP on the bottom trace was
spontaneous. (Modified with permission from Landowne D: Cell Physiology.
New York: Lange Medical Books/McGraw-Hill, 2006.)
In this low-Ca2+ and high-Mg2+ case, the EPP is not large
enough to reach threshold and elicit an action potential. Action
potentials are actively propagated; the EPP spreads passively
and will not be visible a few centimeters from the neuromus-
cular junction. These two potentials are produced by the activ-
ity of different channels that have differing pharmacology.
Curare will block AChRs and the EPP without affecting the
action potential seen following direct electrical stimulation of
the muscle. A toxin from a cone snail (μ-conotoxin) will block
the muscle action potential but not the EPP. The μ-conotoxin
blocks muscle NaV channels but not nerve NaV channels, which
are a different gene product.
If the Ca2+/Mg2+ ratio is sufficiently low, the response to
stimulation will appear as in Figure 7–11. Each trace repre-
sents the response to a stimulation that is repeated every 5 sec-
onds. Three of the traces show a small EPP; in the third trial
there was no response. The first response is about 1 mV high;
the second and fourth responses are about 0.5 mV. When this
experiment was repeated many times, the responses were
found to be quantized with a unit response of about 0.5 mV.
That is, there were many 0.5-, 1-, and 1.5-mV responses but
very few with amplitudes in between. In addition, there are
sometimes spontaneous 0.5-mV responses without any stimu-
lation; one of these was caught on the fourth trace. These min-
iature endplate potentials (MEPPs) represent the postsynap-
tic response to the release of one, two, or three quanta of ACh.
Each quantum is the contents of a single vesicle. The exact
number of vesicles released on any particular stimulation can-
not be known; only the average number or the mean quantal
content can be predicted. The EPP in normal Ca2+/Mg2+ con-
ditions is the response to about 200 quanta.
The average rate of spontaneous MEPPs is about 1 vesicle/s.
In a normal EPP, the 200 vesicles are released within 1 milli-
second, which means that stimulation increased the rate of
release by 200,000-fold. If BWSV is applied to a neuromuscu-
lar junction, the MEPP frequency increases to a few hundred
per second for about 30 minutes and then stops. In total about
CHAPTER 7 Synapses 69
200,000 vesicles are released, which is equal to the number
seen by the electron microscope in an unstimulated neuro-
muscular junction. After BWSV treatment, no vesicles are
visible. BWSV paralyzes by depleting the nerve terminals of
synaptic vesicles. It can be deadly if the nerve endings control-
ling breathing are compromised.
TRANSMITTER–RECEPTOR
INTERACTION
The nicotinic AChR at the neuromuscular junction has five
subunits, each with four TM segments. Two of the subunits are
called alpha subunits and bind ACh at the α–γ and α–δ inter-
faces near the top of the molecule, about 5 nm from the center
of the membrane. The channel then undergoes a conforma-
tional change that is transmitted through the molecule to open
the pore, most likely by causing the M2 TM segments to move
out away from the axis of the pore, making it larger. The open
pore allows Na+ and K+ and, to a lesser extent, Ca2+ to pass. The
pore stays open about 1 millisecond and about 20,000 ions
pass at a rate of 2 × 107/s, which is equivalent to about 3 pA. If
a single AChR is captured in a patch of membrane and main-
tained with a –90 mV potential, application of ACh will cause
the channel to open and close several times, each opening ap-
pearing as a 3-pA current pulse of varying duration averaging
about 1 millisecond. A single quantum opens about 2,000
channels; 200 quanta open about 400,000. A neuromuscular
junction has many more channels, about 20 million; thus, only
a small fraction is used at any one time.
The number of open channels is proportional to the concen-
tration of ACh squared and the effective number of receptors.
A kinetic scheme for the reaction is shown in Figure 7–12. The
receptor can open with one or two ACh molecules bound; it
stays open about 10 times longer with two bound. It is the con-
centration of R • 2ACh that is proportional to the concentra-
tion of ACh squared:
Number of open channels = k[R][ACh]2 (1)
DESENSITIZATION
If a single AChR is exposed to continuous ACh for several
minutes, its response will slow and openings will become
less frequent. If ACh is added to the bath containing a
neuromuscular junction, the muscle membrane potential will
R R • ACh R • 2ACh Closed
R∗ • ACh R∗ • 2ACh Open
FIGURE 7–12 A kinetic scheme of the reaction between
acetylcholine and the nicotinic acetylcholine receptor. The receptor
(R) can bind two ACh molecules. Once ACh is bound the receptors can
open (R*) and allow the passage of ions. (Modified with permission from
Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
70 SECTION II Cell Physiology
10 μM ACh
10 mV
1 min
FIGURE 7–13 Desensitization of acetylcholine receptors
(AChRs). With prolonged ACh exposure the AChRs first open and
then enter a desensitized and closed state where they no longer
respond to ACh. (Modified with permission from Landowne D: Cell Physiology.
New York: Lange Medical Books/McGraw-Hill, 2006.)
depolarize but the response will reach a peak and then decline,
as shown in Figure 7–13. This decline is called desensitiza-
tion; the AChR molecule has entered an inactivated state from
which it does not open. This is functionally somewhat similar
to the inactivation of NaV channels except that the time course,
the agent that causes the inactivation, and the molecular basis
in the channels are completely different. Desensitization prob-
ably does not occur with normal use of neuromuscular junc-
tions but may become a problem when drugs are used that
block AChE. A patient with desensitized AChRs may be para-
lyzed and unable to breathe due to a lack of functional
AChRs.
SOME DRUGS THAT ACT AT THE
NEUROMUSCULAR JUNCTION
d-Tubocurare is a classic neuromuscular blocking agent,
originally discovered as an arrow poison from South America.
Curare binds AChRs reversibly and prevents ACh from open-
ing the channels. After application of curare, the EPP becomes
smaller; if there is sufficient curare, the EPP becomes so small
that it no longer elicits an action potential, similar to the
dashed response in Figure 7–10, and the junction is effectively
blocked. Higher doses of curare can eliminate the EPP. Curare
reduces the EPP by reducing the number of receptors available
to respond to ACh. Curare or a related drug is often used dur-
ing surgery to immobilize muscles; it can also facilitate tra-
cheal intubation and mechanical ventilation.
Anticholinesterases such as neostigmine and physostigmine
combine with AChE and prevent hydrolysis of ACh, which leads
to a larger EPP. Neostigmine is used to speed recovery from the
effects of curare and to reduce the symptoms of myasthenia
gravis. There are dangers associated with neostigmine; an excess
of ACh can lead to desensitization of the remaining receptors.
Also, the body uses ACh to slow the heart and release saliva;
both of these effects may be enhanced by physostigmine.
Botulism is a potentially fatal food poisoning caused by the
anaerobic bacterium Clostridium botulinum. Some of the tox-
ins released by this organism are endopeptidases, which are
taken up by nerve cells and cleave synaptobrevin, thus
preventing transmitter release. The purified toxins are used
clinically to prevent unwanted neuromuscular transmission.
The Bungarus snake paralyzes its prey with α-bungarotoxin,
which binds AChRs irreversibly and prevents their opening.
Bungarotoxin has been fluorescently labeled and used experi-
mentally to identify and locate nAChRs.
MYASTHENIA GRAVIS
Myasthenia gravis is a disease associated with muscle weakness
and fatigability on exertion. It is an autoimmune disease that
leads to the destruction of AChRs. Patients may have only
10–30% of the number of AChRs found in healthy individuals.
Treatment with anticholinesterases increases the amount of
available ACh, which makes it more likely that the remaining
AChRs will be activated (equation (1)). There is a danger of
giving too much anticholinesterase, which can lead to desensiti-
zation of the AChRs and further weakness. If this weakness is
misinterpreted as insufficient anticholinesterase therapy, a tragic
positive feedback loop leading to myasthenic crisis can ensue.
LAMBERT–EATON SYNDROME
The Lambert–Eaton syndrome is seen with an autoimmune
disease that reduces the number of CaV channels in the presyn-
aptic terminal. With prolonged effort, these patients gain
strength, the opposite of myasthenic patients. Prolonging the
presynaptic action potentials with drugs that block KV chan-
nels, such as diaminopyridine, may alleviate some of the symp-
toms. The prolonged depolarization opens the remaining CaV
channels for a longer time, allowing more Ca2+ entry and there-
fore more release. If the experiment shown in Figure 7–11 is
performed on these neuromuscular junctions, they will be
found to have a lower quantal content, that is, they release a
lower number of vesicles per stimulus. This is in contrast to
myasthenia gravis, which will show the normal quantal content
but a smaller MEPP, the depolarization for each quantum.
REPETITIVE STIMULATION
The amount of transmitter released by a synapse is not con-
stant from impulse to impulse but depends on the past history
of activity. If the nerve leading to a neuromuscular junction is
stimulated once every 10 seconds or slower, it will consistently
release about 200 vesicles. If the stimulation rate is abruptly
changed to 50/s, which is roughly the rate used by the CNS to
cause normal muscle contraction, the amount released per im-
pulse will increase in the first half second and then decrease
(Figure 7–14). The increase, called facilitation, is related to a
buildup in residual calcium in the nerve terminal. The de-
crease, called depression, is thought to reflect a depletion of
vesicles at the release sites.
This variation does not affect the functioning of the neuro-
muscular junction in a healthy individual. Each of those
nerve impulses releases sufficient ACh to produce an EPP
large enough to fire a muscle action potential. However, the

Facilitation
1 posttetanic potentiation (PTP) was seen that lasted for sev-
X Normal
Depression
40 80 120
Impulses
FIGURE 7–14 Facilitation and depression of synaptic
transmission at the neuromuscular junction. With repetitive
stimulation the amount of transmitter released by each stimulus
changes, first increasing and later decreasing. (Modified with
permission from Landowne D: Cell Physiology. New York: Lange Medical Books/
McGraw-Hill, 2006.)
myasthenic person may have functional neuromuscular trans-
mission only early in the task and experience weakness as the
depression occurs with a prolonged effort and the amount of
ACh released falls below what is necessary to trigger a muscle
action potential. An anticholinesterase with a short duration
of action, edrophonium chloride (Tensilon), is often used as a
test for myasthenia gravis in patients who show rapid weaken-
ing when asked to perform a sustained contraction.
POSTTETANIC POTENTIATION
When the 50/s stimulus is stopped, there is an increase in the
amount of transmitter that can be released by a single nerve
impulse (Figure 7–15). The nerve was stimulated once every
30 seconds before and after the tetanic stimulation. During the
PTP
1
x Normal
1 2 3 4
Minutes
FIGURE 7–15 Posttetanic potentiation (PTP) of synaptic
transmission at the neuromuscular junction. After the end of a
period of repetitive stimulation the amount of transmitter released
by subsequent infrequent stimuli is increased for several minutes.
(Modified with permission from Landowne D: Cell Physiology. New York: Lange
Medical Books/McGraw-Hill, 2006.)
CHAPTER 7 Synapses 71
tetanus, the release increased and decreased, as in Figure 7–14.
After the tetanus, as the synapse recovered from depression, a
eral minutes. PTP is also related to an increase in residual Ca2+
concentration in the nerve terminal, but it has a slower onset
and slower decline than facilitation.
PTP is used as a diagnostic procedure following surgical
procedures when curare or other neuromuscular blocking
agents have been used to prevent unwanted motion. The anes-
thesiologist will give the patient cholinesterase inhibitors, but
she or he wants to know when just enough inhibitor has been
given to avoid giving too much and desensitizing the AChRs.
The anesthesiologist will repeat the experiment shown in
Figure 7–15, stimulating the thenar branch of the patient’s me-
dian nerve and feeling the strength of contraction of the thenar
muscles. Two shocks are given before the tetanus and then one
30 seconds later. Under deep curare, none of these will pro-
duce a palpable contraction. As more ACh is made available
by blocking the esterase, the stimulus following the tetanus
will give a larger response than the two before the tetanus be-
cause it will be the first one with an EPP large enough to excite
the muscle. The endpoint is when enough esterase has been
given that all three responses are the same because all three
EPPs are above threshold for muscle activation.
AUTONOMIC SYNAPSES
The autonomic nervous system (ANS) has two divisions,
both with two synapses outside the CNS (Figure 7–16). The
synapse closer to the CNS is referred to as the ganglionic syn-
apse; the nerves leading into and out of the ganglia are called
preganglionic and postganglionic. The sympathetic ganglia
lie in a chain adjacent to the spinal column; the parasympa-
thetic ganglia are close to the end organs where the second
synapse occurs. The second synapses are onto smooth muscles
or cardiac cells or gland cells. Many tissues receive both sym-
pathetic and parasympathetic innervations.
The primary transmitter in the ganglionic synapse of both
divisions is ACh; the receptors are nicotinic nAChRs that are
heteromeric pentamers of related but different gene products
than the nAChR of the skeletal muscle. The ganglionic recep-
tors are less sensitive to curare and more easily blocked by
hexamethonium. The primary postganglionic transmitter in
the sympathetic nervous system is NE, and there are two cat-
egories of GPCRs on the postsynaptic cells called alpha- and
beta-adrenergic receptors. The primary postganglionic recep-
tor in the parasympathetic division is ACh and the receptors
are muscarinic mAChRs, which are also GPCRs but generally
with different G proteins than the NE receptors.
The ganglionic synapses are usually described as behaving
more or less like the neuromuscular junction. However, the
situation is more complicated; the postsynaptic neurons have
dendrites with more than one presynaptic nerve ending on
them. Different subpopulations of presynaptic and postsynap-
tic cells have been distinguished by looking at the peptide
72 SECTION II Cell Physiology
CNS
Parasympathetic
Preganglionic
ACh Sympathetic
Postganglionic
ACh
Epinephrine
Motor
FIGURE 7–16 A schematic view of the efferent fibers of the autonomic nervous system and the motoneurons. From top to bottom:
parasympathetic, sympathetic, adrenal medulla, motoneuron. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/
McGraw-Hill, 2006.)
transmitters that are in these cells along with their classic
transmitters. Postganglionic cells also have mAChRs that pro-
duce a slow EPSP by closing a K channel. There are also small,
intensely fluorescent cells in the ganglia that are innervated by
preganglionic fibers and release NE or dopamine. All in all, it
seems that some computation must be carried out in the gan-
glia, more than the simple passthrough circuit seen at the neu-
romuscular junction.
The synapses between the postganglionic cells and the end or-
gans are different from those in the neuromuscular junction. The
presynaptic processes are similar, but postganglionic cells make
“en passant” synapses on tissue targets over a length of axon.
Synaptic vesicles are stored in varicosities of the nerve, which
continues on to other varicosities before reaching its terminal.
Activation of mAChRs by the ANS increases GI tone and
motility, increases urinary bladder tone and motility, increases
salivation and sweating, constricts bronchioles, and decreases
heart rate and blood pressure. The ANS activates α-, β1-, and
β2-adrenergic receptors, and α-adrenergic receptors raise
blood pressure. β1-Adrenergic receptors increase heart rate
and strength of contraction and blood pressure. β2-Adrenergic
receptors dilate bronchioles in the lungs. The mechanism of
the effects on cardiac and smooth muscle is discussed in the
next section.
Many agonist and antagonist drugs have been used to control
these processes, some with more specificity than others. Thus,
there are specific α agonists and β blockers. Amphetamines and
cocaine have an indirect adrenergic effect by stimulating NE
release. Some compounds, such as ephedrine, have both direct
and indirect adrenergic effects. Atropine is the archetypical
mAChR antagonist; its effects are the opposite of those attrib-
uted to ACh above. At many sites there is a tonic release of both
ACh ACh
Target
NE
Target
ACh
Muscle
ACh and NE from the ANS, so the blocking of one set of recep-
tors may produce effects similar to activating the other.
CENTRAL NERVOUS
SYSTEM SYNAPSES
The human CNS has billions of neurons with trillions of syn-
apses between them. A single neuron may have thousands of
both excitatory and inhibitory inputs; some larger neurons
may have over 100,000 endings on them. In order to accom-
modate this convergence of synaptic inputs, most neurons
have a dendritic tree that greatly expands the area available for
synaptic contact. The cell body (soma) and the initial region of
the axon (axon hillock) integrate the incoming synaptic sig-
nals and determine when and how often the neuron will fire
action potentials (Figure 7–17). The axon carries the output of
the neuron to the next group of neurons or to skeletal muscle
cells if it is a motoneuron. Usually only a single axon leaves
the cell body, but it later branches to allow the neuron to syn-
apse with many other cells. This divergence of information
combined with the convergence of many inputs onto a neuron
gives the CNS much of its computational power.
Each neuron in the CNS acts as one or more small comput-
ers. While each cell performs its computations in milliseconds,
millions of times slower than the central processing unit of a
modern computer, the billions of neurons operating in parallel
make the CNS shine in comparison. The CNS is capable of
creating every thought in recorded history while simultane-
ously regulating both walking and chewing gum. The synapses
make this possible. Learning and memory are accomplished
by the modification of synapses.

Axons converge
Dendrites on neuron
Synaptic inputs
cover most of the
surface of the
soma and dendrites
Soma
Axon hillock or
initial segment
Synapses
Axon diverge
There are two general types of synapses in the CNS, elec-
trical and chemical. Electrical synapses operate by direct
electrical current flow from the presynaptic neuron into the
postsynaptic neuron through gap-junction channels between
the membranes of the two cells (Figure 7–18). Neurotrans-
mitters are not involved and electrical synapses can have less
synaptic delay than chemical synapses. However, unlike
chemical synapses, electrical synapses cannot amplify the
signal, nor can they reverse the direction of current flow. Gap
junctions, which work as electrical synapses and allow action
potentials to flow selectively from one cell to another, also
connect cells in the heart and some types of smooth muscle.
FIGURE 7–18 An electrical synapse. Current passes directly
from the presynaptic cell to the postsynaptic cell through specialized
cell–cell channels. (Modified with permission from Landowne D: Cell Physiology.
New York: Lange Medical Books/McGraw-Hill, 2006.)
CHAPTER 7 Synapses 73
FIGURE 7–17 The convergence and divergence of
synapses in the CNS. (Modified with permission from Landowne D:
Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
There are two general types of chemical synapses in the
CNS, excitatory and inhibitory. Excitatory synapses generate
EPSPs that depolarize the membrane toward threshold. In-
hibitory synapses generate IPSPs that either hyperpolarize the
membrane or resist depolarization to threshold. Each of these
types can be further divided into chemosensitive ion channels
(or ionotropic receptors) and G protein–linked ion channels
(or metabotropic receptors). Chemosensitive ion channels
typically give rise to fast synaptic events that last a few milli-
seconds; G protein–linked ion channels may produce effects
for hundreds of milliseconds.
INTEGRATION OF SYNAPTIC CURRENTS
Excitatory and inhibitory synapses inject current (positive or
negative) into cells. These currents flow into the cell body and
are summed. The PSPs passively spread to the spike initiation
site or the part of the cell with the lowest threshold because of
the cable properties of the cell. More distal synapses will be
decremented compared to those near the site. The cell pro-
duces the spike initiation site by controlling the local density
of NaV channels. Often the spike initiation site is the axon hill-
ock near the start of the axon (see Figure 7–17) or at the first
node of Ranvier.
Because the PSPs last for several to many milliseconds, they
can add together even though they do not occur synchronous-
ly; this is called temporal summation. The effects of synapses
at different locations on the same postsynaptic cell can also
add up; this is called spatial summation. Spatial summation is
weighted inversely by the distance from the synapse to the ini-
tiation site of the action potential.
74 SECTION II Cell Physiology
Synaptic
cleft
Postsynaptic
spine on
Axon dendrite
Presynaptic
nerve terminal
Synaptic
Postsynaptic
vesicles
density
FIGURE 7–19 A CNS synapse. These are less elaborate than
the synapse at the neuromuscular junction (Figure 6–9). (Modified with
permission from Landowne D: Cell Physiology. New York: Lange Medical Books/
McGraw-Hill, 2006.)
Figure 7–19 is a schematic drawing of a chemical synapse in
the CNS. The presynaptic terminal is about 1 μm in diameter
and contains mitochondria and synaptic vesicles filled with
neurotransmitter. Depolarization of the terminal opens CaV
channels, and Ca2+ flows with its electrochemical gradient to
act on synaptotagmin and trigger the fusion of a few vesicles
with the presynaptic membrane in order to exocytose the neu-
rotransmitter. The membrane is then recycled and the vesicles
are refilled. The postsynaptic receptors are often on protru-
sions from dendrites, called spines, although synapses are also
found on the dendritic shaft, the neuronal cell body, and other
synaptic endings.
CNS synapses share many features with the neuromuscular
junction but differ in several important respects. CNS synaps-
es are much smaller and release far fewer vesicles, typically less
than 5 per impulse, compared to about 200 at the motor end-
plate. In the CNS, synaptic clefts are narrower, about 20 nm,
and cadherins and other cell adhesion molecules span the gap.
ACh is the transmitter at the neuromuscular junction; there is
a wide variety of transmitters in the CNS. The EPP is always
excitatory and large enough to bring the muscle membrane to
threshold; synapses in the CNS are excitatory or inhibitory
and threshold is reached by the combination of hundreds of
EPSPs.
There are some exceptional CNS synapses. In the cerebel-
lum, a climbing fiber axon may make dozens of synapses on a
Purkinje cell. In the calyx of Held, in the auditory pathway, the
presynaptic ending forms a cap with fingerlike stalks that en-
velop the postsynaptic neuron, covering about 40% of its soma.
At both of these synapses a single presynaptic impulse releases
hundreds of quanta, and the resulting EPSP is large enough to
trigger a postsynaptic action potential.
Glutamate is the principal excitatory neurotransmitter in
the CNS. There are several postsynaptic glutamate receptors,
both channels and GPCRs. The channels can be grouped into
two major types, NMDA and non-NMDA channels, accord-
ing to their sensitivity to the synthetic agonist N-methyl-d-
aspartate. Both types respond to glutamate. The non-NMDA
channels may be called AMPA, quisqualate, or kainate chan-
nels, according to which of these nonphysiologic agonists
opens them. Non-NMDA channels typically generate fast
EPSPs lasting about 5 milliseconds.
When they are activated by glutamate, non-NMDA chan-
nels allow Na+ and K+ to flow through their pores. Each ion
moves in the direction that will tend to bring the membrane
potential to its Nernst equilibrium potential. Because both are
moving, the membrane potential tends to approach the aver-
age of the two equilibrium potentials, which is about –10 mV.
This potential, where the two ionic currents are equal, is called
the reversal potential for the channel. When these channels
open at potentials more negative than the reversal potential,
the tendency for Na+ to enter the cell will dominate and the
membrane will depolarize toward the reversal potential. If the
starting potential were more positive than the reversal poten-
tial, the K+ ions would dominate and the cell would hyperpo-
larize toward the reversal potential.
NMDA receptor channels generate EPSPs lasting hundreds
of milliseconds. Open NMDA channels allow Na+ and K+ and
also Ca2+ to pass through their pores. In the presence of gluta-
mate, NMDA channels open only if the postsynaptic cell is
also depolarized by some other means. This dual control of
Ca2+ entry has a key role in learning, as discussed below.
GABA is the major inhibitory transmitter in the brain.
Glycine is an inhibitory transmitter in the brainstem and spi-
nal cord. GABA opens GABAA channels directly, which allows
Cl− ions to pass through their pores. GABA can also cause in-
hibition through GABAB receptors, which are GPCRs that
lead to the opening of K channels. The reversal potential for
GABAA channels is at the Nernst potential for Cl−, about –80
mV. If the membrane is more positive than ECl, Cl− will enter
the cell and make the membrane potential more negative,
which will make it less likely to initiate an action potential.
Benzodiazepines such as diazepam (Valium) and barbitu-
rates enhance the open probability of activated GABAARs.
Both have been used as sedatives and anticonvulsants. General
anesthetics such as ether, chloroform, and halothane increase
the duration of IPSPs and decrease the amplitude and duration
of EPSPs.
CNS—MODULATORY
NEUROTRANSMITTERS
In the CNS, ACh, NE, dopamine, and serotonin primarily act
as diffuse modulators of activity, acting over timeframes that
are long compared to action potentials, as opposed to being
involved in specific discrete tasks. Each of these neurotrans-
mitters has its own set of neurons and targets; some of these
neurons may influence more than 100,000 postsynaptic neu-
rons. The postsynaptic receptors are metabotropic and alter
the responsiveness of the postsynaptic neurons through sec-
ond messenger pathways. There are also ionotropic nAChRs
in the CNS, but there are 10–100 times more mAChRs. The
ACh and NE modulatory systems are part of the ascending

Axon
FIGURE 7–20 Presynaptic inhibition can occur by a synapse (A and B) on another synaptic ending. (Modified with permission from Landowne
D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
reticular activating system that arouses the forebrain in re-
sponse to stimuli. In some general ways, the modulatory sys-
tems play a role in the CNS similar to the role played by the
ANS in the rest of the body.
PRESYNAPTIC INHIBITION
Some CNS synapses act directly on other synaptic endings
rather than on dendrites or cell bodies (Figure 7–20). Termi-
nal A releases GABA on to terminal B, activating Cl channels
that tend to hyperpolarize terminal B. If an action potential
arrives in B while the Cl channels are open, the action poten-
tial’s amplitude will be reduced, so that it will open fewer CaV
channels and therefore fewer vesicles will be released by termi-
nal B, and it will have a smaller effect on neuron C.
RETROGRADE FREELY DIFFUSIBLE
CHEMICAL TRANSMITTERS
In addition to the classic transmitters that are released from
vesicles and bind to receptors, there are chemical messengers
in the CNS with a different mode of operation. Nitric oxide
(NO) is not stored but rather produced when needed. It can
freely diffuse across cell membranes from the inside of one cell
(typically a postsynaptic cell body) to the inside of other cells
(typically presynaptic endings), where it alters some chemical
reactions. NO may spread to several presynaptic endings in
the vicinity. It is removed from the tissue by binding to hemo-
globin.
Anandamide, an endogenous cannabinoid, is also pro-
duced as needed in postsynaptic cells and reaches the extra-
CHAPTER 7 Synapses 75
Neuron C
cellular space by a nonvesicular process. It binds to presyn-
aptic cannabinoid receptors (CB1), which are GPCRs, and
can alter the subsequent release of traditional neurotrans-
mitters.
REPETITIVE FIRING OF NERVE CELLS
If an axon or a muscle cell is subjected to a maintained depo-
larization, it will respond with one or perhaps two action po-
tentials and then stop firing because the NaV channels enter
the inactivated state and require a brief period near the resting
potential to recover. Many CNS cells and the slowly adapting
sensory nerve endings will respond to a sustained depolariza-
tion with a train of action potentials at about 50/s. This is made
possible by CaV channels and Ca-activated K channels. The ac-
tion potential depolarization opens the CaV channels and the
Ca2+ that enters opens the Ca-activated K channels by binding
to the intracellular portion of the molecule. The Ca-activated
K channel then allows K+ to leave and the membrane potential
to approach EK for a long-lasting hyperpolarization, long
enough for the NaV channels to recover from inactivation
(Figure 7–21). The balance between the sustained stimulus
and the rate that Ca2+ is removed from the Ca-activated K
channels determines the firing rate.
LEARNING, MEMORY, AND
SYNAPTIC PLASTICITY
The cellular basis of learning and memory is a functional re-
modeling of synaptic connections, often called synaptic plas-
ticity. This includes both explicit or declarative memory when
76 SECTION II Cell Physiology
+40
0 Unlike PTP, which disappears in a few minutes, with LTP, the
mV
−60
−70
0 200 400
Sustained excitatory synaptic input
FIGURE 7–21 Repetitive firing of a motoneuron. Unlike axons,
many nerve cells respond repetitively to a sustained input. (Modified
with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/
McGraw-Hill, 2006.)
the person can recall and describe some fact or past event and
implicit or procedural memory, as in a learned motor skill.
Memory is often subdivided into short-term, minutes to
hours, and long-term, days to a lifetime. Short-term memory
formation involves the modification of existing proteins, often
by phosphorylation. Long-term changes involve gene activa-
tion, protein synthesis, and membrane rearrangement, includ-
ing the formation and/or resorption of presynaptic terminals
and postsynaptic spines. In a few studies, the volume of cere-
bral cortex dedicated to a task has been shown to increase with
specific training.
The most intensively studied cellular learning phenomenon
is long-term potentiation (LTP) in hippocampal synapses.
The hippocampus is required for the formation of new long-
term memories. If both hippocampi are compromised, the per-
son will live continuously in the present with no recollection of
events after the damage. In the hippocampus, LTP occurs at
glutamate synapses between presynaptic CA3 cells and post-
synaptic CA1 cells. LTP and the related long-term depression
(LTD) also occur in other locations in the CNS. The classic
3
mV
0
10
FIGURE 7–22 Long-term potentiation. A brief conditioning stimulus (blue bar) causes a long-term increase in synaptic efficacy. (Modified
with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)
experiment is similar to the PTP demonstration shown in
Figure 7–15; the synapse is tested infrequently, subjected to
high-frequency stimulation, and then tested infrequently again.
potentiation remains for many hours or days (Figure 7–22).
Also unlike PTP, LTP is primarily a postsynaptic event. It is
not necessary to provide the high-frequency stimulation to the
presynaptic terminals; simple depolarization of the postsynap-
tic cell paired with the presynaptic stimulation will induce LTP.
This response to pairs of inputs made LTP a candidate basis for
associative learning. There are two types of glutamate receptors
ms
on the postsynaptic membranes: AMPA (non-NMDA) and
NMDA receptors. During low-frequency unpaired stimulation,
only the AMPA receptors are activated; the NMDA receptors
are plugged by external Mg2+ ions. The AMPA receptor chan-
nels are permeable to Na+ and K+; near the resting potential,
Na+ movement into the cell is favored. When the postsynaptic
membrane is depolarized, either by high-frequency synaptic
input or by injecting current into the postsynaptic cell, the Mg2+
is driven off the NMDA receptors and they respond to gluta-
mate and allow Na+ and Ca2+ to enter the cell. The elevated Ca2+
activates a series of biochemical events that lead to the insertion
of more AMPA receptors into the postsynaptic membrane.
LTP has been associated with learning in rats using a water
maze. Rats with surgically removed hippocampi do not learn
the maze, neither do rats that have been treated with a specific
antagonist for NMDA receptor channels. There are other ex-
amples of synaptic plasticity in other regions of the brain and
there may well be additional mechanisms, including retro-
grade action of NO or anandamide.
CLINICAL CORRELATION
About a month before coming to the hospital, a 56-year-
old woman noticed she was unable to hold her shopping
bag and that her head fell forward when she knelt to tie
her shoes. Two weeks later she had to remain in bed and
had difficulty sitting up. Her jaw began to droop, she had
20 30 40 50 60
Minutes

to hold it up with her hand, and her left eyelid began to
droop. Her speech became indistinct when she was ex-
cited, swallowing was difficult and fluid sometimes re-
gurgitated through her nose. A few days after admission
to the hospital, she developed weakness in the middle
and ring fingers of both hands that was increased by ex-
citement and lessened by rest. There was no muscle wast-
ing and tendon reflexes were all present. Her masseter
muscles showed a decremental response to tetanic elec-
trical stimulation.
In the hospital, she was injected with 1 mg of physostig-
mine. About 1 hour later, her left eyelid elevated, her arm
movements were stronger, her jaw drooped less, swallow-
ing was improved, and she reported feeling “less heavy.”
The effect wore off gradually in 2–4 hours. With 1.3 mg
the improvement was greater and lasted 4–5 hours. Still
greater improvements, lasting 6–7 hours, followed an in-
jection of 1.5 mg but the patient felt faint as if “something
were going to happen.”
The diagnosis is myasthenia gravis. It is an autoim-
mune disease that affects about 1 in 5,000 people. The im-
mune system produces antibodies to the nicotinic AChR
of the neuromuscular junction and neuromuscular trans-
mission is impaired. With fewer receptors the effects of
depression of synaptic transmission lead to a failure of
neuromuscular transmission during sustained effort. This
fatigability is a characteristic of the disease.
Physostigmine is an inhibitor of AChE. In its presence
more of the released ACh can interact with the receptor
and transmission is more reliable. AChE inhibitors are
used to relieve the symptoms of myasthenia gravis. Im-
munosuppressants, for example, the synthetic corticoster-
oid prednisone, are used to reduce antibody production.
In some cases thymectomy (surgical removal of the thy-
mus) is performed to suppress the immune system.
Edrophonium chloride (Tensilon) is a short-acting
AChE inhibitor that has been used to assist in diagnosis.
Electrical stimulation and testing for circulating antibod-
ies are also used diagnostically.
CHAPTER SUMMARY
■ Synapses may be chemical or electrical. Chemical synapses
may be excitatory or inhibitory.
■ In chemical synapses, the presynaptic terminal packages a
neurotransmitter into vesicles. When the synapse is activated,
the vesicle’s contents are released and then a recycling process
recovers some of the released transmitter and vesicular
components.
■ ACh is the neurotransmitter at the neuromuscular junction.
It is also an important component of the autonomic and central
nervous system synapses.
■ Glutamate is the major excitatory neurotransmitter in the CNS.
CHAPTER 7 Synapses 77
■ GABA and glycine are the major inhibitory neurotransmitters
in the CNS.
■ Several biogenic amines are important neurotransmitters.
NE is released by sympathetic nerves to control the heart
and vascular smooth muscle.
■ Neuropeptides are small proteins released as neurotransmitters.
■ Synaptic release involves many proteins and is controlled by
CaV channels, which are opened when an action potential
invades the presynaptic terminal.
■ Axons have a microtubule-based transport system to move
materials from the cell body to the presynaptic terminal
(orthograde transport) and in the other direction (retrograde
transport).
■ PSPs are excitatory (EPSPs) if they make the postsynaptic cell
more likely to initiate an action potential and inhibitory
(IPSPs) if they make it less likely.
■ Neuromuscular transmission is a well-studied example of
synaptic transmission.
■ Hypocalcemia reduces the number of vesicles released when an
action potential invades the presynaptic terminal.
■ At the neuromuscular junction, the number of open channels is
proportional to the concentration of ACh squared times the
effective number of AChR channels.
■ Several clinically important drugs act at the neuromuscular
junction.
■ The number of vesicles released per action potential depends
on the rate and pattern of arrival of the action potentials.
■ The ANS has two synapses outside the central nervous system.
The first is cholinergic; the second is either adrenergic or
cholinergic.
■ In general, CNS synapses are similar to the neuromuscular
junction, but they differ in many important ways.
■ In the CNS, several transmitters act through G protein–cou-
pled receptors to modulate the activity of the brain.
■ In order to fire repetitively, nerve cells use Ca-activated K
channels to hyperpolarize the cell and allow the NaV channels
to recover from their inactivation.
■ Learning and memory involve changes in synaptic
efficacy.
STUDY QUESTIONS
1. Ca2+ ions are needed in the extracellular solution for synaptic
transmission because
A) Ca2+ ions enter the presynaptic nerve terminal with depolar-
ization and trigger synaptic vesicles to release their contents
into the synaptic cleft.
B) Ca2+ ions are required to activate glycogen metabolism in
the presynaptic cell.
C) Ca2+ ions must enter the postsynaptic cell to depolarize it.
D) Ca2+ ions prevent Mg2+ ions from releasing the transmitter
in the absence of nerve impulses.
E) Ca2+ ions inhibit the acetylcholine esterase, enabling
the released acetylcholine to reach the postsynaptic
membrane.
78 SECTION II Cell Physiology
2. Inhibitory postsynaptic potentials can arise from all of the
following except
A) increased permeability of the nerve membrane
to Cl− ion.
B) direct application of GABA to neurons.
C) increased permeability of the nerve membrane to K+ ion.
D) increased permeability of the cell membrane to Na+ ion.
3. Electrical and chemical synapses differ in that
A) electrical synapses have a longer synaptic delay than
chemical synapses.
B) chemical synapses can amplify a signal while electrical
synapses cannot.
C) chemical synapses do not have a synaptic cleft while
electrical synapses do have a synaptic cleft.
D) electrical synapses use agonist-activated channels and
chemical synapses do not.
E) electrical synapses are found only in invertebrate animals
while chemical synapses are found in all animals.
4. Which one of the following does not contribute to the integration
of synaptic potentials by neurons?
A) convergence of many synaptic inputs on one neuron,
allowing spatial summation
B) the presence of EPSPs having amplitudes that exceed the
threshold for generation of an action potential in the
neuron
C) temporal summation of synaptic potentials in neurons due
to the time constant of the neurons
D) the flow of currents from the distal regions of the dendrites
to the soma due to the length constants of the dendrites
E) inhibitory synaptic inputs
5. Which of the following ions is countertransported to energize
neurotransmitter transport into presynaptic vesicles?
A) Na+
B) K+
C) H+
D) Cl−
E) Ca2+
6. A branch of a 26-year-old man’s ulnar nerve was crushed in his
left forearm, severing axons at a point about about 6 in (15 cm)
from the skin on the medial part of the palm, where cutaneous
sensation was lost. About how long will it likely take before the
patient begins to feel stimuli in that part of the palm?
A) 1 day
B) 10 days
C) 100 days
D) 1,000 days
E) never, since peripheral axons do not regenerate
7. Treatments for nerve gas poisoning target which of the following
proteins?
A) acetylcholinesterase (AChE) and choline acetyltransferase
(CAT)
B) AChE and nicotinic acetylcholine receptors
C) muscarinic and nicotinic acetylcholine receptors
D) muscarinic acetylcholine receptors and AChE
E) CAT and synaptic choline transporters
 SECTION III MUSCLE PHYSIOLOGY

8
C H A P T E R

Overview of Muscle
Function
Kathleen H. McDonough

O B J E C T I V E S

■ Explain the differences in skeletal, cardiac, and smooth muscle with

reference to appearance, contractile proteins, calcium-binding proteins,
and neural input.
■ Describe how the sarcolemma and the sarcoplasmic reticulum are involved
in muscle contraction.
■ Explain the energy source for contraction.
■ Describe the role of the following proteins: actin, myosin, dihydropyridine
receptors, ryanodine receptors, calmodulin, and troponin.

GENERAL COMPARISON the overriding unifier is that cytosolic calcium concentra-

Muscle is the largest organ system of the body. It consists of
three different types based on factors such as morphology, cel-
lular signaling pathways, ways to alter strength of contraction,
contraction pattern (cyclic vs. graded), and the role of the ner-
vous system in muscle function. The three types of muscle are
skeletal, cardiac, and smooth muscle. Skeletal muscle is, for
the most part, attached to bone and represents approximately
40% of the body mass of a typical healthy person. Cardiac
muscle is the main component of the heart and contracts in a
cyclic fashion for the lifetime of the individual. Smooth muscle
is the major component of the organs of the gastrointestinal
tract, bladder, uterus, airways, and blood vessels—in general,
smooth muscle makes up the walls of hollow structures in the
body except the heart.
The requirement for calcium to initiate contraction is
uniform in all muscle. Mechanisms for increasing calcium
for contraction may vary from muscle type to muscle type
and removal of calcium for relaxation also varies. However,
tions must increase in order for contraction to occur and
cytosolic calcium concentrations must decrease for relax-
ation to occur. Since, in smooth muscle, there is usually
some moderate level of contraction, cytosolic calcium must
increase for the strength of the contraction to increase and
must decrease for the strength of the contraction to de-
crease. Thus, the organelles such as the sarcolemma (SL)
and the sarcoplasmic reticulum (SR) that contain proteins
that effect calcium fluxes are highly organized and efficient
in muscle. Calcium levels in resting cardiac muscle, for ex-
ample, are only 0.1 μM and can increase 100-fold during
excitation. Removal of calcium for relaxation to occur is
therefore critical. Processes involved in calcium movement
are important in the understanding of muscle contraction in
all three types of muscle.
Muscle contraction is supported by hydrolysis of adenos-
ine triphosphate (ATP). ATP is produced mainly by
mitochondrial oxidative phosphorylation from substrates sup-
plied by glycogen or triacylglycerol stores in the tissue or by

79

Ch08_079-082.indd 79 11/26/10 9:41:53 AM

80 SECTION III Muscle Physiology
blood-borne substrates such as glucose and fatty acids. Glyco-
lysis also produces ATP but not as efficiently as oxidative
phosphorylation. In some types of skeletal muscle, glycogen
supplies glucose for glycolysis that provides energy for rapid,
short-term contraction. Energy is additionally provided by
creatine phosphate (CP), which can rapidly supply a source of
high-energy phosphate bonds for resynthesis of ATP from
ADP. The ADP is produced by ATPase enzymes located in the
muscle cell. CP is not used directly by the ATPase but is used
for rapid regeneration of ATP at the site of ATP use. ATP is
used for both contraction and relaxation of muscle. The myo-
sin ATPase hydrolyzes ATP to provide the energy for the slid-
ing of the actin filament over the myosin filament; ATP also
provides the energy for removal of calcium from the cytosol by
calcium ATPases so that relaxation can take place.
DIFFERENCES IN SKELETAL,
CARDIAC, AND SMOOTH MUSCLE
Skeletal and cardiac muscle are both striated in appearance
due to the orderly arrangement of the contractile proteins
actin and myosin. In smooth muscle, the contractile pro-
teins actin and myosin are responsible for contraction but
they are not arranged in such an organized pattern; there-
fore, striations do not appear. Skeletal muscle is the only
muscle type that is voluntary—you decide when to contract
skeletal muscle for the most part and the muscle has to be
activated by neurons regulated by the central nervous
system.
Cardiac muscle is involuntary; it contracts spontaneously.
Action potentials are generated by specialized cells within the
heart itself; thus, hearts can be transplanted from one person
to another and the heart functions adequately even without
neural input in the transplanted heart of the recipient. The
beating rate of the heart as well as the strength of contraction
of the cardiac muscle cells can, however, be modulated by the
autonomic nervous system (ANS; see Chapter 19). The sym-
pathetic nervous system (SNS) component of the ANS will
increase the heart rate, whereas the parasympathetic nervous
system (PNS) will decrease the heart rate.
Smooth muscle is also involuntary. It has the potential to
contract from many different types of stimuli but does not re-
quire neural input for contraction to occur. Even changes in
the resting membrane potential and stretch of the muscle can
change the strength of contraction. Smooth muscle does not
usually exhibit contractions followed by complete relaxation
as do skeletal and cardiac muscle but rather demonstrates in-
creased or decreased strength of contraction. For example, if
all of the vascular smooth muscle making up the blood vessels
to the systemic organs were to relax completely, the individual
would go into shock; blood pressure would decrease to dan-
gerously low levels. This occurs under pathological conditions
such as severe brain injury causing withdrawal of all neural
control of vascular smooth muscle and resulting in neurogenic
shock. Blood pressure cannot be maintained if all of the vascu-
lar smooth muscle in the blood vessels is completely relaxed.
In smooth muscle, gradations of contraction are regulated and
affected by many different influences, depending on the loca-
tion and function of the smooth muscle.
CALCIUM
Although calcium is uniformly required for muscle to con-
tract or increase strength of contraction, the calcium-binding
proteins in the three types of muscle differ, as do the sources
of calcium. Troponin is the calcium-binding protein that ini-
tiates contraction in skeletal and cardiac muscle. Calmodulin
binds calcium in smooth muscle and initiates increases in
strength of contraction. Actin and myosin form the cross-
bridges in all three types of muscle. The source of the calcium
that initiates contraction is different in the three muscle types.
Calcium released from the SR through ryanodine receptors
or channels raises the cytosolic calcium concentration and
contraction begins in skeletal muscle (see Chapter 9). In car-
diac muscle, the calcium that binds to troponin comes
from both the SR and the extracellular space through SL volt-
age-gated calcium channels (dihydropyridine receptors).
In addition, it is the calcium entering the cell through the
calcium channels that activates the release of calcium from
the SR through the ryanodine receptors or channels (see
Chapter 10). In smooth muscle, calcium can enter the cytosol
from extracellular fluid via the voltage-gated calcium chan-
nels in the SL and from the SR via receptors activated by sig-
naling molecules from SL receptor pathways. Smooth muscle
also has other receptors on the SL and SR for calcium mobili-
zation that will be discussed in Chapter 11. In all three muscle
types, increases in cytosolic calcium initiate cycling of cross-
bridge attachments between actin and myosin.
CONTRACTION PERIOD
The time course of muscle contraction is different in skeletal,
cardiac, and smooth muscle. Skeletal muscle contractions take
several milliseconds to occur, cardiac muscle contractions take
hundreds of milliseconds, while smooth muscle is much slow-
er and can take up to minutes for contractions to occur. This
difference in contraction time is mainly due to the rate of ATP
hydrolysis occurring in the myosin head. Fast rates of ATP hy-
drolysis by the myosin ATPase result in more rapid contrac-
tions such as in skeletal muscle. Muscles with slower rates of
ATP hydrolysis exhibit slower contractions such as in smooth
muscle. Signaling pathways that cause increases in calcium in
the cytosol can contribute to the delay between the signal and
the contraction.
CHANGES IN STRENGTH
OF CONTRACTION
The strength of muscle contraction can be altered in all three
muscle types but by different means. Phosphorylation of
 CHAPTER 8 Overview of Muscle Function 81

proteins results in stronger contractions in both cardiac mus- TABLE 8–1 Comparison of skeletal, cardiac,
cle (Chapter 10) and smooth muscle (Chapter 11), whereas and smooth muscle.
skeletal muscle achieves stronger contractions by recruiting
more muscle cells or activating muscle cells with a higher fre- Skeletal Cardiac Smooth
quency of nerve firing (Chapter 9).
Appearance Striated Striated Nonstriated

Sarcoplasmic Most Less Least

SIMILARITIES IN SKELETAL, reticulum

CARDIAC, AND SMOOTH Voluntary Yes No No

Calcium- Troponin Troponin Calmodulin

MUSCLE binding
protein
As stated above, actin and myosin are the contractile proteins
involved in crossbridge cycling in all three types of muscle al- Source of SR SR and SL SL and SR
calcium
though the anatomic distribution of the actin and myosin is
different in smooth muscle compared to skeletal and cardiac Innervation Motor SNS; PNS SNS; PNS
neuron
muscle (nonstriated vs. striated, respectively). The myosin
head contains a binding site for actin. This site is blocked when Contraction Milliseconds 100 ms 100 ms –
calcium levels are low but open when calcium binds to tro- length minutes
ponin (skeletal and cardiac muscle) or calmodulin (smooth Strength of Recruitment Phosphorylation; Phosphorylation;
muscle). With binding of actin and myosin, the ATPase site contraction length–tension length–tension
located on the myosin head can release energy from the ATP Metabolism Oxidative, Oxidative Oxidative
to allow cycling of the crossbridges, that is, actin sliding across glycolytic
myosin. Velocity of Rapid Less rapid Slow
All three types of muscle demonstrate the property of in- ATPase
creasing strength of contraction by increasing the precontrac- reaction
tion (resting) length of the muscle. This phenomenon is
termed the length–tension relationship. Since skeletal mus-
cle is attached to bones by tendons, variations in resting cell ■ Muscle can increase strength of contraction by increasing the
length are very limited and the muscle is usually operating at length of the muscle prior to the contraction—length–tension
the peak of the length–tension relationship. In the heart, rest- relationship.
ing muscle cell length is usually not at the optimum length, so ■ The energy for contraction is released from ATP by the
there is reserve, that is, stronger contractions can be elicited myosin ATPase.
when the resting length is increased prior to the contraction. ■ Skeletal muscle requires neural input from a motor neuron to
Smooth muscle also demonstrates the length–tension rela- initiate contraction (voluntary muscle).
tionship but other influences on the muscle can override the ■ Cardiac and smooth muscle can contract without neural input
effects of increased cell length. For example, in certain types but the strength of contraction can be altered by input from the
of vascular smooth muscle, when the cell is stretched, the cell ANS—sympathetic and parasympathetic branches of the ANS
responds with an increased level of contraction. This phe- (involuntary muscle).
nomenon is called the myogenic response. In the gastrointes-
tinal tract, this occurs with the presence of food in the stomach STUDY QUESTIONS
and small intestines. Hollow organs with specialized functions
such as the bladder and uterus can be “stretched” but contrac- 1. Which of the following statements about muscle is true?
tion is not stimulated due to other influences on muscle A) The calcium source for skeletal muscle contraction is solely
function. calcium entering the cell through the dihydropryidine
A comparison of skeletal, cardiac, and smooth muscle is receptors.
B) The calcium source for smooth muscle contraction is solely
given in Table 8–1. More details on the individual muscle types
calcium entering the cell through the dihydropyridine
will be given in the next three chapters. receptors.
C) The calcium source for cardiac muscle contraction is solely
CHAPTER SUMMARY calcium entering the cell through the dihydropryidine
receptors.
■ There are three types of muscle in the body classified by D) The calcium source for skeletal muscle contraction is
morphology, function, and cellular mechanisms of solely calcium entering the cytosol through the ryanodine
contraction—skeletal, cardiac, and smooth. receptors.
■ All types of muscle require calcium to initiate contraction. E) The calcium source for cardiac muscle contraction is
■ SL and SR have specialized functions that increase cytosolic solely calcium entering the cytosol through the ryanodine
calcium for contraction and remove calcium for relaxation. receptors.
82 SECTION III Muscle Physiology

2. Which of the following statements about muscle is true? 4. Which of the following statements about muscle is true?
A) Both smooth and cardiac muscle remain partially A) In all three muscle types (cardiac, skeletal, and smooth)
contracted at all times. all cells contract as a unit.
B) Both cardiac and skeletal muscle contraction is initiated by B) All three muscle types are innervated by the autonomic
calcium binding to troponin. nervous system.
C) Both cardiac and smooth muscle must have action C) In all three muscle types, calcium is involved in contraction.
potentials to initiate contraction. D) In all three muscle types, dihydropryidine antagonists or
D) Both cardiac and smooth muscle initiate contraction by blockers increase strength of contraction.
calcium binding to troponin.
3. Which of the following statements about muscle is true?
A) Skeletal muscle can increase strength of contraction by
recruiting more motor units.
B) Cardiac muscle can increase strength of contraction by
recruiting more muscle cells.
C) Smooth muscle cannot change strength of contraction.
D) Cardiac muscle cannot change strength of contraction.
 9
C H A P T E R

Skeletal Muscle
Structure and Function
Kathleen H. McDonough

O B J E C T I V E S

■ Describe the processes that take place at the neuromuscular junction.

■ Explain excitation–contraction coupling in skeletal muscle.
■ Describe the role of the proteins that are involved in contraction.
■ Describe what happens during an isometric contraction.
■ Describe what happens during an isotonic contraction. How does the load
affect shortening and velocity of shortening?
■ Explain how muscle fiber strength of contraction can be increased by
summation and tetanus.
■ Explain the length–tension relationship in skeletal muscle.
■ Explain the motor unit.
■ Explain how whole muscle strength of contraction can be increased by
recruitment of motor units.
■ Explain the force–velocity relationship in skeletal muscle; explain the basis for
the Vmax.
■ Describe the three different types of skeletal muscle fibers and the bases for
their differences. State when these fibers are recruited.

STRUCTURE
Skeletal muscle is distinctive because of its anatomic
structure—striations due to the regular pattern of sarcomeres
that are composed of the orderly positioning of the actin and
myosin proteins. Figure 9–1 shows sarcomeres composed of
parallel alignments of thick filaments (i.e., myosin) and thin
filaments (i.e., actin, tropomyosin, and troponin). Myosin
makes up the A band. Actin, along with the two other proteins,
tropomyosin and troponin, makes up the I band (portion of
the sarcomere where actin does not overlap with myosin). Part
of the actin filament overlaps with the myosin filament, thus
allowing interaction of these two proteins to initiate contrac-
tion. The degree of overlap of thick and thin filaments is
important in determining the amount of force that skeletal
muscle, and cardiac muscle, can generate. The Z lines repre-
sent the borders of the sarcomere and, during shortening, the
Z lines come closer to each other as the actin filament is pulled
over the myosin filament. The A band remains the same length
(myosin does not shorten) but the I band becomes smaller as
actin is pulled over the myosin. The sliding of the actin over
the myosin, with energy provided by the myosin ATPase that
is located on the myosin head, is the molecular basis of skeletal
muscle contraction (Figure 9–2). Activation of the complex
occurs when the calcium concentration in the cytosol increases
and binds to the calcium-binding site on the troponin. Tro-
ponin has three components designated as TnT that attaches it
to tropomyosin, TnI that inhibits interactions between actin
and myosin, and TnC that binds the calcium. When calcium
binds to TnC, there is a conformational change in the troponin/
tropomyosin position, removing the hindrance by TnI and tro-
pomyosin and allowing the actin and myosin head to interact,
thereby hydrolyzing ATP to supply the energy for the
contraction—sliding of the actin over the myosin or cross-
bridge cycling. The cross-bridges will continue to cycle, that
is, myosin heads will continue to bind to adjacent sites on actin

83

Ch09_083-092.indd 83 11/26/10 9:41:31 AM

84 SECTION III Muscle Physiology

(a) Sarcomere

I band A band

(b) H zone

Z line Z line
Titin Thin filament M line Thick filament

FIGURE 9–1 (a) Magnified section of a sarcomere within a skeletal muscle cell showing the pattern of striation due to the
orientation of the actin and myosin filaments. (b) Drawing of the components of the sarcomeres from Z band to Z band showing the
structural protein titin and the thick filaments (myosin) and the thin filaments (actin, tropomyosin, and troponin). (Reproduced with permission
from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

Thick filament Cross-bridge

Thin filament
(a)
Actin binding sites

ATP binding sites

Light chains
Tropomyosin
Heavy chains Cross-bridge

Troponin Actin Myosin

(b)

FIGURE 9–2 (a) Drawing of the thick filament with the myosin heads or cross-bridges extending from the thick filament. Also shown
is the twisted structure of the thin filaments. (b) Magnification of the myosin and actin showing the three components of the thin filament—
actin, tropomyosin, and troponin—and the heavy and light chains of the myosin. Note the actin- and ATP-binding sites on the myosin. The
actin-binding sites are blocked by tropomyosin when calcium levels in the cytosol are low. With calcium binding to troponin, tropomyosin is
moved away and the binding site for actin is available. The energy for sliding the actin filament across the myosin filament is provided by the
ATP hydrolyzed by the myosin ATPase that is located on the myosin head. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human
Physiology, 11th ed. McGraw-Hill, 2008.)
 CHAPTER 9 Skeletal Muscle Structure and Function 85

and slide the actin further over the myosin, until the contrac-
tion is terminated by removal of calcium.
Cross-bridge cycling results in either tension development
or shortening or a combination of the two, depending on the
load on the muscle. If the load is too great, there will be
an isometric contraction in which there is tension develop-
ment but no shortening of the muscle. If the load is less, there
will be an isotonic contraction in which the muscle short-
ens after developing tension (discussed in more detail in
Chapter 10). Other proteins are involved in maintaining the
precise structure of the sarcomeres. Titin, a large structural
protein in the skeletal muscle cell, extends from the Z line to
the center of the sarcomere, stabilizing the structure. Another
large protein complex consists of dystrophin and several gly-
coproteins. This complex is instrumental in attaching the
sarcomere, in particular, actin, to the sarcolemma (SL) and
the extracellular matrix, again for maintaining structure and
stability of the sarcomeres. The gene that codes for the dys-
trophin complex is large and subject to mutations resulting
in disorders of skeletal muscle termed muscular dystrophy.
One symptom of this disease is progressive muscle weakness
due to the loss of the proper structural integrity of the muscle
fibers. Duchenne muscular dystrophy is one type of dystro-
phy in which there is a complete absence of the dystrophin
protein resulting in rapid decline in skeletal muscle function
and early death.
NEUROMUSCULAR JUNCTION
Skeletal muscle cells or fibers generally extend from one ten-
don to the other tendon that attaches the muscle to the bones.
Skeletal muscle is classified as voluntary muscle since its
contraction is mandated by the central nervous system—we
can contract muscles at will. Thus, the innervation of skeletal
muscle is essential for activation of contraction. Each fiber is
activated by one motor neuron, whereas one motor neuron
can innervate a number of muscle fibers forming a motor
unit. When one motor neuron is activated, all of the fibers
innervated by that motor neuron will contract. The motor
neurons from the spinal cord or brainstem, in response to
action potentials traveling down the axon toward the skeletal
muscle cell, release the neurotransmitter acetylcholine as
shown in Figure 9–3 at the neuromuscular junction.

1 Motor neuron
action potential

Acetylcholine
vesicle
2 Ca2+ enters 8 Propagated action
voltage-gated potential in muscle
channels plasma membrane

Voltage-gated
3 Acetylcholine Na+ channels
release
+ + + + + + + +
+
– – – – + 4 Acetylcholine binding – – – –
+ – opens ion channels 5 Na+ entry – +
+
– + + + + + +
+ +
– – – – – – –
–
9 Acetylcholine 7 Muscle fiber
Acetylcholine receptor
degradation action potential
Acetylcholinesterase initiation

Motor end plate 6 Local current between

depolarized end plate and
adjacent muscle plasma
membrane

FIGURE 9–3 The neuromuscular junction is the specialized part of the muscle cell—motor end plate—at which the motor
neuron releases the neurotransmitter acetylcholine to activate the muscle cell or fiber. Events at the junction are listed in chronological
order. Note that each muscle fiber receives impulses from only one motor neuron and all of the fibers receiving input from that motor neuron
make up the motor unit and will contract in synchrony. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed.
McGraw-Hill, 2008.)
86 SECTION III Muscle Physiology
The amount of acetylcholine released is proportional to the
frequency of action potentials.
Acetylcholine diffuses across the synaptic cleft and binds to
a cholinergic receptor—the nicotinic receptor—on the mus-
cle cell membrane (SL). The part of the muscle SL that is asso-
ciated with the neuromuscular junction is called the motor
end plate. Within the cleft is the enzyme acetylcholine
esterase that can hydrolyze unbound acetylcholine and thereby
limit the activation of the muscle cell membrane nicotinic
receptors. This receptor is a channel that allows sodium and
potassium flux. The predominant ion movement is sodium
entering the muscle cell causing partial depolarization of the
cell membrane in the synaptic cleft—an end plate potential
(see Chapter 7). Since motor neurons cause only depolariza-
tion of the postsynaptic membrane and not necessarily an
action potential, the change is similar to an excitatory post-
synaptic potential (EPSP) occurring in neurons.
EXCITATION–CONTRACTION
COUPLING
This depolarization is conducted to the SL outside of the neu-
romuscular junction and if strong enough will induce an action
potential. The action potential is transmitted along the SL, into
the T-tubules, which are invaginations of the SL that allow the
cell membrane to come in close contact with an intracellular
membrane system called the sarcoplasmic reticulum (SR;
Figure 9–4). In skeletal muscle, the T-tubule makes contact
with two components (cisternae or lateral sacs) of the SR
forming a triad. Calcium is released from ryanodine recep-
tors located on the cisternae when the T-tubule is depolarized
during an action potential. Dihydropyridine (DHP) recep-
tors, also known as calcium channels, on the SL cause a con-
formational change in the ryanodine receptors causing them
to open and allowing calcium to diffuse from the SR into the
cytosol. Contraction is initiated when calcium levels in the
cytosol reach a critical level and bind to TnC. In skeletal muscle,
all of the calcium used for contraction is released from the SR.
For relaxation to occur, calcium must be returned to the SR. As
seen in Figure 9–4, the SR consists of longitudinal components
as well as the cisternal component. The longitudinal portion of
the SR contains the calcium ATPase enzyme, referred to as
SERCA. SERCA has a high Vmax and, using the energy from
ATP, pumps calcium against its concentration gradient into
the SR. Proteins such as calsequestrin within the SR bind cal-
cium, providing a storage function in the SR but also maintain-
ing an optimal free calcium concentration so that the calcium
gradient for pumping calcium out of cytosol and back into the
SR is not excessive. This process in which an action potential
leads to increased calcium leading to contraction is termed
excitation–contraction coupling.
Due to the complexity of the neuromuscular junction, many
disease states can occur when there is dysfunction. For exam-
ple, nerve gases inhibit the acetylcholine esterase, thereby
resulting in continuous activation of the nicotinic receptors
Sarcolemma T tubule
Ca ATPase
Sarcoplasmic Ryanodine Dihydropyridine
reticulum receptor, receptor
cisterna channel
FIGURE 9–4 The connection between the sarcolemmal (SL)
T-tubules and the cisternae of the sarcoplasmic reticulum (SR) is
the mechanism for the coupling of the action potential traveling
along the SL to the release of calcium from the SR. The connection
between the calcium channels (dihydropyridine receptors) on the SL
and the ryanodine receptors on the SR is altered by the action
potential allowing opening of the SR calcium channels and release of
calcium into the cytosol.
and continuous activation of the skeletal muscle. Eventually
the cells can no longer generate action potentials because the
cells remain depolarized and sodium ion channels that would
normally open and initiate depolarization are inactivated.
Muscle weakness ensues and since the diaphragm contains
skeletal muscle, respiratory failure leads to death. Autoim-
mune diseases such as myasthenia gravis can result in pro-
duction of antibodies to the nicotinic cholinergic receptor.
Binding of antibodies to the receptors results in impaired sig-
naling or communication between the motor neuron and the
skeletal muscle fibers. Contractions are impaired and with
time the entire structure of the motor end plate deteriorates.
Degeneration of the motor neuron, which is required to initi-
ate contraction, results in diseases such as amyotrophic lateral
sclerosis (ALS or Lou Gehrig’s disease). The motor neuron
shrinks and degenerates, leading to denervation of the muscle
cells and resulting in impaired ability of skeletal muscle to
contract. Eventually the muscle cells atrophy. An early symp-
tom of ALS is muscle weakness.
FUNCTION
TYPES OF CONTRACTIONS
Contraction can occur in two modalities: isometric and iso-
tonic and combinations thereof. Isometric, as its name
implies, refers to contractions in which the length (metric) of
the muscle stays the same (iso) but tension or force increases.
Figure 9–5 shows the schematic of the apparatus for measur-
ing the output of isometric contractions. A thin skeletal mus-
cle strip is suspended between a force transducer and an
immovable bar. Since the muscle is tethered at both ends,
 CHAPTER 9 Skeletal Muscle Structure and Function 87

Isometric contractions Force

transducer
Isotonic contractions

Muscle 100

75
Stimulator
Muscle Stimulator
50
length

25

0
Force transducer Load (preload)
Afterload
FIGURE 9–5 Isolated muscle preparation to study isometric
muscle contractions. The muscle is not allowed to shorten. The
FIGURE 9–6 Isolated muscle preparation to study isotonic
contractions. The passive tension is set by the preload, and the
passive tension on the muscle as a function of resting muscle length
muscle length is measured. A bar is place under the muscle so that
is measured with a force transducer and then the muscle is stimulated
when the afterload is added, the muscle does not lengthen (does
to contract.
not sense the afterload). On stimulation, the bar is removed and the
muscle develops tension to just match the afterload. During the
remainder of the contraction, the tension remains constant and the
when the muscle is stimulated, cross-bridge cycling results muscle shortens. The length of the muscle and the rate of shortening
only in tension (dyne/cm) or force (dyne) development. The are measured.
length of the muscle does not change during contraction.
Isotonic refers to contractions in which the tension (tonic)
stays the same but the length changes. Prior to the shorten-
ing, however, the muscle must increase tension or force to
exceed the load it is lifting or contracting against; thus, the
B C A B C
contraction consists of tension development followed by
Shortening

shortening. Figure 9–6 shows the apparatus for measuring CE

CE
isotonic contractions. The change in muscle length (short- CE
ening) can be measured after the muscle is stimulated.
There are two loads on the muscle: (1) the preload that sets
SE
the resting muscle length and (2) the afterload that the
Tension

SE
muscle does not sense until after the contraction begins. In Load SE
the protocol, the preload is added to the muscle strip, the L
passive or resting length is established, and then the hori- Time L L
zontal bar is placed under the muscle such that addition of Stimulation L = Load

the more weight, the afterload, does not allow the muscle to
lengthen anymore. When the stimulator excites the muscle,
the bar is removed and the muscle contraction results in the
muscle generating force to equal the afterload and then
shortening.
Figure 9–7 shows a model for skeletal muscle contraction.
Muscle consists of the contractile element (CE; the contractile
proteins actin and myosin) and a series elastic component. The
load can be considered the weight the muscle must lift in an
isotonic contraction. Note that prior to shortening, the CE is
getting smaller, that is, the cross-bridges are cycling and pulling
actin across myosin, but the entire muscle is not shortening—
the cross-bridge cycling is generating tension (Figure 9–7, B).
When the tension or force matches the load (afterload), the
remainder of the cross-bridge cycling (contraction) results in
shortening of the muscle (Figure 9–7, C). Note that the afterload
determines how much tension the muscle will have to generate
FIGURE 9–7 A model of skeletal muscle consists of the
contractile element (CE) made up of the thick and thin filaments,
and the series elastic (SE) component that consists of
noncontractile components of the muscle. Phase A is the muscle
at rest. Using the model to represent an isotonic contraction, after
stimulation, the muscle develops tension (phase B) and stretches the
series elastic component, that is, tension is developed (to match
the load) but the whole muscle does not shorten. Note the contractile
element is shortening, that is, cross-bridges are cycling and actin
filament is being pulled over the myosin, but the whole muscle is not
shortening. At point C, the tension developed by the contractile
element stretching the series elastic component just exceeds the
afterload and during the remainder of the contraction, the cross-
bridge cycling is actually shortening the whole muscle. The load
on the muscle determines how much tension the muscle will have to
develop in order to shorten and lift the load. (Reproduced with permission
from Sonnenblick EH: The Myocardial Cell: Structure, Function and Modification. Briller
SA, Conn HL (editors). University of Pennsylvania Press, 1966.)
88 SECTION III Muscle Physiology
prior to shortening. A heavier load will require more tension
development, and a lighter load will require less tension devel-
opment. With a heavier load and more tension to develop, the
muscle will exhibit less shortening. With a lighter load, and less
tension to develop, the muscle will exhibit more shortening.
When afterload is plotted on the x-axis and shortening
velocity is plotted on the y-axis, an inverse relationship is dem-
onstrated—the force–velocity curve (Figure 9–8). Where the
curve intersects with the x-axis, there is no shortening (zero
velocity of shortening)—this is an isometric contraction—
maximum force is developed but there is no shortening. If
afterload is decreased—red circle—less force must be devel-
oped and some shortening occurs and therefore the velocity of
shortening can be depicted. If the afterload is decreased again,
still less force is developed and even more shortening occurs
and velocity of shortening increases. At the y-axis intercept,
there is the maximum velocity of shortening—Vmax. Note the
dashed line connecting the curve to the y-axis—this denotes
that the intercept is an extrapolation of the curve—one cannot
study a contraction in a muscle with zero load; therefore, Vmax
is an estimate of the maximum velocity of shortening. One
other fact to note is that shortening and velocity of shortening
are changing in the same direction—increases in shortening
occur with increases in shortening velocity. The force–velocity
Vmax
Velocity
Po
Force or load
FIGURE 9–8 The force–velocity curve is generated from the
study of isolated muscle during isotonic contractions. To
generate a typical curve, the preload on the muscle is held constant,
that is, the resting length is the same for each contraction studied,
but the afterload is varied. At the intercept of the x-axis, the greatest
afterload, there is no shortening—this represents a maximal
isometric contraction (Po). As the load decreases—the red point, less
tension must be developed to match the afterload and therefore
some shortening can occur. With more shortening there is a greater
initial velocity of shortening that is plotted on the y-axis. With a
further decrease in afterload to the light red point, there is even less
tension developed and even more shortening can occur, so a greater
velocity of shortening occurs. The green point represents an even
lighter afterload and therefore an even greater velocity of
shortening. The curve is extrapolated to the intercept of the y-axis
that yields the maximum velocity of shortening (Vmax). This is a
theoretical point because the muscle cannot be studied under
conditions of zero load.
relationship will also be discussed in Chapter 10 with reference
to cardiac muscle contraction.
REGULATION OF CONTRACTION—
LENGTH–TENSION
The type of contraction, isometric versus isotonic, is deter-
mined by the loading conditions on the muscle. If the muscle
is not allowed to shorten, tension development is the total out-
come of cross-bridge cycling resulting in an isometric contrac-
tion. For example, pulling on an immoveable object results in
an isometric contraction—the muscle is developing tension
but cannot shorten. The amount of force generated during
that contraction (twitch) is determined by the amount of cal-
cium released from the SR. Under normal circumstances, the
amount of calcium released in response to an action potential
is maximal in skeletal muscle fibers.
The length (preload) of the muscle prior to the contraction
also affects the strength of the contraction. The length of the
muscle fibers prior to contraction determines how much
overlap there will be between actin and myosin and, thus,
how many cross-bridges can be formed. Since the energy for
the contraction is released by the myosin ATPase activity,
altering the number of cross-bridges that interact alters the
amount of myosin ATPase that is activated and thus the
amount of ATP that will be hydrolyzed to provide the energy
for contraction and relaxation. This has a significant effect
on the strength of the contraction. As seen in Figure 9–9,
length of the muscle (preload) affects developed tension,
passive tension, and total tension. In skeletal muscle, pas-
sive tension is low until the Po point at which it begins to
increase substantially. Total tension increases as a function of
muscle length as does active or developed tension. Active
tension is the tension that is developed during contraction by
Total
Active or developed
Tension,
dynes/cm
Passive
Po
Length, mm
FIGURE 9–9 The relationship between the length of muscle
(set by the preload on the isolated muscle) and the tension that
can be measured is shown. The active or developed tension is the
difference between the total tension and the passive tension. It is the
tension that the muscle produces during the contraction. At Po the
muscle is at the optimum length to give the greatest tension—
maximum isometric tension.

cross-bridge cycling and is therefore the difference between
total tension and passive tension. Passive tension is due to the
structural properties of skeletal muscle. Skeletal muscle dem-
onstrates the length–tension relationship but in the body,
since most of the skeletal muscle is attached to the bone by
tendons, the optimum length is generally set by anatomy.
REGULATION OF STRENGTH OF
CONTRACTION IN SKELETAL MUSCLE—
RECRUITMENT, SUMMATION, AND
TETANUS
The physiological way for intact skeletal muscle to increase
tension is via changes in the stimulation pattern by the motor
neurons. Spatial recruitment refers to increased numbers of
motor neurons firing, and, therefore, more motor units con-
tracting. Temporal recruitment refers to increased number of
action potentials in a motor neuron thereby affecting the con-
traction of the muscle fibers within that motor unit. Within a
muscle, usually only a small percent of the muscle cells or
fibers will contract at any one time but the contraction of each
fiber will be maximal. All of the muscle fibers innervated
by the same motor neuron will contract at the same time. The
strength of the contraction of the entire muscle increases if
more motor neurons are activated and therefore more muscle
fibers are stimulated to contract—spatial recruitment. The
order of recruitment of motor units will be discussed below
with the presentation of muscle fiber types.
Temporal recruitment results from increasing the number
of action potentials in the motor neuron. In Figure 9–10, curve
A shows the contraction or twitch in response to one stimulus.
More rapid firing (more action potentials per second) repeti-
tively releases acetylcholine to activate nicotinic receptors giv-
ing more action potentials in the muscle membrane. If two
stimuli are far enough apart (e.g., 300-millisecond delay as
shown for B in Figure 9–10), two separate identical contrac-
tions occur. When the two stimuli are approximately 40–50
milliseconds apart, the muscle contraction appears to be one
twitch but the strength of the contraction is greater than that
generated by a single stimulus (curve D, Figure 9–10). This
response is called summation. The mechanism for summa-
tion is that the second contraction begins prior to the begin-
ning of relaxation of the first contraction. Therefore, the total
contraction is measurable tension development with no energy
spent in overcoming the series elastic component or the resis-
tance to contraction by all of the “noncontractile elements”
present in the muscle. If the stimuli are more than 40–50 mil-
liseconds apart (curve C), the first contraction begins to wane
prior to initiation of the second contraction giving a biphasic
appearance to the contractions. The optimum delay between
two stimuli may vary in different types of skeletal muscle but
the capacity to increase force by summation is present in all
skeletal muscle. As the delay between the stimuli becomes
smaller and smaller, the contraction becomes weaker and
weaker until eventually the “summated” contraction will
CHAPTER 9 Skeletal Muscle Structure and Function 89
Tetanic contraction
Summation
A B C D
E
Tension
Twitch
Single 300 msec 120 40–50 60 stimuli 1
stimulus delay msec msec per sec msec
delay delay delay
FIGURE 9–10 Muscle tension developed during
contractions performed under different patterns of stimulation
is shown. (A) With a single stimulus, one twitch occurs. (B) With two
stimuli that are 300 milliseconds apart, two identical twitches occur.
(C) When the second stimulus occurs prior to complete relaxation
from the first twitch, the second contraction shows greater tension
development. (D) When the two stimuli are approximately 40–50
milliseconds apart, there appears to be only one contraction but the
tension is 2–3-fold greater than that with one stimulus. When the
muscle is stimulated with a rapid burst of stimuli (60 stimuli/s),
tetanus occurs—the greatest amount of tension is developed and
there is no relaxation. During this stimulation pattern, the release
of calcium with each stimulus outstrips the calcium uptake
mechanisms, so cytosolic calcium remains elevated and relaxation
does not occur. Depending on the muscle type, tension will remain
elevated until the stimulation ends or until fatigue develops and the
muscle can no longer maintain tension. (E) When the two stimuli are
approximately 1 millisecond apart, the contraction looks identical
to the contraction given after one stimulus—the muscle cannot
respond to the second stimulus because it is in the refractory
period—the muscle cell membrane is not responsive to a normal
stimulus.
become identical to the single stimulus–initiated contrac-
tion—all fibers will have become refractory to the second
stimulus—responding only to the first stimulus. This gener-
ally occurs with stimuli that are 1–2 milliseconds apart (E).
The maximum tension that can be developed occurs during
tetanic contractions (Figure 9–10). The basis for this increase
in tension is that there are so many action potentials (e.g., 60/s)
that the calcium release mechanisms occurring with every
action potential outstrip the calcium uptake mechanisms;
thus, cytosolic calcium levels remain elevated continuously
and the muscle does not relax in between stimuli. The
cross-bridges continue to cycle either until stimulation stops
and cytosolic calcium concentrations decrease or until the
cells fatigue. Both summation and tetanus (tetanic contrac-
tions) are examples of temporal recruitment—the same fibers
are stimulated to contract by the same motor neurons but the
frequency of stimulation by the neuron alters the muscle
response. In summary, strength of contraction of an intact
90 SECTION III Muscle Physiology

muscle made up of many different motor units can be increased
by: (1) increasing the number of motor neurons activated,
thereby increasing the number of motor units contracting; and
(2) increasing the frequency of action potentials of the motor
neuron, thereby eliciting summation or tetanus of those mus-
cle fibers in the motor unit.
FIBER TYPES
As mentioned above, the strength of contraction of skeletal
muscle can be increased by spatial recruitment. Spatial
recruitment occurs when more motor neurons participate in a
contraction, thus “recruiting” more motor units, that is, more
muscle fibers to contract.
There are three basic types of muscle fibers in skeletal
muscle—type I, type IIa, and type IIb (Table 9–1). These were
formerly called red and white muscle for the color imbued by
the presence of myoglobin and many mitochondria in red
muscle and little myoglobin in white muscle. Since the red
muscle has many mitochondria, it has the capacity, by oxida-
tive phosphorylation production of ATP, to sustain contrac-
tions over long periods of time.
The fiber types have different diameters as do the motor
neurons that innervate them.
The pattern of spatial recruitment is governed by the size of
the muscle fibers with smallest fibers being most easily recruited
(earliest recruitment), and largest fibers recruited last. The type
I fibers have the smallest diameter and are innervated by motor
neurons that are also the smallest in diameter. This makes both
the neurons and the fibers easy to activate. These small fibers
that are recruited earliest have a high oxidative capacity and
can perform work for long periods of time without fatiguing.
Adequate blood flow and high concentrations of mitochondria
for oxidative metabolism allow these fibers to contract for
hours. These fibers have been called slow twitch because their
myosin ATPase activity is low. These fibers also contain myo-
globin, a heme-containing protein that binds oxygen and can
therefore serve as an oxygen store that can be used when oxida-
tive phosphorylation is occurring at elevated rates to support
elevated rates of contraction. These type I fibers were classified
as “red” fibers in the past because the high concentration of
myoglobin gives color to the muscle fibers.
Type II fibers have a higher myosin ATPase activity and
therefore a faster rate of contraction. There are two subtypes in
this group—type IIa are fibers with a fast twitch and both oxi-
dative and glycolytic capacity, and type IIb are fibers with a
fast twitch but rely almost entirely on glycolysis for ATP pro-
duction. The type IIb fibers have high concentrations of the
enzymes involved in glycolysis. These fibers have the largest
diameter and are recruited last. They are innervated by motor
neurons with large diameters that require a greater stimulus in
order to generate an action potential, thereby making them
the last to be recruited. They are more likely to fatigue than the
other types of fibers due to the dependence on glycogen as a
substrate for ATP to provide the energy for contraction. The
supply of glycogen is limited and since they have a relatively
sparse blood supply, glucose may not be as readily available. If

TABLE 9–1 Comparison of skeletal muscle fiber (cell) types.

Type I Type IIa Type IIb

Metabolism Oxidative Oxidative/glycolytic Glycolytic

Twitch Slow Intermediate Fast

Mitochondria Abundant Intermediate Few

Myoglobin Abundant Abundant Few

Color Red Red White

Glycogen Little Intermediate Abundant

Myosin ATPase rate of Lowest Fastest Fastest

hydrolysis of ATP

Speed of contraction Slowest Intermediate Fastest

Blood flow Great Intermediate Low

Fatigue Not readily Intermediate Rapid onset

Force Least Intermediate Greatest

Size of motor neuron Smallest Intermediate Largest

Size of fiber Smallest Intermediate Largest

Recruitment First Second Last

Total tension Least Intermediate Greatest


glycolysis results in lactic acid production because oxygen is
not readily available, the cells will fatigue in a matter of min-
utes and decrease tension development in spite of repeated
motor neuron firing. These fibers were formerly classified as
“white” fibers because they had lower levels of mitochondria,
myoglobin, and blood flow—all of which lend the red color to
the type I fibers. The type IIa fibers are of intermediate size
and therefore are recruited after the type I slow fibers are acti-
vated. Type IIa fibers can use both glycolysis and oxidative
phosphorylation for their energy supply and therefore also
exhibit an intermediate time course for fatigue to occur. The
ATPase activity and therefore speed of contraction is fast as in
the type IIb fibers and the time for fatigue to occur is interme-
diate. The capacity for oxidative phosphorylation to provide
some of the ATP for contraction prolongs the time of sustained
contraction before fatigue occurs.
In general, the diameter of the muscle fiber is indicative of
the amount of actin and myosin in the fiber. Therefore, larger-
diameter fibers have more actin and myosin, more cross-
bridges that can form, and can develop more tension. Smaller
fibers develop less tension due to lower amounts of actin and
myosin but again can contract for prolonged period due to
their abundant blood supply and oxidative capacity.
Most muscles in the body are made up of combinations of
the three muscle fiber types with a predominance of either fast
or slow fibers. Muscles involved in maintaining posture must
have long-lasting capacity to contract and not to fatigue, so
these have more of the type I, slow-twitch fibers. Of course, in
maintaining posture, not all muscle fibers will be contracted at
any one time but different motor units will take over contrac-
tion cyclically. Muscles that are involved in rapid changes such
as eye movements are predominantly type IIb fibers—fast
contractions that are not sustained for long periods of time.
Many muscles have intermediate amounts of the different fiber
types. For example, people who do prolonged activities such as
endurance running have slower-twitch, oxidative fibers in
their muscle responsible for running. Sprinters have more
fast-twitch, glycolytic fibers that are best for bursts of activity
but not for sustained activity.
CLINICAL CORRELATION
A 45-year-old woman notices that she has been feeling
unusually tired after work for the past month. She also
notices that her left eyelid begins to droop at the end of
the day. Gradually she is noticing that the eyelid begins to
droop even by the end of the work day if it has been a
particularly stressful day. She is also experiencing more
and more severe fatigue but both of these problems are
gone after a good night’s sleep. She is concerned and
makes an appointment with her physician. On physical
examination, her physician notes that all measured vari-
ables were in the normal range except for movement of
the left eye. Lateral movement was impaired and ptosis
CHAPTER 9 Skeletal Muscle Structure and Function 91
(eyelid drooping) occurred with repeated, rapid eye
movements. The physician suspects myasthenia gravis
and orders tests to confirm the diagnosis.
Myasthenia gravis is an autoimmune disease in which
the immune system produces antibodies to the nicotinic
receptor. Initially small motor units, especially in ocular
muscles for eye movement, demonstrate the defect. Rapid
motor neuron firing for rapid muscle contractions for eye
movement eventually leads to release of less acetylcholine
(production lags behind release). In normal individuals,
there are adequate receptors to compensate for the
decreased amount of acetylcholine released. With myas-
thenia gravis, antibodies bound to the receptors prevent
the acetylcholine binding, thus leading to impaired
muscle contractions. Rest can replenish the acetylcho-
line stores. Antibodies bound to the nicotinic receptor
seem to trigger an immune response and degeneration
of the muscle motor end plate. Eventually, with more
antibody production, more muscle units become
involved and can eventually lead to large muscle weak-
ness including impaired respiratory muscle function.
Treatments to decrease antibody production, often
exacerbated by the thymus gland, include removal of
the thymus and treatment with immunosuppressive
drugs such as corticosteroids. Cholinesterase inhibitors
are also used since they inhibit the enzyme that hydro-
lyzes acetylcholine at the neuromuscular junction,
thereby maintaining higher concentrations of acetyl-
choline and greater stimulation of the motor end plate.
CHAPTER SUMMARY
■ Skeletal muscle cells are also called fibers.
■ Skeletal muscle cells have a specialized section of SL called the
motor end plate where the motor neuron forms a synapse with
the muscle. Acetylcholine is the neurotransmitter and nicotinic
receptors on the SL bind the acetylcholine and increase sodium
influx, causing partial depolarization, and eventually an action
potential in the adjacent SL.
■ The action potential travels down the invaginations of the SL
(T-tubules) and, via the dihydropyridine receptors, causes the
ryanodine receptors to open and release calcium.
■ Troponin binds calcium and begins the contraction process.
■ The motor neuron can innervate more than one skeletal
muscle fiber—the motor neuron and the fibers it innervates
are called a motor unit. All of these muscle cells contract at the
same time.
■ Contraction can be either isometric or isotonic.
■ In isotonic contractions, the load determines how much
tension or force the muscle must develop before the shortening
phase of the contraction can occur.
■ Skeletal muscle can increase strength of contraction by
recruiting more motor units (spatial recruitment).
■ The motor units with the smallest diameter of the neurons
and fibers are recruited most readily (first). These are the
92 SECTION III Muscle Physiology
type I fibers that are highly oxidative and have a low
myosin ATPase rate and therefore exhibit a slower contrac-
tion time.
■ Type II fibers have a high myosin ATPase rate and therefore a
faster contraction time. Type IIa are both glycolytic and
oxidative and are recruited second. Type IIb are mainly
glycolytic and recruited last (fibers and neurons have the
greatest diameter).
■ Type II fibers fatigue more quickly than do type I fibers, with
type IIb fibers fatiguing most rapidly—in a few minutes after
repeated stimulation.
■ Skeletal muscle can also increase strength of contraction by
more rapid firing of the motor neuron—summation and
tetanus.
STUDY QUESTIONS
1. Which of the following statements about skeletal muscle
contraction is correct?
A) Acetylcholine release at the neuromuscular junction
initiates an action potential in the motor end plate.
B) Acetylcholine binds to a nicotinic receptor on the postsyn-
aptic membrane.
C) The depolarization in skeletal muscle results from influx of
calcium through voltage-gated calcium channels (dihydro-
pyridine receptors).
D) Depolarization of the muscle fiber is not essential for
skeletal muscle contraction.
E) Norepinephrine activating adrenergic receptors causes
increased strength of contraction.
2. Which of the following statements about muscle contraction is
true for skeletal muscle?
A) All cells have pacemaker potential.
B) The strength of contraction is correlated with the degree of
phosphorylation of the myosin light chains.
C) The strength of contraction is increased by recruiting more
motor units.
D) All muscle cells have a high oxidative capacity due to the
abundant presence of mitochondria and myoglobin.
3. Which of the following statements about muscle contraction is
true for skeletal muscle?
A) In the body, strength of contraction is altered physiologi-
cally by changing the resting cell length from 25% up to
100% of the maximum length.
B) Strength of contraction is altered physiologically by altering
the frequency of motor neuron firing.
C) Tetanus cannot occur because the muscle action potential
keeps the cell refractory to stimuli that are closer than 1
second apart.
D) Muscle contraction consists only of tension development.
 10
C H A P T E R

Cardiac Muscle Structure

and Function
Kathleen H. McDonough

O B J E C T I V E S

■ Explain the process of excitation–contraction coupling in cardiac muscle and

how it differs from that of skeletal muscle.
■ Explain the effects of changes in resting cell length on muscle tension
development, that is, the length–tension relationship.
■ Describe the sequence of events in isotonic contractions—tension
development and shortening.
■ Describe the effects of afterload on isotonic contractions in cardiac muscle.
■ Explain the effects of changes in resting cell length on isotonic contractions
at different afterloads, that is, explain the force–velocity curve.
■ Describe the effects of increased contractility on the force–velocity curve.
■ Explain the terms preload, afterload, contractility, force, and tension.

INTRODUCTION
Cardiac muscle, like skeletal muscle, is striated due to the orderly
structure of the actin and myosin filaments and the accessory
proteins that stabilize the sarcomere. Like type I skeletal muscle,
cardiac muscle appears to be red in color due to the high content
of mitochondria and myoglobin and its blood supply. The heart
uses large amounts of ATP in beating 60–100 times/min (dur-
ing normal resting conditions) for the lifetime of the normal
adult and oxidative phosphorylation is the main source of that
ATP, thus the high myoglobin concentration and large mito-
chondrial content. There are estimates that the myocardial ATP
pool turns over every 10 seconds. The heart is able to use any
substrate provided to it in the blood and uptake is dependent on
the concentration of those substrates such as glucose, pyruvate,
lactate, free fatty acids, and ketone bodies. Normally fatty acid
oxidation provides 60–90% of the ATP used by the adult heart.
Like skeletal muscle, calcium is essential for contraction and is
provided by excitation–contraction coupling. Although cardiac
muscle can contract spontaneously due to pacemaker activity
in the sinoatrial (SA) node, the individual muscle cells (myo-
cytes) normally contract only when an action potential is initi-
ated by the conduction system present in the heart and
transmitted through cells specialized to conduct action poten-
tials rapidly. Cardiac muscle cells have gap junctions through
which cells communicate information about membrane poten-
tial—that is, if one cell depolarizes, the adjacent cells will also
depolarize due to communication through the gap junctions.
Thus, all cardiac myocytes in the atria contract together and
then all of the myocytes in the ventricle contract together
(Chapter 23). Because of this unified contraction of the ventri-
cles (or the atria), the heart is said to be a functional syncytium.
Since all ventricular muscle cells contract together, there is no
type of spatial recruitment in the heart. The heart relies on other
mechanisms to increase strength of contraction.
EXCITATION–CONTRACTION
COUPLING
Cardiac muscle cells contract when calcium levels in the cells
increase from approximately 10−7 M (0.1 μM) to 10−6 to 10−5 M
(1–10 μM). The level of calcium present in the cytosol to initi-
ate contraction has a profound effect on the strength of the con-
traction (contractility). Excitation–contraction coupling in
cardiac muscle varies somewhat from the process in skeletal
muscle. The anatomy of the sarcolemma (SL)–sarcoplasmic
reticulum (SR) interaction is different—diads are formed

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94 SECTION III Muscle Physiology
rather than triads as in skeletal muscle. There is less SR in car-
diac muscle, so the calcium release process relies on entry of
calcium into the cardiac cell through the voltage-gated chan-
nels (dihydropyridine receptors). These open when the mem-
brane potential reaches approximately −40 mV. These calcium
channels are also called “slow” or L-type calcium channels
because they open more slowly than sodium channels and
remain open longer, generally about 200–300 milliseconds.
Therefore, the action potential in cardiac ventricular cells is
much longer than the action potential in skeletal muscle
in which the calcium channels do not actually open (see
Chapter 9). Calcium entry through SL calcium channels is
essential for contraction to occur. Absence of calcium in the
extracellular fluid would prevent the heart from contracting.
The process of excitation–contraction coupling is initiated by
the pacemaker cells in the SA node that spontaneously generate
action potentials (termed slow action potentials because they
lack fast sodium channels and depolarization is due to calcium
entry through the slow calcium channels). Action potentials are
transmitted through the atrial conduction fibers across the
atrioventricular valves and finally to the conduction system in
the ventricles. All ventricular muscle cells depolarize at the same
time due to the rapid influx of sodium down its electrochemical
gradient (higher concentration of sodium outside of the cell and
negative membrane potential on the inside of the SL) through
SL fast sodium channels. When the membrane potential
reaches ~−40 mV, the slow calcium channels open, allowing cal-
cium to diffuse down its concentration gradient into the cytosol.
Some of this calcium causes opening of ryanodine channels
(receptors) on the SR and calcium diffuses out of the SR down
its concentration gradient. Some of the calcium from the SL
binds to troponin as does all of the calcium released from the
SR. Calcium binding to troponin results in a similar type of
interaction of actin and myosin and cross-bridge cycling to that
which occurs in skeletal muscle. Relaxation occurs when the
calcium concentration in the cytosol is lowered by the calcium
ATPase on the longitudinal part of the SR pumping calcium
back into the SR. Calsequestrin is also present in cardiac muscle
to serve as a “sink” for calcium. When calcium levels decrease,
calcium diffuses from the troponin and the cells relax.
Two other proteins are involved in removing calcium from
the cardiac cell. Since calcium enters the cell with each action
potential, there must be mechanisms to remove calcium or the
cell calcium content would increase with each heartbeat. The
SL contains a calcium ATPase that has a high affinity for cal-
cium and can therefore pump calcium out of the cell probably
even during diastole. The other protein is the sodium–calcium
exchanger. The exchanger operates on the basis of the sodium
ion gradient. The sodium ion concentration is greater outside
of the cell than in the cell. Via the exchanger, sodium ion enters
the cell and calcium ion is removed from the cell. Three sodium
ions enter for every one calcium ion leaving the cell. Manipula-
tion of the sodium gradient can have significant effects on cal-
cium extrusion from the cell and thus affect contraction.
Since calcium levels change during each action potential,
there is some evidence that increases in heart rate (more action
potentials per minute) can increase calcium availability for
contraction, thereby increasing the amount of tension that can
be generated. This phenomenon is called the staircase phe-
nomenon or treppe. Physiologically heart rate is altered by
autonomic nervous system (ANS) modulation of SA node
firing rate and, as will be seen later, the sympathetic nervous
system (SNS) component of the ANS not only increases heart
rate, but also increases contractility. Therefore, the physiologic
role of treppe is difficult to assess independent of SNS modu-
lation of heart rate and contractility.
There are two additional variations in contraction that occur
in cardiac muscle that do not occur in skeletal muscle. Phos-
phorylation of contractile proteins alters the strength of con-
traction in the heart. The heart is very responsive to the
SNS— the “fight or flight” component of the ANS. With acti-
vation of the SNS, beta-adrenergic receptors on the cardiac
muscle cells are activated and an intracellular signaling scheme
results in production of cAMP and activation of protein
kinase A. Phosphorylation of proteins follows. Several pro-
teins involved in contraction are phosphorylated and their
activity is altered. SL calcium channels are phosphorylated and
allow more calcium to enter the cell and the strength of con-
traction is increased (contractility is enhanced). A protein
called phospholamban normally inhibits the SR calcium
ATPase; when phospholamban is phosphorylated, it exerts
less inhibition of the ATPase, so calcium uptake is enhanced.
Phosphorylation of the calcium channels does not seem to
occur in skeletal muscle in which the maximum amount of
calcium is released during each action potential and therefore
cannot be increased. Remember that skeletal muscle has two
SR cisternae in conjunction with the T-tubule, whereas car-
diac muscle has only one cisterna associated with the T-tubule.
Skeletal muscle does not seem to have a functional phospho-
lamban, so the calcium ATPase activity is always operating at
its maximal capacity. Increasing the amount of calcium enter-
ing the cytosol is an important mechanism for increasing
strength of contraction (contractility); removing calcium
faster for relaxation is an important mechanism when the
heart rate increases with SNS stimulation and there is less time
during the contraction-relaxation cycle.
CONTRACTION—LENGTH–
TENSION, ISOMETRIC
CONTRACTIONS
The strength of contraction in cardiac muscle can be altered by
changes in the initial or resting length of the muscle cells (pre-
load) similar to the phenomenon in skeletal muscle. Cardiac
muscle, unlike skeletal muscle, can have physiologic changes in
the length of the muscle cells. For example, when the volume in
the ventricle at the end of diastole (the relaxation phase of the
cardiac cycle) is changed, the muscle cell length is changed in
the same direction. Increased ventricular end-diastolic volume
results in increased ventricular muscle cell length prior to the

Tension, dynes/cm
Active or developed
Passive – cardiac
muscle
Passive – skeletal
muscle
Po
Length, mm
FIGURE 10–1 The length–tension relationship in cardiac
muscle is slightly different from that in skeletal muscle—
primarily due to the presence of passive tension at shorter
lengths. This is in part due to the anatomic differences in structure of
skeletal muscle (all of the fibers in parallel) and cardiac muscle (fibers
exist in a basket weave-type pattern) as well as the properties of the
noncontractile components in skeletal muscle versus cardiac muscle.
Note that in skeletal muscle, the fibers are usually operating at the
blue point—resting length is optimum because most skeletal muscle
is held in place by the bones and resting length cannot vary greatly.
Cardiac muscle normally operates at lower (red point) than optimum
length and therefore has reserve capacity to increase tension
development, that is, have stronger contractions, when resting length
is increased. In the intact heart, cardiac cell resting length is set by the
volume in the ventricle at the end of diastole (the relaxed state of
cardiac muscle).
onset of contraction. The heart normally operates at lower than
maximal cell length or preload (Figure 10–1, red circle),
whereas skeletal muscle usually works at maximal preloads
(blue circle). Note also that the passive tension properties of the
heart differ from those of skeletal muscle. Skeletal muscle does
not increase passive tension until the muscle cell length is close
to the length that gives the maximum active tension. Cardiac
muscle has passive tension even at low cell lengths. These dif-
ferences are due to the anatomic arrangement of the muscle
cells with the noncontractile components in the muscle. Skeletal
muscle is more distensible than cardiac muscle. In Figure 10–1,
the effects of increases in preload are shown through isometric
contractions—that is, greater tension is developed from greater
resting cell length. The principle for the length–tension rela-
tionship, as in skeletal muscle, is that the change in cell and
sarcomere length alters the degree of overlap of the actin and
myosin filaments and therefore increases the potential for
cross-bridges to form. Changes in the resting length of the
whole muscle are associated with proportional changes in the
individual sarcomere length. Maximum tension development
occurs at sarcomere lengths of 2.2–2.3 μm. At shorter sarcom-
CHAPTER 10 Cardiac Muscle Structure and Function 95
ere lengths, the opposing thin filaments may overlap with each
other and interfere with interaction with myosin. At long sar-
comere lengths, overlap may be insufficient for optimal cross-
bridge formation.
More cross-bridge interaction leads to a stronger contraction.
Two other factors may contribute to the length–tension phe-
nomenon in cardiac muscle. The second mechanism may result
from a length-dependent change in calcium sensitivity of the
myofilaments. For a similar cytosolic calcium concentration, a
less stretched muscle develops less force than does a more
stretched (longer) cardiac muscle preparation. This change in
calcium sensitivity occurs immediately after a change in length
with no delay. The sensitivity of the contractile proteins, specifi-
cally troponin C, seems to increase at greater resting lengths.
Finally, there is some evidence that the amount of calcium
released from the SR is greater at longer resting lengths. How
much these two factors contribute to the greater tension devel-
opment is open to speculation since studies to demonstrate
these two effects of length on calcium dynamics are generally
performed in isolated cells or organelles. In summary, the heart
usually operates at lower than maximal preloads and therefore
has reserve—increasing muscle length can have a profound
effect on strength of contraction that allows the heart to meet
the demands of increased work such as occurs during exercise.
CONTRACTION—
FORCE–VELOCITY,
ISOTONIC CONTRACTIONS
The effects of altered preload on heart function can also be
observed with isotonic contractions that represent a better
match to physiologic contractions of the heart as a pump. The
left ventricle must develop tension (pressure) to match the
afterload (aortic pressure) in order to open the aortic valve
and then allow the shortening phase of the contraction to
pump blood (stroke volume) into the aorta. Recall from the
discussion of skeletal muscle that there is an inverse relation-
ship between afterload and velocity of shortening and there-
fore between afterload and shortening. Greater afterload
results in less shortening. Using isotonic contractions, the
effects of increased preload, that is, more cross-bridge cycling,
on the force–velocity curve can be analyzed. When shorten-
ing and velocity of shortening are measured as a function of
afterload, higher afterloads result in less shortening (see
Figures 9–8 and 10–2, black curve). If the preload is increased
from length 1 (L1) to length 2 (L2) and the same afterloaded
contractions are studied from the higher preload, velocity of
shortening (and shortening) is greater for each afterload. If
more cross-bridges can interact, there is more myosin ATPase
activity and therefore more energy from ATP hydrolysis avail-
able for the contraction. The cross-bridges develop the greater
tension needed to match the greater afterload and more
energy is available for more shortening and a greater velocity
of shortening to occur (blue curve, labeled L2). Note that the
96 SECTION III Muscle Physiology

maximum isometric tension (x-axis intercept) is increased
but the Vmax is not increased compared to the Vmax at L1.
Preload shifts only the maximum tension, not the maximum
velocity of shortening.
INCREASES IN STRENGTH
OF CONTRACTION IN
CARDIAC MUSCLE
As stated above, cardiac muscle can increase strength of con-
traction when the preload is increased as demonstrated by the
length–tension relationship. Another way that cardiac muscle
can increase strength of contraction is by increases in cytosolic
calcium resulting in increased contractility. Contractility
increases the velocity of cross-bridge cycling; therefore,
increasing contractility can alter shortening and the velocity of
shortening. In comparing the force–velocity curve during
enhanced contractility (red curve in Figure 10–2), one can
notice that increasing contractility causes the entire force–
velocity curve to shift to the right—both the maximum iso-
metric tension (intercept on the x-axis) and the Vmax
(extrapolated intercept on the y-axis) increase. This increased
contractility should be compared to the curve generated at the
same preload (L1), the black curve. Generally, increases in
contractility result in more rapid contractions such that
indexes of speed of tension development or maximum velocity
of shortening (Vmax) are used to indicate increases in contrac-
tility. The figure demonstrates that there are two ways to
increase the velocity of shortening at the same afterload (the
three points in the figure), one is by increasing preload (blue
curve), and the other is by increasing contractility (red curve).
The mechanisms by which the contractions are stronger are,
however, different. More optimum overlap of the actin and
myosin filaments mediates the preload effect, whereas more
cytosolic calcium to induce more rapid cross-bridge cycling
mediates the contractility effect.
The effects of increasing contractility can also be demon-
strated by looking at the length–tension relationship. In Figure
10–3, sympathetic nerve stimulation to the heart results in a
shift of the length–tension relationship upward and to the left.
This indicates that for any given resting length of cardiac mus-
cle, the tension that can be developed is greater as a result of SNS
stimulation. The mechanism is the increase in calcium that
results from the activation of beta-adrenergic receptors with the

Vmax

L1 ↑Contractility
Velocity

↑Preload or
length - L2
L1

Po
Force or load
FIGURE 10–2 The force–velocity curve in cardiac muscle can be altered by changes in resting cell length and by changes in
contractility. L1 represents the shorter resting cell length and L2 represents a greater resting cell length. In comparing the muscle at the same
afterload (black point vs. blue point), the muscle can shorten more if the contraction starts from a greater preload or resting cell length (L2). In
both contractions, the tension developed is set by the afterload. Note that the curve for increased preload intercepts the x-axis further to the
right—greater resting length allows for greater maximum isometric tension (the length–tension relationship). If the muscle is studied at L1, and
a drug that increases contractility is given, the entire force–velocity curve shifts upward and to the right from the black curve to the red
curve—both Po and Vmax are increased. More calcium results in stronger contractions and a greater velocity of contraction, that is, a greater
velocity of cross-bridge cycling. In comparing the black point to the red point, when contractility is greater, the muscle can develop the same
tension to match the load and there is more capacity to shorten and a greater velocity of shortening. Changes in Vmax therefore indicate changes
in contractility. Changes in Po can result from changes in preload or from changes in contractility.

↑SNS
Developed tension
Length
FIGURE 10–3 The effects of changes in contractility on
the length–tension relationship are shown. With sympathetic
stimulation (SNS) of cardiac muscle, contractility increases and
developed tension is greater at each resting cell length.
consequent production of cyclic AMP and activation of phos-
phorylation of the SL calcium channels by protein kinase A. The
importance of these two mechanisms will become very obvious
in discussions of the cardiovascular system in Section 5.
CHAPTER SUMMARY
■ Excitation–contraction coupling in cardiac muscle is similar
to that in skeletal muscle except that calcium must enter the
cardiac muscle cell through the voltage-gated calcium channels
to cause release of calcium from the SR ryanodine channels.
■ In cardiac muscle, strength of contraction can be altered by
changes in resting cell length (length–tension) and by changes
in contractility.
■ Indices of contractility, such as the maximum velocity of
shortening (Vmax), are increased by beta-adrenergic agonists.
■ Since the heart has cells with pacemaker potential, innerva-
tion of the heart is not required for contraction to occur.
Ventricular cells contract at the same time (a functional
syncytium) due to the conduction system and gap junctions
between the cardiac cells.
■ Sympathetic and parasympathetic nerves modulate the
intrinsic beating rate.
■ Sympathetic nerves modulate the strength of contraction
(contractility) of cardiac cells.
CHAPTER 10 Cardiac Muscle Structure and Function 97
STUDY QUESTIONS
1. Which of the following statements about cardiac muscle
contraction is correct?
A) Acetylcholine release at the neuromuscular junction
initiates an action potential in the postsynaptic membrane.
B) Acetylcholine binds to a nicotinic receptor on the
postsynaptic membrane.
C) Depolarization of the muscle fiber is not essential for
cardiac muscle contraction.
D) Norepinephrine activating adrenergic receptors causes
increased strength of contraction.
2. Which of the following statements about muscle contraction is
true for cardiac muscle?
A) All cells in the heart contract at their own rate.
B) The strength of contraction is independent of the degree of
phosphorylation of cellular proteins.
C) The strength of contraction is increased by recruiting more
motor units.
D) All muscle cells have a high oxidative capacity due to the
abundant presence of mitochondria and myoglobin.
3. Which of the following statements about muscle contraction is
true for cardiac muscle?
A) Strength of contraction is altered physiologically by
changing the resting cell length from approximately
25% up to 100% of the maximum length.
B) Strength of contraction is altered physiologically by altering
the frequency of motor neuron firing.
C) Tetanus occurs because the muscle action potential keeps
the cell refractory to stimuli that are closer than 1 second
apart.
D) Muscle contraction consists only of tension development.
4. Which of the following statements about muscle contraction is
true for cardiac muscle?
A) The Po (maximum isometric tension) is altered by both
contractility and the length–tension relationship.
B) On the force–velocity curve the Vmax is altered by both
contractility and the length–tension relationship.
C) Afterload determines how many cross-bridges can interact
during a contraction.
D) Preload determines the phosphorylation state of the
myosin light chain.
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 11
C H A P T E R

Smooth Muscle Structure

and Function
Kathleen H. McDonough

O B J E C T I V E S

■ Explain the contraction process in smooth muscle and compare it to

those of skeletal and cardiac muscle.
■ Describe how smooth muscle can be activated to induce a contraction
or to change the strength of a contraction.
■ Explain the relationship between vascular smooth muscle membrane
potential, voltage-gated calcium channels, and strength of contraction.
■ Describe the difference between multiunit and unitary smooth muscle.
■ Explain the following terms and their role in smooth muscle function:
calmodulin, myosin light chain kinase, and myosin light chain phosphatase.

INTRODUCTION
Smooth muscle makes up the walls of most of the hollow
organs of the body except the heart. As such, the function and
control of contraction of the smooth muscle will vary depend-
ing on the organ in which it is located and the function of that
organ or organ system. For example, smooth muscle in the
gastrointestinal tract will be activated not only by mechanical
stimulation by the presence of food in the GI tract, but also by
its neural and hormonal input. Smooth muscle in the uterus
will respond differently during development of an embryo/
fetus than during the normal menstrual cycle. Hormones and
neural input will even change the morphology of smooth
muscle during pregnancy, making the uterus work as a unit
rather than as independent muscle cells in the nonpregnant
uterus.
The myosin ATPase activity in smooth muscle has a much
slower rate of hydrolysis of ATP (10–100 times lower than that
of skeletal muscle); therefore, contractions are much slower
and sometimes the mode of contraction results in increases
and decreases in the strength of contraction rather than com-
plete relaxation after a contraction as occurs in skeletal and
cardiac muscle.
CONTRACTION
The general contractile process is uniform in all types of
smooth muscle. An increase in calcium in the cytosol results
in binding of calcium to a calcium-binding protein, calmod-
ulin (Figure 11–1). This complex will bind to, and activate,
myosin light chain kinase (MLCK) that, in turn, phosphory-
lates the myosin light chain located on the myosin head. In
smooth muscle, the myosin light chain must be phosphory-
lated in order for the actin and myosin to form crossbridges
and initiate the crossbridge cycling or contraction. Relaxation
or decreased tension development requires dephosphoryla-
tion of the myosin light chain by myosin light chain
phosphatase. The balance of phosphorylation and dephos-
phorylation is important in regulating tension development
in smooth muscle since the kinase and the phosphatase are
always active. Increasing cytosolic calcium tips the balance
toward more kinase activity and therefore more tension
development. Lower calcium levels tip the balance toward
less kinase and therefore more phosphatase activity and less
tension development.
There are other mechanisms to increase and decrease the
activity of the kinase and the phosphatase. For example,

99

Ch11_099-104.indd 99 11/26/10 9:49:20 AM

100 SECTION III Muscle Physiology

Smooth muscle cell

Contractions

Myosin light
Inactive MLCK ATP chain phosphatase

↑Cytosolic Active ~P myosin Myosin

Ca calmodulin
Ca2+ MLCK light chain light chain

Cross bridge cycling Relaxation

FIGURE 11–1 Scheme of steps in smooth muscle contraction. As in other types of muscle, calcium initiates the contraction. Calcium binds
to calmodulin that activates the myosin light chain kinase to phosphorylate the myosin light chain. On phosphorylation the myosin can interact
with the actin resulting in crossbridge cycling. Phosphatases can dephosphorylate the myosin light chain leading to relaxation or less tension
development. The balance of kinase and phosphatase activities determines the level of tension development in smooth muscle. Phosphorylation
of both the kinase and the phosphatase leads to a decrease in their activity—one resulting in weaker contraction and one in stronger contraction.

phosphorylation of the MLCK enzyme decreases its activity, would theoretically utilize large amounts of ATP. The latch state
thereby decreasing phosphorylation of myosin and resulting seems to occur because the crossbridges do not dissociate very
in more relaxation. This occurs when a specific receptor, the rapidly in spite of the fact that the myosin light chain is dephos-
beta2-adrenergic receptor, on the vascular smooth muscle phorylated; thereby, energy expenditure is minimized. The exact
and bronchiolar smooth muscle sarcolemma (SL) is acti- mechanism by which the latch state occurs is unknown. The
vated and increases intracellular cAMP levels. Subsequent physiologic significance, however, is remarkable—maintenance
activation of protein kinase A phosphorylates the MLCK of tension with very little energy expenditure.
and decreases its activity. Nitric oxide causes a similar relax-
ation of smooth muscle although the kinase that phosphory-
lates the MLCK is protein kinase G that is activated by cyclic VASCULAR VERSUS VISCERAL;
GMP. Regulation of the phosphatase is also important.
For example, phosphorylation of the myosin light chain MULTIUNIT VERSUS UNITARY
phosphatase decreases its activity, resulting in less dephos-
Smooth muscle can be divided into visceral and vascular
phorylation and therefore more phosphorylation of the myo-
muscle—visceral muscle making up the walls of most of the
sin light chains and more contraction. The Rho kinase
hollow organs and vascular making up the walls of blood
pathway leads to phosphorylation of the phosphatase. There
vessels. Vascular smooth muscle and to some extent, visceral
are several other types of regulation of the MLC kinase and
smooth muscle, can also be divided into two cell types—
phosphatase that alter the contraction properties of smooth
multiunit and unitary (Table 11–1). These two types of
muscle and are more specific for each organ’s particular func-
muscle cells have unique features that contribute to the vari-
tion and therefore will be discussed in the organ-specific sec-
ety of functions of smooth muscle. Multiunit smooth muscle
tions of this book.

ENERGY FOR CONTRACTION TABLE 11-1 Comparison of smooth muscle cell types.
AND RELAXATION Multiunit Unitary

The ATP used in contraction and relaxation in smooth muscle is Functional Individual units Syncytium
produced primarily by oxidative phosphorylation. The sub- Innervation Yes Little
strates such as glucose and fatty acids are provided in the blood
Gap junctions Few Yes
and mitochondrial oxidative processes produce adequate energy
for the slower contractions that occur in smooth muscle due to Response to stretch Little Yes
the lower rate of the myosin ATPase enzyme. An interesting Response to SNS Yes Little
adaptation of smooth muscle ensures that sustained contractions
Control of Central or neural Local factors
can occur at a lower-than-predicted ATP utilization. Smooth contraction factors
muscle can maintain tension by a phenomenon termed the latch
state. This is thought to be important in sphincter muscles where Examples Airway smooth muscle Small blood
vessels
tension development must occur for long periods of time that
 CHAPTER 11 Smooth Muscle Structure and Function
Autonomic
nerve fiber
Sheet of
cells
Varicosities
FIGURE 11–2 Pattern of innervation of smooth muscle. Note that the nerve has multiple branches and varicosities on each of the branches.
Neurotransmitter is released at the varicosities and diffuses to the smooth muscle. Binding to the appropriate receptor will result in the neural
modulation of smooth muscle contraction. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
consists of cells that act as independent units—they are
innervated and can respond strongly to nerves of the sympa-
thetic and parasympathetic nervous systems. These types
of cells have very few gap junctions and therefore activation
of one cell does not necessarily lead to activation of cells in
juxtaposition to that activated cell. Other cells receiving the
same neural input will respond but only because the nerve is
releasing neurotransmitters from varicosities (Figure 11–2)
that release neurotransmitter near the muscle cell membrane.
Note that the same nerve will release neurotransmitter onto
many cells. Released neurotransmitter diffuses to the muscle
cell membrane and binds to appropriate receptors—there is
no specialized motor end plate on the muscle cell membrane,
just the presence of receptors. Both sympathetic and para-
sympathetic nerves can innervate the same smooth muscle
causing opposite effects on the cells as described below.
Unitary muscle, on the other hand, has many gap junctions
(as described in Chapter 3), so activation of one cell leads
rapidly to activation of cells juxtaposed to that cell. Thus, the
cells contract as a “unit.” These cells generally have little
innervation and exhibit a response to stretch, that is, cells
will increase tension in response to stretch, a property that
will be discussed in more detail in Sections 5 and 8. Table 11–1
presents a list of the properties of multiunit versus unitary
smooth muscle.
METHODS OF STIMULATION
Smooth muscle can be stimulated to contract or alter the
strength of a contraction by many different stimuli—action
potentials, changes in membrane potential that do not achieve
101
Varicosity
Mitochondrion
Synaptic
vesicles
an action potential, activation of receptors that initiate an
intracellular signaling network, activation of receptors that
are ion channels, and stretch, by itself. The exact stimuli
that alter smooth muscle contraction may differ in various
organs and even in two different types of muscle—unitary and
multiunit. In Figure 11–3, the effects of sympathetic and para-
sympathetic nerve stimulation on the membrane potential of
visceral smooth muscle are shown. Acetylcholine, the neu-
rotransmitter of the parasympathetic nervous system, gener-
ally causes the membrane potential to become less negative
and for spikes (action potentials) to occur—generating more
contractile activity. Sympathetic stimulation generally results
in the opposite—more negative membrane potential and
resultant decreased contractile activity and relaxation. Note
that stretch is also conducive to more action potential spikes,
and, subsequently, more contraction; food in the gut induces
increased contractile activity of the gut.
Many other stimuli lead to activation or relaxation of smooth
muscle. Figure 11–4 shows a smooth muscle cell and some of
the many mechanisms involved in eliciting contraction and
relaxation. Calcium can be provided by both influx of calcium
from the extracellular fluid through the L-type voltage-gated
calcium channels on the SL and release of calcium from the
sarcoplasmic reticulum (SR). The SR, which is less abundant
than in skeletal and cardiac muscle, can, nevertheless, release
calcium through activation of IP3 receptors. The IP3 receptors
are channels similar to the ryanodine receptors in the other
two muscle types and when the channel is open, calcium dif-
fuses down its concentration gradient into the cytosol to initi-
ate contraction. IP3 is a product of receptor-mediated activation
of phospholipase C (PLC) that hydrolyzes phosphatidylinos-
itol (PIP2). Diacyglycerol, the other product, activates protein
102 SECTION III Muscle Physiology

0 Acetylcholine, parasympathetic bind acetylcholine, and specific endothelin receptors that

stimulation, cold, stretch bind endothelin 1.
Influx of calcium through the voltage-gated calcium chan-
nels can be modulated by the resting membrane potential
that is primarily a function of K+ movement. Opening of
mV

K channels (by calcium) or closing of K channels (by ATP)

Membrane potential
−50
Epinephrine, sympathetic
stimulation
FIGURE 11–3 Examples of stimuli such as the SNS and the
PNS on smooth muscle membrane potential and action potential
generation. At more negative membrane potentials, as with
epinephrine or SNS stimulation, there are no action potentials and
muscle becomes more relaxed. At less negative action potentials, action
potentials occur and the muscle is more likely to have more tension or
tone. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H:
Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
kinase C. There are several different receptors on smooth
muscle that are linked to the PLC pathway resulting in stronger
contractions. Some of these include alpha-adrenergic recep-
tors that bind norepinephrine, muscarinic receptors that
alters the membrane potential. Hyperpolarization of the cell
(by opening the K channels) results in closure of the voltage-
gated calcium channels and relaxation or dilation if the cell is
a vascular smooth muscle cell. Depolarization of the cell (not
necessarily enough to generate an action potential) causes
opening of the voltage-gated calcium channels leading to
contraction (constriction of smooth muscle if the cell is vas-
cular smooth muscle). Notice also the presence of storage-
operated channels (SOC) on the SL. These channels allow
entry of calcium into smooth muscle in order to replenish SR
calcium stores. The mechanisms sensing decreased SR cal-
cium levels and the communication between the SR and the
SL are not clear but do seem to be effective in maintaining
adequate calcium stores in the smooth muscle cell. Finally,
receptor-operated channels exist on smooth muscle cells.
These receptors are literally channels that allow ion move-
ments. Purinergic channels represent this type of control—
ATP, which is a purine, opens this type of channel allowing
calcium entry into the cell and promoting contraction. In the
renal vascular smooth muscle, adenosine, which is normally
considered a vasodilator, binds to ROC allowing calcium
entry and contraction.
Not shown in Figure 11–4 is the modulation of smooth
muscle contraction that occurs by products from the other
cells associated with smooth muscle. For example, endothelial

Smooth muscle cell

Receptor

PLC

IP3 SR
PIP2 IP3
receptor Ca2+
+ release
DAG ROC
PKC SOC
~P proteins

Ca2+
(opens K
ATP channel)
Voltage gated
(closes K
calcium channel
channel) Channels
FIGURE 11–4 A smooth muscle cell with some of the many influences on contraction. Contractions can be initiated by action potentials,
by receptors that couple to phospholipase C, and by alterations in the open state of the voltage-gated calcium channels that are sensitive to the
membrane potential as controlled primarily by potassium movements across the membrane. SOC are the storage-operated channels that open
when SR calcium stores are low. ROC are receptor-operated channels—primarily responsive to agents such as adenosine and ATP. Calcium release
from the SR or calcium entry through voltage-gated calcium channel leads to the calmodulin binding and ultimately contraction.
 CHAPTER 11 Smooth Muscle Structure and Function
cells that line the blood vessels release several factors that
modulate vascular smooth muscle force development. As
stated above, acetylcholine, which activates muscarinic recep-
tors on vascular smooth muscle, can cause contraction by a
PLC mechanism. However, acetylcholine binding to muscar-
inic receptors on endothelial cells causes the production of
nitric oxide that diffuses to the vascular smooth muscle cell,
and activates guanylate cyclase to produce cGMP. The cGMP
activates protein kinase G that phosphorylates MLCK and
decreases contraction. Thus, the site at which acetylcholine
binds to the receptor (smooth muscle vs. endothelial cell)
determines the response. In the body, due to the anatomy of
the endothelial cells and the vascular smooth muscle cells and
the presence of acetylcholine esterase, acetylcholine from the
parasympathetic varicosities would predominantly release
acetylcholine that would bind to muscarinic receptors on
endothelial cells resulting in relaxation or dilation.
Other biological responses of smooth muscle to stimulation
are also site specific. For example, visceral smooth muscle in
the gastrointestinal tract becomes quiescent with sympathetic
nerve stimulation (Figure 11–3), whereas vascular smooth
muscle in the blood vessels of the gastrointestinal tract devel-
ops stronger contraction when stimulated by sympathetic
nerves. This site-specific response is due to the type of recep-
tors on the cells—beta-adrenergic receptors cause relaxation
in response to sympathetic stimulation in visceral smooth
muscle, whereas alpha-adrenergic receptors cause stronger
contraction in response to sympathetic stimulation in vascular
smooth muscle.
In summary, smooth muscle is the most diverse muscle in
the body. Its functions are dependent to a great extent on the
tissue in which they are found. Therefore, more specific
detail about smooth muscle function will be presented in
Sections 5, 7–9.
CHAPTER SUMMARY
■ In smooth muscle, the calcium-binding protein is calmodulin
rather than troponin as in skeletal and cardiac muscle.
■ The calcium–calmodulin complex activates MLCK.
■ Contraction is dependent on MLCK phosphorylating the
myosin light chain allowing for binding of the myosin to
the actin.
■ MLC phosphatase removes the phosphate from the myosin
light chain resulting in decreased strength of contraction.
■ Many different stimuli can induce contraction or increase the
strength of contraction of smooth muscle—voltage-gated
calcium channels, voltage-gated potassium channels, receptor-
operated channels, SOC, and receptor-mediated pharmacom-
echanical coupling. Even stretch can activate smooth muscle
contraction.
103
■ The myosin ATPase activity is lowest in smooth muscle,
resulting in the slowest contractions or changes in tension
development.
■ Multiunit smooth muscle cells are innervated, have few gap
junctions, and contract individually.
■ Unitary smooth muscle cells can respond to stretch and have
gap junctions that enable them to contract as a “unit.”
STUDY QUESTIONS
1. Which of the following statements about smooth muscle is true?
A) Phosphorylation of myosin light chains is required for
contraction.
B) Inhibition of myosin light chain kinase increases strength
of contraction.
C) Inhibition of myosin light chain phosphatase decreases
contraction.
D) Stimulation of the smooth muscle cells by nitric oxide
will increase contraction.
2. Which of the following statements about smooth muscle
contraction is correct?
A) Acetylcholine release at the neuromuscular junction
initiates an action potential in the postsynaptic membrane.
B) Acetylcholine binds to a nicotinic receptor on the
postsynaptic membrane.
C) Depolarization of the muscle fiber is not essential for
smooth muscle contraction.
D) Norepinephrine activating adrenergic receptors always
causes increased strength of contraction in all smooth
muscle cells.
3. Which of the following statements about muscle contraction is
true for smooth muscle?
A) All cells have pacemaker potential.
B) The strength of contraction is correlated with the degree
of phosphorylation of the myosin light chains.
C) The strength of contraction is increased by recruiting
more motor units.
D) All muscle cells have a high myosin ATPase velocity and
therefore a rapid contraction.
4. Which of the following statements about muscle contraction is
true for smooth muscle?
A) Strength of contraction cannot be altered physiologically by
changing the resting cell length from 25% up to 100% of the
maximum length.
B) Strength of contraction is altered physiologically by altering
the frequency of motor neuron firing.
C) Strength of contraction can be changed by changing the
balance of the myosin light chain kinase and phosphatase
activities.
D) Muscle contraction occurs as contractions followed by
complete relaxation of the cell.
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 SECTION IV CNS/NEURAL PHYSIOLOGY
Introduction to the
Nervous System
Susan M. Barman
O B J E C T I V E S
■ Name the various types of glia and their functions.
■ Name the parts of a neuron and their functions.
■ Describe the role of myelin in nerve conduction.
■ List the types of nerve fibers found in the mammalian nervous system.
■ Describe the general organization of thalamic, cortical, and reticular
formation neurons.
■ Describe the function of neurotrophins.
■ Compare peripheral and central nerve regeneration.
INTRODUCTION
The nervous system can be divided into two parts: the central
nervous system (CNS), which is composed of the brain and spi-
nal cord, and the peripheral nervous system, which is com-
posed of nerves that connect the CNS to muscles, glands, and
sense organs. Neurons are the basic building blocks of the ner-
vous system. The human brain contains about 1011 (100 billion)
neurons. It also contains 10–50 times this number of glial cells
or glia. The CNS is a complex organ; it has been calculated that
40% of the human genes participate, at least to a degree, in its
formation.
CELLULAR ELEMENTS IN THE CNS
GLIAL CELLS
The word glia is Greek for glue; for many years, glia were
thought to function merely as connective tissue. However,
Ch12_105-114.indd 105
12
C H A P T E R
these cells are now recognized for their role in communica-
tion within the CNS in partnership with neurons. Unlike neu-
rons, glial cells continue to undergo cell division in adulthood
and their ability to proliferate is particularly noticeable after
brain injury.
There are two major types of glia, microglia and macroglia.
Microglia are scavenger cells that resemble tissue macrophages
and remove debris resulting from injury, infection, and disease.
Microglia arise from macrophages outside of the CNS and are
physiologically and embryologically unrelated to other neural
cell types.
There are three types of macroglia: oligodendrocytes,
Schwann cells, and astrocytes (Figure 12–1). Oligodendro-
cytes and Schwann cells are involved in myelin formation
around axons in the CNS and peripheral nervous system,
respectively. Astrocytes, which are found throughout the
brain, are of two subtypes. Fibrous astrocytes, which con-
tain many intermediate filaments, are found primarily in
white matter. Protoplasmic astrocytes are found in gray
105
11/26/10 9:49:36 AM
106 SECTION IV CNS/Neural Physiology

A Oligodendrocyte B Schwann cell C Astrocyte

Oligodendrocyte Perineural
in white matter oligodendrocytes
Nodes of Ranvier Capillary

End-foot

Neuron
Layers
of myelin

Axons
Schwann End-foot Fibrous
cell astrocyte
Nucleus

Inner
tongue Axon
Neuron

FIGURE 12–1 Principal types of glial cells in the nervous system. A) Oligodendrocytes are small with relatively few processes. Those in
the white matter provide myelin, and those in the gray matter support neurons. B) Schwann cells provide myelin to the peripheral nervous
system. Each cell forms a segment of myelin sheath about 1 mm long; the sheath assumes its form as the inner tongue of the Schwann cell turns
around the axon several times, wrapping in concentric layers. Intervals between segments of myelin are the nodes of Ranvier. C) Astrocytes are
the most common glia in the CNS and are characterized by their starlike shape. They contact both capillaries and neurons and are thought to
have a nutritive function. They are also involved in forming the blood–brain barrier. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM
[editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

matter and have a granular cytoplasm. Both types of astro-
cytes send processes to blood vessels, where they induce
capillaries to form the tight junctions making up the
blood–brain barrier. The blood–brain barrier prevents the
diffusion of large or hydrophilic molecules (e.g., proteins)
into the cerebrospinal fluid and brain, while allowing
diffusion of small molecules. The astrocytes also send pro-
cesses that envelop synapses and the surface of nerve cells.
Protoplasmic astrocytes have a membrane potential that var-
ies with the external K+ concentration but do not generate
propagated potentials. They help maintain the appropriate
concentration of ions and neurotransmitters by taking up K+
and the neurotransmitters glutamate and γ-aminobutyrate
(GABA).
NEURONS
Neurons in the mammalian CNS come in many different
shapes and sizes. Most have the same parts as the typical spi-
nal motor neuron illustrated in Figure 12–2. The cell body
(soma) contains the nucleus and is the metabolic center of the
neuron. Dendrites extend outward from the cell body and
arborize extensively. Particularly in the cerebral and cerebel-
lar cortex, the dendrites have small knobby projections called
dendritic spines. A typical neuron has a long fibrous axon
that originates from a thickened area of the cell body, the
axon hillock. The first portion of the axon is called the initial
segment. The axon divides into presynaptic terminals, each
ending in a number of synaptic knobs that are also called ter-
minal buttons or boutons. They contain granules or vesicles
that store the synaptic transmitters secreted by the nerves.
Based on the number of processes that emanate from the cell
body, neurons can be classified as unipolar, bipolar, and mul-
tipolar (Figure 12–3).
The axons of many neurons are myelinated, that is, they
acquire a sheath of myelin, a protein–lipid complex that is
wrapped around the axon (Figure 12–2). In the peripheral
nervous system, myelin forms when a Schwann cell wraps its
membrane around an axon. This can occur up to 100 times,
resulting in many layers of myelin around an axon
(Figure 12–1). The myelin is then compacted when the ex-
tracellular portions of a membrane protein called protein
zero (P0) lock to the extracellular portions of P0 in the appos-
ing membrane. Various mutations in the gene for P0 cause
peripheral neuropathies. The myelin sheath envelops the
axon except at its ending and at the nodes of Ranvier, peri-
odic 1-μm constrictions that are about 1 mm apart (Figure
12–2). The insulating function of myelin is critical for salta-
tory conduction of action potentials (see Chapter 6). Some
neurons have axons that are unmyelinated, that is, they are
simply surrounded by Schwann cells without the wrapping
of the Schwann cell membrane that produces myelin around
the axon.
Within the CNS, the cells that form the myelin are oligoden-
drocytes (Figure 12–1). Unlike the Schwann cell, which forms
the myelin on a single neuron, oligodendrocytes emit multiple
processes that form myelin on many neighboring axons. In
 CHAPTER 12 Introduction to the Nervous System 107

Cell body
(soma)

Initial segment
of axon Node of Ranvier Schwann cell

Axon hillock
Nucleus Terminal buttons

Dendrites

FIGURE 12–2 Motor neuron with a myelinated axon. A motor neuron is comprised of a cell body (soma) with a nucleus, several processes
called dendrites, and a long fibrous axon that originates from the axon hillock. The first portion of the axon is called the initial segment. A myelin
sheath forms from Schwann cells and surrounds the axon except at its ending and at the nodes of Ranvier. Terminal buttons (boutons) are located at
the terminal endings. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

multiple sclerosis (MS), a crippling autoimmune disease,
patchy destruction of myelin occurs in the CNS. The loss of
myelin is associated with delayed or blocked conduction in the
demyelinated axons.
PERIPHERAL NERVOUS SYSTEM
The peripheral nervous system transmits information from
the CNS to the effector organs throughout the body. It
contains 12 pairs of cranial nerves and 31 pairs of spinal
nerves. The cranial nerves have rather well-defined sensory
and motor functions (Table 12–1). Many of these functions
are described individually in more detail in later chapters in
this section. Spinal nerves are named on the basis of the ver-
tebral level from which the nerve exits (cervical, thoracic,
lumbar, sacral, and coccygeal). These nerves include motor
and sensory fibers of muscles, skin, and glands throughout
the body.
NERVE FIBER TYPES AND FUNCTION
Axonal conduction velocity is the speed by which an action
potential travels along the axon. In general, there is a direct
relationship between the diameter of a given nerve fiber and
its speed of conduction. Nerve conduction tests are often used
by neurologists in the diagnosis of some diseases.
Axonal conduction velocity and other characteristics have
led to the classification of nerve fibers as shown in Table
12–2. Mammalian nerve fibers are divided into three major
groups (A, B, and C); the A group is further subdivided into
α, β, γ, and δ fibers. In Table 12–2, the various fiber types are
listed with their diameters, electrical characteristics, and
functions. Large axons are concerned primarily with propri-
oceptive sensation, somatic motor function, conscious touch,
and pressure, while smaller axons subserve pain and
temperature sensations and autonomic function. Dorsal root
C fibers conduct some impulses generated by touch and oth-
er cutaneous receptors in addition to impulses generated by
pain and temperature receptors. A numerical system (Ia, Ib,
II, III, IV) has also been used to classify sensory fibers. A
comparison of the number system and the letter system is
shown in Table 12–3.
In addition to variations in speed of conduction and fiber
diameter, the various classes of fibers in peripheral nerves
differ in their sensitivity to hypoxia and anesthetics (Table
12–4). This fact has clinical as well as physiological signifi-
cance. For example, local anesthetics depress transmission in
group C fibers before they affect group A touch fibers. Con-
versely, pressure on a nerve can cause loss of conduction in
large-diameter motor, touch, and pressure fibers while pain
sensation remains relatively intact. This is sometimes seen in
individuals who sleep with their arms under their heads for
long periods, causing compression of the nerves in the arms.
Because of the association of deep sleep with alcoholic in-
toxication, the syndrome is most common on weekends and
has acquired the interesting name Saturday night or Sunday
morning paralysis.
ORGANIZATION OF THE
THALAMUS, CEREBRAL CORTEX,
& RETICULAR FORMATION
The thalamus is a large collection of neuronal groups within
the diencephalon; it participates in sensory, motor, and limbic
functions that will be described in later chapters in this section.
Virtually all information that reaches the cerebral cortex is
first processed by the thalamus, leading to its being called the
“gateway” to the cortex.
108 SECTION IV CNS/Neural Physiology

A Unipolar cell B Bipolar cell C Pseudo-unipolar cell

Dendrites Peripheral axon

Dendrite to skin and
muscle

Cell body

Axon
Single bifurcated
Cell body process

Axon Central
axon
Cell body
Axon terminals
Invertebrate neuron Bipolar cell of retina Ganglion cell of dorsal root

D Three types of multipolar cells

Dendrites
Apical
dendrite
Cell body
Cell
body

Basal
dendrite
Axon
Dendrites Cell body

Axon
Axon

Motor neuron of Pyramidal cell of Purkinje cell of cerebellum

spinal cord hippocampus

FIGURE 12–3 Different types of neurons in the mammalian nervous system. A) Unipolar neurons have one process, with different
segments serving as receptive surfaces and releasing terminals. B) Bipolar neurons have two specialized processes: a dendrite that carries
information to the cell and an axon that transmits information from the cell. C) Some sensory neurons are in a subclass of bipolar cells called
pseudounipolar cells. As the cell develops, a single process splits into two, both of which function as axons—one going to skin or muscle and
another to the spinal cord. D) Multipolar cells have one axon and many dendrites. Examples include motor neurons, hippocampal pyramidal
cells with dendrites in the apex and base, and cerebellar Purkinje cells with an extensive dendritic tree in a single plane. (Adapted from Ramon Y Cajal:
Histology. 10th ed. Baltimore: Wood, 1933.)

The thalamus is divided into nuclei that project diffusely to
wide regions of the neocortex and nuclei that project to spe-
cific portions of the neocortex and limbic system. The nuclei
that project to wide regions of the neocortex are the midline
and intralaminar nuclei. The nuclei that project to specific
areas include the specific sensory relay nuclei and the nuclei
concerned with efferent control mechanisms. The specific
sensory relay nuclei include the medial and lateral geniculate
bodies, which relay auditory and visual impulses to the audi-
tory and visual cortices, and the ventral posterior lateral
(VPL) and ventral posteromedial, which relay somatosensory
information to the postcentral gyrus. The ventral anterior
and ventral lateral nuclei are concerned with motor function;
they receive input from the basal ganglia and cerebellum and
project to the motor cortex. The anterior nuclei receive affer-
ents from the mamillary bodies and project to the limbic cor-
tex (memory and emotion). Most thalamic neurons are excit-
atory and release glutamate. The thalamic reticular nucleus
neurons are inhibitory and release GABA; they modulate the
responses of other thalamic neurons to input coming from
the cortex.
The neocortex is arranged in six layers (Figure 12–4). The
most common neuronal type is the pyramidal cell with an
extensive vertical dendritic tree (Figure 12–5) that may ex-
tend to the cortical surface. Their cell bodies can be found in
all cortical layers except layer I. The axons of these cells give
off recurrent collaterals that turn back and synapse on the su-
perficial portions of the dendritic trees. Afferents from the
 CHAPTER 12 Introduction to the Nervous System 109

TABLE 12–1 Functions of cranial nerves.

Cranial Nerve Type Function

I. Olfactory Sensory Smell

II. Optic Sensory Vision

III. Occulomotor Motor Upward, downward, and medial eye movements; pupil diameter; lens shape

IV. Trochlear Motor Downward and lateral eye movement

V. Trigeminal Motor Chewing

Sensory Proprioception from skin and muscle of the face

VI. Abducens Motor Lateral eye movements

VII. Facial Motor Facial expression; salivary gland secretions

Sensory Sensation from skin of external ear canal; taste from anterior two thirds of the tongue

VIII. Vestibulocochlear Sensory Hearing; sense of motion

IX. Glossopharyngeal Motor Swallowing; parotid salivary gland secretions

Sensory Taste from posterior one third of the tongue; baroreceptor and chemoreceptors
X. Vagus Motor Skeletal muscles of larynx and pharynx; smooth muscle and glands in pharynx,
larynx, thorax, and abdomen
Sensory Receptors in thorax and abdomen; taste from posterior tongue and oral cavity

XI. Accessory Motor Skeletal muscles in the neck

XII. Hypoglossal Motor Skeletal muscle of tongue

specific nuclei of the thalamus terminate primarily in corti-
cal layer IV, and the nonspecific afferents are distributed to
layers I–IV.
Pyramidal neurons are the only projection neurons of the
cortex, and they are excitatory neurons that release glutamate.
The other cortical cell types are local circuit neurons
(interneurons) that are classified based on their shape, pattern
of projection, and neurotransmitter. Inhibitory interneurons
(basket cells and chandelier cells) release GABA. Basket cells
account for most inhibitory synapses on the pyramidal soma
and dendrites. Chandelier cells are a powerful source of inhi-
bition of pyramidal neurons because they terminate on the
initial segment of the pyramidal cell axon. Their terminal bou-
tons form short vertical rows that resemble candlesticks, thus
accounting for their name. Spiny stellate cells, excitatory
interneurons that release glutamate, are located primarily in

TABLE 12–2 Classification of mammalian nerve fibers.a

Fiber Conduction Spike Duration Absolute Refractory
Fiber Type Function Diameter (μm) Velocity (m/s) (milliseconds) Period (milliseconds)

α Proprioception; 12–20 70–120

somatic motor

β Touch, pressure 5–12 30–70 0.4–0.5 0.4–1

γ Motor to muscle spindles 3–6 15–30

δ Pain, cold, touch 2–5 12–30

B Preganglionic autonomic <3 3–15 1.2 1.2

Dorsal root Pain, temperature, some 0.4–1.2 0.5–2 2 2

mechanoreception

Sympathetic Postganglionic sympathetic 0.3–1.3 0.7–2.3 2 2

a
A and B fibers are myelinated; C fibers are unmyelinated.
110 SECTION IV CNS/Neural Physiology

TABLE 12–3 Numerical classification sometimes Pial surface Golgi stain Nissl stain Weigert stain
used for sensory fibers. Molecular
I layer
Number Origin Fiber Type
External
II granule
Ia Muscle spindle, annulospiral ending Aα cell layer

Ib Golgi tendon organ Aα

II Muscle spindle, flower-spray ending; Aβ External

touch, pressure III pyramidal
cell layer
III Pain and cold receptors; some Aδ
touch receptors

IV Pain, temperature, and Dorsal root C Internal

other receptors IV granule
cell layer

Internal
V pyramidal
cell layer

layer IV and are a major recipient of sensory information aris-

ing from the thalamus.
In addition to being organized into layers, the cortex is also
organized into columns. Neurons within a column have simi-
VI Multiform
lar response properties, suggesting they comprise a local layer
processing network (e.g., orientation and ocular dominance
columns in the visual cortex, as described in Chapter 15).
The reticular formation is a complex neural network in the
central core of the medulla and midbrain. It is made up of
White matter
various neural clusters and ascending and descending fibers. It
contains the cell bodies and fibers of many of the serotonergic,
noradrenergic, adrenergic, and cholinergic systems. Some of
the descending fibers in it inhibit transmission in sensory and FIGURE 12–4 Structure of the cerebral cortex. The cortical
motor pathways in the spinal cord; various reticular areas and layers are indicated by the numbers. Golgi stain shows neuronal cell
the pathways from them are concerned with spasticity (in- bodies and dendrites, Nissl stain shows cell bodies, and Weigert
myelin sheath stain shows myelinated nerve fibers. (Modified with
creased resistance to passive stretch of a muscle) and adjust-
permission from Ranson SW, Clark SL: The Anatomy of the Nervous System, 10th ed.
ment of stretch reflexes.
Saunders, 1959.)
The reticular activating system (RAS) is a complex
polysynaptic pathway arising from the brain stem reticular
formation with projections to the intralaminar and reticular
nuclei of the thalamus that, in turn, project diffusely and non- by different sensory stimuli. The system is therefore nonspe-
specifically to wide regions of the cortex (Figure 12–6). cific, whereas the classic sensory pathways are specific in that
Collaterals funnel into it not only from the long ascending the fibers in them are activated by only one type of sensory
sensory tracts, but also from the trigeminal, auditory, visual, stimulation. The RAS is concerned with consciousness and
and olfactory systems. The complexity of the neural network sleep (see Chapter 20).
and the degree of convergence in it abolish modality specific-
ity, and most reticular neurons are activated with equal facility
NEUROTROPHINS: TROPHIC
TABLE 12–4 Relative susceptibility of mammalian A, SUPPORT OF NEURONS
B, and C nerve fibers to conduction block produced by Proteins necessary for survival and growth of neurons are
various agents. called neurotrophins. Many are products of the muscles or
other structures that the neurons innervate, but others are
Most Least produced by astrocytes. These proteins bind to receptors at the
Susceptibility To Susceptible Intermediate Susceptible
endings of a neuron. They are internalized and then transport-
Hypoxia B A C ed by retrograde transport to the neuronal cell body, where
Pressure A B C they foster the production of proteins associated with neu-
ronal development, growth, and survival. Other neurotrophins
Local anesthetics C B A
are produced in neurons and transported in an anterograde

B maintenance of cholinergic neurons in the basal forebrain
C
A
D
B
Axon
FIGURE 12–5 Neocortical pyramidal cell, showing the
distribution of neurons that terminate on it. A) Nonspecific
afferents from the reticular formation and the thalamus; B) recurrent
collaterals of pyramidal cell axons; C) commissural fibers from mirror
image sites in the contralateral hemisphere; D) specific afferents from
thalamic sensory relay nuclei. (Modified with permission from Chow KL,
Leiman AL: The structural and functional organization of the neocortex. Neurosci
Res Program Bull 1970;8(2):157–220.)
fashion to the nerve ending, where they maintain the integrity
of the postsynaptic neuron.
The first neurotrophin to be characterized was nerve growth
factor (NGF), a protein that is necessary for the growth and
maintenance of sympathetic neurons and some sensory
Cortex
Intralaminar nuclei
of thalamus
Midbrain reticular formation
FIGURE 12–6 Diagram showing the ascending reticular
system in the human midbrain, its projections to the intralaminar
nuclei of the thalamus, and the output from the intralaminar
nuclei to many parts of the cerebral cortex. Activation of these
areas is shown by PET scans when subjects shift from a relaxed awake
state to an attention-demanding task. (Reproduced with permission from
Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology,
23rd ed. McGraw-Hill Medical, 2009.)
CHAPTER 12 Introduction to the Nervous System 111
neurons. It is found in many different tissues. NGF is picked
up by neurons and transported in retrograde fashion from the
endings of the neurons to their cell bodies. It is also present in
the brain and appears to be responsible for the growth and
and striatum.
AXONAL DEGENERATION &
REGENERATION
When a motor nerve to skeletal muscle is cut and allowed to
degenerate, the muscle will become extremely sensitive to ace-
tylcholine, the transmitter normally released at the nerve end-
ing. This denervation supersensitivity (or hypersensitivity)
of the postsynaptic structure to the transmitter previously
secreted by the axon endings is largely due to the synthesis or
activation of more receptors. This and other reactions trig-
gered by damage to an axon are summarized in Figure 12–7.
Orthograde degeneration (Wallerian degeneration) and ret-
rograde degeneration of the axon stump to the nearest collat-
eral (sustaining collateral) occur commonly when a nerve is
cut. Also, a series of changes occur in the cell body including a
decrease in Nissl substance (chromatolysis).
Peripheral nerve damage is often reversible. Although the
axon will degenerate distal to the damage, connective elements
of the distal stump often survive. Axonal sprouting occurs
Axon branch Receptor
(sustaining collateral)
Retrograde Receptor
degeneration hypersensitive
Site of injury
X
Retrograde Regenerative Orthograde
reaction: sprouting (wallerian)
chromatolysis degeneration
FIGURE 12–7 Summary of changes occurring in a neuron and
the structure it innervates when its axon is crushed or cut at the
point marked X. Hypersensitivity of the postsynaptic structure to the
transmitter previously secreted by the axon occurs largely due to the
synthesis or activation of more receptors. There is both orthograde
(Wallerian) degeneration from the point of damage to the terminal and
retrograde degeneration of the axon stump to the nearest collateral
(sustaining collateral). Changes also occur in the cell body, including
chromatolysis. The nerve starts to regrow, with multiple small branches
projecting along the path the axon previously followed (regenerative
sprouting). (Reproduced with permission from Barrett KE, Barman SM, Boitano S,
Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
112 SECTION IV CNS/Neural Physiology
from the proximal stump, growing toward the nerve ending.
This results from growth-promoting factors secreted by
Schwann cells that attract axons toward the distal stump.
Adhesion molecules of the immunoglobulin superfamily
promote axon growth along cell membranes and extracellular
matrices. Inhibitory molecules in the perineurium, the connec-
tive tissue sheath that covers a nerve bundle, assure that the re-
generating axons grow in a correct trajectory. Denervated distal
stumps are able to increase the production of neurotrophins
that promote growth. Once the regenerated axon reaches its tar-
get, a new functional connection is formed. Regeneration allows
for considerable, although not full, recovery. For example, fine
motor control may be permanently impaired because some mo-
tor neurons are guided to an inappropriate muscle fiber.
Recovery of peripheral nerves from damage far surpasses
that of CNS pathways. The proximal stump of a damaged axon
in the CNS will form short sprouts, but distant stump recovery
is rare, and the damaged axons are unlikely to form new
synapses. This is because CNS neurons do not have the growth-
promoting chemicals needed for regeneration. In fact, CNS
myelin is a potent inhibitor of axonal growth. Also, follow-
ing CNS injury, several events—astrocytic proliferation,
activation of microglia, scar formation, inflammation, and
invasion of immune cells—provide an inappropriate environ-
ment for regeneration. Thus, treatment of brain and spinal
cord injuries often focuses on rehabilitation rather than re-
versing the nerve damage. Researchers are trying to identify
ways to initiate and maintain axonal growth, to direct regener-
ating axons to reconnect with their target neurons, and to re-
constitute original neuronal circuitry.
CLINICAL CORRELATION
A 27-year-old school teacher awakens one morning with
rather severe pain in her left eye and blurry vision (optic
neuritis). She is out of the country on a summer vacation
and decides to wait until she returns home to see her phy-
sician. Over the next couple of days, the pain and visual
loss worsen. But by the time she returns home 10 days lat-
er, the symptoms have abated enough that she decides it is
not necessary to see her physician. About 8 months later
she develops a sudden onset of weakness in her right leg
after a difficult day in the classroom. She decides to relax in
a hot bath, but this exacerbates the symptoms. Her prob-
lem rapidly progresses to the point where she cannot walk.
Three days later, she is seen by her physician and also re-
ports the incident that occurred while on her summer va-
cation. A brain magnetic resonance imaging (MRI) and a
visual evoked potential test are ordered. About 1 week
later, she notes significant improvement but she is notified
by her physician that the MRI showed multiple periven-
tricular white matter lesions, and the visual evoked poten-
tial test showed a delayed response (slowed conduction).
The woman is diagnosed with multiple sclerosis (MS), an
autoimmune disease that affects over 3 million people
worldwide, usually striking people between the ages of 20
and 50 and affecting women about twice as often as men. In
MS, antibodies and white blood cells in the immune system
attack myelin, causing inflammation and injury to the sheath
and eventually the nerves that it surrounds. Loss of myelin
leads to leakage of K+ through voltage-gated channels, hy-
perpolarization, and failure to conduct action potentials.
Deficits may include muscle weakness, fatigue, diminished
coordination, slurred speech, blurred or hazy vision, blad-
der dysfunction, and sensory disturbances. Symptoms are
often exacerbated by increased body temperature or ambi-
ent temperature. In most cases, transient episodes appear
suddenly, last a few weeks or months, and then gradually
disappear. Subsequent episodes can appear years later, and
eventually full recovery does not occur. Others have a pro-
gressive form of the disease in which there are no periods of
remission. Diagnoses of MS is generally delayed until there
are multiple episodes with deficits separated in time and
space. Nerve conduction tests can detect slowed conduction
in motor and sensory pathways. Cerebral spinal fluid analy-
sis can detect the presence of oligoclonal bands indicative
of an abnormal immune reaction against myelin. The most
definitive assessment is MRI to detect multiple scarred (scle-
rotic) areas in the brain. Although there is no cure for MS,
some drugs such as beta-interferon and corticosteroids
that suppress the immune response can reduce the severity
and slow the progression of the disease.
CHAPTER SUMMARY
■ Glia are abundant in the CNS. Microglia are scavenger cells.
Macroglia include oligodendrocytes, Schwann cells, and
astrocytes. The first two are involved in myelin formation.
Astrocytes help maintain the appropriate concentration of ions
and neurotransmitters in the CNS.
■ Neurons are composed of a cell body (soma) that is the
metabolic center of the neuron, dendrites that extend outward
from the cell body and arborize extensively, and a long fibrous
axon that originates from a somewhat thickened area of the
cell body, the axon hillock.
■ Axons of many neurons acquire a sheath of myelin, a protein–
lipid complex that is wrapped around the axon. Myelin is
an effective insulator, and depolarization in myelinated axons
jumps from one node of Ranvier to the next (saltatory
conduction).
■ Nerve fibers are divided into different categories based on their
axonal diameter, conduction velocity, and function.
■ Thalamic nuclei that project to wide regions of the neocortex
are the midline and intralaminar nuclei and those that project
to specific areas include the specific sensory relay nuclei.
■ The neocortex is arranged in six layers; the most common
neuronal type is the pyramidal cell whose cell bodies are
located in all layers except layer I.

■ Neurotrophins are produced by astrocytes and transported by
retrograde transport to the neuronal cell body, where they
foster the production of proteins associated with neuronal
development, growth, and survival.
■ After a peripheral nerve is damaged, Schwann cells secrete a
growth-promoting factor that attracts the proximal stump of
the axon toward the distal stump, allowing for regeneration.
In the CNS, neural regeneration is impaired by factors such
as astrocytic proliferation, scar formation, and inflammation.
STUDY QUESTIONS
1. The distance from one stimulating electrode to recording
electrode is 4.5 cm. When the axon is stimulated, the latent
period is 1.5 milliseconds. What is the conduction velocity
of the axon?
A) 15 m/s
B) 30 m/s
C) 40 m/s
D) 67.5 m/s
E) This cannot be determined from the information given.
2. Which of the following has the slowest conduction velocity?
A) Aα fibers
B) Aβ fibers
C) Aγ fibers
D) B fibers
E) C fibers
CHAPTER 12 Introduction to the Nervous System 113
3. A man falls into a deep sleep with one arm under his head.
This arm is paralyzed when he awakens, but it tingles, and pain
sensation in it is still intact. The reason for the loss of motor
function without loss of pain sensation is that in the nerves to
his arm
A) A fibers are more susceptible to hypoxia than B fibers.
B) A fibers are more sensitive to pressure than C fibers.
C) C fibers are more sensitive to pressure than A fibers.
D) motor nerves are more affected by sleep than sensory
nerves.
E) sensory nerves are nearer the bone than motor nerves and
hence are less affected by pressure.
4. The thalamus
A) is organized into six layers.
B) does not relay auditory or visual information to
the neocortex.
C) is a component of the reticular activating system.
D) contains neurons that project diffusely throughout
the neocortex.
E) is a component of the brain stem.
5. Which of the following is not true about the neocortex?
A) It is organized into six layers.
B) The most common neuronal type is the pyramidal cell.
C) It receives direct input from the thalamus.
D) It contains a group of inhibitory interneurons called
basket cells.
E) It contains a group of excitatory interneurons called
chandelier cells.
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General Sensory
Systems: Touch, Pain,
and Temperature
Susan M. Barman
O B J E C T I V E S
■ List common senses and their receptors.
■ Explain the terms hyperalgesia and allodynia.
■ Explain sensory coding.
■ Compare the pathway that mediates sensory input from touch,
proprioceptive, and vibratory senses to that mediating information
from pain and thermoreceptors.
■ Describe mechanisms to modulate transmission in pain pathways.
INTRODUCTION
Information about the internal and external environment acti-
vates the central nervous system (CNS) via sensory receptors.
These receptors are transducers that convert various forms of
energy into action potentials in neurons. The characteristics of
some of these receptors and the way they generate impulses in
afferent neurons were considered in Chapter 5. Cutaneous
receptors for touch and pressure are mechanoreceptors.
Potentially harmful stimuli such as pain, extreme heat, and
extreme cold are mediated by nociceptors. Chemoreceptors
are stimulated by a change in the chemical composition of the
environment in which they are located. These include recep-
tors for taste and smell as well as visceral receptors such as
those sensitive to changes in the plasma level of O2, pH, and
osmolality. Photoreceptors are those in the rods and cones in
the retina that respond to light. This chapter will focus primar-
ily on cutaneous receptors and transmission in somatosensory
pathways mediating touch and proprioception (dorsal
column–medial lemniscus pathway) and pain and tempera-
ture (spinothalamic tract).
SENSORY RECEPTORS
CUTANEOUS MECHANORECEPTORS
Sensory receptors can be specialized dendritic endings of
afferent nerve fibers and are often associated with nonneural
Ch13_115-124.indd 115
13
C H A P T E R
cells that surround them, forming a sense organ. Touch and
pressure are sensed by four types of mechanoreceptors
(Figure 13–1). Meissner’s corpuscles are dendrites encapsu-
lated in connective tissue and respond to changes in texture
and slow vibrations. Merkel cells are expanded dendritic end-
ings, and they respond to sustained pressure and touch.
Ruffini corpuscles are enlarged dendritic endings with elon-
gated capsules, and they respond to sustained pressure.
Pacinian corpuscles consist of unmyelinated dendritic end-
ings of a sensory nerve fiber, encapsulated by concentric
lamellae of connective tissue that give the organ the appear-
ance of a cocktail onion. These receptors respond to deep pres-
sure and fast vibration.
NOCICEPTORS AND
THERMORECEPTORS
Pain and temperature sensations arise from unmyelinated den-
drites of sensory neurons located around hair follicles through-
out the glabrous and hairy skin, as well as in deep tissue.
Impulses from nociceptors (pain) are transmitted via two fiber
types. One system comprises thinly myelinated Aδ fibers that
conduct at rates of 12–30 m/s. The other is unmyelinated
C fibers that conduct at low rates of 0.5–2 m/s. Thermorecep-
tors also span the following two fiber types: cold receptors are
on dendritic endings of Aδ fibers and C fibers, whereas warm
receptors are on C fibers. Mechanical nociceptors respond to
strong pressure. Thermal nociceptors are activated by skin
115
11/26/10 9:49:50 AM
116 SECTION IV CNS/Neural Physiology

A Modality Touch

Receptors

Meissner’s Merkel Pacinian Ruffini

corpuscle cells corpuscle endings

B Location

Receptive
field

C Intensity and time course

Neural
spike train

Stimulus

FIGURE 13–1 Sensory systems encode four elementary attributes of stimuli: modality, location (receptive field), intensity, and
duration (timing). A) The human hand has four types of mechanoreceptors; their combined activation produces the sensation of contact with
an object. Selective activation of Merkel cells and Ruffini endings causes sensation of steady pressure; selective activation of Meissner’s and
Pacinian corpuscles causes tingling and vibratory sensation. B) Location of a stimulus is encoded by spatial distribution of the population of
receptors activated. A receptor fires only when the skin close to its sensory terminals is touched. These receptive fields of mechanoreceptors
(shown as red areas on fingertips) differ in size and response to touch. Merkel cells and Meissner’s corpuscles provide the most precise
localization as they have the smallest receptive fields and are most sensitive to pressure applied by a small probe. C) Stimulus intensity is
signaled by firing rates of individual receptors; duration of stimulus is signaled by time course of firing. The spike trains indicate action potentials
elicited by pressure from a small probe at the center of each receptive field. Meissner’s and Pacinian corpuscles adapt rapidly; the others adapt
slowly. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

temperatures above 45°C or by severe cold. Chemically sensi-
tive nociceptors respond to various agents such as bradykinin,
histamine, high acidity, and environmental irritants. Polymodal
nociceptors respond to combinations of these stimuli.
Pain is defined by the International Association for the
Study of Pain (IASP) as “an unpleasant sensory and emo-
tional experience associated with actual or potential tissue
damage….” This is different from nociception, which the
IASP defines as the unconscious activity induced by a harm-
ful stimulus applied to sense receptors.
Pain can be classified as physiological (or acute) pain and
pathological (or chronic) pain, which includes inflamma-
tory pain and neuropathic pain. Acute pain typically has a
sudden onset and recedes during the healing process. It can be
considered “good pain” because it serves an important protec-
tive mechanism. The withdrawal reflex is an example of this
protective role of pain (see Chapter 14). Chronic pain can be
considered “bad pain” because it persists long after recovery
from an injury and is often refractory to common analgesic
agents, including nonsteroidal anti-inflammatory drugs
(NSAIDs) and opiates. It can result from nerve injury includ-
ing diabetic neuropathy, toxin-induced nerve damage, and
ischemia.
Pain is often accompanied by hyperalgesia, an exaggerated
response to a noxious stimulus, and allodynia, a sensation of
pain in response to an innocuous stimulus. An example of the
latter is the painful sensation from a warm shower when the
skin is damaged by sunburn.
Hyperalgesia and allodynia signify increased sensitivity of
nociceptive afferent fibers. Figure 13–2 shows how chemicals
released at the site of injury can further activate nociceptors
leading to inflammatory pain. Injured cells release chemicals
such as K+ that depolarize nerve terminals, making nocicep-
tors more responsive. Injured cells also release bradykinin and
substance P, which can further sensitize nociceptive termi-
nals. Histamine is released from mast cells, serotonin (5-HT)
 CHAPTER 13 General Sensory Systems: Touch, Pain, and Temperature 117

Mast cell

CGRP
Substance P

Histamine Dorsal root

Bradykinin ganglion neuron
Lesion 5-HT
Prostaglandin
K+
CGRP
Substance P

Blood
vessel
Spinal cord

FIGURE 13–2 In response to tissue injury, chemical mediators can sensitize and activate nociceptors. These factors contribute to
hyperalgesia and allodynia. Tissue injury releases bradykinin and prostaglandins that sensitize or activate nociceptors, which in turn releases
substance P and calcitonin gene-related peptide (CGRP). Substance P acts on mast cells to cause degranulation and release histamine, which
activates nociceptors. It causes plasma extravasation and CGRP dilates blood vessels; the resulting edema causes additional release of
bradykinin. Serotonin (5-HT) is released from platelets and activates nociceptors. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM
[editors]: Principles of Neural Science. McGraw-Hill, 2000.)

from platelets, calcitonin gene-related peptide (CGRP) from
nerve terminals, and prostaglandins from cell membranes, all
contributing to the inflammatory process and activating
or sensitizing the nociceptors. Some released substances act by
releasing another one (e.g., bradykinin activates both Aδ and
C fibers and increases synthesis and release of prostaglandins).
Prostaglandin E2 (a cyclooxygenase metabolite of arachidonic
acid) is released from damaged cells and produces hyperalge-
sia. This is why aspirin and other NSAIDs (inhibitors of
cyclooxygenase) alleviate pain.
SENSORY RECEPTORS IN
SKELETAL MUSCLES & JOINTS
Skeletal muscles contain receptors called muscle spindles and
Golgi tendon organs that are important for proprioception.
They play major roles in motor control and are described in
Chapter 14. Muscles also contain nociceptors that respond to
pressure and the release of metabolites during ischemia. Limb
joints also contain mechanoreceptors (Pacinian and Ruffini
corpuscles) and nociceptors.
SENSORY CODING
Converting a receptor stimulus to a recognizable sensation is
termed sensory coding. All sensory systems code for four
elementary attributes of a stimulus: modality, location, inten-
sity, and duration. These attributes of sensory coding are
shown for the modality of touch in Figure 13–1.
Modality is the type of energy transmitted by the stimu-
lus. The particular form of energy to which a receptor is
most sensitive is called its adequate stimulus. Location is
the site on the body or space where the stimulus originated.
A sensory unit is a single sensory axon and all its peripheral
branches; the receptive field of a sensory unit is the spatial
distribution from which a stimulus produces a response in
that unit (Figure 13–1). One of the most important mecha-
nisms that enable localization of a stimulus site is lateral
inhibition. Activity arising from sensory neurons whose
receptors are at the peripheral edge of the stimulus is inhib-
ited compared to that from the sensory neurons at the cen-
ter of the stimulus. Thus, lateral inhibition enhances the
contrast between the center and periphery of a stimulated
area and increases the ability of the brain to localize a sen-
sory input.
Lateral inhibition underlies the neurological assessment
called the two-point discrimination test, which is used to test
the integrity of the dorsal column (medial lemniscus) system,
the central pathway for touch and proprioception. In this pro-
cedure, the two points on a pair of calipers are simultaneously
positioned on the skin and one determines the minimum dis-
tance between the two caliper points that can be perceived as
separate points of stimulation. This is called the two-point
discrimination threshold and is a measure of tactile acuity. If
the distance is very small, each caliper point is touching the
receptive field of only one sensory neuron. If the distance
between stimulation points is less than this threshold, only
one point of stimulation can be felt. The magnitude of two-
point discrimination thresholds varies from place to place on
the body and is smallest where touch receptors are most abun-
118 SECTION IV CNS/Neural Physiology
dant. Stimulus points on the back, for instance, must be sepa-
rated by at least 65 mm before they can be distinguished as
separate, whereas on the fingertips, two stimuli are recognized
if they are separated by as little as 2 mm.
Intensity is signaled by the response amplitude or fre-
quency of action potential generation. Duration refers to the
time from start to end of a response in the receptor. If a stim-
ulus of constant strength is applied to a receptor, the fre-
quency of the action potentials in its sensory nerve declines
over time. This phenomenon is known as adaptation or
desensitization. The degree to which adaptation occurs var-
ies from one sense to another. Receptors can be classified
into rapidly adapting (phasic) receptors and slowly adapt-
ing (tonic) receptors. This is illustrated for different types of
touch receptors in Figure 13–1.
SOMATOSENSORY PATHWAYS
DORSAL HORN
The dorsal horn in the spinal cord is divided on the basis of
histologic characteristics into laminae I–VII, with I being
the most superficial and VII the deepest. Lamina II and part
of lamina III make up the substantia gelatinosa, the area
near the top of each dorsal horn. Three types of primary
afferent fibers (with cell bodies in the dorsal root ganglia)
mediate cutaneous sensation: (1) large myelinated Aα and
Aβ fibers that transmit impulses generated by mechanical
stimuli; (2) small myelinated Aδ fibers that transmit impulses
from cold receptors, nociceptors, or mechanoreceptors; and
(3) small unmyelinated C fibers that are concerned primar-
ily with pain and temperature. The orderly distribution of
these fibers in various layers of the dorsal horn is shown in
Figure 13–3.
DORSAL COLUMN PATHWAY
The principal direct pathways to the cerebral cortex for
touch, vibratory sense, and proprioception (position sense)
are shown in Figure 13–4. Fibers mediating these sensations
ascend ipsilaterally in the dorsal columns to the medulla,
where they synapse in the gracilis and cuneate nuclei. The
second-order neurons from these nuclei cross the midline
and ascend in the medial lemniscus to end in the contralat-
eral ventral posterior lateral (VPL) nucleus and related
specific sensory relay nuclei of the thalamus. This ascending
system is called the dorsal column or medial lemniscal sys-
tem. The fibers within the dorsal column pathway are joined
in the brain stem by fibers mediating sensation from the
head. Touch and proprioception are relayed mostly via the
main sensory and mesencephalic nuclei of the trigeminal
nerve.
Within the dorsal columns, fibers arising from different lev-
els of the cord are somatotopically organized. Specifically,
To dorsal columns
Mechanoreceptors Aβ
Mechanoreceptors
Nociceptors Aδ
Cold receptors
I Nociceptors
II Thermoreceptors C
III
Mechanoreceptors
IV
V
VI
VII
FIGURE 13–3 Schematic representation of the terminations
of the three types of primary afferent neurons in the various
layers of the dorsal horn of the spinal cord. (Reproduced with
permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of
Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
fibers from the sacral cord are positioned most medially and
those from the cervical cord most laterally. This arrangement
continues in the medulla with lower body (e.g., foot) represen-
tation in the gracilis nucleus and upper body (e.g., finger)
representation in cuneate nucleus. The medial lemniscus is
organized dorsal to ventral, representing neck to foot.
Somatotopic organization continues through the thalamus
and cortex. VPL thalamic neurons carrying sensory informa-
tion project in a highly specific way to the two somatic sensory
areas of the cortex (Figure 13–5): somatic sensory area I (SI)
in the postcentral gyrus and somatic sensory area II (SII) in
the wall of the Sylvian fissure. In addition, SI projects to SII. SI
corresponds to Brodmann’s areas 3, 2, and 1.
The arrangement of projections to SI is such that the parts of
the body are represented in order along the postcentral gyrus,
with the legs on top and the head at the foot of the gyrus
(Figure 13–5). Not only is there detailed localization of the
fibers from the various parts of the body in the postcentral
gyrus, but also the size of the cortical receiving area for
impulses from a particular part of the body is proportionate to
the use of the part. The relative sizes of the cortical receiving
areas are shown dramatically in Figure 13–6, in which the
proportions of the homunculus are distorted to correspond to
the size of the cortical receiving areas for each. Note that the
cortical areas for sensation from the trunk and back are small,
whereas very large areas are concerned with impulses from the
hand and the parts of the mouth concerned with speech.
SII is located in the superior wall of the Sylvian fissure, the
fissure that separates the temporal from the frontal and pari-
etal lobes. The head is represented at the inferior end of the
postcentral gyrus, and the feet at the bottom of the Sylvian fis-
sure. The representation of the body parts is not as complete
or detailed as it is in the postcentral gyrus.
 CHAPTER 13 General Sensory Systems: Touch, Pain, and Temperature 119

Postcentral
gyrus

Axons of
third-order
neurons

Thalamus

Cerebral
cortex

Medial lemniscal tract

(axons of second-order
neurons)

Medulla oblongata

Fasciculus cuneatus
Lateral spinothalamic tract
(axons of first-order
(axons of second-order neurons)
sensory neurons)

Joint stretch receptor

(proprioceptor)
Pain receptor
Spinal cord
Axons of first-order
Fasciculus gracilis neurons (not part of
(axons of first-order spinothalamic tract)
sensory neurons)

Temperature
receptor
(a) Touch receptor (b)

FIGURE 13–4 Ascending tracts carrying sensory information from peripheral receptors to the cerebral cortex. a) Dorsal column
pathway mediating touch, vibratory sense, and proprioception. b) Ventrolateral spinothalamic tract mediating pain and temperature.
(Reproduced with permission from Fox SI: Human Physiology. McGraw-Hill, 2008.)

Sl
Posterior VENTROLATERAL
8 6 4
3 1 2 parietal SPINOTHALAMIC TRACT
9 cortex
Trunk
Fibers from nociceptors and thermoreceptors synapse on neu-
Hand rons in the dorsal horn (Figure 13–3). The axons from these
neurons cross the midline and ascend in the ventrolateral
Sll Face
Tongue quadrant of the spinal cord, where they form the lateral
spinothalamic tract (Figure 13–4). Fibers within this tract
Auditory
synapse in the VPL nuclei. Other dorsal horn neurons that
al
receive nociceptive input synapse in the reticular formation of
su
Vi the brain stem (spinoreticular pathway) and then project to
the centrolateral nucleus of the thalamus.
FIGURE 13–5 Brain areas concerned with somatic sensation, Positron emission tomographic (PET) and functional
and some of the cortical receiving areas for other sensory
magnetic resonance imaging (fMRI) studies in normal
modalities in the human brain. The numbers are those of
Brodmann’s cortical areas. The primary auditory area is actually
humans indicate that pain activates cortical areas SI, SII, and
located in the Sylvian fissure on the top of the superior temporal the cingulate gyrus on the side opposite the stimulus. Also,
gyrus and is not normally visible in a lateral view of the cortex. the mediofrontal cortex and insular cortex are activated.
(Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks These technologies were important in distinguishing
H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.) two components of pain pathways. From VPL nuclei in the
120 SECTION IV CNS/Neural Physiology

afferent terminals that also synapse in the dorsal horn. This is

called the gate-control hypothesis.

Neck
Head

Hip
Trunk
Shoulder
Arm
MORPHINE & ENKEPHALINS

Leg
Elbow
Forea
Wris d
Han
ot

Litt g
Fo

t
Ri ddle

rm
le
M i dex b
n e s
To One of the most effective analgesic agents is morphine. The
In um

.
Gen
Th

E
No ye
s
Fa e
ce
Upp
er li
p stem, and spinal cord. There are at least three sites at which
Lips
Lower lip
Teeth, gums, and jaw
Tongue
Pharynx
Intra-
abdominal
FIGURE 13–6 Sensory homunculus, drawn overlying a
coronal section through the postcentral gyrus. Gen., genitalia.
(Reproduced with permission from Penfield W, Rasmussen G: The Cerebral Cortex
of Man. Macmillan, 1950.)
thalamus, fibers project to SI and SII. This is called the neo-
spinothalamic tract, and it is responsible for the immediate
awareness of the painful sensation and the awareness of the
location of the noxious stimulus. The pathway that includes
synapses in the brain stem reticular formation and centrolat-
eral thalamic nucleus projects to the frontal lobe, limbic sys-
tem, and insula. This is called the paleospinothalamic tract,
and it mediates the emotional response to pain.
In the CNS, visceral sensation travels along the same path-
ways as somatic sensation in the spinothalamic tracts and
thalamic radiations, and the cortical receiving areas for vis-
ceral sensation are intermixed with the somatic receiving
areas. This likely contributes to the phenomenon called
referred pain. Irritation of a visceral organ produces pain
that is felt not at that site but in a somatic structure. Such
pain is said to be referred to the somatic structure. Perhaps
the best-known example is referral of cardiac pain to the
inner aspect of the left arm.
MODULATION OF
PAIN TRANSMISSION
Many people have learned from practical experience that
touching or shaking an injured area decreases the pain due to
the injury. The relief may result from inhibition of pain path-
ways in the dorsal horn gate by stimulation of large-diameter
touch–pressure afferents. Figure 13–3 shows that collaterals
from these myelinated afferent fibers synapse in the dorsal
horn. These collaterals may modify the input from nociceptive
receptors that bind morphine and the endogenous mor-
phines, the opioid peptides, are found in the midbrain, brain
opioids can act to produce analgesia: peripherally, at the site
of an injury; in the dorsal horn, where nociceptive fibers syn-
apse on dorsal root ganglion cells; and at more rostral sites in
the brain stem.
Figure 13–7 shows various modes of action of opiates to
decrease transmission in pain pathways. Opioid receptors are
located on dorsal root ganglion cells and on afferent nerve
fibers. In the periphery, inflammation causes the production
of opioid peptides by immune cells, and these may act on the
receptors in the afferent nerve fibers to reduce the pain that
would otherwise be felt. The opioid receptors in the dorsal
horn region may act presynaptically to decrease release of sub-
stance P.
Injections of morphine into the periaqueductal gray matter
(PAG) of the midbrain relieve pain by activating descending
pathways that produce inhibition of primary afferent transmis-
sion in the dorsal horn. This activation may occur via projections
from the PAG to the raphe magnus nucleus and descending
serotonergic fibers from this nucleus mediate the inhibition.
Acupuncture at a location distant from the site of a pain may
act by releasing endorphins in the brain; acupuncture at the
site of the pain appears to act primarily in the same way as
touching or shaking (gate-control mechanism).
NEUROLOGICAL EXAM
The sensory component of a neurological exam includes an
assessment of various sensory modalities including touch,
proprioception, vibratory sense, and pain. The integrity of the
pain pathway is assessed by stimulating the skin with a pin and
asking the patient if the stimulus is perceived as sharp. To test
for proprioception, a physician holds the patient’s finger (toe,
hand, or foot) and, with the subject’s eyes closed, asks whether
the digit is being moved up or down. Vibratory sensibility is
tested by applying a vibrating (128-Hz) tuning fork to the skin
on the fingertip, tip of the toe, or bony prominences of the
toes. The normal response is a “buzzing” sensation. The sensa-
tion is most marked over bones. A pattern of rhythmic pres-
sure stimuli is interpreted as vibration. The impulses
responsible for the vibrating sensation are carried in the dorsal
columns. Degeneration of this part of the spinal cord occurs in
poorly controlled diabetes mellitus, pernicious anemia, and
vitamin B12 deficiencies. Elevation of the threshold for vibra-
tory stimuli is an early symptom of this degeneration. Vibratory
sensation and proprioception are closely related; when one is
diminished, so is the other.
 CHAPTER 13 General Sensory Systems: Touch, Pain, and Temperature 121

A Norepinephrine
Nociceptor Serotonin

ENK

Projection
neuron

B1 Sensory input B2 Sensory input + opiates/opioids

Control Control
Opiate
Nociceptor Morphine

Glutamate
Neuropeptides

Glutamate Neuropeptides

Enkephalin Enkephalin
Morphine

Ca2+ Ca2+

No input + opiates
No input Enkephalin

Sensory input Sensory input + opiates

Control Control
Projection Enkephalin
neuron

FIGURE 13–7 Local circuit interneurons in the superficial dorsal horn of the spinal cord integrate descending and afferent
pathways. A) Possible interactions of nociceptive afferent fibers, interneurons, and descending fibers in the dorsal horn. Nociceptive fibers
terminate on second-order spinothalamic projection neurons. Enkephalin (ENK)-containing interneurons exert both presynaptic and
postsynaptic inhibitory actions. Serotonergic and noradrenergic neurons in the brain stem activate opioid interneurons and suppress the
activity of spinothalamic projection neurons. B1) Activation of nociceptors releases glutamate and neuropeptides from sensory terminals,
depolarizing and activating projection neurons. B2) Opiates decrease Ca2+ influx leading to a decrease in the duration of nociceptor action
potentials and a decreased release of transmitter. Also, they hyperpolarize the membrane of dorsal horn neurons by activating K+ conductance
and decrease the amplitude of the EPSP (see Chapter 7) produced by stimulation of nociceptors. (Reproduced with permission from Kandel ER,
Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

Stereognosis is the perception of the form and nature of
an object without looking at it. Healthy subjects can readily
identify objects such as keys and coins of various denomina-
tions. This ability depends on relatively intact touch and
pressure sensation and is compromised when the dorsal col-
umns are damaged. The inability to identify an object by
touch is called tactile agnosia. Impaired stereognosis is an
early sign of damage to the cerebral cortex and sometimes
occurs in the absence of any detectable defect in touch and
pressure sensation when there is a lesion in the parietal lobe
posterior to the postcentral gyrus. Stereoagnosis can also be
expressed by the failure to identify an object by sight (visual
agnosia), the inability to identify sounds or words (audi-
tory agnosia) or color (color agnosia), or the inability to
identify the location or position of an extremity (position
agnosia).
122 SECTION IV CNS/Neural Physiology
CLINICAL CORRELATION
A 55-year-old female executive at a large corporation
developed a burning sensation in the palm of her right
hand about 6 months ago. She also noticed tingling and
numbness in her right thumb, index finger, and middle
finger. These symptoms first developed after spending
many long hours at the computer preparing annual report
documents for the corporation. Initially, symptoms were
most prominent at night, interrupting her sleep. The
problem has recently intensified, and she now has pain in
her right wrist and difficulty picking up small objects
from her desk. She visited her doctor because working on
the computer has become increasingly more difficult.
Her physician performed several simple diagnostic tests.
When the doctor pressed on her median nerve in the wrist,
she experienced a shocklike sensation (Tinel’s sign). When
the doctor had her hold her forearms upright by pointing
the fingers down and pressing the backs of the hands
together, within 1 minute she felt tingling and increasing
numbness in her fingers (Phalen’s sign). Nerve conduction
tests indicated slowed conduction in the median nerve.
She was diagnosed with carpal tunnel syndrome,
which is due to compression (possibly due to inflamma-
tion) of the median nerve that passes through the tun-
nel. It is more prevalent in women than men and is
diagnosed primarily in individuals who use their wrists
in repetitive activities (computer operators, cashiers,
musicians, painters). About 3% of women and 2% of
men are likely to be diagnosed with this syndrome dur-
ing their lifetime. The median nerve provides sensory
information from the thumb, index, and ring fingers,
and the nine tendons that flex the fingers. The syndrome
is characterized by pain, paresthesia, and weakness in
the distribution of the median nerve. Wrist or hand pain
or numbness and tingling of the fingers (except the little
finger which is not innervated by the median nerve) are
often the first symptoms. Patients sometimes report
weakness in the hand and a tendency to drop things.
Symptoms often first appear at night rather than during
activity. Wrist splinting, NSAIDs, or corticosteroids are
frequently the therapy of choice. If pain persists follow-
ing these treatments, surgery may be required.
CHAPTER SUMMARY
■ Sensory receptors are commonly classified as mechanoreceptors,
nociceptors, chemoreceptors, or photoreceptors.
■ Touch and pressure are sensed by four types of
mechanoreceptors: Meissner’s corpuscles (respond to
changes in texture and slow vibrations), Merkel cells
(respond to sustained pressure and touch), Ruffini corpuscles
(respond to sustained pressure), and Pacinian corpuscles
(respond to deep pressure and fast vibrations).
■ Nociceptors and thermoreceptors are free nerve endings on
unmyelinated or lightly myelinated fibers in hairy and glabrous
skin and deep tissues.
■ Hyperalgesia is an exaggerated response to a noxious stimulus;
allodynia is a sensation of pain in response to an innocuous
stimulus.
■ Converting a receptor stimulus to a recognizable sensation
is termed sensory coding. All sensory systems code for four
elementary attributes of a stimulus: modality, location,
intensity, and duration.
■ Discriminative touch, proprioception, and vibratory sensations
are relayed via the dorsal column (medial lemniscus) pathway
to SI. Pain and temperature sensations are mediated via the
ventrolateral spinothalmic tract to SI.
■ Descending pathways from the mesencephalic PAG inhibit
transmission in nociceptive pathways. This descending
pathway includes a synapse in the raphe nucleus and the
release of endogenous opiates.
■ Morphine is an effective antinociceptive agent that binds to
endogenous opiate receptors in the midbrain, brain stem, and
spinal cord.
STUDY QUESTIONS
1. Pacinian corpuscles are
A) a type of thermoreceptor.
B) usually innervated by Aδ nerve fibers.
C) rapidly adapting touch receptors.
D) slowly adapting touch receptors.
E) nociceptors.
2. Adaptation to a sensory stimulus produces
A) a diminished sensation when other types of sensory stimuli
are withdrawn.
B) a more intense sensation when a given stimulus is applied
repeatedly.
C) a sensation localized to the hand when the nerves of the
brachial plexus are stimulated.
D) a diminished sensation when a given stimulus is applied
repeatedly over time.
E) a decreased firing rate in the sensory nerve from the
receptor when one’s attention is directed to another
matter.
3. Sensory systems code for which of the following attributes
of a stimulus?
A) modality, location, intensity, and duration
B) threshold, receptive field, adaptation, and discrimination
C) touch, taste, hearing, and smell
D) threshold, laterality, sensation, and duration
E) sensitization, discrimination, energy, and projection
4. Thermoreceptors
A) are activated only by severe cold or severe heat.
B) are located on superficial layers of the skin.
C) are a subtype of nociceptor.
D) are on dendritic endings of Aδ fibers and C fibers.
E) All of the above.
 CHAPTER 13 General Sensory Systems: Touch, Pain, and Temperature 123

5. A 50-year-old woman undergoes a neurological exam that

indicates loss of pain and temperature sensitivity, vibratory sense,
and proprioception in both legs. These symptoms could be
explained by
A) a tumor on the medial lemniscal pathway in the sacral
spinal cord.
B) a peripheral neuropathy.
C) a large tumor in the sacral dorsal horn.
D) a large tumor affecting the posterior paracentral gyri.
E) a large tumor in the ventral posterolateral and
posteromedial thalamic nuclei.
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Spinal Reflexes
Susan M. Barman
O B J E C T I V E S
■ Describe the components of a reflex arc.
■ Describe the muscle spindles and their role in the stretch reflex.
■ Describe the functions of the Golgi tendon organs as part of a
feedback system that maintains muscle force.
■ Define reciprocal innervation, inverse stretch reflex, and clonus.
■ Describe the short- and long-term effects of spinal cord injury on
spinal reflexes.
INTRODUCTION
The basic unit of integrated reflex activity is the reflex arc.
This arc consists of a sense organ, an afferent neuron, synapses
within a central integrating station, an efferent neuron, and an
effector organ. The afferent neurons enter the central nervous
system (CNS) via the spinal dorsal roots or cranial nerves and
have their cell bodies in the dorsal root ganglia or in the
homologous ganglia for the cranial nerves. The efferent fibers
leave the CNS via the spinal ventral roots or corresponding
motor cranial nerves.
Activity in the reflex arc starts in a sensory receptor with a
generator potential whose magnitude is proportional to the
strength of the stimulus (Figure 14–1). This generates all-or-
none action potentials in the afferent nerve, the number of
action potentials being proportional to the size of the genera-
tor potential. In the CNS, the responses are again graded in
terms of excitatory postsynaptic potentials (EPSPs) and
inhibitory postsynaptic potentials (IPSPs) at the synaptic
junctions (see Chapter 7). All-or-none responses are generated
in the efferent nerve. When these reach the effector organ, they
again set up a graded response. When the effector is smooth
muscle, responses summate to produce action potentials in the
smooth muscle, but when the effector is skeletal muscle, the
graded response is adequate to produce action potentials that
bring about muscle contraction. Activity within the reflex arc
is modified by the multiple inputs converging on the efferent
neurons or at any synaptic station within the reflex loop.
Ch14_125-132.indd 125
14
C H A P T E R
The simplest reflex arc is one with a single synapse between
the afferent and efferent neurons. Such arcs are monosynaptic,
and reflexes occurring in them are called monosynaptic
reflexes. Reflex arcs in which one or more interneuron is
interposed between the afferent and efferent neurons are called
polysynaptic reflexes. There can be anywhere from two to
hundreds of synapses in a polysynaptic reflex arc.
As will be evident from the description below, reflex activity
is stereotyped and specific in terms of both the stimulus and
the response; a particular stimulus elicits a particular response.
The fact that reflex responses are stereotyped does not
exclude the possibility of their being modified by experience.
Reflexes are adaptable and can be modified to perform motor
tasks and maintain balance. Descending inputs from higher
brain regions play an important role in modulating and adapt-
ing spinal reflexes.
MONOSYNAPTIC REFLEX:
THE STRETCH REFLEX
When a skeletal muscle with an intact nerve supply is stretched,
it contracts. This response is called the stretch reflex. The stim-
ulus that initiates the reflex is stretch of the muscle, and the
response is contraction of the same muscle. The sense organ
(receptor) is a small encapsulated spindlelike or fusiform-
shaped structure called the muscle spindle, located within the
fleshy part of the muscle. The impulses originating from the
125
11/26/10 9:49:10 AM
126 SECTION IV CNS/Neural Physiology
Sense Afferent
organ neuron
Generator Action
potential potentials
FIGURE 14–1 Reflex arc. At the receptor and in the CNS a nonpropagated, graded response occurs that is proportionate to the magnitude
of the stimulus. The response at the neuromuscular junction is also graded, though under normal conditions it is always large enough to
produce a response in skeletal muscle. On the other hand, in the portions of the arc specialized for transmission (afferent and efferent axons,
muscle membrane), the responses are all-or-none action potentials. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s
Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
spindle are transmitted to the CNS by fast sensory fibers
(group Ia) that pass directly to the motor neurons that supply
the same muscle.
The stretch reflex is the best-known and studied monosyn-
aptic reflex and is typified by the knee-jerk reflex. Tapping
the patellar tendon elicits the knee jerk, a stretch reflex of the
quadriceps femoris muscle, because the tap on the tendon
stretches the muscle. The knee-jerk reflex is an example of a
deep tendon reflex in a neurological exam. Absence of the
knee jerk can signify an abnormality anywhere within the
reflex arc, including the muscle spindle, the Ia afferent nerve
fibers, or the motor neurons to the quadriceps muscle. The
most common cause is a peripheral neuropathy from such
things as diabetes mellitus, alcoholism, and toxins. A hyper-
active reflex can signify an interruption of inhibitory corti-
cospinal and other descending pathways that influence the
reflex arc.
STRUCTURE OF MUSCLE SPINDLES
Figure 14–2A illustrates the composition of a muscle spindle
and its innervation. Each muscle spindle has three essential
elements: (1) a group of specialized intrafusal muscle fibers
with contractile polar ends and a noncontractile center,
(2) large-diameter myelinated afferent nerves (types Ia and II)
originating in the central portion of the intrafusal fibers, and
(3) small-diameter myelinated efferent nerves supplying the
polar contractile regions of the intrafusal fibers. It is important
to understand the relationship of these elements to each other
and to the skeletal muscle itself to appreciate the role of this
sense organ in signaling changes in the length of the muscle in
which it is located. Changes in muscle length are associated
with changes in joint angle; thus, muscle spindles provide
information on position (i.e., proprioception).
The intrafusal fibers are located in parallel to the extra-
fusal fibers (the regular contractile units of the muscle) with
Synapse Efferent Neuromuscular Muscle
neuron junction
EPSPs Action Endplate Action
(and IPSPs) potentials potentials potentials
the ends of the spindle capsule attached to the tendons at either
end of the muscle. They do not contribute to the overall con-
tractile force of the muscle, but rather serve a purely sensory
function. There are two types of intrafusal fibers in mamma-
lian muscle spindles. The first type contains many nuclei in a
dilated central area and is called a nuclear bag fiber (Figure
14–2B). There are two subtypes of nuclear bag fibers, dynamic
and static. Typically, there are two or three nuclear bag fibers
per spindle. The second intrafusal fiber type, the nuclear
chain fiber, is thinner and shorter and lacks a definite bag.
Each spindle has about five nuclear chain fibers.
There are two kinds of sensory endings in each spindle, a sin-
gle primary (group Ia) ending and up to eight secondary
(group II) endings. The Ia afferent fiber wraps around the center
of the dynamic and static nuclear bag fibers and nuclear chain
fibers. Group II sensory fibers are located adjacent to the centers
of the static nuclear bag and nuclear chain fibers; these fibers do
not innervate the dynamic nuclear bag fibers. Ia afferent fibers
are very sensitive to the velocity of the change in muscle length
during a stretch (dynamic response); thus, they provide infor-
mation about the speed of movements and allow for quick cor-
rective movements. The steady-state (tonic) activity of group Ia
and II afferent fibers provides information on steady-state length
of the muscle (static response). The top trace in Figure 14–2C
shows the dynamic and static components of activity in a Ia affer-
ent fiber during muscle stretch. Note that they discharge most
rapidly while the muscle is being stretched (shaded area of
graphs) and less rapidly during sustained stretch.
The spindles have their own efferent motor nerve supply
called γ-motor neurons. They are small-diameter (3–6 μm)
fibers and constitute about 30% of the fibers in the ventral
roots. There are two types of γ-motor neurons: dynamic,
which supply the dynamic nuclear bag fibers, and static,
which supply the static nuclear bag fibers and the nuclear
chain fibers. Activation of dynamic γ-motor neurons increases
the dynamic sensitivity of the group Ia afferent endings.
Activation of the static γ-motor neurons increases the tonic
 CHAPTER 14 Spinal Reflexes 127

A Muscle spindle B Intrafusal fibers of the muscle spindle C Response of Ia sensory fiber to selective
activation of motor neurons
Static nuclear 200
bag fiber
Dynamic nuclear

Imp/s
bag fiber Dynamic response

Intrafusal Steady-state response

muscle 0 Stretch alone
fibers Nuclear
chain fiber
200
Capsule

Imp/s
II
Sensory Ia
endings
0
Stimulate static gamma fiber
Static
Afferent
200
axons

Imp/s
Efferent
axons Dynamic

0
Stimulate dynamic gamma fiber
Gamma
motor 6

Stretch
endings
0

0.2 s

FIGURE 14–2 Mammalian muscle spindle. A) Diagrammatic representation of the main components of mammalian muscle spindle
including intrafusal muscle fibers, afferent sensory fiber endings, and efferent motor fibers (γ-motor neurons). B) Three types of intrafusal muscle
fibers: dynamic nuclear bag, static nuclear bag, and nuclear chain fibers. A single Ia afferent fiber innervates all three types of fibers to form a
primary sensory ending. A group II sensory fiber innervates nuclear chain and static bag fibers to form a secondary sensory ending. Dynamic
γ-motor neurons innervate dynamic bag fibers; static γ-motor neurons innervate combinations of chain and static bag fibers. C) Comparison of
discharge pattern of Ia afferent activity during stretch alone and during stimulation of static or dynamic γ-motor neurons. Without γ-stimulation,
Ia afferent fibers show a small dynamic response to muscle stretch and a modest increase in steady-state firing. When static γ-motor neurons are
activated, the steady-state response increases and the dynamic response decreases. When dynamic γ-motor neurons are activated, the dynamic
response is markedly increased but the steady-state response gradually returns to its original level. (Reproduced with permission from Kandel ER, Schwartz
JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

level of activity in both group Ia and II afferent endings, is the time taken for the reflex activity to traverse the spinal
decreases the dynamic sensitivity of group Ia afferent fibers, cord. In humans, the central delay for the knee jerk is 0.6–0.9
and can prevent silencing of Ia afferent fibers during muscle millisecond. Since the minimal synaptic delay is 0.5 millisec-
stretch (Figure 14–2C). ond, only one synapse could have been traversed.
Muscle spindles also make connections that cause muscle con-
traction via polysynaptic pathways, and the afferent fibers
CENTRAL CONNECTIONS OF involved are probably those from the secondary group II
AFFERENT FIBERS endings.

Group Ia afferent fibers end directly on α-motor neurons sup-

plying the extrafusal fibers of the same muscle (Figure 14–3).
The time between the application of the stimulus and the
response is called the reaction time. In humans, the reaction
time for a stretch reflex such as the knee jerk is 19–24 millisec-
onds. Because the conduction velocities of the afferent and
efferent fiber types are known and the distance from the mus-
cle to the spinal cord can be measured, it is possible to calcu-
late how much of the reaction time was taken up by conduction
to and from the spinal cord. When this value is subtracted
from the reaction time, the remainder, called the central delay,
FUNCTION OF MUSCLE SPINDLES
When the muscle spindle is stretched, its sensory endings
are distorted and receptor potentials are generated. These
in turn set up action potentials in the sensory fibers at a
frequency proportional to the degree of stretching. Because
the spindle is in parallel with the extrafusal fibers, when the
muscle is passively stretched, the spindles are also stretched,
referred to as “loading the spindle.” This initiates reflex
contraction of the extrafusal fibers in the skeletal muscle. On
128 SECTION IV CNS/Neural Physiology

Dorsal root Spindle

Tendon Extrafusal fiber
Sensory nerve
Interneuron releasing
inhibitory mediator

Motor neuron Impulses in

Ib fiber sensory nerve
from I a fiber Muscle at rest
Golgi from
tendon muscle
organ spindle Ventral root

Motor endplate
on extrafusal fiber
Muscle stretched

FIGURE 14–3 Diagram illustrating the pathways responsible

for the stretch reflex and the inverse stretch reflex. Stretch
stimulates the muscle spindle, which activates Ia afferent fibers that
excite the motor neuron. It also stimulates the Golgi tendon organ,
which activates Ib afferent fibers that excite an interneuron that
releases the inhibitory mediator glycine. With strong stretch, the
resulting hyperpolarization of the motor neuron is so great that it
stops discharging. (Reproduced with permission from Barrett KE, Barman SM, Muscle contracted
Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill
Medical, 2009.)

the other hand, the muscle spindle afferent fibers character-

istically stop firing when the muscle is made to contract by
electrical stimulation of the α-motor neurons to the extra-
fusal fibers because the muscle shortens while the spindle is
unloaded (Figure 14–4). Thus, the spindle and its reflex con- Increased γ efferent discharge
nections constitute a feedback device that operates to main-
tain muscle length; if the muscle is stretched, spindle
discharge increases and reflex shortening is produced,
whereas if the muscle is shortened without a change in
γ-motor neuron discharge, spindle afferent activity decreases
and the muscle relaxes.
When a stretch reflex occurs, the muscles that antagonize
the action of the muscle involved (antagonists) relax. This
phenomenon is due to reciprocal innervation. Impulses in Increased γ efferent
the Ia afferent fibers from the muscle spindles of the protago- discharge—muscle stretched
nist muscle cause postsynaptic inhibition of the α-motor FIGURE 14–4 Effect of various conditions on muscle spindle
neurons to the antagonists. The pathway mediating this effect discharge. When the whole muscle is stretched, the muscle spindle
is bisynaptic. A collateral from each Ia afferent fiber passes in is also stretched and its sensory endings are activated at a
the spinal cord to an inhibitory interneuron that synapses on a frequency proportional to the degree of stretching (“loading the
motor neuron supplying the antagonist muscles. spindle”). Spindle afferent fibers stop firing when the muscle
contracts (“unloading the spindle”). Stimulation of γ-motor neurons
EFFECTS OF γ-MOTOR causes the contractile ends of the intrafusal fibers to shorten. This
stretches the nuclear bag region, initiating impulses in sensory fibers.
NEURON DISCHARGE If the whole muscle is stretched during stimulation of the γ-motor
neurons, the rate of discharge in sensory fibers is further increased.
Stimulation of γ-motor neurons causes the contractile ends of (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H:
the intrafusal fibers to shorten and therefore stretches the Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

nuclear bag portion of the spindles, deforming the endings
and initiating impulses in the Ia afferent fibers (Figure 14–4).
This can lead to reflex contraction of the muscle. Thus, skeletal
muscle can be made to contract via stimulation of the α-motor
neurons that innervate the extrafusal fibers or the γ-motor
neurons that initiate contraction indirectly via the stretch
reflex. Increased γ-motor neuron activity increases spindle
sensitivity during stretch.
In response to descending excitatory input to spinal motor
circuits, both α- and γ-motor neurons are activated. Because
of this “α–γ coactivation,” intrafusal and extrafusal fibers
shorten together, and spindle afferent activity can occur
throughout the period of muscle contraction. In this way, the
spindle remains capable of responding to stretch and adjusting
reflexly α-motor neuron discharge.
Input from various brain regions to the γ-motor neurons
influences the sensitivity of the muscle spindles. Thus, the
threshold of the stretch reflexes in various parts of the body
can be adjusted and shifted to meet the needs of postural con-
trol. Anxiety causes an increased γ-motor neuron discharge,
which may explain the appearance of hyperactive tendon
reflexes in anxious patients. Also, unexpected movement is
associated with a greater discharge.
INVERSE STRETCH REFLEX
Up to a point, the harder a muscle is stretched, the stronger is
the reflex contraction. However, when the tension becomes
great enough, contraction suddenly ceases and the muscle
relaxes. This relaxation in response to strong stretch is called
the inverse stretch reflex.
The receptor for the inverse stretch reflex is in the Golgi
tendon organ (Figure 14–5). This organ consists of a netlike
collection of knobby nerve endings among the fascicles of a
tendon. There are 3–25 muscle fibers per tendon organ. The
sensory fibers from the Golgi tendon organs form the Ib group
of myelinated, rapidly conducting nerve fibers. Stimulation of
these Ib afferent fibers leads to the production of IPSPs on the
α-motor neurons that supply the muscle from which the fibers
arise. The Ib afferent fibers end in the spinal cord on inhibi-
Nerve fiber
Organ of Golgi, showing
ramification of nerve fibrils
FIGURE 14–5 Golgi tendon organ. (Reproduced with permission from Gray H [editor]: Gray’s Anatomy of the Human Body, 29th ed. Lea & Febiger, 1973.)
CHAPTER 14 Spinal Reflexes 129
tory interneurons that in turn terminate directly on the
α-motor neurons (Figure 14–3). They also make excitatory
connections with α-motor neurons supplying antagonists to
the muscle.
Unlike the spindles, the Golgi tendon organs are in series
with the muscle fibers. Thus, they are stimulated by both pas-
sive stretch and active contraction of the muscle. The thresh-
old of the Golgi tendon organs is low. The degree of stimulation
by passive stretch is not great because the more elastic muscle
fibers take up much of the stretch, and this is why it takes a
strong stretch to produce relaxation. However, discharge is
regularly produced by contraction of the muscle, and the Golgi
tendon organ thus functions as a transducer in a feedback
circuit that regulates muscle force in a fashion analogous to
the spindle feedback circuit that regulates muscle length.
The importance of the primary endings in the spindles and
the Golgi tendon organs in regulating the velocity of the muscle
contraction, muscle length, and muscle force is illustrated by
the fact that that section of the afferent nerves to an arm causes
the limb to hang loosely in a semi-paralyzed state. The organi-
zation of the system is shown in Figure 14–6.
MUSCLE TONE
The resistance of a muscle to stretch is often referred to as its
tone. If the motor nerve to a skeletal muscle is cut, the muscle
offers very little resistance and is said to be flaccid. A hypertonic
(spastic) muscle is one in which the resistance to stretch is high
because of hyperactive stretch reflexes. Somewhere between the
states of flaccidity and spasticity is the ill-defined area of normal
tone. The muscles are generally hypotonic when the rate of
γ-motor neuron discharge is low and hypertonic when it is high.
When the muscles are hypertonic, the sequence of moderate
stretch → muscle contraction, and strong stretch → muscle
relaxation is seen. Passive flexion of the elbow, for example,
meets immediate resistance as a result of the stretch reflex in
the triceps muscle. Further stretch activates the inverse stretch
reflex. The resistance to flexion suddenly collapses, and the
arm flexes. Continued passive flexion stretches the muscle
again, and the sequence may be repeated. This sequence of
Tendon bundles
Muscular fibers
130 SECTION IV CNS/Neural Physiology

Interneuronal
control
signal Inter- Force feedback Tendon
neurons organs
External
Internal forces
disturbances
α Control − Muscular + Muscle
signal + Efferent signal force length
α Muscle Load
−
+
Length and velocity
Length and velocity
feedback
γ-Dynamic Spindles
control
signal
γd
γ-Static
control
signal
γs

FIGURE 14–6 Block diagram of peripheral motor control system. Non-neural feedback from muscle (“Length and velocity”) that limits
length and velocity via the inherent mechanical properties of muscle. γd, dynamic γ-motor neurons; γs, static γ-motor neurons. (Reproduced with
permission from Houk J: Medical Physiology, 13th ed. In: Mountcastle VB (editor). Mosby, 1974.)

resistance followed by give when a limb is moved passively is
known as the clasp-knife effect because of its resemblance to
the closing of a pocket knife.
Clonus is the occurrence of regular, repetitive, rhythmic
contractions of a muscle subjected to sudden, maintained
stretch. Sustained clonus with five or more beats is considered
abnormal. During a neurological exam, ankle clonus can be
initiated by brisk, maintained dorsiflexion of the foot, and the
response is rhythmic plantar flexion at the ankle.
Clonus may also occur after disruption of descending cor-
tical input to a spinal glycinergic inhibitory interneuron called
the Renshaw cell. This cell receives excitatory input from
α-motor neurons via axon collaterals (and in turn the
Renshaw cell inhibits the motor neuron). In addition, cortical
fibers activating ankle flexors contact Renshaw cells (as well
as inhibitory interneurons activated by Ia afferent fibers) that
inhibit the antagonistic ankle extensors. This circuitry pre-
vents reflex stimulation of the extensors when flexors are
active. Therefore, when the descending cortical fibers
are damaged (upper motor neuron lesion), the inhibition of
antagonists is absent. The result is repetitive, sequential
contraction of ankle flexors and extensors (clonus). Clonus
may be seen in patients with amyotrophic lateral sclerosis,
stroke, multiple sclerosis, spinal cord damage, and hepatic
encephalopathy.
POLYSYNAPTIC REFLEXES:
THE WITHDRAWAL REFLEX
The withdrawal reflex is a typical polysynaptic reflex that
occurs in response to a painful stimulation of the skin or sub-
cutaneous tissues and muscle. The response is flexor muscle
contraction and inhibition of extensor muscles, so that the
body part stimulated is flexed and withdrawn from the stimu-
lus. When a strong stimulus is applied to a limb, the response
includes not only flexion and withdrawal of that limb, but also
extension of the opposite limb. This crossed extensor response
is part of the withdrawal reflex.
Flexor responses can be produced by innocuous stimula-
tion of the skin or by stretch of the muscle, but strong flexor
responses with withdrawal are initiated only by stimuli that
are noxious or at least potentially harmful (nociceptive
stimuli). Flexion of the stimulated limb gets it away from the
source of irritation, and extension of the other limb supports
the body.
As the strength of a noxious stimulus is increased, the reac-
tion time is shortened. Spatial and temporal facilitation
occurs at synapses in the polysynaptic pathway. Stronger stim-
uli produce more action potentials per second in the active
branches and cause more branches to become active; summa-
tion of the EPSPs to the firing level therefore occurs more
rapidly.
Another characteristic of the withdrawal response is the
fact that supramaximal stimulation of any of the sensory
nerves from a limb never produces as strong a contraction of
the flexor muscles as that elicited by direct electrical stimula-
tion of the muscles themselves. This indicates that the affer-
ent inputs fractionate the α-motor neuron pool, that is, each
input goes to only part of the motor neuron pool for the flex-
ors of that particular extremity. On the other hand, if all the
sensory inputs are dissected out and stimulated one after the
other, the sum of the tension developed by stimulation of each
is greater than that produced by direct electrical stimulation
of the muscle or stimulation of all inputs at once. This indi-
cates that the various afferent inputs share some of the motor
neurons and that occlusion occurs when all inputs are stimu-
lated at once.

SPINAL INTEGRATION
The spinal α-motor neurons that supply the extrafusal fibers
in skeletal muscles are the efferent side of many reflex arcs. All
neural influences affecting muscular contraction ultimately
funnel through them to the muscles, and they are therefore
called the final common pathway. The surface of the average
α-motor neuron and its dendrites accommodates about 10,000
synaptic knobs, allowing for numerous synaptic inputs. At
least five inputs go from the same spinal segment to a typical
spinal motor neuron. In addition to these, there are excitatory
and inhibitory inputs, generally relayed via interneurons, from
other levels of the spinal cord and multiple long-descending
tracts from the brain. All of these pathways converge on and
determine the activity in the final common pathway.
SPINAL CORD INJURY
A key component of neurological exams includes an assess-
ment of the integrity of spinal reflexes. Abnormalities in the
reflexes often point to the location of a spinal cord injury
(SCI). The deficits after SCI vary, of course, depending on the
level and severity of the injury. Transection of the spinal cord
is followed by a period of spinal shock during which all spinal
reflex responses are profoundly depressed. Subsequently,
reflex responses return and become hyperactive. In humans,
spinal shock usually lasts for a minimum of 2 weeks.
Cessation of tonic bombardment of spinal neurons by
excitatory impulses in descending pathways undoubtedly
plays a role in spinal shock. The recovery of reflex excitability
may be due to the development of denervation hypersensitiv-
ity to the mediators released by the remaining spinal excit-
atory endings (see Chapter 12). Another possibility is the
sprouting of collaterals from existing neurons, with the for-
mation of additional excitatory endings on interneurons and
motor neurons.
The first reflex response to appear as spinal shock wears off
is often a slight contraction of the leg flexors and adductors in
response to a noxious stimulus. In some patients, the knee-
jerk reflex recovers first. Once the spinal reflexes begin to
reappear after spinal shock, their threshold steadily drops.
CLINICAL CORRELATION
A 21-year-old male medical student was stabbed in the
back during a robbery attempt. A bystander called 911
and, when the paramedics arrived, the student could not
move his right leg. He was rushed to the emergency room
of the local hospital. In addition to examination and treat-
ment of the injury site, he was given a neurological exam.
The muscle spindle reflex was normal in both arms and
the left leg but was hyperactive in the right leg. He had
normal sensation to pinprick and pinch in upper extremi-
CHAPTER 14 Spinal Reflexes 131
ties and the right leg, but he was unable to detect the nox-
ious stimuli applied to the left leg. He also lost the
sensation of touch and vibration on his right leg but sen-
sation was normal on his left leg and upper limbs. There
was little, if any, spontaneous movement in the right leg,
although all other limbs appeared to have normal move-
ment. A magnetic resonance image showed that the right
side of his spinal cord was severely damaged at the 10th
thoracic level.
It has been estimated that the worldwide annual inci-
dence of sustaining SCI is between 10 and 83 per million
of the population. Leading causes are vehicle accidents,
violence, and sports injuries. Approximately 52% of SCI
cases result in quadriplegia and about 42% lead to para-
plegia. The mean age of patients who sustain an SCI is
33 years old, and males outnumber females nearly 4 to 1.
This patient’s injury led to a hemisection of the spinal
cord at the 10th thoracic level. Such an injury causes a
characteristic clinical picture that reflects damage to
ascending sensory (dorsal column pathway, ventrolateral
spinothalamic tract) and descending motor (corticospi-
nal tract) pathways, which is called the Brown-Séquard
syndrome. The lesion to fasciculus gracilus or fasciculus
cuneatus leads to ipsilateral loss of discriminative touch,
vibration, and proprioception below the level of lesion.
The loss of the spinothalamic tract leads to contralateral
loss of pain and temperature sensation beginning one or
two segments below the lesion. Damage to the corticospi-
nal tract produces weakness and spasticity in certain
muscle groups on the same side of the body. Although a
precise spinal hemisection is rare, the syndrome is fairly
common because it can be caused by spinal cord tumor,
trauma, degenerative disc disease, and ischemia.
CHAPTER SUMMARY
■ A reflex arc consists of a sense organ, an afferent neuron,
one or more synapses within a central integrating station,
an efferent neuron, and an effector response.
■ A muscle spindle is a group of specialized intrafusal muscle
fibers with contractile polar ends and a noncontractile center
that is located in parallel to the extrafusal muscle fibers and is
innervated by types Ia and II afferent fibers and γ-motor
neurons. Muscle stretch activates the muscle spindle to initiate
reflex contraction of the extrafusal muscle fibers in the same
muscle (stretch reflex).
■ A Golgi tendon organ is a netlike collection of knobby nerve
endings among the fascicles of a tendon that is located in
series with extrafusal muscle fibers and innervated by type
Ib afferent fibers. They are stimulated by both passive stretch
and active contraction of the muscle to relax the muscle
(inverse stretch reflex) and function as a transducer to
regulate muscle force.
■ A collateral from an Ia afferent branches to terminate on an
inhibitory interneuron that synapses on an antagonistic muscle
132 SECTION IV CNS/Neural Physiology

(reciprocal innervation) to relax that muscle when the agonist 3. Which of the following is not characteristic of a reflex?
contracts. Clonus is the occurrence of regular, rhythmic A) modification by impulses from various parts of the CNS
contractions of a muscle subjected to sudden, maintained stretch. B) may involve simultaneous contraction of some muscles
■ Spinal cord transection is followed by a period of spinal and relaxation of others
shock during which all reflexes are profoundly depressed. C) chronically suppressed after spinal cord transection
This is followed by a period of hyperactive reflexes. D) always involves transmission across at least one synapse
E) frequently occurs without conscious perception
4. Withdrawal reflexes are not
STUDY QUESTIONS A) initiated by nociceptive stimuli.
B) an example of a polysynaptic reflex.
1. The inverse stretch reflex C) prolonged if the stimulus is strong.
A) has a lower threshold than that of the stretch reflex. D) an example of a flexor reflex.
B) is a monosynaptic reflex. E) accompanied by the same response on both sides of
C) is a relaxation of a muscle in response to a strong stretch the body.
of the muscle.
D) has the muscle spindle as its receptor.
E) requires the discharge of central neurons that release
acetylcholine.
2. When γ-motor neuron discharge increases at the same time as
α-motor neuron discharge to muscle
A) prompt inhibition of discharge in spindle Ia afferent fibers
takes place.
B) contraction of the muscle is prolonged.
C) the muscle will not contract.
D) the muscle will not relax.
E) the number of impulses in spindle Ia afferent fibers is
greater than when α discharge alone is increased.
 15
C H A P T E R

Special Senses I: Vision

Susan M. Barman

O B J E C T I V E S

■ Describe the various parts of the eye and list the functions of each.
■ Explain how light rays in the environment are brought to a focus on the retina
and the role of accommodation in this process.
■ Define the following terms: hyperopia, myopia, astigmatism, presbyopia,
and strabismus.
■ Describe the electrical responses produced by rods and cones and explain
how these responses are produced.
■ Trace the neural pathways that transmit visual information from the rods and
cones to the visual cortex.
■ Name the four types of eye movements and the function of each.

INTRODUCTION junction. In front of the lens is the pigmented and opaque

The eyes are complex sense organs. Within its protective cas-
ing, each eye has a layer of receptors, a lens system that focuses
light on these receptors, and a system of nerves that conducts
impulses from the receptors to the brain. The way these com-
ponents operate to set up conscious visual images is the sub-
ject of this chapter.
ANATOMY OF THE EYE
The principal structures of the eye are shown in Figure 15–1.
The outer protective layer of the eyeball, the sclera, is modi-
fied anteriorly to form the transparent cornea, through which
light rays enter the eye. Inside the sclera is the choroid, a layer
that contains many of the blood vessels that nourish the struc-
tures in the eyeball. Lining the posterior two thirds of the
choroid is the retina, the neural tissue containing the recep-
tor cells.
The crystalline lens is a transparent structure held in
place by a circular lens suspensary ligament (zonule) that
is attached to the thickened anterior part of the choroid,
the ciliary body. The ciliary body contains circular and lon-
gitudinal muscle fibers that attach near the corneoscleral
iris, the colored portion of the eye, which contains circular
muscle fibers that constrict and radial fibers that dilate the
pupil. Variations in the diameter of the pupil can produce
up to a 5-fold change in the amount of light reaching the
retina.
The space between the lens and the retina is filled primar-
ily with a clear gelatinous material called the vitreous
humor. Aqueous humor, a clear liquid that nourishes the
cornea and lens, is produced in the ciliary body by diffusion
and active transport from plasma. It flows through the pupil
and fills the anterior chamber of the eye. It is normally reab-
sorbed through the canal of Schlemm, a venous channel
at the junction between the iris and the cornea (anterior
chamber angle). Obstruction of this outlet leads to increased
intraocular pressure. One cause of increased pressure
is decreased permeability through the trabecular mesh-
work, the tissue around the base of the cornea that drains
the aqueous humor from the eye (open-angle glaucoma),
and another is forward movement of the iris, obliterating
the angle (angle-closure glaucoma). Glaucoma can be
treated with β-adrenergic blocking drugs or carbonic anhy-
drase inhibitors, both of which decrease the production of
aqueous humor, or with cholinergic agonists, which increase
aqueous outflow.

133

Ch15_133-146.indd 133 11/26/10 9:42:37 AM

134 SECTION IV CNS/Neural Physiology
Superior rectus muscle
Sclera
Choroid
Retina
Fovea centralis
Central artery
Central vein
Optic nerve
Inferior rectus muscle
FIGURE 15–1 The internal anatomy of the eye. (Reproduced with permission from Fox SI: Human Physiology. McGraw-Hill, 2008.)
The eye is well protected from injury by the bony walls of
the orbit. The cornea is moistened and kept clear by tears
that course from the lacrimal gland in the upper portion of
each orbit across the surface of the eye to empty via the
lacrimal duct into the nose. Blinking helps keep the cornea
moist.
RETINA
The retina extends anteriorly almost to the ciliary body. It is
organized into 10 layers and contains rods and cones, which
are the visual receptors, plus four types of neurons: bipolar
cells, ganglion cells, horizontal cells, and amacrine cells
(Figure 15–2). Rods and cones, which are next to the chor-
oid, synapse with bipolar cells, and bipolar cells synapse with
ganglion cells. The axons of ganglion cells converge and leave
the eye as the optic nerve. Horizontal cells connect receptor
cells to the other receptor cells in the outer plexiform layer.
Amacrine cells connect ganglion cells to one another in the
inner plexiform layer via processes of varying length and
patterns. Gap junctions also connect retinal neurons to one
another.
The receptor layer of the retina rests on the pigment epithe-
lium next to the choroid, so light rays must pass through the
ganglion cell and bipolar cell layers to reach the rods and
cones. The pigment epithelium absorbs light rays, preventing
the reflection of rays back through the retina. Such reflection
would produce blurring of the visual images.
The optic nerve leaves the eye and the retinal blood vessels
enter it at a point 3 mm medial to and slightly above the pos-
Conjunctiva
Ciliary body
Posterior
chamber Anterior
Anterior cavity
chamber
Cornea
Pupil
Lens
Iris
Posterior chamber
Zonular fibers of
suspensory ligament
Vitreous chamber
(posterior cavity)
terior pole of the globe. This region is visible through the oph-
thalmoscope as the optic disk. There are no visual receptors
over the disk, and consequently it is a blind spot.
Near the posterior pole of the eye is a yellowish pigmented
spot, the macula lutea. This marks the location of the fovea
centralis, a thinned-out, rod-free portion of the retina. In it,
the cones are densely packed, and each synapses to a single
bipolar cell, which, in turn, synapses on a single ganglion
cell, providing a direct pathway to the brain. There are very
few overlying cells and no blood vessels; thus, the fovea is the
point where visual acuity is greatest. When attention is
attracted to or fixed on an object, the eyes are normally
moved so that light rays coming from the object fall on
the fovea.
VISUAL RECEPTORS IN THE RETINA
Rods are responsible for vision in low light (night vision)
and provide only black and white vision. Cones are respon-
sible for color vision. Each rod and cone is divided into an
outer segment, an inner segment that includes a nuclear
region, and a synaptic zone (Figure 15–3). The outer seg-
ments are modified cilia and are made up of regular stacks
of flattened saccules or disks composed of membrane. These
saccules and disks contain the photosensitive compounds
that react to light, initiating action potentials in the visual
pathways. The inner segments are rich in mitochondria. The
rods are named for the thin, rodlike appearance of their
outer segments. Cones generally have thick inner segments
and conical outer segments, although their morphology var-
ies from place to place in the retina. In cones, the saccules
 CHAPTER 15 Special Senses I: Vision 135

Pigment epithelium

Rod and cone

Outer segments

Inner segments

Outer nuclear layer C C C C

R R R R
R

Outer plexiform layer

H
FB
Inner nuclear layer MB
RB FB
MB RB
A
A

Inner plexiform layer

Ganglion cell layer MG DG MG

DG

Optic nerve fibers

FIGURE 15–2 Neural components of the extrafoveal portion of the retina. Direction of light is from the bottom to the top of the figure.
C, cone; R, rod; MB, RB, and FB, midget, rod, and flat bipolar cells; DG and MG, diffuse and midget ganglion cells; H, horizontal cells; A, amacrine
cells. (Modified with permission from Dowling JE, Boycott BB: Organization of the primate retina: electron microscopy. Proc R Soc Lond B 1966;166:80–111.)

are formed in the outer segments by infoldings of the cell
membrane, but in rods the disks are separated from the cell
membrane.
In the extrafoveal portions of the retina, rods predominate
(Figure 15–4), and there is a good deal of convergence. Flat
bipolar cells (Figure 15–2) make synaptic contact with several
cones, and rod bipolar cells make synaptic contact with several
rods. Because there are approximately 6 million cones and
120 million rods in each human eye but only 1.2 million nerve
fibers in each optic nerve, the overall convergence of receptors
through bipolar cells on ganglion cells is about 105:1. However,
there is divergence from this point on. There are twice as many
fibers in the geniculocalcarine tracts as in the optic nerves, and
in the visual cortex, the number of neurons concerned with
vision is 1,000 times the number of fibers in the optic nerves.
THE IMAGE-FORMING
MECHANISM
The eyes convert energy in the visible spectrum into action
potentials in the optic nerve. The images of objects in the envi-
ronment are focused on the retina. The light rays striking the
retina generate potentials in the rods and cones. Impulses ini-
tiated in the retina are conducted to the cerebral cortex, where
they produce the sensation of vision.
136 SECTION IV CNS/Neural Physiology

Rod Cone at the anterior surface of the cornea (Figure 15–5). The retinal
Plasma membrane image is inverted. The connections of the retinal receptors are
such that from birth any inverted image on the retina is viewed
right side up and projected to the visual field on the side
30 nm Outer
segment opposite to the retinal area stimulated. This perception is pres-
Disks Sacs ent in infants and is innate.

Ciliary neck

Mitochondria
Inner
segment
Nucleus
Synaptic
terminal
FIGURE 15–3 Schematic diagram of a rod and a cone.
Each rod and cone is divided into an outer segment, an inner
segment with a nuclear region, and a synaptic zone. The saccules
and disks in the outer segment contain photosensitive compounds
that react to light to initiate action potentials in the visual
pathways. (Reproduced with permission from Lamb TD: Electrical responses
of photoreceptors. In: Recent Advances in Physiology, No.10. Baker PF [editor].
Churchill Livingstone, 1984.)
Light rays are bent when they pass from a medium of one den-
sity into a medium of a different density, except when they strike
perpendicular to the interface (Figure 15–5). The bending of
light rays is called refraction and is the mechanism that allows
one to focus an accurate image onto the retina. Parallel light rays
striking a biconvex lens are refracted to a point behind the lens.
In the eye, light is actually refracted at the anterior surface of
the cornea and at the anterior and posterior surfaces of the
lens. The process of refraction can be represented diagram-
matically by drawing the rays of light as if all refraction occurs
COMMON DEFECTS OF THE
IMAGE-FORMING MECHANISM
In some individuals, the eyeball is shorter than normal and the
parallel rays of light are brought to a focus behind the retina.
This abnormality is called hyperopia or farsightedness (Figure
15–6). Sustained accommodation (focusing due to contrac-
tion of the ciliary muscle), even when viewing distant objects,
can partially compensate for the defect, but the prolonged
muscular effort is tiring and may cause headaches and blur-
ring of vision. The defect can be corrected by using glasses
with convex lenses, which aid the refractive power of the eye in
shortening the focal distance.
In myopia (nearsightedness), the anteroposterior diameter
of the eyeball is too long (Figure 15–6). The shape of the eye
appears to be determined in part by the refraction presented to
it. In young adult humans, the extensive close work involved
in activities such as studying accelerates the development of
myopia. This defect can be corrected by glasses with biconcave
lenses, which make parallel light rays diverge slightly before
they strike the eye.
Astigmatism is a common condition in which the curvature
of the cornea is not uniform (Figure 15–6). When the curva-
ture in one meridian is different from that in others, light rays
in that meridian are refracted to a different focus, so that part
of the retinal image is blurred. Astigmatism can usually be

2000
Cones
Number of rods or cones in an area

Rods
1600
of 0.0069 mm2

1200
Blind spot

800

400

0
100° 80° 60° 40° 20° 0° 20° 40° 60° 80°
Nasal retina Fovea Temporal retina
Distance from the fovea

FIGURE 15–4 Rod and cone density along the horizontal meridian through the human retina. A plot of the relative acuity of vision in
the various parts of the light-adapted eye would parallel the cone density curve; a similar plot of relative acuity of the dark-adapted eye would
parallel the rod density curve. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill
Medical, 2009.)
 CHAPTER 15 Special Senses I: Vision 137

(a)

Glass Air
Refraction
Point source
of light
No refraction

Refraction

(b)

b' a

a' b

FIGURE 15–5 Focusing point sources of light. a) When diverging light rays enter a dense medium at an angle to its convex surface,
refraction bends them inward. b) Refraction of light by the lens system. For simplicity, refraction is shown only at the corneal surface (site
of greatest refraction) although it also occurs in the lens and elsewhere. Incoming light from a (above) and b (below) is bent in opposite
directions, resulting in b′ being above a′ on the retina. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed.
McGraw-Hill, 2008.)

corrected with cylindrical lenses placed in such a way that they
equalize the refraction in all meridians.
Strabismus is a misalignment of the eyes usually due to
problems with eye muscles and one of the most common eye
problems in children, affecting about 4% of children under 6
years of age. It is characterized by one or both eyes turning
inward (crossed-eyes), outward (wall eyes), upward, or down-
ward. Strabismus is also commonly called “wandering eye” or
“crossed-eyes.” It occurs when visual images do not fall on cor-
responding retinal points. When visual images chronically fall
on noncorresponding points in the two retinas in young chil-
dren, one is eventually suppressed (suppression scotoma).
ACCOMMODATION
When the ciliary muscle is relaxed, parallel light rays striking
the optically normal (emmetropic) eye are brought to a focus
on the retina. As long as this relaxation is maintained, rays from
objects closer than 6 m from the observer are brought to a focus
behind the retina, and consequently the objects appear blurred.
The problem of bringing diverging rays from close objects to a
focus on the retina can be solved by increasing the curvature of
the lens, a process called accommodation. At rest, the lens is
held under tension by the lens ligaments and is pulled into a
flattened shape. The ciliary muscle contracts when the gaze is
directed at a near object. This decreases the distance between
the edges of the ciliary body and relaxes the lens ligaments, so
that the lens springs into a more convex shape (Figure 15–7).
The degree to which the lens curvature can be increased is
limited, and light rays from an object very near the individual
cannot be brought to a focus on the retina, even with the
greatest of effort. The nearest point to the eye at which an
object can be brought into clear focus by accommodation is
called the near point of vision. Due to increasing hardness of
the lens, the near point recedes throughout life, slowly at first
and then rapidly with advancing age, from 9 cm at age 10 to
83 cm at age 60. By the time a healthy individual reaches age
40–45, the loss of accommodation is usually sufficient to
make reading and close work difficult. This condition, which
is known as presbyopia, can be corrected by wearing glasses
with convex lenses.
138 SECTION IV CNS/Neural Physiology

(a)

Normal sight (faraway object is clear)

Nearsighted (eyeball too long)

FIGURE 15–7 Accommodation. Solid lines represent the shape

Nearsightedness corrected
(b)
Normal sight (near object is clear)
of the lens, iris, and ciliary body at rest; dashed lines represent the
shape during accommodation. Ciliary muscles contract when gaze is
directed at a near object, which decreases the distance between the
edges of the ciliary body and relaxes the lens ligaments, and the lens
becomes more convex. (Reproduced with permission from Barrett KE, Barman
SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill
Medical, 2009.)

segment maintains ionic equilibrium. Release of synaptic

Farsighted (eyeball too short)
Farsightedness corrected
transmitter is steady in the dark. When light strikes the outer
segment, the reactions that are initiated close some of the Na+
channels, and the result is a hyperpolarizing receptor poten-
tial. The hyperpolarization reduces the release of synaptic
transmitter, and this generates a signal in the bipolar cells that
ultimately leads to action potentials in ganglion cells. The
action potentials are transmitted to the brain.

FIGURE 15–6 Common defects of the optic system of the eye.

a and b) In hyperopia (farsightedness), the eyeball is too short and Na+
light rays come to a focus behind the retina. A biconvex lens corrects
this by adding to the refractive power of the lens of the eye. In myopia
(nearsightedness), the eyeball is too long and light rays focus in front
of the retina. Placing a biconcave lens in front of the eye causes the
light rays to diverge slightly before striking the eye, so that they are
brought to a focus on the retina. (Reproduced with permission from Widmaier
EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
K+ K+

THE PHOTORECEPTOR
MECHANISM
IONIC BASIS OF PHOTORECEPTOR
POTENTIALS
Na+ channels in the outer segments of the rods and cones are
open in the dark, so current flows from the inner to the outer
segment (Figure 15–8). Current also flows to the synaptic end-
ing of the photoreceptor. The Na+, K+-ATPase in the inner
Na+ Na+
Dark Light
FIGURE 15–8 Effect of light on current flow in visual
receptors. In the dark, Na+ channels in the outer segment are
held open by cGMP. Light leads to increased conversion of cGMP
to 5′-GMP, and some of the channels close. This produces
hyperpolarization of the synaptic terminal of the photoreceptor.
(Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H:
Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

Incident light
Structural change in the
retinene1 of photopigment
Conformational change
of photopigment
Activation of transducin
Activation of
phosphodiesterase
Decreased
intracellular cGMP
Closure of Na+ channels
Hyperpolarization
Decreased release of
synaptic transmitter
Response in bipolar cells
and other neural elements
FIGURE 15–9 Sequence of events involved in
phototransduction in rods and cones. (Reproduced with permission
from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical
Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
PHOTOSENSITIVE COMPOUNDS
The photosensitive compounds in the rods and cones of the
eyes are made up of a protein called an opsin and retinal,
the aldehyde of vitamin A. The photosensitive pigment in the
rods is called rhodopsin, one of the many receptors coupled to
G proteins. Its opsin is called scotopsin. Rhodopsin has a peak
sensitivity to light at a wavelength of 505 nm.
Figure 15–9 summarizes the sequence of events in photore-
ceptors by which incident light produces a signal in the next
succeeding neural unit in the retina. Light activates rhodopsin
that then activates the associated heterotrimeric G protein,
transducin (Figure 15–10). The G protein exchanges GDP for
GTP, and the α-subunit separates. This subunit remains active
until its intrinsic GTPase activity hydrolyzes the GTP. The
α-subunit activates cGMP phosphodiesterase, which converts
cGMP to 5′-GMP. cGMP normally acts directly on Na+ chan-
nels to maintain them in the open position, so the decline in
the cytoplasmic cGMP concentration causes some Na+ chan-
nels to close. This produces the hyperpolarizing potential. This
cascade of reactions occurs very rapidly and amplifies the light
signal. The amplification helps explain the remarkable sensi-
tivity of rod photoreceptors; these receptors are capable of pro-
ducing a detectable response to as little as one photon of light.
CHAPTER 15 Special Senses I: Vision 139
Outer segment membrane
cGMP
phospho-
Rhodopsin Transducin diesterase
Disk
GTP cGMP
5'-GMP
Na+
Light
cGMP-gated
channel ECF
Rod outer segment
FIGURE 15–10 Initial steps in phototransduction in rods.
Light activates rhodopsin, which activates transducin to bind GTP.
This activates phosphodiesterase, which catalyzes the conversion of
cGMP to 5′-GMP. The resulting decrease in the cytoplasmic cGMP
concentration causes cGMP-gated ion channels to close. (Reproduced
with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of
Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
Cone receptors subserve color vision and respond maxi-
mally to light at wavelengths of 440, 535, and 565 nm. The
cone opsin resembles rhodopsin. The cell membrane of cones
is invaginated to form the saccules, but the cones have no sep-
arate intracellular disks like those in rods. The details of the
responses of cones to light are similar to those in rods.
PROCESSING OF VISUAL
INFORMATION IN THE RETINA
A characteristic of the bipolar and ganglion cells is that they
respond best to a small, circular stimulus and that, within their
receptive field, an annulus of light around the center (surround
illumination) inhibits the response to the central spot (Figure
15–11). The center can be excitatory with an inhibitory sur-
round (an “on-center” cell) or inhibitory with an excitatory
surround (an “off-center” cell). The inhibition of the center
response by the surround is probably due to inhibitory feed-
back from one photoreceptor to another mediated via horizontal
cells. The inhibition of the response to central illumination by
an increase in surrounding illumination is an example of lat-
eral inhibition in which activation of a particular neural unit is
associated with inhibition of the activity of nearby units. It is a
general phenomenon in sensory systems and helps to sharpen
the edges of a stimulus and improve discrimination.
VISUAL PATHWAYS
The axons of the retinal ganglion cells pass caudally in the
optic nerve and optic tract to end in the lateral geniculate
body in the thalamus (Figure 15–12). The fibers from each
140 SECTION IV CNS/Neural Physiology

On-center field Off-center field

Light Light

Central
illumination

Surround
illumination

FIGURE 15–11 Responses of retinal ganglion cells to light on the portions of their receptive fields indicated in white. Beside each
receptive field diagram is a diagram of the ganglion cell response, indicated by extracellularly recorded action potentials. Note that in three of
the four situations, there is increased discharge when the light is turned off. (Adapted with permission from Kuffler SW: Discharge patterns and functional
organizations of mammalian retina, J Neurophysiol. 1953;16(1):37–68.)

Temporal Nasal
field field LEFT RIGHT

A
LEFT RIGHT
EYE EYE

B
Ganglion
cell B Optic
nerve
A C
Optic chiasm

Pretectal
C region D
Optic
tract

Lateral
geniculate
body
Geniculocalcarine
tract

Occipital cortex
FIGURE 15–12 Visual pathways. Transection of the pathways at the locations indicated by the letters causes the visual field defects
shown in the diagrams on the right. The fibers from the nasal half of each retina decussate in the optic chiasm, so fibers in the optic tracts are
those from the temporal half of one retina and the nasal half of the other. A lesion that interrupts one optic nerve causes blindness in that eye
(A). A lesion in one optic tract causes blindness in half of the visual field (C) and is called homonymous (same side of both visual fields)
hemianopia (half-blindness). Lesions affecting the optic chiasm destroy fibers from both nasal hemiretinas and produce a heteronymous
(opposite sides of the visual fields) hemianopia (B). Occipital lesions may spare the fibers from the macula (as in D) because of the separation
in the brain of these fibers from the others subserving vision (see Figure 15–13). (Reproduced with permission from Barrett KE, Barman SM, Boitano S,
Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
 CHAPTER 15 Special Senses I: Vision 141

Upper peripheral
quadrant of retina

Upper Optic
quadrant nerves
of macula Optic
chiasm
Lower
quadrant
of macula
Lower peripheral Lateral geniculate
quadrant of retina Optic nucleus
tracts C Dorsal
FIGURE 15–13 Medial view of the human right cerebral I
hemisphere showing projection of the retina on the primary
C
visual cortex (Brodmann’s area 17; also known as V1) in the
occipital cortex around the calcarine fissure. The geniculocalcarine I
fibers from the medial half of the lateral geniculate terminate on the I
superior lip of the calcarine fissure, and those from the lateral half C
6
terminate on the inferior lip. The fibers from the lateral geniculate 5
Ventral 4
body that relay macular vision separate from those that relay 1 2
3
peripheral vision and end more posteriorly on the lips of the calcarine
fissure. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Magnocellular Parvocellular
pathway pathway
Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

nasal hemiretina decussate in the optic chiasm. In the genic-
ulate body, the fibers from the nasal half of one retina and
the temporal half of the other synapse on the cells whose
axons form the geniculocalcarine tract. This tract passes to
the occipital lobe of the cerebral cortex. The effects of lesions
in these pathways on visual function are discussed below.
The primary visual receiving area (primary visual cortex,
Brodmann’s area 17; also known as V1) is located princi-
pally on the sides of the calcarine fissure (Figure 15–13).
The organization of the primary visual cortex is discussed
below.
The axons of retinal ganglion cells project a detailed spatial
representation of the retina on the lateral geniculate body.
Each geniculate body contains six well-defined layers (Figure
15–14). Layers 3–6 have small parvocellular cells, and layers
1 and 2 have large magnocellular cells. On each side, layers 1,
4, and 6 receive input from the contralateral eye; layers 2, 3,
and 5 receive input from the ipsilateral eye. In each layer, there
is a precise point-for-point representation of the retina, and all
six layers are in register so that along a line perpendicular to
the layers, the receptive fields of the cells in each layer are
almost identical. Only 10–20% of the input to the lateral genic-
ulate nucleus comes from the retina; major inputs also come
from the visual cortex and other brain regions. The feedback
pathway from the visual cortex is involved in visual processing
related to the perception of orientation and motion.
There are two kinds of retinal ganglion cells: large magno or
M cells, which are concerned with movement and stereopsis,
and small parvo or P cells, which are concerned with color,
texture, and shape. The M and P ganglion cells project to the
magnocellular and parvocellular portions of the lateral genic-
ulate, respectively. From the lateral geniculate nucleus, a mag-
nocellular pathway and a parvocellular pathway project to the
visual cortex. The magnocellular pathway, from layers 1 and 2,
Primary visual cortex
(area 17)
FIGURE 15–14 Ganglion cell projections from the right
hemiretina of each eye to the right lateral geniculate body and from
this nucleus to the right primary visual cortex. Note the six layers of
the geniculate. P ganglion cells project to layers 3–6, and M ganglion
cells project to layers 1 and 2. The ipsilateral (I) and contralateral (C) eyes
project to alternate layers. Not shown are the interlaminar area cells,
which project via a separate component of the P pathway to blobs in
the visual cortex. (Modified with permission from Kandel ER, Schwartz JH, Jessell TM
[editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)
carries signals for detection of movement, depth, and flicker.
The parvocellular pathway, from layers 3–6, carries signals for
color vision, texture, shape, and fine detail.
Cells in the interlaminar region of the lateral geniculate
nucleus also receive input from P ganglion cells, probably via
dendrites of interlaminar cells that penetrate the parvocellular
layers. They project via a separate component of the P pathway
to the “blobs” in the visual cortex. These are clusters of cells
about 0.2 mm in diameter that, unlike the neighboring cells,
contain a high concentration of the mitochondrial enzyme
cytochrome oxidase.
PRIMARY VISUAL CORTEX
The lateral geniculate body projects a point-for-point repre-
sentation on the primary visual cortex (Figure 15–13). Like
the rest of the neocortex, the visual cortex has six layers. The
axons from the lateral geniculate nucleus that form the mag-
nocellular pathway end in layer 4. Many of the axons that form
the parvocellular pathway also end in layer 4; however, the
axons from the interlaminar region end in layers 2 and 3.
142 SECTION IV CNS/Neural Physiology
Layers 2 and 3 of the cortex contain blobs. They are arranged
in a mosaic in the visual cortex and are concerned with color
vision. However, the parvocellular pathway also carries color-
opponent data to the deep part of layer 4.
Like the ganglion cells, the lateral geniculate neurons and
the neurons in layer 4 of the visual cortex respond to stimuli in
their receptive fields with on-centers and inhibitory surrounds
or off-centers and excitatory surrounds. A bar of light cover-
ing the center is an effective stimulus for them because it stim-
ulates the entire center and relatively little of the surround.
However, the bar has no preferred orientation and, as a stimu-
lus, is equally effective at any angle.
The responses of the neurons in other layers of the visual cor-
tex are strikingly different. Simple cells respond to bars of light,
lines, or edges, but only when they have a particular orientation.
When a bar of light is rotated as little as 10° from the preferred
orientation, the firing rate of the simple cell is usually decreased,
and if the stimulus is rotated much more, the response disap-
pears. Complex cells, which resemble simple cells in requiring
a preferred orientation of a linear stimulus, are less dependent
on the location of a stimulus in the visual field than the simple
cells and the cells in layer 4. They often respond maximally
when a linear stimulus is moved laterally without a change in its
orientation. They may receive input from the simple cells.
The visual cortex is arranged in vertical columns that are
concerned with orientation (orientation columns). Each is
about 1 mm in diameter. However, the orientation preferences
of neighboring columns differ in a systematic way; as one
moves from column to column across the cortex, sequential
changes occur in orientation preference of 5°–10°. Thus, it
seems likely that for each ganglion cell receptive field in the
visual field, there is a collection of columns in a small area of
visual cortex representing the possible preferred orientations
at small intervals throughout the full 360°. The simple and
complex cells have been called feature detectors because they
respond to and analyze certain features of the stimulus.
Another feature of the visual cortex is the presence of ocular
dominance columns. The geniculate cells and the cells in layer
4 receive input from only one eye, and the layer 4 cells alter-
nate with cells receiving input from the other eye.
About half the simple and complex cells receive an input
from both eyes. The inputs are identical or nearly so in terms
of the portion of the visual field involved and the preferred
orientation. However, they differ in strength, so that between
the cells to which the input comes totally from the ipsilateral
or the contralateral eye, there is a spectrum of cells influenced
to different degrees by both eyes.
EFFECT OF LESIONS IN
THE OPTIC PATHWAYS
Lesions along the neural pathways from the eyes to the brain
can be localized with a high degree of accuracy by the effects
they produce in the visual fields (Figure 15–12). The fibers
from the nasal half of each retina decussate in the optic chiasm,
so that the fibers in the optic tracts are those from the tempo-
ral half of one retina and the nasal half of the other. Since
each optic tract subserves half of the field of vision, a lesion of
one optic nerve causes blindness in that eye, but a lesion in one
optic tract causes blindness in half of the visual field. This
defect is classified as a homonymous (same side of both visual
fields) hemianopia (half-blindness). Lesions affecting the
optic chiasm (e.g., pituitary tumors) cause disruption of the
fibers from both nasal hemiretinas and produce a heterony-
mous (opposite sides of the visual fields) hemianopia. Because
the fibers from the maculas are located posteriorly in the optic
chiasm, hemianopic scotomas develop before vision in the two
hemiretinas is completely lost. Selective visual field defects are
further classified as bitemporal, binasal, and right or left.
The optic nerve fibers from the upper retinal quadrants
subserving vision in the lower half of the visual field terminate
in the medial half of the lateral geniculate body, whereas the
fibers from the lower retinal quadrants terminate in the lateral
half. The geniculocalcarine fibers from the medial half of the
lateral geniculate terminate on the superior lip of the calcarine
fissure, and those from the lateral half terminate on the infe-
rior lip. The fibers from the lateral geniculate body that sub-
serve macular vision separate from those that subserve
peripheral vision and end more posteriorly on the lips of the
calcarine fissure (Figure 15–13). Because of this anatomic
arrangement, occipital lobe lesions may produce discrete
quadrantic visual field defects (upper and lower quadrants of
each half visual field). Macular sparing (i.e., loss of peripheral
vision with intact macular vision) is also common with occip-
ital lesions (Figure 15–12) because the macular representation
is separate from that of the peripheral fields and very large
relative to that of the peripheral fields. Therefore, occipital
lesions must extend considerable distances to destroy macular
as well as peripheral vision. Bilateral destruction of the occipi-
tal cortex in humans causes subjective blindness.
COLOR VISION
Colors have three attributes: hue, intensity, and saturation
(degree of freedom from dilution with white). For any color there
is a complementary color that, when properly mixed with it,
produces a sensation of white. Black is the sensation produced by
the absence of light, but it is probably a positive sensation because
the blind eye does not “see black;” rather, it “sees nothing.”
The sensation of white, any spectral color, and even the
extraspectral color, purple, can be produced by mixing various
proportions of red light (wavelength 723–647 nm), green light
(575–492 nm), and blue light (492–450 nm). Red, green, and
blue are therefore called the primary colors. Also, the color
perceived depends in part on the color of other objects in the
visual field. Thus, for example, a red object is seen as red if the
field is illuminated with green or blue light, but as pale pink or
white if the field is illuminated with red light.
Color is mediated by ganglion cells that subtract or add input
from one type of cone to input from another type. Processing in

the ganglion cells and the lateral geniculate nucleus produces
impulses that pass along three types of neural pathways that
project to V1: a red-green pathway that signals differences
between L- and M-cone responses, a blue-yellow pathway that
signals differences between S-cone and the sum of L- and
M-cone responses, and a luminance pathway that signals the
sum of L- and M-cone responses. These pathways project to the
blobs and the deep portion of layer 4 of V1. From the blobs and
layer 4, color information is projected to V8. However, it is not
known how V8 converts color input into the sensation of color.
Color blindness is most often an inherited condition in which
individuals are unable to distinguish certain colors. The most
common type is a red-green color vision deficit, a genetically
sex-linked condition that occurs in about 8% of males and 0.4%
of females. Blue-yellow color vision deficits are less common
and show no gender selectivity. Color blindness is usually due to
an inherited absence of cones for specific colors. It can also
occur in individuals with lesions of area V8 of the visual cortex.
PUPILLARY LIGHT REFLEX
When light is directed into one eye, the pupil constricts
(pupillary light reflex). The optic nerve fibers that carry the
impulses initiating these pupillary responses leave the optic
nerves near the lateral geniculate bodies. On each side, they
enter the midbrain via the brachium of the superior colliculus
and terminate in the pretectal nucleus. From this nucleus, the
FIGURE 15–15 Extraocular muscles subserving six cardinal positions of gaze. The eye is adducted by the medial rectus and
abducted by the lateral rectus. The adducted eye is elevated by the inferior oblique and depressed by the superior oblique; the abducted
eye is elevated by the superior rectus and depressed by the inferior rectus. (Reproduced with permission from Squire LR, et al [editors]: Fundamental
Neuroscience, 3rd ed. Academic Press, 2008.)
CHAPTER 15 Special Senses I: Vision 143
second-order neurons project to the ipsilateral and contralat-
eral Edinger–Westphal nucleus. The third-order neurons
pass from this nucleus to the ciliary ganglion in the oculomo-
tor nerve, and the fourth-order neurons pass from this gan-
glion to the ciliary body.
EYE MOVEMENTS
The eye is moved within the orbit by six ocular muscles
(Figure 15–15). These are innervated by the oculomotor, tro-
chlear, and abducens (cranial) nerves. Because the oblique
muscles pull medially, their actions vary with the position of
the eye. When the eye is turned nasally, the inferior oblique
elevates it and the superior oblique depresses it. When it is
turned laterally, the superior rectus elevates it and the inferior
rectus depresses it.
Because much of the visual field is binocular, a very high
order of coordination of the movements of the two eyes is nec-
essary if visual images are to fall at all times on corresponding
points in the two retinas and diplopia (double vision) is to be
avoided.
There are four types of eye movements, each controlled by a
different neural system but sharing the same final common
path, the motor neurons that supply the external ocular mus-
cles. Saccades, sudden jerky movements, occur as the gaze
shifts from one object to another. They bring new objects of
interest onto the fovea and reduce adaptation in the visual
144 SECTION IV CNS/Neural Physiology
pathway that would occur if gaze were fixed on a single object
for long periods. Smooth pursuit movements are tracking
movements of the eyes as they follow moving objects. Vestibu-
lar movements, adjustments that occur in response to stimuli
initiated in the semicircular canals, maintain visual fixation as
the head moves. Convergence movements bring the visual
axes toward each other as attention is focused on objects near
the observer. The similarity to a human-made tracking system
on an unstable platform such as a ship is apparent: saccadic
movements seek out visual targets, pursuit movements follow
them as they move about, and vestibular movements stabilize
the tracking device as the platform on which the device is
mounted (i.e., the head) moves about. Saccades are pro-
grammed in the frontal cortex and the superior colliculi and
pursuit movements in the cerebellum.
CLINICAL CORRELATION
A 33-year-old salesman was driving his car in a rural area
and did not notice the bicyclist riding on the sidewalk to
the right of his car. He made a right-hand turn at the cor-
ner and accidentally hit the young woman. Luckily she
was not hurt, but he recalled that a few days ago as he was
walking along a sidewalk, he did not notice a dog
approaching him from the left. He was now aware that he
has reduced peripheral vision. He made an appointment
with an ophthalmologist for a visual field exam. The
results showed that he had reduced vision on the tempo-
ral half of the visual field of both eyes. When asked
whether he had noticed an increase incidence of head-
aches recently, he responded positively. He had thought
the headaches were due to recent stress of his job.
The results of the visual field exam indicated bitempo-
ral hemianopia (a type of heteronymous hemianopia).
This signifies damage to the optic chiasm that carries
axons of ganglion cells from the nasal halves of the retina
that transmits visual information from the temporal visual
fields. A common cause for this defect is a pituitary tumor
such as a pituitary adenoma. The pituitary gland is located
ventral to the optic chiasm. When the tumor grows, it
presses on the optic chiasm. Headaches and decreased
libido often occur as a result of the tumor that is typically
benign. A magnetic resonance image of the pituitary gland
in this patient revealed a tumor pressing on the optic chi-
asm. Medical treatment caused the tumor to shrink and
his visual fields were restored to normal. (See Chapter 62
for more details about tumors of the anterior pituitary.)
CHAPTER SUMMARY
■ The major parts of the eye are the sclera (protective covering),
cornea (transfer light rays), choroids (nourishment), retina
(receptor cells), lens, and iris.
■ The bending of light rays (refraction) allows one to focus an
accurate image onto the retina. Light is refracted at the anterior
surface of the cornea and at the anterior and posterior surfaces
of the lens. To bring diverging rays from close objects to a focus
on the retina, the curvature of the lens is increased, a process
called accommodation.
■ In hyperopia (farsightedness), the eyeball is too short and light
rays come to a focus behind the retina. In myopia (nearsighted-
ness), the anteroposterior diameter of the eyeball is too long.
Astigmatism is a common condition in which the curvature of
the cornea is not uniform. Presbyopia is the loss of accommo-
dation for near vision. Strabismus is a misalignment of the eyes
usually due to problems with eye muscles.
■ Na+ channels in the outer segments of the rods and cones are
open in the dark, so current flows from the inner to the outer
segment. When light strikes the outer segment, some of the Na+
channels are closed and the cells are hyperpolarized.
■ Neurons in layer 4 of the visual cortex respond to stimuli in
their receptive fields with on-centers and inhibitory surrounds
or off-centers and excitatory surrounds. Neurons in other
layers are called simple cells if they respond to bars of light,
lines, or edges, but only when they have a particular orienta-
tion. Complex cells also require a preferred orientation of a
linear stimulus but are less dependent on the location of a
stimulus in the visual field.
■ The visual pathway is from the rods and cones to bipolar cells
to ganglion cells, and then via the optic tract to the thalamic
lateral geniculate body to the occipital lobe of the cerebral
cortex. The fibers from each nasal hemiretina decussate in the
optic chiasm; the fibers from the nasal half of one retina and
the temporal half of the other synapse on the cells whose axons
form the geniculocalcarine tract.
■ Saccades (sudden jerky movements) occur as the gaze shifts
from one object to another, and they reduce adaptation in the
visual pathway that would occur if gaze were fixed on a single
object for long periods. Smooth pursuit movements are
tracking movements of the eyes as they follow moving objects.
Vestibular movements occur in response to stimuli in the
semicircular canals to maintain visual fixation as the head
moves. Convergence movements bring the visual axes toward
each other as attention is focused on objects near the observer.
STUDY QUESTIONS
1. A visual exam in an 80-year-old man shows he has a reduced
ability to see objects in the upper and lower quadrants of the left
visual fields of both eyes but some vision remains in the central
regions of the visual field. The diagnosis is
A) central scotoma.
B) heteronymous hemianopia with macular sparing.
C) lesion of the optic chiasm.
D) homonymous hemianopia with macular sparing.
E) retinopathy.
2. Visual accommodation involves
A) increased tension on the lens ligaments.
B) a decrease in the curvature of the lens.
C) relaxation of the sphincter muscle of the iris.
D) contraction of the ciliary muscle.
E) increased intraocular pressure.
 CHAPTER 15 Special Senses I: Vision 145

3. The fovea of the eye 6. Vitamin A is a precursor for the synthesis of

A) has the lowest light threshold. A) transducin.
B) is the region of highest visual acuity. B) retinals.
C) contains only cones. C) the pigment of the iris.
D) contains only rods. D) scotopsin.
E) is situated over the head of the optic nerve. E) aqueous humor.
4. Which of the following parts of the eye has the greatest 7. Which of the following is not involved in color vision?
concentration of rods? A) activation of a pathway that signals differences between
A) ciliary body S-cone responses and the sum of L- and M-cone responses
B) iris B) geniculate layers 3–6
C) optic disk C) P pathway
D) fovea D) area V3A of visual cortex
E) extrafoveal region E) area V8 of visual cortex
5. The correct sequence of events involved in phototransduction in
rods and cones in response to light is
A) activation of transducin, decreased release of glutamate,
structural changes in rhodopsin, closure of Na+ channels,
and decrease in intracellular cGMP.
B) decreased release of glutamate, activation of transducin,
closure of Na+ channels, decrease in intracellular cGMP, and
structural changes in rhodopsin.
C) structural changes in rhodopsin, decrease in intracellular
cGMP, decreased release of glutamate, closure of Na+
channels, and activation of transducin.
D) structural changes in rhodopsin, activation of transducin,
decrease in intracellular cGMP, closure of Na+ channels, and
decreased release of glutamate.
E) activation of transducin, structural changes in rhodopsin,
closure of Na+ channels, decrease in intracellular cGMP, and
decreased release of glutamate.
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 16
C H A P T E R

Special Senses II:

Hearing and Equilibrium
Susan M. Barman

O B J E C T I V E S

■ Describe the components and functions of the external, middle, and

inner ear.
■ Describe the way that movements of molecules in the air are converted into
impulses generated in hair cells in the cochlea.
■ Trace the path of auditory impulses in the neural pathways from the cochlear
hair cells to the auditory cortex, and discuss the function of the auditory
cortex.
■ Explain how pitch and loudness are coded in the auditory pathways.
■ Describe the various forms of deafness and tests for their diagnosis.
■ Explain how the receptors in the semicircular canals detect rotational
acceleration and how the receptors in the saccule and utricle detect linear
acceleration.
■ List the major sensory inputs that provide the information synthesized in the
brain into the sense of position in space.

INTRODUCTION
Receptors for hearing and equilibrium are housed in the ear.
The external ear, middle ear, and cochlea of the inner ear are
concerned with hearing. The semicircular canals, utricle, and
saccule of the inner ear are concerned with equilibrium.
Receptors in the semicircular canals (hair cells) detect rota-
tional acceleration, receptors in the utricle detect linear accel-
eration in the horizontal direction, and receptors in the saccule
detect linear acceleration in the vertical direction.
ANATOMY OF THE EAR
EXTERNAL AND MIDDLE EAR
The external ear funnels sound waves to the external
auditory meatus (Figure 16–1). Sound waves pass inward to
the tympanic membrane (eardrum). The middle ear is an
air-filled cavity in the temporal bone that opens via the
auditory (Eustachian) tube into the nasopharynx and
through the nasopharynx to the exterior. The tube is usually
closed, but during swallowing, chewing, and yawning it
opens, equalizing air pressure on the two sides of the ear-
drum. The three auditory ossicles (malleus, incus, and
stapes) are in the middle ear (Figure 16–2). The manubrium
(handle of the malleus) is attached to the back of the tym-
panic membrane. Its head is attached to the wall of the mid-
dle ear, and its short process is attached to the incus, which
articulates with the head of the stapes. The foot plate of the
stapes is attached by an annular ligament to the walls of the
oval window. Two small skeletal muscles (tensor tympani
and stapedius) are located in the middle ear. Contraction of
the former pulls the manubrium of the malleus medially and
decreases the vibrations of the tympanic membrane; con-
traction of the latter pulls the foot plate of the stapes out of
the oval window.

147

Ch16_147-158.indd 147 11/26/10 9:45:37 AM

148 SECTION IV CNS/Neural Physiology

FIGURE 16–1 Structures of the outer, middle, and inner portions of the human ear. For clarity, the cochlea has been turned slightly
and the middle ear muscles have been omitted. (Reproduced with permission from Fox SI: Human Physiology. McGraw-Hill, 2008.)

FIGURE 16–2 The medial view of the middle ear. The locations of auditory muscles attached to the middle ear ossicles are indicated.
(Reproduced with permission from Fox SI: Human Physiology. McGraw-Hill, 2008.)
 CHAPTER 16 Special Senses II: Hearing and Equilibrium 149

INNER EAR AND COCHLEA
The inner ear (labyrinth) is made up of two parts, one within
the other. The bony labyrinth is a series of channels in the
temporal bone. Inside these channels, surrounded by a fluid
(perilymph) is the membranous labyrinth (Figure 16–3) that
is filled with a K+-rich fluid (endolymph). There is no com-
munication between the spaces filled with endolymph and
those filled with perilymph.
The cochlear portion of the labyrinth is a coiled tube that, in
humans, is 35-mm long and makes approximately 2.75 turns.
The basilar membrane and Reissner’s membrane divide it
into three chambers or scalae (Figure 16–4). The upper scala
vestibuli and the lower scala tympani contain perilymph and
communicate with each other at the apex of the cochlea via a
small opening (helicotrema). At the base of the cochlea, the
scala vestibuli ends at the oval window, which is closed by the
footplate of the stapes. The scala tympani end at the round
window, a foramen on the medial wall of the middle ear that
is closed by the flexible secondary tympanic membrane.
The scala media is continuous with the membranous laby-
rinth and does not communicate with the other two scalae.
The organ of Corti contains the auditory receptors (hair
cells) whose processes pierce the reticular lamina that is sup-
ported by the pillar cells or rods of Corti (Figure 16–4). The
hair cells are arranged in four rows: three rows of outer hair
cells lateral to the tunnel formed by the rods of Corti, and one
row of inner hair cells medial to the tunnel. Covering the rows
of hair cells is the tectorial membrane in which the tips of the
hairs of the outer cells are embedded. The cell bodies of
the sensory neurons are located in the spiral ganglion within
the modiolus; ~95% of these sensory neurons innervate inner
hair cells, ~5% innervate outer hair cells, and each sensory
neuron innervates several outer hair cells. By contrast, most
efferent fibers in the auditory nerve terminate on the outer
hair cells. The axons of afferent neurons that innervate hair
cells form the auditory (cochlear) division of the eighth cranial
nerve.
The semicircular canals are oriented in the three planes.
Inside the bony canals, the membranous canals are suspended

Cupula

Semicircular canal

VIII

Tectorial membrane

Basilar
membrane

Otolithic membrane
Cochlea

Sacculus
FIGURE 16–3 Schematic of the human inner ear showing the membranous labyrinth with enlargements of the structures in which
hair cells are embedded. The membranous labyrinth is suspended in perilymph and filled with K+-rich endolymph that bathes the receptors.
Hair cells (darkened for emphasis) are in different arrays characteristic of the receptor organs. The semicircular canals are sensitive to angular
acceleration that deflects the gelatinous cupula and associated hair cells. In the cochlea, hair cells spiral along the basilar membrane in the organ
of Corti. Airborne sounds set the eardrum in motion, which is conveyed to the cochlea by bones of the middle ear. This flexes the membrane up
and down. Hair cells in the organ of Corti are stimulated by shearing motion. The otolithic organs (saccule and utricle) are sensitive to linear
acceleration in vertical and horizontal planes. Hair cells are attached to the otolithic membrane. VIII, eighth cranial nerve, with auditory and
vestibular divisions. (Adapted with permission from Hudspeth AJ. How the ear’s works work. Nature. 1989;341:397. Copyright 1989 by Macmillan Magazines.)
150 SECTION IV CNS/Neural Physiology

AUDITORY RECEPTORS:
Scala Stria HAIR CELLS
vestibuli vascularis
Reissner’s Spiral The hair cells in the organ of Corti signal hearing, the hair cells
membrane ligament in the utricle signal horizontal acceleration, the hair cells in the
Tectorial
membrane Scala saccule signal vertical acceleration, and a patch in each of the
Limbus media three semicircular canals signals rotational acceleration. These
hair cells have a common structure (Figure 16–5). Each is
Spiral embedded in an epithelium made up of supporting cells, with
prominence the basal end in close contact with afferent neurons. Project-
Spiral ing from the apical end are 30–150 rod-shaped processes or
ganglion Scala Spiral
tympani ligament hairs. Except in the cochlea, one of these, the kinocilium, is a
Modiolus
true but nonmotile cilium with nine pairs of microtubules
around its circumference and a central pair of microtubules. It
Spiral Basilar
lamina Organ
membrane is one of the largest processes and has a clubbed end. The
of Corti
kinocilium is lost from the hair cells of the cochlea in adults;
however, the other processes (stereocilia) are found in all hair
Reticular Outer cells. They have cores composed of parallel filaments of actin
lamina hair cells DCs that is coated with isoforms of myosin. Within the clump of
processes on each cell there is an orderly structure. Along an
axis toward the kinocilium, the stereocilia increase progres-
Tectorial
membrane sively in height; along the perpendicular axis, all stereocilia are
Inner the same height.
hair cell Arch
IPC
Tunnel
ELECTRICAL RESPONSES
Nerve
fibers Habenula Pillar cell Basilar
The resting membrane potential of the hair cells is about
perforata (rod of Corti) membrane –60 mV. When the stereocilia are pushed toward the kinocil-
Spiral ium, the membrane potential is decreased to about –50 mV.
lamina The hair processes provide a mechanism to generate changes
FIGURE 16–4 Top: Cross-section of the cochlea, showing the in membrane potential proportional to the direction and dis-
organ of Corti and the three scalae of the cochlea. Bottom: tance the hair moves. When the bundle of processes is pushed
Structure of the organ of Corti, as it appears in the basal turn of the in the opposite direction, the cell is hyperpolarized. Displac-
cochlea. DC, outer phalangeal cells (Deiters’ cells) supporting outer ing the processes in a direction perpendicular to this axis pro-
hair cells; IPC, inner phalangeal cell supporting inner hair cell.
vides no change in membrane potential, and displacing the
(Reproduced with permission from Pickels JO: An Introduction to the Physiology of
processes in directions that are intermediate between these
Hearing, 2nd ed. Academic Press, 1988.)
two directions produces depolarization or hyperpolarization
that is proportionate to the degree to which the direction is
in perilymph. A receptor structure (crista ampullaris) is toward or away from the kinocilium.
located in the expanded end (ampulla) of each of the mem-
branous canals. Each crista consists of hair cells and support-
ing (sustentacular) cells surmounted by a gelatinous partition GENESIS OF ACTION POTENTIALS
(cupula) that closes off the ampulla (Figure 16–3). The pro- IN AFFERENT NERVE FIBERS
cesses of the hair cells are embedded in the cupula, and the
bases of the hair cells contact the afferent fibers of the vestibu- Very fine processes called tip links (Figure 16–6) tie the tip of
lar division of the eighth cranial nerve. each stereocilium to the side of its higher neighbor, and at the
Within each membranous labyrinth is an otolithic organ junction are mechanosensitive cation channels. If shorter ste-
(macula). Another macula is located on the wall of the saccule reocilia are pushed toward higher ones, the open time of the
in a semivertical position. The maculae contain supporting channels increases. K+ and Ca2+ enter via the channel and pro-
cells and hair cells, surmounted by an otolithic membrane in duce depolarization. A molecular motor in the higher neigh-
which are embedded crystals of calcium carbonate, the oto- bor then may move the channel toward the base, releasing
liths (Figure 16–3), which are also called otoconia or ear dust. tension in the tip link. This causes the channel to close and
The processes of the hair cells are embedded in the membrane. permits restoration of the resting state. Depolarization of hair
The nerve fibers from the hair cells join those from the cristae cells causes them to release a neurotransmitter that initiates
in the vestibular division of the eighth cranial nerve. depolarization of neighboring afferent neurons.
 CHAPTER 16 Special Senses II: Hearing and Equilibrium 151

OM OM
OL

K
S

RC SC

A E

FIGURE 16–5 Structure of a hair cell in the saccule. Left: Hair cells in the membranous labyrinth of the ear have a common structure,
and each is within an epithelium of supporting cells (SC) surmounted by an otolithic membrane (OM) embedded with the otoliths (OL).
Projecting from the apical end are rod-shaped processes, or hair cells (RC), in contact with afferent (A) and efferent (E) nerve fibers. Except in the
cochlea, one of these, kinocilium (K), is a true but nonmotile cilium with nine pairs of microtubules around its circumference and a central pair
of microtubules. The other processes, stereocilia (S), are found in all hair cells; they have cores of actin filaments coated with isoforms of myosin.
There is an orderly structure within the clump of processes on each cell. Along an axis toward the kinocilium, the stereocilia increase
progressively in height; along the perpendicular axis, all stereocilia are the same height. (Reproduced with permission from Hillman DE: Morphology of
peripheral and central vestibular systems. In: Frog Neurobiology. Llinas R, Precht W (editors). Springer, 1976.) Right: Scanning electron photomicrograph of
processes on a hair cell in the saccule. The otolithic membrane has been removed. The small projections around the hair cell are microvilli on
supporting cells. (Courtesy of A.J. Hudspeth.)

Myosin
K+
Ca2+

Tip link

FIGURE 16–6 Schematic representation of the role of tip links in the responses of hair cells. When a stereocilium is pushed
toward a taller stereocilium, the tip link is stretched and opens an ion channel in its taller neighbor. The channel next is moved down the taller
stereocilium by a molecular motor, so the tension on the tip link is released. When hairs return to their resting position, the motor moves back
up the stereocilium. (Modified with permission from Kandel ER, Schwartz JH, Jessel TM [editors]: Principles of Neuroscience, 4th ed. McGraw-Hill, 2000.)
152 SECTION IV CNS/Neural Physiology
Scala vestibuli SL and
SV
Na+ 150
K+ 5 erate, and 30 dB (e.g., whisper, library) is faint.
Cl− 125
Na+ 1 sounds. The threshold of the human ear varies with the pitch
K+ 150
−
Cl 130
Organ of Corti Na+ 150
K+ 3 about 2,000, but trained musicians can improve on this figure
Cl− 125
Scala tympani
FIGURE 16–7 Ionic composition (mmol/L) of perilymph in
the scala vestibuli, endolymph in the scala media, and perilymph
in the scala tympani. SL, spiral ligament; SV, stria vascularis. The
dashed arrow indicates the path by which K+ recycles from the hair
cells to the supporting cells to the spiral ligament and is then
secreted back into the endolymph by cells in the stria vascularis.
(Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H:
Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
The K+ that enters hair cells via the mechanosensitive cation
channels is recycled (Figure 16–7). It enters supporting cells
and then passes on to other supporting cells via tight junc-
tions. In the cochlea, it eventually reaches the stria vascularis
and is secreted back into the endolymph, completing the cycle.
The processes of the hair cells project into the endolymph and
the bases are bathed in perilymph. The perilymph is formed
mainly from plasma; endolymph is formed in the scala media
by the stria vascularis and has a high concentration of K+ and
a low concentration of Na+. Cells in the stria vascularis have a
high concentration of Na+,K+-ATPase.
HEARING
SOUND WAVES
Sound is the sensation produced when vibrations of molecules in
the external environment strike the tympanic membrane. The
loudness of a sound is typically correlated with the amplitude of
a sound wave and its pitch with its frequency (number of waves
per unit of time). The amplitude of a sound wave is expressed on
a relative scale, called a decibel scale. The intensity of a sound in
bels is the logarithm of the ratio of the intensity of that sound to a
standard sound. A value of 0 dB does not mean the absence of
sound; rather, it is a sound level whose intensity is equal to that of
a standard. The 0–160-dB range from threshold pressure to a
pressure that is potentially damaging to the organ of Corti actu-
ally represents a 107-fold variation in sound pressure.
A range of 120–160 dB (e.g., firearms, jackhammer, jet plane
on takeoff) is painful, 90–110 dB (e.g., subway, bass drum,
chain saw, lawn mower) is extremely high, 60–80 dB (e.g., alarm
clock, busy traffic, dishwasher, conversation) is very loud,
40–50 dB (e.g., moderate rainfall, normal room noise) is mod-
The sound frequencies audible to humans range from about
20 to 20,000 cycles per second (cps, Hz). The range decreases
with age, especially difficulty detecting higher frequency
of the sound; the greatest sensitivity is in the 1,000–4,000-Hz
range. The pitch of the average male and female voice in con-
versation is 120 and 250 Hz, respectively. The number of
pitches that can be distinguished by an average individual is
considerably.
SOUND TRANSMISSION
The ear converts sound waves in the environment into action
potentials in the auditory nerves. The waves are transformed
by the eardrum and auditory ossicles into movements of the
foot plate of the stapes. These movements set up waves in the
fluid of the inner ear. The action of the waves on the organ of
Corti generates action potentials in the nerve.
The tympanic membrane moves in and out in response to
the pressure changes produced by sound waves on its external
surface. Thus, the membrane functions as a resonator that
reproduces the vibrations of the sound source. It stops vibrat-
ing almost immediately when the sound wave stops. The
motions of the tympanic membrane are imparted to the man-
ubrium. The malleus rocks on an axis through the junction of
its long and short processes, so that the short process transmits
the vibrations of the manubrium to the incus. The incus moves
in such a way that the vibrations are transmitted to the head of
the stapes. Movements of the head of the stapes swing its foot
plate to and fro like a door hinged at the posterior edge of the
oval window. The auditory ossicles function as a lever system
that converts the resonant vibrations of the tympanic mem-
brane into movements of the stapes against the perilymph-
filled scala vestibuli of the cochlea (Figure 16–8). This system
increases the sound pressure that arrives at the oval window,
because the lever action of the malleus and incus multiplies
the force 1.3 times and the area of the tympanic membrane is
much greater than the area of the foot plate of the stapes.
When the middle ear muscles (tensor tympani and stape-
dius) contract, the manubrium of the malleus pulls inward
and the foot plate of the stapes pushes outward (Figure 16–2),
decreasing sound transmission. Loud sounds initiate the tym-
panic reflex, which contracts the middle ear muscles to pre-
vent strong sound waves from causing excessive stimulation of
the auditory receptors.
BONE AND AIR CONDUCTION
Ossicular conduction is the normal conduction of sound
waves to the fluid of the inner ear via the tympanic
 CHAPTER 16 Special Senses II: Hearing and Equilibrium
Malleus
Pivot
Incus
Stapes
Oval Reissner's
window membrane
Organ
of Corti
Round
window
Basilar
Auditory tube membrane
FIGURE 16–8 Schematic representation of the auditory
ossicles and the way their movement translates movements of
the tympanic membrane into a wave in the fluid of the inner ear.
The wave is dissipated at the round window. The movements of
the ossicles, the membranous labyrinth, and the round window are
indicated by dashed lines. (Reproduced with permission from Barrett KE,
Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed.
McGraw-Hill Medical, 2009.)
membrane and the auditory ossicles. Sound waves also ini-
tiate vibrations of the secondary tympanic membrane that
closes the round window; this process, unimportant in nor-
mal hearing, is called air conduction. Bone conduction is
the transmission of vibrations of the bones of the skull to
the fluid of the inner ear; this plays a role in transmission of
extremely loud sounds. Considerable bone conduction also
occurs when a vibrating tuning fork is applied directly to
the skull.
TRAVELING WAVES
The movements of the foot plate of the stapes set up a series
of traveling waves in the perilymph of the scala vestibuli.
The bony walls of the scala vestibuli are rigid, but Reissner’s
membrane is flexible. The basilar membrane is not under
tension, and it also is readily depressed into the scala tym-
pani by the peaks of waves in the scala vestibuli. Displace-
ments of the fluid in the scala tympani are dissipated into air
at the round window. Sound distorts the basilar membrane,
and the site at which this distortion is maximal is deter-
mined by the frequency of the sound wave. The tops of the
hair cells in the organ of Corti are held rigid by the reticular
lamina, and the processes of the outer hair cells are embed-
ded in the tectorial membrane (Figure 16–4). When the sta-
pes moves, both membranes move in the same direction, but
they are hinged on different axes, so a shearing motion
bends the hairs. The processes of the inner hair cells are not
attached to the tectorial membrane, but they are bent by
fluid moving between the membrane and the underlying
hair cells.
153
ACTION POTENTIALS IN
AUDITORY NERVE FIBERS
Inner hair cells are the primary sensory cells that generate
action potentials in auditory nerves and are stimulated by the
fluid movements noted above. Outer hair cells respond to
sound, but depolarization makes them short and hyperpolar-
ization makes them lengthy. They do this over a very flexible
part of the basal membrane, and this action increases the
amplitude and clarity of sounds. The frequency of the action
potentials in auditory nerve fibers is proportional to the loud-
ness of the sound stimuli.
The major determinant of the pitch perceived when a sound
wave strikes the ear is the place in the organ of Corti that is
maximally stimulated. The traveling wave set up by a tone pro-
duces peak depression of the basilar membrane, and conse-
quently maximal receptor stimulation, at one point. The
distance between this point and the stapes is inversely related
to the pitch of the sound, with low tones producing maximal
stimulation at the apex of the cochlea and high tones produc-
ing maximal stimulation at the base.
CENTRAL PATHWAY
The afferent fibers in the auditory division of the eighth cranial
nerve end in dorsal and ventral cochlear nuclei (Figure 16–9).
From there, auditory impulses pass by various routes to the
inferior colliculi, the centers for auditory reflexes, and via the
medial geniculate body in the thalamus to the auditory cor-
tex. Other impulses enter the reticular formation. Information
from both ears converges on each superior olive, and beyond
this, most of the neurons respond to inputs from both sides.
The primary auditory cortex is Brodmann’s area 41. Low
tones are represented anterolaterally and high tones postero-
medially in the auditory cortex.
In the primary auditory cortex, most neurons respond to
inputs from both ears, but strips of cells are stimulated
by input from the contralateral ear and inhibited by input
from the ipsilateral ear. There are several additional auditory
receiving areas, just as there are several receiving areas for
cutaneous sensation. The auditory association areas adjacent
to the primary auditory receiving areas are widespread.
The olivocochlear bundle is a prominent bundle of efferent
fibers in each auditory nerve that arises from both ipsilateral
and contralateral superior olivary complexes and ends primar-
ily around the bases of the outer hair cells of the organ of
Corti.
SOUND LOCALIZATION
Determination of the direction from which a sound ema-
nates in the horizontal plane depends on detecting the dif-
ference in time between the arrival of the stimulus in the
two ears and the consequent difference in phase of the sound
154 SECTION IV CNS/Neural Physiology
waves on the two sides; it also depends on the fact that the
sound is louder on the side closest to the source. The detect-
able time difference, which can be as little as 20 microsec-
onds, is the most important factor at frequencies below
3,000 Hz and the loudness difference the most important
factor at frequencies above 3,000 Hz. Neurons in the audi-
tory cortex that receive input from both ears respond maxi-
mally or minimally when the time of arrival of a stimulus at
one ear is delayed by a fixed period relative to the time of
arrival at the other ear. This fixed period varies from neuron
to neuron.
Sounds coming from directly in front of the individual dif-
fer in quality from those coming from behind because each
pinna (the visible portion of the exterior ear) is turned slightly
forward. Also, reflections of sound waves from the pinnal sur-
face change as sounds move up or down; the change in the
sound waves is the primary factor in locating sounds in the
vertical plane. Lesions of the auditory cortex disrupt sound
localization.
DEAFNESS
Hearing loss is the most common sensory defect in humans.
Presbycusis, the gradual hearing loss associated with aging,
affects more than one third of those over 75 and is probably
due to gradual cumulative loss of hair cells and neurons. In
most cases, hearing loss is a multifactorial disorder caused by
both genetic and environmental factors.
Conductive deafness refers to impaired sound transmission
in the external or middle ear and impacts all sound frequen-
cies. Causes of conduction deafness include plugging of the
external auditory canals with wax (cerumen) or foreign bod-
ies, fluid accumulation due to otitis externa (inflammation of
the outer ear, “swimmer’s ear”) or otitis media (inflammation
of the middle ear), perforation of the eardrum, and osteoscler-
osis in which bone is resorbed and replaced with sclerotic
bone that grows over the oval window.
Sensorineural deafness is usually due to the loss of
cochlear hair cells but can also be due to problems with the
TABLE 16–1 Common tests with a tuning fork to distinguish between sensorineural and conduction deafness.
Weber
Method Base of vibrating tuning fork placed on
vertex of skull
Normal Hears equally on both sides
Conduction deafness Sound louder in diseased ear because
(one ear) masking effect of environmental noise
is absent on diseased side
Sensorineural deafness Sound louder in normal ear
(one ear)
eighth cranial nerve or within central auditory pathways. It
can impair the ability to hear certain pitches while others
are unaffected. Aminoglycoside antibiotics such as strepto-
mycin and gentamicin obstruct the mechanosensitive chan-
nels in the stereocilia of hair cells and can cause the cells to
degenerate, producing sensorineural hearing loss and
abnormal vestibular function. Damage to the outer hair cells
by prolonged exposure to noise is associated with hearing
loss. Other causes include tumors of the eighth cranial nerve
and cerebellopontine angle and vascular damage in the
medulla.
Conduction and sensorineural deafness can be differenti-
ated by simple tests with a tuning fork. Three of these tests,
named for the individuals who developed them, are outlined
in Table 16–1. The Weber and Schwabach tests demonstrate
the important masking effect of environmental noise on the
auditory threshold.
VESTIBULAR SYSTEM
The vestibular system is divided into the vestibular apparatus
and central vestibular nuclei. The vestibular apparatus within
the inner ear detects head motion and position and transduces
this information into a neural signal. The vestibular nuclei are
concerned with maintaining the position of the head in space;
the tracts that descend from these nuclei mediate head-on-
neck and head-on-body adjustments.
The vestibular ganglia contain the cell bodies of the neurons
supplying the cristae and maculae. Each vestibular nerve ter-
minates in the ipsilateral vestibular nucleus and in the floccu-
lonodular lobe of the cerebellum (Figure 16–9). Fibers from
the semicircular canals end in the superior and medial divi-
sions of the vestibular nucleus and project mainly to nuclei
controlling eye movement. Fibers from the utricle and saccule
end in Deiters’ nucleus, which projects to the spinal cord.
The vestibular nuclei also project to the thalamus and from
there to the primary somatosensory cortex. The ascending
connections to cranial nerve nuclei are concerned with eye
movements.
Rinne Schwabach
Base of vibrating tuning fork placed on Bone conduction of patient
mastoid process until subject no longer compared with that of healthy
hears it, and then held in air next to ear subject
Hears vibration in air after bone
conduction is over
Vibrations in air not heard after bone Bone conduction better than
conduction is over normal (conduction defect
excludes masking noise)
Vibration heard in air after bone Bone conduction worse than
conduction is over, as long as nerve normal
deafness is partial
 CHAPTER 16 Special Senses II: Hearing and Equilibrium 155

To somatosensory
cortex
To cortex (superior
temporal gyrus)

Thalamus

Thalamus
Medial
geniculate III
body
IV
Medial
Pineal To longitudinal
cerebellum fasciculus
Inferior colliculus VI
Reticular
formation
IV ventricle

Dorsal and ventral

cochlear nuclei Vestibular
ganglion
Vestibular nuclei:
superior, lateral
(Deiters’), medial,
Spiral Medulla Lateral spinal
ganglion vestibulo-
Superior spinal tract Anterior vestibulo-
olives spinal tracts
From utricle,
From semicircular
cochlea canals

AUDITORY VESTIBULAR
FIGURE 16–9 Simplified diagram of main auditory (left) and vestibular (right) pathways superimposed on a dorsal view of the
brain stem. Cerebellum and cerebral cortex have been removed. III, IV, and VI are the 3rd, 4th, and 6th cranial nerves. (Reproduced with permission
from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

RESPONSES TO ROTATIONAL Nystagmus is the characteristic jerky movement of the eye

ACCELERATION
Rotational acceleration in the plane of a given semicircular
canal stimulates its crista. The endolymph is displaced in a
direction opposite to the rotation, and the fluid pushes on the
cupula, deforming it. This bends the processes of the hair cells
(Figure 16–3). When a constant speed of rotation is reached,
the fluid spins at the same rate as the body and the cupula
swings back into the upright position. When rotation is
stopped, deceleration produces displacement of the endo-
lymph in the direction of the rotation, and the cupula is
deformed in a direction opposite to that during acceleration. It
returns to mid position in 25–30 seconds. Movement of the
cupula in one direction increases the activity of nerves from
the crista, and movement in the opposite direction inhibits
neural activity.
Rotation causes maximal stimulation of the semicircular
canals in the plane of rotation. Because the canals on one side
of the head are a mirror image of those on the other side, the
endolymph is displaced toward the ampulla on one side and
away from it on the other. The pattern of stimulation reaching
the brain varies with the direction and the plane of rotation.
observed at the start and end of a period of rotation. It is a reflex
that maintains visual fixation on stationary points while the
body rotates. When rotation starts, the eyes move slowly in a
direction opposite to the direction of rotation, maintaining
visual fixation (vestibulo-ocular reflex). At the end of this
movement, the eyes quickly snap back to a new fixation point
and then again move slowly in the other direction. The slow
component is initiated by impulses from the vestibular laby-
rinths; the quick component is triggered by a center in the brain
stem. By convention, the direction of eye movement in nystag-
mus is identified by the direction of the quick component. The
direction of the quick component is the same as that of the rota-
tion; postrotatory nystagmus, which is due to displacement of
the cupula, is in the opposite direction. Nystagmus can be
observed at rest in patients with lesions of the brain stem. Caloric
stimulation can be used to test the function of the vestibular
labyrinth. The semicircular canals are stimulated by instilling
warm (40°C) or cold (30°C) water into the ear. The temperature
difference sets up convection currents in the endolymph, with
consequent motion of the cupula. In normal subjects, warm
water causes nystagmus that bears toward the stimulus, and cold
water induces nystagmus that bears toward the opposite ear.
156 SECTION IV CNS/Neural Physiology
RESPONSES TO LINEAR ACCELERATION
The utricular and saccular maculae respond to horizontal and
vertical acceleration, respectively. The otoliths are denser than
the endolymph, and acceleration in any direction causes them
to be displaced in the opposite direction, distorting the hair
cell processes and generating neural activity. The maculae also
discharge tonically in the absence of head movement, because
of the pull of gravity on the otoliths.
The labyrinth righting reflexes are a series of responses
integrated in midbrain nuclei in response to head tilt. The
response is a compensatory contraction of neck muscles to
keep the head level. These reflexes stabilize the head and keep
the eyes fixed on visual targets despite movements of the
body.
Vestibular impulses that reach the cerebral cortex are likely
responsible for conscious perception of motion and supply
part of the information necessary for orientation in space.
Vertigo is the sensation of rotation in the absence of actual
rotation and is a prominent symptom when one labyrinth is
inflamed.
SPATIAL ORIENTATION
Orientation in space depends on input from the vestibular
receptors as well as visual cues, information from propriocep-
tors in joint capsules, and cutaneous touch and pressure recep-
tors. These four inputs are synthesized at a cortical level into a
continuous picture of the individual’s orientation in the envi-
ronment.
CLINICAL CORRELATION
A 26-year-old woman came to her primary care physi-
cian’s office because of a recent series of episodes in which
she has experienced severe dizziness, tinnitus (ringing in
the ears), and nausea and vomiting. During her latest epi-
sode, she realized that she could barely hear her daughter
calling for her in the next room. When queried by the
physician’s assistant, she recalled that similar, although
less severe, incidences of these symptoms had occurred
while she was in college. In particular, she experienced
tinnitus, vertigo, and nausea on various occasions. Because
the symptoms occurred only sporadically and lasted for
only hours or a day, she did not seek medical advice. The
latest episodes have her fearful that something serious is
wrong with her.
A hearing test detected reduced hearing in one ear.
Based on the symptoms, her physician suspected that she
had Ménière disease. She was later seen by an otolaryn-
gologist and a neurologist to rule out other causes of her
symptoms. Ménière disease is an abnormality of the inner
ear causing vertigo or severe dizziness, tinnitus, fluctuat-
ing hearing loss, and the sensation of pressure or pain in
the affected ear lasting for several hours. Symptoms can
occur suddenly and recur daily or very rarely. The hearing
loss is initially transient but can become permanent. The
pathophysiology may involve an immune reaction. An
inflammatory response can increase fluid volume within
the membranous labyrinth, causing it to rupture and
allowing the endolymph and perilymph to mix together.
There is no cure for Ménière disease but the symptoms
can be controlled by reducing the fluid retention through
dietary changes (low-salt or salt-free diet, no caffeine, no
alcohol) or medication.
CHAPTER SUMMARY
■ The external ear funnels sound waves to the external auditory
meatus and tympanic membrane. From there, sound waves
pass through three auditory ossicles (malleus, incus, and
stapes) in the middle ear. The inner ear, or labyrinth, contains
the cochlea and organ of Corti.
■ The hair cells in the organ of Corti signal hearing. The
stereocilia provide a mechanism for generating changes in
membrane potential proportional to the direction and distance
the hair moves. Sound is the sensation produced when
longitudinal vibrations of air molecules strike the tympanic
membrane.
■ The activity within the auditory pathway passes from the eighth
cranial nerve afferent fibers to the dorsal and ventral cochlear
nuclei to the inferior colliculi to the thalamic medial geniculate
body and then to the auditory cortex.
■ Loudness is correlated with the amplitude of a sound wave and
pitch with the frequency.
■ Conductive deafness is due to impaired sound transmission in
the external or middle ear and impacts all sound frequencies.
Sensorineural deafness is due to loss of cochlear hair cells or to
damage to the eighth cranial nerve or central auditory pathways.
■ Rotational acceleration stimulates the crista in the semicircular
canal, displacing the endolymph in a direction opposite to the
direction of rotation, deforming the cupula and bending the
hair cell. The utricle responds to horizontal acceleration and
the saccule to vertical acceleration. Acceleration in any
direction displaces the otoliths, distorting the hair cell
processes and generating neural activity.
■ Spatial orientation is dependent on input from vestibular
receptors, visual cues, proprioceptors in joint capsules, and
cutaneous touch and pressure receptors.
STUDY QUESTIONS
1. A 40-year-old male, employed as a road construction worker for
nearly 20 years, went to his physician to report that he has been
having difficulty hearing during normal conversations. A Weber
test showed that sound from a vibrating tuning fork was localized
to the right ear. A Schwabach test showed that bone conduction
was below normal. A Rinne test showed that both air and bone
 CHAPTER 16 Special Senses II: Hearing and Equilibrium
conduction were abnormal, but air conduction lasted longer than
bone conduction. The diagnosis was
A) sensorial deafness in both ears.
B) conduction deafness in the right ear.
C) sensorial deafness in the right ear.
D) conduction deafness in the left ear.
E) sensorineural deafness in the left ear.
2. What would the diagnosis be if a patient had the following test
results? Weber test showed that sound from a vibrating tuning
fork was louder than normal; Schwabach test showed that bone
conduction was better than normal; and Rinne test showed that
air conduction did not outlast bone conduction.
A) sensorial deafness in both ears
B) conduction deafness in both ears
C) normal hearing
D) both sensorial and conduction deafness
E) a possible tumor on the eighth cranial nerve
3. Postrotational nystagmus is caused by continued movement of
A) aqueous humor over the ciliary body in the eye.
B) cerebrospinal fluid over the vestibular nuclei.
C) endolymph in the semicircular canals, with consequent
bending of the cupula and stimulation of hair cells.
D) endolymph toward the helicotrema.
E) perilymph over hair cells with processes embedded in the
tectorial membrane.
157
4. Some diseases damage the hair cells in the ear. When the damage to
the outer hair cells is greater than the damage to the inner hair cells
A) perception of vertical acceleration is disrupted.
B) K+ concentration in endolymph is decreased.
C) K+ concentration in perilymph is decreased.
D) there is severe hearing loss.
E) affected hair cells fail to shorten when exposed to sound.
5. Which of the following are incorrectly paired?
A) tympanic membrane:manubrium of malleus
B) helicotrema:apex of cochlea
C) foot plate of stapes:oval window
D) otoliths:semicircular canals
E) basilar membrane:organ of Corti
6. The direction of nystagmus is vertical when a subject is rotated
A) after warm water is put in one ear.
B) with the head tipped backward.
C) after cold water is put in both ears.
D) with the head tipped sideways.
E) after section of one vestibular nerve.
7. In the utricle, tip links in hair cells are involved in
A) formation of perilymph.
B) depolarization of the stria vascularis.
C) movements of the basement membrane.
D) perception of sound.
E) regulation of mechanosensitive ion channels.
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 17
C H A P T E R

Special Senses III:

Smell and Taste
Susan M. Barman

O B J E C T I V E S

■ Describe the basic features of the olfactory epithelium and olfactory bulb.
■ Explain signal transduction in odorant receptors.
■ Outline the pathway by which impulses generated in the olfactory epithelium
reach the olfactory cortex.
■ Describe the location and cellular composition of taste buds.
■ Name the five major taste receptors and their signal transduction
mechanisms.
■ Outline the pathways by which impulses generated in taste receptors reach
the insular cortex.

INTRODUCTION
Smell and taste are classified as visceral senses because of their
close association with gastrointestinal function. Physiologi-
cally, they are related to each other; the flavors of various foods
are in large part a combination of their taste and smell. This
explains why food may taste “different” if one has a cold that
depresses the sense of smell. Both smell and taste receptors are
chemoreceptors that are stimulated by molecules in solution
in mucus in the nose and saliva in the mouth.
SMELL
OLFACTORY EPITHELIUM
AND OLFACTORY BULBS
A specialized portion of the nasal mucosa, the yellowish, pig-
mented olfactory epithelium (Figure 17–1), contains 10–20
million bipolar olfactory sensory neurons interspersed with
glia-like supporting (sustentacular) cells and basal stem cells.
The olfactory epithelium is the place in the body where the ner-
vous system is closest to the external world. Each neuron has a
short, thick dendrite that projects into the nasal cavity where it
terminates in a knob containing 10–20 cilia (Figure 17–2). The
cilia are unmyelinated processes that contain odorant recep-
tors. The axons of the olfactory sensory neurons pass through
the cribriform plate of the ethmoid bone and enter the olfac-
tory bulbs (Figure 17–1). New olfactory sensory neurons are
generated by basal stem cells as needed to replace those dam-
aged by exposure to the environment.
In the olfactory bulbs, the axons of the olfactory sensory
neurons (first cranial nerve) contact the primary dendrites
of the mitral cells and tufted cells (Figure 17–3) to form
anatomically discrete synaptic units called olfactory glom-
eruli. Both types of neurons send axons into the olfactory
cortex. The olfactory bulbs also contain periglomerular
cells, which are inhibitory neurons connecting one glomeru-
lus to another, and granule cells, which have no axons and
make reciprocal synapses with the lateral dendrites of the
mitral and tufted cells. At these synapses, the mitral or tufted
cell excites the granule cell by releasing glutamate, and the
granule cell in turn inhibits the mitral or tufted cell by releas-
ing γ-Aminobutyric acid (GABA).
OLFACTORY CORTEX
The axons of the mitral and tufted cells pass posteriorly
through the lateral olfactory stria to terminate on apical
dendrites of pyramidal cells in five regions of the olfactory
cortex: anterior olfactory nucleus, olfactory tubercle, piri-
form cortex, amygdala, and entorhinal cortex (Figure 17–4).

159

Ch17_159-166.indd 159 11/26/10 4:40:38 PM

160 SECTION IV CNS/Neural Physiology

Olfactory
bulb Olfactory
bulb

Cribriform
plate

Olfactory
Olfactory
epithelium
sensory
neurons

FIGURE 17–1 Olfactory sensory neurons embedded within the olfactory epithelium in the dorsal posterior recess of the nasal
cavity. These neurons project axons to the olfactory bulb of the brain, a small ovoid structure that rests on the cribriform plate of the ethmoid
bone. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

From these regions, information travels directly to the frontal is involved with the emotional responses to olfactory stimuli,
cortex or via the thalamus to the orbitofrontal cortex. Con- and the pathway to the entorhinal cortex is concerned with
scious discrimination of odors relies on the pathway to the olfactory memories.
orbitofrontal cortex. The orbitofrontal activation is generally
greater on the right side than the left; thus, cortical representa-
tion of olfaction is asymmetric. The pathway to the amygdala

To olfactory bulb

Basal Axon
cells

Olfactory
sensory
neuron

Dendrite

Supporting
cell

Mucus Cilia

FIGURE 17–2 Structure of the olfactory epithelium. There

are three cell types: olfactory sensory neurons, supporting cells, and
basal stem cells at the base of the epithelium. Each sensory neuron
has a dendrite that projects to the epithelial surface. Numerous cilia
protrude into the mucosal layer lining the nasal lumen. A single axon
projects from each neuron to the olfactory bulb. Odorants bind to
specific odorant receptors on the cilia and initiate a cascade of events
leading to generation of action potentials in the sensory axon.
(Modified with permission from Kandel ER, Schwartz JH, Jessell TM [editors]:
Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)
FIGURE 17–3 Basic neural circuits in the olfactory bulb. Note
that olfactory receptor cells with one type of odorant receptor project to
one olfactory glomerulus (OG) and olfactory receptor cells with another
type of receptor project to a different olfactory glomerulus. CP, cribriform
plate; PG, periglomerular cell; M, mitral cell; T, tufted cell; Gr, granule cell.
White arrows, excitatory synapses; black arrows, inhibitory synapses.
(Adapted with permission from Mori K, Nagao H, Yoshihara Y. The olfactory bulb: Coding
and processing of odor molecular information. Science. 1999;286(5440):711–715.)
 CHAPTER 17 Special Senses III: Smell and Taste 161

Accessory
Lateral
olfactory
olfactory tract
bulb
Mitral
cell
Mitral
cell
Tufted
cell

Olfactory Anterior Olfactory Piriform Amygdala Entorhinal

bulb olfactory tubercle cortex cortex
nucleus
Vomeronasal Olfactory
organ epithelium
Hypothalamus
Contralateral
olfactory
bulb
Hippocampus

Thalamus

Orbitofrontal Frontal cortex

cortex

FIGURE 17–4 Diagram of the olfactory pathway. Information is transmitted from the olfactory bulb by axons of mitral and tufted relay
neurons in the lateral olfactory tract. Mitral cells project to five regions of the olfactory cortex: anterior olfactory nucleus, olfactory tubercle,
piriform cortex, and parts of the amygdala and entorhinal cortex. Tufted cells project to anterior olfactory nucleus and olfactory tubercle; mitral
cells in the accessory olfactory bulb project only to the amygdala. Conscious discrimination of odor depends on the neocortex (orbitofrontal
and frontal cortices). Emotive aspects of olfaction derive from limbic projections (amygdala and hypothalamus). In rodents and some mammals,
a well-developed vomeronasal organ is concerned with perception of odors that act as pheromones; its receptors project to the accessory
olfactory bulb. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

OLFACTORY DISCRIMINATION
AND SIGNAL TRANSDUCTION
The olfactory epithelium is covered by a thin layer of mucus
secreted by the supporting cells and Bowman glands that lie
beneath the epithelium. The mucus bathes the odorant recep-
tors on the cilia and provides the appropriate molecular and
ionic environment for odor detection. Odor-producing mole-
cules are usually small, containing from 3 to 20 carbon atoms,
and molecules with the same number of carbon atoms but dif-
ferent structural configurations have different odors. Rela-
tively high water and lipid solubility are characteristic of
substances with strong odors.
Anosmia (inability to smell) and hyposmia or hypesthesia
(diminished olfactory sensitivity) can result from simple nasal
congestion or from damage to the olfactory nerves due to
fractures of the cribriform plate, neuroblastomas or menin-
giomas, or infections (such as abscesses). Aging is also associ-
ated with abnormalities in smell sensation; more than 75% of
humans over the age of 80 have an impaired ability to identify
odors.
The genes that code for about 1,000 different types of odor-
ant receptors make up the largest gene family so far described
in mammals. The amino acid sequences of odorant receptors
are diverse, but all the odorant receptors are coupled to het-
erotrimeric G proteins. When an odorant molecule binds to
its receptor, the G protein subunits (α, β, γ) dissociate
(Figure 17–5). The α-subunit activates adenylate cyclase to
catalyze the production of cAMP, which acts as a second mes-
senger to open cation channels, causing an inward-directed
Ca2+ current. This produces the graded receptor potential,
which then leads to an action potential in the olfactory
nerve.
Although there are millions of olfactory sensory neurons,
each expresses only 1 of the 1,000 different odorant recep-
tors. Each neuron projects to one or two glomeruli
(Figure 17–3). This provides a distinct two-dimensional map
in the olfactory bulb that is unique to the odorant. The mitral
cells with their glomeruli project to different parts of the
olfactory cortex.
The olfactory glomeruli demonstrate lateral inhibition
mediated by periglomerular and granule cells. This sharpens
and focuses olfactory signals. In addition, the extracellular
field potential in each glomerulus oscillates, and the granule
cells can regulate the frequency of the oscillation. The exact
function of the oscillation is unknown, but it may also help to
focus the olfactory signals reaching the cortex.
TASTE
TASTE BUDS
The specialized sense organ for taste (gustation) consists of
approximately 10,000 taste buds. There are four morphologi-
cally distinct types of cells within each taste bud: basal cells,
162 SECTION IV CNS/Neural Physiology
(a)
Odorant
FIGURE 17–5 Signal transduction in an odorant receptor.
Olfactory receptors are G protein–coupled receptors that
dissociate on binding to the odorant. The α-subunit of G proteins
activates adenylate cyclase to catalyze production of cAMP. cAMP
acts as a second messenger to open cation channels. Inward
diffusion of Na+ and Ca2+ produces depolarization. (Reproduced with (b)
permission from Fox SI: Human Physiology. McGraw-Hill, 2008.)
dark cells, light cells, and intermediate cells (Figure 17–6).
The latter three cell types are referred to as Type I, II, and III
taste cells. They are the sensory neurons that respond to taste
stimuli. The apical ends of taste cells have microvilli that proj-
ect into the taste pore, a small opening on the dorsal surface of
the tongue where taste cells are exposed to the oral contents.
Each taste bud is innervated by about 50 nerve fibers, and con-
versely, each nerve fiber receives input from an average of five
taste buds. The basal cells arise from the epithelial cells sur-
rounding the taste bud. They differentiate into new taste cells,
and the old cells are replaced with a half-time of about 10 days.
If the sensory nerve is cut, the taste buds it innervates degener-
ate and eventually disappear.
The taste buds are located in the mucosa of the epiglottis,
palate, and pharynx and in the walls of papillae of the tongue
(Figure 17–6). The fungiform papillae are rounded structures
most numerous near the tip of the tongue; the circumvallate
papillae are prominent structures arranged in a V on the back
of the tongue; the foliate papillae are on the posterior edge of
the tongue. Each fungiform papilla has up to 5 taste buds,
mostly located at the top of the papilla; each vallate and foliate
papilla contains up to 100 taste buds, mostly located along the
sides of the papillae.
TASTE PATHWAYS
The sensory nerve fibers from the taste buds on the anterior
two thirds of the tongue travel in the chorda tympani branch
of the facial nerve, and those from the posterior third of the
Odorant
Adenylate Na+/Ca2+
Odorant cyclase channel
receptor
G-proteins
Ca2+ Na+
Odorant Adenylate
receptor cyclase Na+/Ca2+
channel
cAMP
ATP
cAMP
tongue reach the brain stem via the glossopharyngeal nerve
(Figure 17–7). The fibers from areas other than the tongue
(e.g., pharynx) reach the brain stem via the vagus nerve. On
each side, the myelinated but relatively slowly conducting taste
fibers in these three nerves unite in the gustatory portion of
the nucleus of the tractus solitarius (NTS) in the medulla
oblongata (Figure 17–7). From there, axons of second-order
neurons ascend in the ipsilateral medial lemniscus to pass
directly to the ventral posteromedial nucleus of the thala-
mus, from which fibers project to the anterior insula and
frontal operculum in the ipsilateral cerebral cortex. This
region is rostral to the face area of the postcentral gyrus, which
may be the area that mediates conscious perception of taste
and taste discrimination.
TASTE MODALITIES, RECEPTORS,
AND TRANSDUCTION
A 30% change in the concentration of the substance being
tasted is necessary before an intensity difference can be
detected. A protein that binds taste-producing molecules is
produced by the Ebner gland that secretes mucus into the
cleft around vallate papillae. Ageusia (absence of the sense of
taste) and hypogeusia (diminished taste sensitivity) can be
caused by damage to the lingual or glossopharyngeal nerve.
Neurological disorders such as vestibular schwannoma,
Bell’s palsy, familial dysautonomia, multiple sclerosis, and
certain infections (e.g., primary amoeboid meningoenceph-
alopathy) can also cause problems with taste sensitivity.
 CHAPTER 17 Special Senses III: Smell and Taste 163

Chorda tympani Taste pore

nerve (VII)
Saliva
Glossopharyngeal
nerve (IX)

Epithelial cell

Circumvallate Taste cell

Basal cell

Gustatory afferent nerve

Serous
gland
A To sensory ganglion
Foliate
C

Taste
bud

Fungiform
B
FIGURE 17–6 Taste buds located in papillae of the human tongue. A) Taste buds on the anterior two thirds of the tongue are
innervated by the chorda tympani branch of the facial nerve; those on the posterior one third of the tongue are innervated by the lingual branch
of the glossopharyngeal nerve. B) The three major types of papillae (circumvallate, foliate, and fungiform) are located on specific parts of the
tongue. C) Taste buds are composed of basal stem cells and three types of taste cells (dark, light, and intermediate). Taste cells extend from the
base of the taste bud to the taste pore, where microvilli contact tastants dissolved in saliva and mucus. (Modified with permission from Kandel ER,
Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

Ageusia can also be an adverse side effect of various drugs or
vitamin B3 or zinc deficiencies. Aging and tobacco abuse also
contribute to diminished taste. Dysgeusia or parageusia
(unpleasant perception of taste) causes a metallic, salty, foul,
or rancid taste.
Humans have five established basic tastes: sweet, sour, bit-
ter, salt, and umami. All tastants are sensed from all parts of
the tongue and adjacent structures. Afferent nerves to the NTS
contain fibers from all types of taste receptors, without any
clear localization of types. A fifth taste sense, umami, has been
added to the four classic tastes. This taste is triggered by gluta-
mate and particularly by the monosodium glutamate (MSG)
used very extensively in Asian cooking. The taste is pleasant
and sweet but differs from the standard sweet taste.
Figure 17–8 illustrates signal transduction in taste recep-
tors. The salty taste is triggered by NaCl. Salt-sensitive taste is
mediated by a Na+-selective channel known as ENaC, the
amiloride-sensitive epithelial sodium channel. The entry of
Na+ into the salt receptors depolarizes the membrane, gener-
ating the receptor potential. In humans, the amiloride sensi-
tivity of salt taste is less pronounced than in some species,
suggesting that there are additional mechanisms to activate
salt-sensitive receptors.
The sour taste is triggered by protons (H+ ions). ENaCs per-
mit the entry of protons and may contribute to the sensation
of sour taste. The H+ ions can also bind to and block a K+-
sensitive channel. The decrease in K+ permeability can depo-
larize the membrane. A hyperpolarization-activated cyclic
nucleotide–gated cation channel, and other mechanisms
may contribute to sour transduction.
Substances that taste sweet also act via the G protein gust-
ducin. The T1R3 family of G protein–coupled receptors is
expressed by about 20% of taste cells, some of which also
express gustducin. Sugars taste sweet, but so do compounds
such as saccharin that have an entirely different structure. Nat-
ural sugars such as sucrose and synthetic sweeteners may act
via different receptors on gustducin. Like the bitter-responsive
receptors, sweet-responsive receptors act via cyclic nucleotides
and inositol phosphate metabolism.
Bitter taste is produced by a variety of unrelated com-
pounds. Many of these are poisons, and bitter taste serves as
a warning to avoid them. Some bitter compounds bind to
and block K+-selective channels. Many G protein–linked
receptors in the human genome are taste receptors (T2R
family) and are stimulated by bitter substances such as
strychnine. In some cases, these receptors couple to the het-
erotrimeric G protein, gustducin. Gustducin decreases
cAMP and increases the formation of inositol phosphates
that could lead to depolarization. Some bitter compounds
are membrane permeable and may not involve G proteins;
quinine is an example.
Umami taste is due to activation of a truncated metabotro-
pic glutamate receptor, mGluR4, in the taste buds. The way
activation of the receptor produces depolarization is unsettled.
Glutamate in food may also activate ionotropic glutamate
receptors to depolarize umami receptors.
164 SECTION IV CNS/Neural Physiology

Gustatory cortex
(anterior insula-
frontal operculum)

Ventral posterior
medial nucleus of
thalamus

Geniculate
Chorda ganglion
tympani

N. VII

Tongue Nucleus of
N. IX
Petrosal solitary tract
Glossopharyngeal ganglion
N. X Gustatory
area

Nodose
ganglion

Pharynx

FIGURE 17–7 Diagram of taste pathways. Signals from the taste buds travel via different nerves to gustatory areas of the nucleus of
the tractus solitarius that relays information to the thalamus; the thalamus projects to the gustatory cortex N. VII, N. IX, and N. X are the 7th, 9th,
and 10th cranial nerves, respectively. (Modified with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

Salty Sour Predicted sweet Bitter Umami

receptor (L-glutamate)
α γ
N

N N N N
C C C C C C C
ENaC, others ENaC, HCN, others T1R3 (sac locus) T2R family, others Taste mGluR4

FIGURE 17–8 Signal transduction in taste receptors. Salt-sensitive taste is mediated by a Na -selective channel (ENaC); sour taste is
+

mediated by H+ ions permeable to ENaCs; umami taste is mediated by glutamate acting on a metabotropic receptor, mGluR4; bitter taste is
mediated by the T2R family of G protein–coupled receptors; sweet taste may be dependent on the T1R3 family of G protein–coupled receptors
that couple to the G protein gustducin. (Adapted with permission from Lindemann B. Receptors and transduction in taste. Nature. 2001;413:219.)

CLINICAL CORRELATION
A 10-year-old boy was riding in the front passenger seat of
an automobile being driven by his father. He dropped his
MP3 player and released his seat belt to retrieve it. At that
moment, the car was hit from the rear by a speeding motor-
ist. He received a sharp blow to his nose when he struck
the dashboard. He was taken to the emergency room of a
nearby hospital. An x-ray showed that he had broken his
ethmoid bone that separates the nasal cavity from the
brain. Following this accident, he lost the sense of smell
(anosmia), and his sense of taste was also diminished.
The olfactory nerve runs through the ethmoid bone.
The nerve can be damaged when the bone is broken,
resulting in the loss of the ability to smell. Because of the
close relationship between taste and smell, anosmia is
associated with a reduction in taste sensitivity (hypogeusia).
Major causes of anosmia include upper respiratory tract
infection, nasal polyps, head trauma, tumors of the frontal
lobe, toxins, and prolonged use of nasal decongestants.
Anosmia is generally permanent in cases in which the
olfactory nerve or other neural elements in the olfactory
neural pathway are damaged. In addition to not being able
to experience the enjoyment of pleasant aromas and full
spectrum of tastes, individuals with anosmia are at risk
because they are not being able to detect the odor from
such dangers as gas leaks, fire, and spoiled food
CHAPTER SUMMARY
■ Olfactory sensory neurons, supporting (sustentacular) cells,
and basal stem cells are located in the olfactory epithelium
within the upper portion of the nasal cavity.
■ The cilia located on the dendritic knob of the olfactory sensory
neuron contain odorant receptors that are coupled to heterotri-
meric G proteins.
■ Axons of olfactory sensory neurons contact the dendrites of
mitral and tufted cells in the olfactory bulbs to form olfactory
glomeruli.
■ Information from the olfactory bulb travels via the lateral
olfactory stria directly to the olfactory cortex, including the
anterior olfactory nucleus, olfactory tubercle, piriform cortex,
amygdala, and entorhinal cortex.
■ Taste buds are the specialized sense organs for taste and are
composed of basal stem cells and Type I, II, and III taste cells
that may represent various stages of differentiation of develop-
ing taste cells. They are located in the mucosa of the epiglottis,
palate, and pharynx and in the walls of papillae of the tongue.
■ There are taste receptors for sweet, sour, bitter, salt, and umami
tastes. Signal transduction mechanisms include passage
through ion channels, binding to and blocking ion channels,
and second messenger systems.
■ The afferents from taste buds in the tongue travel via the 7th,
9th, and 10th cranial nerves to synapse in the NTS. From there,
axons ascend via the ipsilateral medial lemniscus to the ventral
CHAPTER 17 Special Senses III: Smell and Taste 165
posteromedial nucleus of the thalamus, and on to the anterior
insula and frontal operculum in the ipsilateral cerebral cortex.
STUDY QUESTIONS
1. Odorant receptors are
A) located in the olfactory bulb.
B) located on dendrites of mitral and tufted cells.
C) located on neurons that project directly to the olfactory cortex.
D) located on neurons in the olfactory epithelium that project to
mitral cells and from there directly to the olfactory cortex.
E) located on sustentacular cells that project to the olfactory bulb.
2. Taste receptors
A) for sweet, sour, bitter, salt, and umami tastes are spatially
separated on the surface of the tongue.
B) are synonymous with taste buds.
C) are a type of chemoreceptor.
D) are innervated by afferents in the facial, trigeminal,
and glossopharyngeal nerves.
E) All of the above are correct.
3. Which of the following does not increase the ability to
discriminate many different odors?
A) many different receptors
B) pattern of olfactory receptors activated by a given odorant
C) projection of different mitral cell axons to different parts
of the brain
D) neural processing in the amygdala
E) lateral inhibition
4. Which of the following are incorrectly paired?
A) ENaC:sour
B) α-gustducin:bitter taste
C) nucleus tractus solitarius:taste
D) fungiform papillae:smell
E) Ebner glands:taste acuity
5. Which of the following is true about olfactory transmission?
A) An olfactory sensory neuron expresses a wide range of
odorant receptors.
B) Lateral inhibition within the olfactory glomeruli reduces
the ability to distinguish between different types of odorant
receptors.
C) Conscious discrimination of odors is dependent on the
pathway to the orbitofrontal cortex.
D) Olfaction is closely related to gustation because odorant
and gustatory receptors use the same central pathways.
E) All of the above are correct.
6. Which of the following is not true about gustatory sensation?
A) The sensory nerve fibers from the taste buds on the anterior
two thirds of the tongue travel in the chorda tympani
branch of the facial nerve.
B) The sensory nerve fibers from the taste buds on the
posterior third of the tongue travel in the petrosal branch
of the glossopharyngeal nerve.
C) The pathway from taste buds on the left side of the tongue
is transmitted ipsilaterally to the cerebral cortex.
D) Sustentacular cells in the taste buds serve as stem cells to
permit growth of new taste buds.
E) The pathway from taste receptors includes synapses in the
nucleus of the tractus solitarius in the brain stem and
ventral posterior medial nucleus in the thalamus.
This page intentionally left blank
 18
C H A P T E R

Control of Posture
and Movement
Susan M. Barman

O B J E C T I V E S

■ Describe how skilled movements are planned and carried out.

■ Describe the posture-regulating parts of the central nervous system.
■ Describe decerebrate and decorticate rigidity.
■ Describe the function of the basal ganglia in control of movement.
■ Describe the symptoms of Parkinson’s disease.
■ Discuss the functions of the cerebellum and the neurological abnormalities
produced by diseases of this part of the brain.

INTRODUCTION CONTROL OF AXIAL

Somatic motor activity ultimately depends on the pattern and
rate of discharge of the spinal motor neurons and homologous
neurons in the motor nuclei of the cranial nerves. These neu-
rons, the final common pathway to skeletal muscle, receive in-
put from an array of descending pathways, other spinal neurons,
and peripheral afferents. The integration of these multiple in-
puts regulates the posture of the body and makes coordinated
movement possible. The inputs bring about voluntary activity,
adjust body posture to provide a stable background for move-
ment, and coordinate the action of the various muscles to make
movements smooth and precise. As shown by the scheme in
Figure 18–1, voluntary movement is planned in the cortex,
basal ganglia, and lateral cerebellum. The basal ganglia and
cerebellum funnel information to the premotor and motor cor-
tex via the thalamus. Posture is continually adjusted both before
and during movement by descending brain stem pathways and
peripheral afferents. Movement is smoothed and coordinated
by the connections of medial and intermediate portions of the
cerebellum. The basal ganglia and lateral cerebellum are part of
a feedback circuit to the premotor and motor cortex that is con-
cerned with planning and organizing voluntary movement.
AND DISTAL MUSCLES
Within the brain stem and spinal cord, pathways and neu-
rons that control skeletal muscles of the trunk and proximal
portions of the limbs are located medially or ventrally. Path-
ways and neurons that are concerned with the control of
skeletal muscles in the distal portions of the limbs are lo-
cated laterally. The axial muscles are concerned with pos-
tural adjustments and gross movements; the distal limb
muscles mediate fine, skilled movements. For example, neu-
rons in the medial portion of the ventral horn innervate
proximal limb muscles, particularly the flexors, and lateral
ventral horn neurons innervate distal limb muscles. Simi-
larly, the ventral corticospinal tract and medial descending
brain stem pathways (rubrospinal, reticulospinal, tectospi-
nal, and vestibulospinal tracts) are concerned with adjust-
ments of proximal muscles and posture, and the lateral
corticospinal and rubrospinal tracts are concerned with
distal limb muscles and, particularly in the case of the corti-
cospinal tract, with skilled voluntary movements.

167

Ch18_167-176.indd 167 11/26/10 4:41:35 PM

168 SECTION IV CNS/Neural Physiology

Plan Execute

Basal ganglia

Cortical
Idea association Premotor and Movement
areas motor cortex

Lateral
cerebellum Intermediate
cerebellum

FIGURE 18–1 Control of voluntary movement. Commands for voluntary movement originate in cortical association areas. The cortex,
basal ganglia, and cerebellum work cooperatively to plan movements. Movement executed by the cortex is relayed via the corticospinal tracts
and corticobulbar tracts to motor neurons. The cerebellum provides feedback to adjust and smooth movement. (Reproduced with permission from
Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

CORTICOSPINAL AND Precentral

CORTICOBULBAR TRACTS gyrus
(area 4,
The axons of neurons from the motor cortex that project to etc)
spinal motor neurons form the corticospinal tracts, a large
bundle of about 1 million fibers. About 80% of these fibers
cross the midline in the medullary pyramids to form the lat-
eral corticospinal tract (Figure 18–2). The other 20% form the
ventral corticospinal tract, which does not cross the midline
Corticospinal tract
until it reaches the level of the spinal cord at which it termi-
nates. Lateral corticospinal tract neurons make monosynaptic
connections to motor neurons, especially those concerned Internal capsule
with skilled movements, and on spinal interneurons. The tra-
jectory from the cortex to the spinal cord passes through the Decussation of
corona radiata to the posterior limb of the internal capsule. the pyramids
Within the midbrain corticospinal tract fibers traverse the ce- Pyramids
rebral peduncle and the basilar pons until they reach the med-
ullary pyramids on their way to the spinal cord. Lateral cortico-
The corticobulbar tract is composed of the fibers that pass spinal tract
from the motor cortex to motor neurons in the trigeminal, Ventral cortico- (80% of fibers)
spinal tract
facial, and hypoglossal nuclei. Corticobulbar neurons end ei- (20% of fibers) Anterior
ther directly on the cranial nerve nuclei or on their antecedent horn cell
interneurons within the brain stem. Their axons traverse
through the genu of the internal capsule, the cerebral peduncle Interneuron
Spinal nerve
(medial to corticospinal tract neurons), to descend with corti-
cospinal tract fibers in the pons and medulla.
The motor system can be divided into lower and upper mo-
Distal
tor neurons. Lower motor neurons refer to the spinal and cra- muscle
nial motor neurons that directly innervate skeletal muscles.
Proximal
Upper motor neurons are those in the cortex and brain stem muscle
that activate the lower motor neurons. The pathophysiologic
responses to damage to lower and upper motor neurons are FIGURE 18–2 Corticospinal tracts. This tract originates in the
precentral gyrus and passes through the internal capsule. Most fibers
very distinctive.
decussate in the pyramids and descend in the lateral white matter of
Damage to lower motor neurons is associated with flaccid the spinal cord to form the lateral division of the tract that can make
paralysis, muscular atrophy, fasciculations (visible muscle monosynaptic connections with spinal motor neurons. The ventral
twitches that appear as flickers under the skin), hypotonia division of the tract remains uncrossed until reaching the spinal cord
(decreased muscle tone), and hyporeflexia or areflexia. where axons terminate on spinal interneurons antecedent to motor
Damage to upper motor neurons initially causes muscles to neurons. (Reproduced with permission from Barrett KE, Barman SM, Boitano S,
become weak and flaccid but eventually leads to spasticity, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
 CHAPTER 18 Control of Posture and Movement 169

hypertonia (increased resistance to passive movement),

hyperactive stretch reflexes, and abnormal plantar extensor
reflex (Babinski sign). The Babinski sign is dorsiflexion of the

Shoulder
Elbow
Wrist
great toe and fanning of the other toes when the lateral aspect

Trunk
Hip
Kne Ank

d
Han
of the sole of the foot is scratched. In adults, the normal

e le

R ttle
M ing
To
response to this stimulation is plantar flexion in all the toes.

Li

e
e

dl
s x
de b

id
It is of value in the localization of disease processes, but its In um k
Th Nec w
o
physiologic significance is unknown. Br all
b
d eye
n e
li da Fac
Eye

VOCALIZATION
Lips

MOTOR CORTEX AND

Ja
VOLUNTARY MOVEMENT Ton w

N
Sw gue

TIO
allo
win

LIVA
N
g

IO
AT
Corticospinal and corticobulbar tract neurons are pyramidal

shaped and located in layer V of the cerebral cortex (see
Chapter 12). Figure 18–3 shows the major cortical regions in-
volved in motor control. About 31% of the corticospinal tract
neurons are from the primary motor cortex (M1; Brodmann’s
area 4) in the precentral gyrus of the frontal lobe, extending into
the central sulcus. The premotor cortex and supplementary
motor cortex (Brodmann’s area 6) account for 29% of the cor-
ticospinal tract neurons. The premotor area is anterior to the
precentral gyrus, on the lateral and medial cortical surface, and
the supplementary motor area is on and above the superior bank
of the cingulate sulcus on the medial side of the hemisphere. The
other 40% of corticospinal tract neurons originate in the pari-
etal lobe (Brodmann’s area 5, 7) and primary somatosensory
area (Brodmann’s area 3, 1, 2) in the postcentral gyrus.
The various parts of the body are represented in M1, with the
feet at the top of the gyrus and the face at the bottom (Figure 18–4).
The facial area is represented bilaterally, but the rest of the repre-
sentation is unilateral, with the cortical motor area controlling
Motor cortex
Supplementary
Primary somatic
motor area
Premotor sensory cortex
cortex Posterior
parietal
cortex
6 4
3,1,2 5 sequences, while M1 executes the movements. When human
7 7
Prefrontal
cortex
FIGURE 18–3 A view of the human cerebral cortex, showing
the motor cortex (Brodmann’s area 4) and other areas concerned
with control of voluntary movement, along with the numbers
assigned to the regions by Brodmann. (Reproduced with permission
from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed.
McGraw-Hill, 2000.)
SA
IC
ST
MA
FIGURE 18–4 Motor homunculus. The figure represents, on a
coronal section of the precentral gyrus, the location of the cortical
representation of the various parts. The size of the various parts is
proportionate to the cortical area devoted to them. Compare with
Figure 13–6. (Reproduced with permission from Penfield W, Rasmussen G:
The Cerebral Cortex of Man. Macmillan, 1950.)
the musculature on the opposite side of the body. The size of the
cortical representation of each body part is proportional to the
number of corticospinal neurons supplying the musculature of
that region of the body and its role in fine, voluntary movement.
Thus, the areas involved in speech and hand movements are es-
pecially large. A somatotopic organization continues through-
out the corticospinal and corticobulbar pathways. The cells in
the cortical motor areas are arranged in columns. Neurons in
several cortical columns project to the same muscle; also, the
cells in each column receive extensive sensory input from
the peripheral area in which they produce movement, providing
the basis for feedback control of movement.
The supplementary motor area (Figure 18–3), which proj-
ects to M1, also contains a map of the body, but it is less precise
than in M1. It is involved in organizing or planning motor
subjects count to themselves without speaking, the motor cor-
tex is quiescent, but when they speak the numbers aloud,
blood flow increases in M1 and the supplementary motor area.
Thus, both M1 and the supplementary motor area are involved
in voluntary movement when the movements being performed
are complex and involve planning.
The premotor cortex (Figure 18–3), which also contains a
somatotopic map, receives input from sensory regions of the
parietal cortex and projects to M1, the spinal cord, and the
brain stem reticular formation. This region is concerned with
setting posture at the start of a planned movement and with
getting the individual prepared to move. It is most involved in
control of proximal limb muscles needed to orient the body
for movement.
170 SECTION IV CNS/Neural Physiology

In addition to providing fibers that run in the corticospinal
and corticobulbar tracts, the somatic sensory area and por-
tions of the posterior parietal lobe project to the premotor
area. Some of the neurons in area 5 (Figure 18–3) are con-
cerned with aiming the hands toward an object and manipu-
lating it, whereas some of the neurons in area 7 are concerned
with hand–eye coordination.
MEDIAL AND LATERAL
BRAIN STEM PATHWAYS:
POSTURE AND VOLUNTARY
MOVEMENT
As mentioned above, spinal motor neurons are organized such
that those innervating the most proximal muscles are located
most medially and those innervating the more distal muscles
are located more laterally. This organization is also reflected in
descending brain stem pathways (Figure 18–5).
The medial brain stem pathways, which work in concert
with the ventral corticospinal tract, are the pontine and med-
ullary reticulospinal, vestibulospinal, and tectospinal tracts.
These pathways descend in the ipsilateral ventral columns of
the spinal cord and terminate predominantly on interneurons
in the ventromedial part of the ventral horn to control axial
and proximal muscles. A few medial pathway neurons synapse
directly on motor neurons controlling axial muscles.
The medial and lateral vestibulospinal tracts were briefly
described in Chapter 16. The medial tract originates in the
medial and inferior vestibular nuclei and projects bilaterally to
cervical spinal motor neurons that control neck musculature.
The lateral tract originates in the lateral vestibular nuclei and
projects ipsilaterally to neurons at all spinal levels. It activates
motor neurons to antigravity muscles (e.g., proximal limb ex-
tensors) to control posture and balance.
The pontine and medullary reticulospinal tracts project to
all spinal levels. They are involved in the maintenance of pos-
ture and in modulating muscle tone, especially via an input to
γ-motor neurons. Pontine reticulospinal neurons are primar-
ily excitatory and medullary reticulospinal neurons are
primarily inhibitory. The tectospinal tract originates in the su-
perior colliculus of the midbrain. It projects to the contralat-
eral cervical spinal cord to control head and eye movements.

A Medial brain stem pathways B Lateral brain stem pathways

Tectum Red nucleus

(magnocellular part)

Medial
reticular
formation

Tectospinal
tract
Lateral and medial
vestibular nuclei
Reticulospinal
tract

Vestibulospinal
tracts

Rubrospinal
tract

FIGURE 18–5 Medial and lateral descending brain stem pathways involved in motor control. A) Medial pathways (reticulospinal,
vestibulospinal, and tectospinal) terminate in ventromedial area of spinal gray matter and control axial and proximal muscles. B) Lateral pathway
(rubrospinal) terminates in dorsolateral area of spinal gray matter and controls distal muscles. (Reproduced with permission from Kandel ER, Schwartz JH,
Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

The main control of distal muscles is from the lateral corti-
cospinal tract, but neurons within the red nucleus of the mid-
brain cross the midline and project to interneurons in the
dorsolateral part of the spinal ventral horn to also influence
motor neurons that control distal limb muscles. This rubrospi-
nal tract excites flexor motor neurons and inhibits extensor
motor neurons.
DECEREBRATION AND
DECORTICATION
A complete transection of the brain stem between the supe-
rior and inferior colliculi permits the brain stem pathways
to function independent of their input from higher brain
structures. This is called a midcollicular decerebration and
is diagramed in Figure 18–6 by the dashed line labeled A.
This lesion interrupts all input from the cortex and red nu-
cleus to distal muscles of the extremities. The excitatory and
inhibitory reticulospinal pathways (primarily to postural
extensor muscles) remain intact. The dominance of drive
from ascending sensory pathways to the excitatory reticu-
lospinal pathway leads to decerebrate rigidity, which is
characterized by hyperactivity in extensor muscles in all
four extremities. This resembles what ensues after uncal
herniation resulting from a supratentorial lesion as seen in
patients with large tumors or a hemorrhage in the cerebral
hemisphere.
After decerebration, section of dorsal roots to a limb (dashed
line labeled B in Figure 18–6) eliminates the hyperactivity of
extensor muscles, suggesting that decerebrate rigidity is spas-
ticity due to facilitation of the myotatic stretch reflex. The ex-
citatory input from the reticulospinal pathway activates
γ-motor neurons that indirectly activate α-motor neurons
(via Ia spindle afferent activity; see Chapter 14). This is called
the gamma loop.
Decerebrate rigidity may also lead to direct activation of
α-motor neurons. If the anterior lobe of the cerebellum is re-
moved in a decerebrate animal (dashed line labeled C in
Figure 18–6), extensor muscle hyperactivity is exaggerated
(decerebellate rigidity). This cut eliminates cortical inhibition
of the cerebellar fastigial nucleus and secondarily increases ex-
citation to vestibular nuclei. This rigidity is not reversed by
cutting the dorsal roots.
Removal of the cerebral cortex (decortication; dashed line
labeled D in Figure 18–6) produces decorticate rigidity that is
characterized by flexion of the upper extremities at the elbow
and extensor hyperactivity in the lower extremities. The flex-
ion can be explained by rubrospinal excitation of flexor mus-
cles in the upper extremities; the hyperextension of lower
extremities is due to the same changes that occur after midcol-
licular decerebration. Decorticate rigidity is seen on the hemi-
plegic side in humans after hemorrhages or thromboses in the
internal capsule. Sixty percent of intracerebral hemorrhages
occur in the internal capsule, and 10% each in the cerebral
cortex, pons, thalamus, and cerebellum.
CHAPTER 18 Control of Posture and Movement 171
BASAL GANGLIA
The basal ganglia are comprised of the caudate nucleus,
putamen, globus pallidus, and the functionally related sub-
thalamic nucleus and substantia nigra (Figure 18–7). The
globus pallidus is divided into external and internal segments
(GPe and GPi). The substantia nigra is divided into pars com-
pacta and pars reticulata. The caudate nucleus and putamen
are collectively called the striatum; the putamen and globus
pallidus form the lenticular nucleus.
The main inputs to the basal ganglia terminate in the stri-
atum (Figure 18–8). They include the excitatory corticostri-
ate pathway from M1 and premotor cortex. There is also a
projection from intralaminar nuclei of the thalamus to the
striatum (thalamostriatal pathway). The connections be-
tween the parts of the basal ganglia include a dopaminergic
nigrostriatal projection from the substantia nigra pars com-
pacta to the striatum and a corresponding GABAergic
projection from the striatum to substantia nigra pars reticu-
lata. The striatum projects to both GPe and GPi. GPe proj-
ects to the subthalamic nucleus, which in turn projects to
both GPe and GPi.
The principal output from the basal ganglia is from GPi via
the thalamic fasciculus to the ventral lateral, ventral anterior,
and centromedian nuclei of the thalamus. From the thalamic
nuclei, fibers project to the prefrontal and premotor cortex.
The substantia nigra also projects to the thalamus.
The main feature of the connections of the basal ganglia is
that the cerebral cortex projects to the striatum, the striatum
to GPi, GPi to the thalamus, and the thalamus back to the cor-
tex, completing a loop. The output from GPi to the thalamus is
inhibitory, whereas the output from the thalamus to the cere-
bral cortex is excitatory.
FUNCTION
The basal ganglia are involved in the planning and program-
ming of voluntary movement (Figure 18–1). They influence
the motor cortex via the thalamus. Also, GPi projects to brain
stem nuclei and from there to motor neurons in the brain stem
and spinal cord.
Three biochemical pathways in the basal ganglia normally
operate in a balanced fashion (Figure 18–8): (1) the nigrostri-
atal dopaminergic system, (2) the intrastriatal cholinergic
system, and (3) the GABAergic system, which projects from
the striatum to the globus pallidus and substantia nigra. When
one or more of these pathways become dysfunctional, charac-
teristic motor abnormalities occur. Diseases of the basal gan-
glia lead to two general types of disorders: hyperkinetic and
hypokinetic. The hyperkinetic conditions are those in which
movement is excessive and abnormal, including tremor,
chorea, athetosis, and ballism. Hypokinetic abnormalities
include akinesia and bradykinesia.
Chorea is characterized by rapid, involuntary “dancing”
movements. Athetosis is characterized by continuous, slow
172 SECTION IV CNS/Neural Physiology

FIGURE 18–6 A circuit drawing representing lesions produced in experimental animals to replicate decerebrate and decorticate
deficits seen in humans. Bilateral transections are indicated by dashed lines A–D. Decerebration is at a midcollicular level (A), decortication is
rostral to the superior colliculus, dorsal roots sectioned for one extremity (B), and removal of anterior lobe of cerebellum (C). The objective was
to identify anatomic substrates responsible for decerebrate or decorticate rigidity/posturing seen in humans with lesions that either isolate the
forebrain from the brain stem or separate rostral from caudal brain stem and spinal cord. (Reproduced with permission from Haines DE [editor]: Fundamental
Neuroscience for Basic and Clinical Applications, 3rd ed. Elsevier, 2006.)

writhing movements. Choreiform and athetotic movements PARKINSON’S DISEASE

have been likened to the start of voluntary movements occur-
ring in an involuntary, disorganized way. In ballism, involun-
tary flailing, intense, and violent movements occur. Akinesia
is difficulty in initiating movement and decreased spontane-
ous movement. Bradykinesia is slowness of movement.
Parkinson’s disease has both hypokinetic and hyperkinetic
features. It was the first disease identified as being due to a de-
ficiency in a specific neurotransmitter; it is due to the degen-
eration of dopaminergic neurons in the substantia nigra pars
 CHAPTER 18 Control of Posture and Movement 173

Caudate nucleus
Thalamus
Thalamus
Internal
capsule

Lateral ventricle

Amygdaloid
nucleus Caudate nucleus
Putamen and
globus pallidus Putamen

Lateral view Globus pallidus:

External segment
Caudate nucleus Thalamus Internal segment

Inte Subthalamic
rna Substantia nucleus
l ca
psu nigra
le
Amygdala
Globus
pallidus Tail of Frontal section
Putamen caudate nucleus

Horizontal section
FIGURE 18–7 Basal ganglia. The basal ganglia are composed of the caudate nucleus, putamen, and globus pallidus and the functionally
related subthalamic nucleus and substantia nigra. The frontal (coronal) section shows the location of the basal ganglia in relation to surrounding
structures. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

compacta. It is one of the most common neurodegenerative cogwheel rigidity and tremor at rest. The absence of motor
diseases; it is estimated to occur in 1–2% of individuals over activity and the difficulty in initiating voluntary movements
age 65. Symptoms appear when 60–80% of the nigrostriatal are striking. Normal, unconscious movements such as swing-
dopaminergic neurons degenerate. ing of the arms during walking, facial expressions, and fidg-
The hypokinetic features of Parkinson’s disease are akine- eting are absent in Parkinson’s disease. The rigidity is different
sia and bradykinesia, and the hyperkinetic features are from spasticity because motor neuron discharge increases to
both the agonist and antagonist muscles. Passive motion of
an extremity meets with a plastic, dead-feeling resistance
Cerebral that has been likened to bending a lead pipe and is therefore
cortex
called lead pipe rigidity. Sometimes a series of “catches”
Glu takes place during passive motion (cogwheel rigidity), but
Globus GABA Striatum the sudden loss of resistance seen in a spastic extremity is
pallidus, ES (acetylcholine) absent. The tremor, which is present at rest and disappears
with activity, is due to regular, alternating contractions of an-
GABA Glu GABA GABA DA
tagonistic muscles.
Subthalamic Glu Globus A common treatment for Parkinson’s disease is the adminis-
SNPR SNPC
nucleus pallidus, IS
tration of l-DOPA (levodopa). Unlike dopamine, this dop-
Brain stem GABA GABA GABA amine precursor crosses the blood–brain barrier and helps
and PPN Thalamus repair the dopamine deficiency. However, the degeneration of
spinal cord
these neurons continues and in 5–7 years, the beneficial effects
FIGURE 18–8 Diagrammatic representation of the principal of l-DOPA usually disappear.
connections of the basal ganglia. Solid lines indicate excitatory
pathways, dashed lines inhibitory pathways. The transmitters are
indicated in the pathways, where they are known. Glu, glutamate; DA,
dopamine. Acetylcholine is the transmitter produced by interneurons CEREBELLUM
in the striatum. SNPR, substantia nigra pars reticulata; SNPC,
substantia nigra pars compacta; ES, external segment; IS, internal
The cerebellum sits astride the main sensory and motor sys-
segment; PPN, pedunculopontine nuclei. The subthalamic nucleus tems in the brain stem and is connected to the brain stem by
also projects to the pars compacta of the substantia nigra; this the superior, middle, and inferior peduncles. From a func-
pathway has been omitted for clarity. (Reproduced with permission from tional point of view, the cerebellum is divided into three
Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, parts (Figure 18–9). The vestibulocerebellum has vestibular
23rd ed. McGraw-Hill Medical, 2009.) connections and is concerned with equilibrium and eye
174 SECTION IV CNS/Neural Physiology

Spinocerebellum ning and programming movements. The medial portion of

To medial
descending the cerebellum is called the vermis and it projects to the
systems Motor brain stem area concerned with control of axial and proximal
To lateral execution limb muscles (medial brain stem pathways). The area just
descending lateral to the vermis projects to the brain stem areas con-
systems
cerned with control of distal limb muscles (lateral brain stem
pathways).
To motor
and Motor
premotor planning
CELLULAR ORGANIZATION
cortices OF THE CEREBELLUM
Cerebrocerebellum To Balance
vestibular and eye The cerebellar cortex contains five types of neurons: Purkinje,
nuclei movements
granule, basket, stellate, and Golgi cells (Figure 18–10). The
Vestibulocerebellum Purkinje cells are among the biggest neurons in the CNS, with
FIGURE 18–9 Functional divisions of the cerebellum. extensive dendritic arbors. They are the only output neurons
(Modified with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: of the cerebellar cortex, and their synaptic actions are inhibi-
Principles of Neural Science, 4th ed. McGraw-Hill, 2000.) tory via GABA release. The granule cells innervate the
Purkinje cells; their axons bifurcate to form a T. The branches
of the T are straight and run long distances; thus, they are
movements. The spinocerebellum receives proprioceptive called parallel fibers. The parallel fibers make synaptic con-
input from the body as well as a copy of the “motor plan” tact with the dendrites of many Purkinje cells and release glu-
from the motor cortex. It functions to smooth out and coor- tamate (an excitatory neurotransmitter).
dinate ongoing movements. The cerebrocerebellum in the The other three types of neurons in the cerebellar cortex are
lateral hemisphere interacts with the motor cortex in plan- inhibitory interneurons that release GABA. Basket cells

5 Stellate
cell Parallel fibers:
Axons of granule
cells
Axon
1 Purkinje
cell

Molecular
layer 2
1
Purkinje
layer
5
Axon Granular 4
layer 3 2 Golgi
cell
4 Granule
3 Basket
cell
cell
Axons

FIGURE 18–10 Location and structure of five neuronal types in the cerebellar cortex. Drawings are based on Golgi-stained
preparations. Purkinje cells (1) have processes aligned in one plane; their axons are the only output from the cerebellum. Axons of granule cells
(4) traverse and make connections with Purkinje cell processes in molecular layer. Golgi (2), basket (3), and stellate (5) cells have characteristic
positions, shapes, branching patterns, and synaptic connections. (Reproduced with permission from Kuffler SW, Nicholls JG, Martin AR: From Neuron to Brain,
2nd ed. Sinauer, 1984.)

Parallel fiber
+ + + bellar nuclei to the brain stem and thalamus.
Cerebellar
+
cortex
BC
PC
GC
− GR
−
Climbing + marked ataxia is characterized as incoordination due to errors in
fiber
− tients, but also in defects of the skilled movements involved in
Deep
nuclei NC + Mossy fiber
+ +
Other
inputs
+ an overshoot to one side or the other. This dysmetria promptly
FIGURE 18–11 Diagram of neural connections in the
cerebellum. Plus (+) and minus (–) signs indicate whether endings
are excitatory or inhibitory. BC, basket cell; GC, Golgi cell; GR, granule
cell; NC, cell in deep nucleus; PC, Purkinje cell. Note that PCs and BCs
are inhibitory. The connections of the stellate cells, which are not
shown, are similar to those of the basket cells, except that they end
for the most part on Purkinje cell dendrites. (Reproduced with permission
from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical
Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
receive input from the parallel fibers, and each projects to
many Purkinje cells (Figure 18–10). Their axons form a basket
around the cell body and axon hillock of each Purkinje cell
they innervate. Stellate cells are similar to the basket cells but
more superficial in location. The dendrites of Golgi cells re-
ceive input from the parallel fibers. Their cell bodies receive
input from the mossy fibers, and their axons project to the
dendrites of the granule cells.
The primary afferent inputs to the cerebellum are the mossy
and climbing fibers, both of which are excitatory
(Figure 18–11). The climbing fibers relay proprioceptive in-
put from a single source, the inferior olivary nuclei. The
mossy fibers provide proprioceptive input as well as input
from the cerebral cortex via the pontine nuclei.
The fundamental circuits of the cerebellar cortex are rela-
tively simple (Figure 18–11). Climbing fiber inputs exert a
strong excitatory effect on a single Purkinje cell, and mossy
fiber inputs exert a weak excitatory effect on many Purkinje
cells via the granule cells. The basket and stellate cells are also
excited by granule cells via the parallel fibers, and their output
inhibits Purkinje cell discharge (feed-forward inhibition).
Golgi cells are excited by the mossy fiber collaterals, Purkinje
cell collaterals, and parallel fibers, and they inhibit transmis-
sion from mossy fibers to granule cells.
The output of Purkinje cells is inhibitory to the deep cere-
bellar nuclei. These nuclei also receive excitatory inputs via
collaterals from the mossy and climbing fibers. Thus, almost
all the cerebellar circuitry seems to be concerned solely with
CHAPTER 18 Control of Posture and Movement 175
modulating or timing the excitatory output of the deep cere-
CEREBELLAR DISEASE
Damage to the cerebellum leads to several characteristic
abnormalities, including hypotonia, ataxia, and intention trem-
+
or. Most abnormalities are apparent during movement. The
the rate, range, force, and direction of movement. Ataxia is man-
ifest not only in the wide-based, unsteady, “drunken” gait of pa-
the production of speech. The individual pauses between words
and syllables, a phenomenon referred to as scanning speech.
Voluntary movements are also highly abnormal. As an
example, if one attempts to touch an object with a finger, there is
initiates a gross corrective action, but the correction overshoots
to the other side. Consequently, the finger oscillates back and
forth. This oscillation is the intention tremor of cerebellar dis-
ease. Another characteristic of cerebellar disease is the inability
to stop movement promptly. Normally, for example, flexion of
the forearm against resistance is quickly checked when the re-
sistance force is suddenly broken off. The patient with cerebel-
lar disease cannot stop the movement of the limb, and the
forearm flies backward in a wide arc (rebound phenomenon).
This is one of the reasons these patients show dysdiadochoki-
nesia, the inability to perform rapidly alternating opposite
movements such as repeated pronation and supination of the
hands. Finally, patients with cerebellar disease have difficulty
performing actions that involve simultaneous motion at more
than one joint. They dissect such movements and carry them
out one joint at a time (decomposition of movement).
Motor abnormalities associated with cerebellar damage vary
depending on the region involved. The major dysfunctions
seen after damage to the vestibulocerebellum are ataxia, dyse-
quilibrium, and nystagmus. Damage to the vermis and fastigial
nucleus (part of the spinocerebellum) leads to disturbances in
control of axial and trunk muscles during attempted antigravity
postures and scanning speech. Degeneration of this portion of
the cerebellum can result from thiamine deficiency in alcohol-
ics or malnourished individuals. The major dysfunctions seen
after damage to the cerebrocerebellum are delays in initiating
movements and decomposition of movement.
CLINICAL CORRELATION
About 2 years ago at the age of 34, a man developed pro-
gressive weakness in his right leg and eventually his
whole right side weakened. He was unable to continue
his work as an electrician. He experienced cramps in his
right calf muscle and muscle twitches in his arm and leg.
A neurological examination revealed muscular atrophy,
176 SECTION IV CNS/Neural Physiology
fasciculations (muscle twitches that appear as flickers
under the skin), and hypotonia of muscles in the arm
and leg. He also had marked hyporeflexia. Sensory and
cognitive function tests were normal. All signs were in-
dicative of a lower motor neuron disease affecting mul-
tiple spinal cord levels. He was eventually diagnosed with
amyotrophic lateral sclerosis (ALS). Over the course of
the next year, the disease progressed to the point where
he had difficulty swallowing (dysphagia), so he had to be
fed via a gastric tube. About 6 months ago, he developed
difficulty breathing and was placed on a ventilator. One
week ago, he died of pneumonia.
ALS is a selective, progressive degeneration of α-motor
neurons. “Amyotrophic” means “no muscle nourishment”
and describes the atrophy that muscles undergo because
of disuse. “Sclerosis” refers to the hardness felt when a pa-
thologist examines the spinal cord on autopsy; the hard-
ness is due to proliferation of astrocytes and scarring of
the lateral columns of the spinal cord. This fatal disease is
also known as Lou Gehrig’s disease in recognition of a fa-
mous American baseball player who died of it. The world-
wide annual incidence of ALS is estimated to be 0.5–3
cases per 100,000 people. Most cases are sporadic, but
5–10% of the cases are familial. Forty percent of the famil-
ial cases have a mutation in the gene for Cu/Zn superox-
ide dismutase (SOD-1) on chromosome 21. SOD is a free
radical scavenger that reduces oxidative stress. A defec-
tive SOD-1 gene permits free radicals to accumulate and
kill neurons. The disease has no racial, socioeconomic, or
ethnic boundaries. The life expectancy of ALS patients is
usually 3–5 years after diagnosis. ALS is most commonly
diagnosed in middle age and affects men more often than
women. The causes of ALS are unclear, but may include
viruses, neurotoxins, heavy metals, DNA defects (espe-
cially in familial ALS), immune system abnormalities, and
enzyme abnormalities. There is no cure for ALS; treat-
ments (e.g., physical and occupational therapy) focus on
relieving symptoms and maintaining the quality of life.
CHAPTER SUMMARY
■ The ventral corticospinal tract and medial descending brain
stem pathways (tectospinal, reticulospinal, and vestibulospinal
tracts) regulate proximal muscles and posture. The lateral
corticospinal and rubrospinal tracts control distal limb muscles
and skilled voluntary movements.
■ Decerebrate rigidity leads to hyperactivity in extensor
muscles in all four extremities; it is actually spasticity due
to facilitation of the myotatic stretch reflex. Decorticate
posturing or decorticate rigidity is flexion of the upper
extremities at the elbow and extensor hyperactivity in the
lower extremities.
■ The basal ganglia include the caudate nucleus, putamen, globus
pallidus, subthalamic nucleus, and substantia nigra. The
connections between the parts of the basal ganglia include a
dopaminergic nigrostriatal projection from the substantia nigra
to the striatum and a GABAergic projection from the striatum
to substantia nigra.
■ Parkinson’s disease is due to degeneration of the nigrostriatal
dopaminergic neurons and is characterized by akinesia,
bradykinesia, cogwheel rigidity, and tremor at rest.
■ The cerebellar cortex contains five types of neurons: Purkinje,
granule, basket, stellate, and Golgi cells. The two main inputs
to the cerebellar cortex are climbing fibers and mossy fibers.
Purkinje cells are the only output from the cerebellar cortex
and they generally project to the deep nuclei.
■ Damage to the cerebellum leads to several characteristic
abnormalities, including hypotonia, ataxia, and intention tremor.
STUDY QUESTIONS
1. A primary function of the basal ganglia is
A) sensory integration.
B) short-term memory.
C) planning voluntary movement.
D) neuroendocrine control.
E) slow-wave sleep.
2. The therapeutic effect of l-DOPA in patients with Parkinson’s
disease eventually wears off because
A) antibodies to dopamine receptors develop.
B) inhibitory pathways grow into the basal ganglia from
the frontal lobe.
C) cholinergic neurons in the striatum degenerate.
D) the normal action of nerve growth factor (NGF) is
disrupted.
E) the dopaminergic neurons in the substantia nigra continue
to degenerate.
3. Increased neural activity before a skilled voluntary movement
is first seen in the
A) spinal motor neurons.
B) precentral motor cortex.
C) midbrain.
D) cerebellum.
E) cortical association areas.
4. After falling down a flight of stairs, a young woman is found to
have partial loss of voluntary movement on the right side of her
body and loss of pain and temperature sensation on the left side
below the midthoracic region. It is probable that she has a lesion
A) transecting the left half of the spinal cord in the
lumbar region.
B) transecting the left half of the spinal cord in the upper
thoracic region.
C) transecting sensory and motor pathways on the right
side of the pons.
D) transecting the right half of the spinal cord in the
upper thoracic region.
E) transecting the dorsal half of the spinal cord in the
upper thoracic region.
5. Which of the following are not correctly paired?
A) medial brain stem pathways:axial and proximal
muscle control
B) lateral brain stem pathway:rubrospinal tract
C) upper motor neuron disease:hypotonia
D) cerebellar disease:intention tremor
E) decerebrate rigidity:hyperactivity of extensor muscles

Autonomic Nervous
System
Susan M. Barman
O B J E C T I V E S
■ Describe the location of the cell bodies and axonal trajectories
of preganglionic sympathetic and parasympathetic neurons.
■ Describe the location and trajectories of postganglionic sympathetic
and parasympathetic neurons.
■ Name the neurotransmitters that are released by preganglionic and
postganglionic autonomic neurons.
■ List the major functions of the autonomic nervous system.
■ Identify some of the neural inputs to sympathetic and parasympathetic neurons.
INTRODUCTION
The autonomic nervous system (ANS) is one of the control sys-
tems responsible for homeostasis and is the source of innerva-
tion of organs other than skeletal muscle. Nerve terminals are
located in smooth muscle (e.g., blood vessels, gut wall, urinary
bladder), cardiac muscle, and glands (e.g., sweat glands, salivary
glands). Although survival is possible without an ANS, the abil-
ity to adapt to environmental stressors and other challenges is
severely compromised in diseases that affect this component of
the nervous system. The ANS has two major divisions: sympa-
thetic and parasympathetic nervous systems. It is classically
defined by the preganglionic and postganglionic neurons within
the sympathetic and parasympathetic divisions. A more mod-
ern definition of the ANS takes into account the descending
pathways from several forebrain and brain stem regions as well
as visceral afferent pathways that set the level of activity in sym-
pathetic and parasympathetic nerves.
ANATOMIC ORGANIZATION
OF AUTONOMIC OUTFLOW
Figure 19–1 compares some fundamental characteristics of the
innervation of skeletal muscle and innervation of smooth mus-
cle, cardiac muscle, and glands. As described in Chapter 14,
Ch19_177-184.indd 177
19
C H A P T E R
α-motor neurons serve as the final common pathway linking
the central nervous system (CNS) to skeletal muscles. Simi-
larly, sympathetic and parasympathetic neurons serve as the
final common pathway from the CNS to visceral targets. How-
ever, the peripheral portion of the ANS is composed of two
neurons: preganglionic and postganglionic neurons. The cell
bodies of the preganglionic neurons are located in the inter-
mediolateral column (IML) of the spinal cord and in motor
nuclei of some cranial nerves. In contrast to the large-diameter
and rapidly conducting α-motor neurons, preganglionic axons
are small-diameter and relatively slowly conducting B fibers.
A preganglionic axon diverges to an average of about nine
postganglionic neurons, making autonomic output diffuse.
The axons of the postganglionic neurons are mostly unmyeli-
nated C fibers and terminate on the visceral effectors.
SYMPATHETIC DIVISION
In contrast to α-motor neurons that are located at all spinal
segments, sympathetic preganglionic neurons are located in
the IML of only the first thoracic to the third or fourth lum-
bar segments. This is why the sympathetic nervous system is
sometimes called the thoracolumbar division of the ANS.
The axons of sympathetic preganglionic neurons leave the
spinal cord at the level at which their cell bodies are located
and exit via the ventral root along with axons of α- and
177
11/26/10 9:58:22 AM
178 SECTION IV CNS/Neural Physiology

CNS Somatic nervous system

Effector
organ
ACh

Autonomic nervous system:

CNS Parasympathetic division

Effector
organ

Ganglion ACh

Autonomic nervous system:

CNS Sympathetic division
Effector
organ

ACh Ganglion ACh NE

Effector
(via bloodstream) organ

Adrenal Epi (also NE, DA, peptides)

medulla
FIGURE 19–1 Comparison of peripheral organization and transmitters released by somatomotor and autonomic nervous systems
(NS). ACh, acetylcholine; DA, dopamine; NE, norepinephrine; Epi, epinephrine. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s
Human Physiology. McGraw-Hill, 2008.)

γ-motor neurons (Figure 19–2). They then separate from
the ventral root via the white rami communicans and proj-
ect to the adjacent sympathetic paravertebral ganglion,
where some of them end on the cell bodies of postganglionic
neurons. Paravertebral ganglia are located adjacent to each
thoracic and upper lumbar segment; in addition, there are a
few ganglia adjacent to the cervical and sacral spinal seg-
ments. Paravertebral ganglia form the sympathetic chain
(or sympathetic trunk) bilaterally. The ganglia are connected
to each other via the axons of preganglionic neurons that
travel rostrally or caudally to terminate on postganglionic
neurons located at some distance. This arrangement is
shown in Figures 19–2 and 19–3.
Some preganglionic neurons pass through the sympathetic
chain and end on postganglionic neurons located in preverte-
bral (or collateral) ganglia close to the viscera, including the
celiac, superior mesenteric, and inferior mesenteric ganglia
(Figure 19–3). There are also preganglionic neurons whose
axons terminate directly on an effector organ, the medulla of
the adrenal gland.
The axons of some of the postganglionic neurons leave the
chain ganglia and reenter the spinal nerves via the gray rami
communicans and are distributed to autonomic effectors in
the areas supplied by these spinal nerves (Figure 19–2). These
postganglionic sympathetic nerves terminate on smooth mus-
cle of blood vessels and hair follicles and on sweat glands in the
limbs. Other postganglionic fibers leave the chain ganglia to
enter the thoracic cavity to terminate in visceral organs. Post-
ganglionic fibers from prevertebral ganglia also terminate in
visceral targets.
PARASYMPATHETIC DIVISION
The parasympathetic nervous system is sometimes called the
craniosacral division of the ANS because of the location of its
preganglionic neurons (Figure 19–3). The parasympathetic
nerves supply the visceral structures in the head via the oculo-
motor, facial, and glossopharyngeal nerves, and those in the
thorax and upper abdomen via the vagus nerves. The sacral
outflow supplies the pelvic viscera via branches of the second
to fourth sacral spinal nerves. Parasympathetic preganglionic
fibers synapse on ganglia cells clustered within the walls of vis-
ceral organs; thus, these parasympathetic postganglionic fibers
are very short.
CHEMICAL TRANSMISSION AT
AUTONOMIC JUNCTIONS
ACETYLCHOLINE AND
NOREPINEPHRINE
The principal transmitter agents released by autonomic
nerves are acetylcholine and norepinephrine (Figure 19–1).
The neurons that are cholinergic (i.e., release acetylcholine)
include (1) all preganglionic neurons, (2) all parasympa-
thetic postganglionic neurons, (3) sympathetic postgangli-
onic neurons that innervate sweat glands, and (4) sympathetic
postganglionic neurons that end on blood vessels in some
skeletal muscles and produce vasodilation when stimulated
 CHAPTER 19 Autonomic Nervous System 179

FIGURE 19–2 Projection of sympathetic preganglionic and postganglionic fibers. The drawing shows the thoracic spinal cord,
paravertebral, and prevertebral ganglia. Preganglionic neurons are shown in red, postganglionic neurons in dark blue, afferent sensory pathways
in blue, and interneurons in black. (Reproduced with permission from Boron WF, Boulpaep EL: Medical Physiology. Elsevier, 2005.)

(sympathetic vasodilator nerves). The remaining sympa-
thetic postganglionic neurons are noradrenergic (i.e., release
norepinephrine). The adrenal medulla is essentially a sym-
pathetic ganglion in which the postganglionic cells have lost
their axons and secrete norepinephrine and epinephrine
directly into the bloodstream.
Transmission in autonomic ganglia is mediated primarily
by N2 nicotinic cholinergic receptors that are blocked by
hexamethonium, whereas transmission at the neuromuscu-
lar junction is via N1 nicotinic cholinergic receptors that are
blocked by D-tubocurare. The release of acetylcholine from
postganglionic fibers acts on muscarinic receptors, which
are blocked by atropine. The release of norepinephrine from
sympathetic postganglionic fibers acts on α1-, α2-, β1-, or
β2-adrenoreceptors, depending on the target organ.
Table 19–1 shows the types of receptors at various junctions
within the ANS.
In addition to these “classical” neurotransmitters, some
autonomic fibers also release neuropeptides. The small granu-
lated vesicles in postganglionic noradrenergic neurons contain
ATP and norepinephrine, and the large granulated vesicles
contain neuropeptide Y. Low-frequency stimulation may pro-
mote release of ATP, whereas high-frequency stimulation may
cause release of neuropeptide Y. The viscera contain puriner-
gic receptors, and ATP may be a mediator in the ANS along
with norepinephrine.
RESPONSES OF EFFECTOR
ORGANS TO AUTONOMIC NERVE
IMPULSES
The effects of stimulation of the noradrenergic and cholin-
ergic postganglionic nerve fibers are indicated in Figure
19–3 and Table 19–1. Release of acetylcholine onto smooth
muscle of some organs leads to contraction (e.g., walls of the
gastrointestinal tract), and release onto other organs leads
to relaxation (e.g., sphincters in the gastrointestinal tract).
For some targets innervated by the ANS, one can shift from
contraction to relaxation by switching from activation of
the parasympathetic nervous system to activation of the
180 SECTION IV CNS/Neural Physiology

FIGURE 19–3 Organization of sympathetic (left) and parasympathetic (right) nervous systems. Preganglionic sympathetic and
parasympathetic neurons are shown in red and orange, respectively; postganglionic sympathetic and parasympathetic neurons in blue and
green, respectively. (Reproduced with permission from Boron WF, Boulpaep EL: Medical Physiology. Elsevier, 2005.)
 CHAPTER 19 Autonomic Nervous System 181

TABLE 19–1 Responses of some effector organs to autonomic nerve activity.

Sympathetic Nervous System

Effector Organs Parasympathetic Nervous System Receptor Type Response

Eyes

Radial muscle of iris — a

α1 Contraction (mydriasis)

Sphincter muscle of iris Contraction (miosis) —

Ciliary muscle Contraction for near vision —

Heart

SA node Decreases heart rate β1 Increases heart rate

Atria and ventricle Decreases contractility β 1 , β2 Increases contractility

AV node and Purkinje Decreases conduction velocity β 1 , β2 Increases conduction velocity

Arterioles

Coronary — α1, α2 Constriction

β2 Dilation

Skin — α1, α2 Constriction

Skeletal muscle — α1 Constriction

β2, Muscarinic Dilation

Abdominal viscera — α1 Constriction

Salivary glands Dilation α1, α2 Constriction

Renal — α1 Constriction

Systemic veins — α1, α2 Constriction

β2 Dilation

Lungs

Bronchial muscle Contraction β2 Relaxation

Bronchial glands Stimulation α1 Inhibition

β2 Stimulation

Stomach

Motility and tone Increases α1, α2, β2 Decreases

Sphincters Relaxation α1 Contraction

Secretion Stimulation Unknown Inhibition

Intestine

Motility and tone Increases α1, α2, β1, β2 Decreases

Sphincters Relaxation α1 Contraction (usually)

Secretion Stimulation α2 Inhibition

Gall bladder Contraction β2 Relaxation

Urinary bladder

Detrusor Contraction β2 Relaxation

Sphincter Relaxation α1 Contraction

(Continued)
182 SECTION IV CNS/Neural Physiology

TABLE 19–1 Responses of some effector organs to autonomic nerve activity. (Continued)
Sympathetic Nervous System

Effector Organs Parasympathetic Nervous System Receptor Type Response

Uterus Variable α1 Contraction (pregnant)

β2 Relaxation

Male sex organs Erection α1 Ejaculation

Skin

Pilomotor muscles — α1 Contraction

Sweat glands α1 Slight, localized secretionb

Generalized abundant, dilute

Muscarinic secretion

Liver — α1, β2 Glycogenolysis

Pancreas

Exocrine glands Increases secretion α Decreases secretion

Endocrine glands — α2 Inhibits secretion

Salivary glands Profuse, watery secretion α1 Thick, viscous secretion

β Amylase secretion

Lacrimal glands Secretion —

Adipose tissue — α2, β3 Lipolysis

a
A dash means these cells are not innervated by this division of the autonomic nervous system.
b
On palms of hands and in some other locations (“adrenergic sweating”).
Modified with permission from Hardman JG, Limbird LE, Gilman AG [editors]: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. McGraw-Hill, 2001.

sympathetic nervous system. This is the case for the many
organs that receive dual innervation with antagonistic
effects, including the digestive tract, airways, and urinary
bladder. The heart is another example of an organ with
dual antagonistic control. Stimulation of sympathetic
nerves increases heart rate, and stimulation of parasympa-
thetic nerves decreases heart rate.
In other cases, the effects of sympathetic and parasympa-
thetic activation are complementary. An example is the inner-
vation of salivary glands. Parasympathetic activation causes
release of watery saliva, while sympathetic activation causes
the production of thick, viscous saliva.
The two divisions of the ANS act in a synergistic or coop-
erative manner in the control of some functions. One exam-
ple is the control of pupil diameter in the eye. Both
sympathetic and parasympathetic innervations are excit-
atory, but the former contracts the radial muscle to dilate the
pupil (mydriasis) and the latter contracts the sphincter mus-
cle to constrict the pupil (miosis). Another example is the
synergistic actions of these nerves on sexual function.
Activation of parasympathetic nerves to the penis increases
blood flow and leads to erection while activation of sympa-
thetic nerves to the male genitalia causes ejaculation.
There are also several organs that are innervated by only one
division of the ANS. The adrenal medulla, most blood vessels,
the pilomotor muscles in the skin (hair follicles), and sweat
glands are innervated exclusively by sympathetic nerves. The
lacrimal muscle (tear gland), ciliary muscle (for accommoda-
tion for near vision), and the sublingual salivary gland are
innervated exclusively by parasympathetic nerves.
The parasympathetic nervous system is largely concerned
with the vegetative aspects of day-to-day living and is some-
times called the anabolic nervous system. For example,
parasympathetic action favors digestion and absorption of
food by increasing the activity of the intestinal muscula-
ture, increasing gastric secretion, and relaxing the pyloric
sphincter.
The sympathetic nervous system can prepare an individual
to cope with an emergency and can be called the catabolic ner-
vous system. Sympathetic activity dilates the pupils (letting
more light into the eyes), accelerates the heartbeat and raises
blood pressure (providing better perfusion of the vital organs
and muscles), and constricts blood vessels in the skin (which
limits bleeding from wounds). Sympathetic discharge also
leads to elevated plasma glucose and free fatty acid levels (sup-
plying more energy).

REFLEX AND CENTRAL CONTROL
OF AUTONOMIC ACTIVITY
As is the case for α-motor neurons, the activity of autonomic
nerves depends on reflexes (e.g., baroreceptor and chemore-
ceptor reflexes) and on descending excitatory and inhibitory
inputs from several brain regions. For example, pregangli-
onic sympathetic neurons in the IML receive excitatory input
from the rostral ventrolateral medulla and the paraventric-
ular nucleus of the hypothalamus and inhibitory input from
medullary raphe neurons. In addition to these direct path-
ways to the IML, there are many brain regions that feed into
these pathways to regulate autonomic nerve activity. These
include the caudal ventrolateral medulla, nucleus of the trac-
tus solitarius, and locus ceruleus. This is analogous to the
control of somatomotor function by areas such as the basal
ganglia and cerebellum. Chapters 29 and 30 describe reflex
and central mechanisms that regulate autonomic nerves as
related to the control of the cardiovascular system in health
and disease.
The hypothalamus is often regarded as a major central
autonomic control area. Indeed, many of the complex auto-
nomic mechanisms that maintain homeostasis are integrated
in the hypothalamus. The hypothalamus also functions with
the limbic system as a unit that regulates emotional and
instinctual behavior. It interconnects with nuclei in the mid-
brain, pons, and medulla to regulate autonomic activity. The
autonomic responses triggered by activation of the hypothala-
mus are part of complex phenomena such as eating, emotions
such as rage, and responses to stress.
CLINICAL CORRELATION
A 67-year-old retired biology professor suddenly col-
lapsed at his home when he stood up from a reclining
position. His wife called for an ambulance and reported
he was pale but never lost consciousness. He was taken to
a local hospital. His blood pressure was normal in a reclin-
ing position but decreased to hypotensive levels when he
stood. On questioning, he reported that he began to expe-
rience erectile dysfunction about 6 months ago. He also
has noticed difficulty adapting to altered environmental
temperatures. Episodes of urinary incontinence have also
been experienced. The physician detected a mild degree
of ataxia (staggering gait) and tremor.
After a series of neurological exams, he was diagnosed
with Shy–Drager syndrome that is a subtype of multiple
system atrophy (MSA) in which autonomic failure domi-
nates. MSA is a neurodegenerative disorder associated
with autonomic failure due to loss of preganglionic auto-
nomic neurons in the spinal cord and brain stem. In the
CHAPTER 19 Autonomic Nervous System 183
absence of an ANS, it is difficult to regulate body tem-
perature, fluid and electrolyte balance, and blood pres-
sure. MSA can also present with cerebellar, basal ganglia,
locus ceruleus, inferior olivary nucleus, and pyramidal
tract deficits. It is defined as a sporadic, progressive, adult-
onset disorder characterized by autonomic dysfunction,
parkinsonism, and cerebellar ataxia in any combination.
The pathological hallmark of MSA is cytoplasmic and
nuclear inclusions in oligodendrocytes and neurons in
central motor and autonomic areas. There is also depletion
of monoaminergic, cholinergic, and peptidergic markers in
several brain regions and in the cerebrospinal fluid. Basal
levels of sympathetic activity and plasma norepinephrine
levels are normal in MSA patients, but they fail to increase
in response to standing up or other stimuli and lead to
severe orthostatic hypotension (low blood pressure upon
standing). In addition to the decrease in blood pressure,
orthostatic hypotension can lead to dizziness, dimness of
vision, and fainting because of insufficient perfusion of
the brain. MSA is also accompanied by parasympathetic
dysfunction, including urinary and sexual dysfunction.
MSA is most often diagnosed in individuals between 50
and 70 years of age; it affects more men than women.
Erectile dysfunction is often the first symptom of the dis-
ease. There are also abnormalities in baroreceptor reflex
and respiratory control mechanisms. Although auto-
nomic abnormalities are often the first symptoms, 75% of
patients with MSA also experience motor disturbances.
There is no cure for MSA. Treatment is directed toward
assuring patient comfort and maintaining bodily func-
tions as long as possible.
CHAPTER SUMMARY
■ Preganglionic sympathetic neurons are located in the IML of
the thoracolumbar spinal cord and project to postganglionic
neurons in the paravertebral or prevertebral ganglia or the
adrenal medulla. Preganglionic parasympathetic neurons are
located in motor nuclei of cranial nerves III, VII, IX, and X and
the sacral IML.
■ Nerve terminals of postganglionic neurons are located in
smooth muscle (e.g., blood vessels, gut wall, urinary
bladder), cardiac muscle, and glands (e.g., sweat gland,
salivary glands).
■ Acetylcholine is released at nerve terminals of preganglionic
neurons, postganglionic parasympathetic neurons, and a few
postganglionic sympathetic neurons (sweat glands, sympathetic
vasodilator fibers). The remaining sympathetic postganglionic
neurons release norepinephrine.
■ Sympathetic activity can prepare the individual to cope with an
emergency by accelerating the heartbeat, raising blood pressure
(perfusion of the vital organs), and constricting the blood
vessels of the skin (limits bleeding from wounds). Parasympa-
thetic activity is concerned with the vegetative aspects of
184 SECTION IV CNS/Neural Physiology

day-to-day living and favors digestion and absorption of food 3. Parasympathetic nerve activity
by increasing the activity of the intestinal musculature, A) relaxes most vascular smooth muscle.
increasing gastric secretion, and relaxing the pyloric sphincter. B) affects only smooth muscles and glands.
■ The activity of autonomic nerves is dependent on both reflexes C) causes contraction of the radial muscle of the eye to allow
(e.g., baroreceptor and chemoreceptor reflexes) and descending accommodation for near vision.
excitatory and inhibitory inputs from several brain regions D) contracts smooth muscle of the gastrointestinal wall and
including the hypothalamus and brain stem. relaxes the gastrointestinal sphincter.
E) all of the above
4. Which of the following are correctly paired?
STUDY QUESTIONS A) sinoatrial (SA) node:nicotinic cholinergic receptors
B) autonomic ganglia:muscarinic cholinergic receptors
1. Administration of a β-adrenergic receptor antagonist would
C) pilomotor smooth muscle:β2-adrenergic receptors
not be expected to
D) vasculature of some skeletal muscles:muscarinic cholinergic
A) decrease the conduction velocity in the Purkinje fibers receptors
of the heart. E) sweat glands:α2-adrenergic receptors
B) decrease the heart rate.
C) decrease the force of cardiac contraction.
D) relax the detrusor muscle of the bladder.
E) contract bronchial smooth muscle.
2. Sympathetic nerve activity
A) is essential for survival.
B) causes contraction of some smooth muscles and relaxation
of others.
C) causes relaxation of the radial muscle of the eye to dilate
the pupil.
D) relaxes smooth muscle of the gastrointestinal wall and
gastrointestinal sphincter.
E) all of the above
 20
C H A P T E R

Electrical Activity of the

Brain, Sleep–Wake States,
and Circadian Rhythms
Susan M. Barman

O B J E C T I V E S

■ List the main clinical uses of the electroencephalogram.

■ Describe the primary types of brain rhythms.
■ Summarize the behavioral and electrophysiological characteristics of each
of the stages of nonrapid eye movement and rapid eye movement sleep.
■ Describe the pattern of normal nighttime sleep in adults and the variations
in this pattern from birth to old age.
■ Discuss the circadian rhythm and the role of the suprachiasmatic nuclei
in its regulation.
■ Describe the diurnal regulation of synthesis of melatonin from serotonin
in the pineal gland and its secretion into the bloodstream.

INTRODUCTION malities are often difficult to demonstrate. Seizures are divided

The spectrum of behavioral states ranges from deep sleep to
light sleep, rapid eye movement (REM) sleep, and the two
awake states: relaxed awareness and awareness with concen-
trated attention. Specific patterns of brain electrical activity
correlate with each of these states. Some disease processes lead
to changes in these activity patterns. Arousal can be produced
by sensory stimulation and by impulses ascending in the retic-
ular core of the midbrain. Many of these activities have rhyth-
mic fluctuations that are approximately 24 hours in length
(circadian rhythm).
ELECTROENCEPHALOGRAM
EPILEPSY
The electroencephalogram (EEG) recorded from the scalp is
a measure of the summation of dendritic postsynaptic poten-
tials in underlying cortical neurons. The EEG is of value in
localizing pathologic processes in the brain. Epilepsy is a syn-
drome with multiple causes and is characterized by both
behavioral and EEG changes. In some forms, characteristic
EEG patterns occur during seizures; between attacks, abnor-
into partial (focal) seizures and generalized seizures.
Partial seizures originate in a small group of neurons and
can result from head injury, brain infection, stroke, or tumor.
Symptoms depend on the seizure focus and are subdivided
into simple (without loss of consciousness) and complex par-
tial seizures (with altered consciousness). An example of a
partial seizure is localized jerking movements in one hand
progressing to clonic movements of the entire arm. Auras typ-
ically precede the onset of a partial seizure and include abnor-
mal sensations. The time after the seizure until normal
neurological function returns is called the postictal period.
Generalized seizures are associated with widespread electri-
cal activity and involve both hemispheres simultaneously and
are subdivided into convulsive and nonconvulsive categories
depending on whether tonic or clonic movements occur.
Absence seizures (formerly called petit mal seizures) are one of
the forms of nonconvulsive generalized seizures characterized
by a momentary loss of consciousness.
The most common convulsive generalized seizure is tonic–
clonic seizure (formerly called grand mal seizure). This is
associated with sudden onset of contraction of limb muscles
(tonic phase) lasting about 30 seconds, followed by a phase
with symmetric jerking of the limbs as a result of alternating
contraction and relaxation (clonic phase) lasting 1–2 minutes.

185

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186 SECTION IV CNS/Neural Physiology

beta rhythm (Figure 20–1). This phenomenon is called alpha

(a) Alpha rhythm (relaxed with eyes closed)
block (or arousal or alerting response) and can be pro-
duced by any form of sensory stimulation or mental concen-
tration (e.g., solving arithmetic problems). It has also been
called desynchronization, because it represents breaking up
of the highly synchronized neural activity. However, the rapid
EEG activity seen in the alert state is also synchronized, but at
(b) Beta rhythm (alert) a higher rate. Therefore, the term desynchronization is mis-
leading. Gamma oscillations at 30–80 Hz are often observed
when an individual is aroused and focuses attention on some-
thing. This can be replaced by irregular fast activity when the
Time
individual initiates motor activity in response to the stimulus.

FIGURE 20–1 EEG records showing the alpha and beta

rhythms. a and b) When attention is focused on something, the
8–13-Hz alpha rhythm is replaced by an irregular 13–30-Hz low-voltage
activity, the beta rhythm. (Reproduced with permission from Widmaier EP, Raff H,
Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
There is fast EEG activity during the tonic phase. Slow waves,
each preceded by a spike, occur at the time of each clonic jerk.
For a while after the attack, slow waves are present.
BRAIN RHYTHMS IN
WAKEFULNESS AND SLEEP
In adult humans who are awake but at rest with the mind wan-
dering and the eyes closed, the most prominent component of
the EEG is a fairly regular pattern of waves at a frequency of
8–13 Hz and amplitude of 50–100 μV when recorded from the
scalp. This pattern is the alpha rhythm (Figure 20–1). It is
most marked in the parietal and occipital lobes and is associ-
ated with decreased levels of attention.
When attention is focused on something, the alpha rhythm
is replaced by an irregular 13–30-Hz low-voltage activity, the
SLEEP STAGES
There are two kinds of sleep: REM sleep and non-REM (NREM)
or slow-wave sleep. REM sleep is so named because of the char-
acteristic eye movements that occur during this stage of sleep.
NREM sleep is divided into four stages (Figure 20–2). A person
falling asleep enters stage 1 sleep, and the EEG shows a low-
voltage, mixed frequency pattern. A theta rhythm (4–7 Hz) can
be seen at this early stage of slow-wave sleep. Throughout
NREM sleep, there is some activity of skeletal muscle but no
eye movements. Stage 2 is marked by the appearance of sleep
spindles (12–14 Hz) and occasional high-voltage biphasic
K complexes. In stage 3, a high-amplitude delta rhythm
(0.5–4 Hz) dominates the EEG waves. Maximum slowing with
large waves is seen in stage 4. Thus, the characteristic of deep
sleep is a pattern of rhythmic slow waves, indicating marked
synchronization, and it is referred to as slow-wave sleep.
Whereas theta and delta rhythms are normal during sleep, their
appearance during wakefulness is a sign of brain dysfunction.
The high-amplitude slow waves seen in the EEG during
sleep are periodically replaced by rapid, low-voltage EEG
activity, which resembles that seen in the awake, aroused state
(Figure 20–2). However, sleep is not interrupted; indeed, the
threshold for arousal by sensory stimuli is elevated. Rapid,

Awake Sleep stage 1 2 3 4 REM

EOG

EMG

EEG
50 V
1s

FIGURE 20–2 EEG and muscle activity during various stages of the sleep–wake cycle. NREM sleep has four stages. Stage 1 is
characterized by a slight slowing of the EEG. Stage 2 has high-amplitude K complexes and spindles. Stages 3 and 4 have slow, high-amplitude
delta waves. REM sleep is characterized by eye movements, loss of muscle tone, and a low-amplitude, high-frequency activity pattern. The higher
voltage activity in the EOG tracings during stages 2 and 3 reflects high-amplitude EEG activity in the prefrontal areas rather than eye movements.
EOG, electrooculogram registering eye movements; EMG, electromyogram registering skeletal muscle activity. (Reproduced with permission from
Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)
 CHAPTER 20 Electrical Activity of the Brain, Sleep–Wake States, and Circadian Rhythms 187

roving movements of the eyes occur during this sleep stage, Children
Awake
accounting for its name. Another characteristic of REM sleep
is the occurrence of large phasic potentials that originate in the REM

Sleep stages
cholinergic neurons in the pons and pass rapidly to the lateral 1
geniculate body and from there to the occipital cortex. They 2
are called pontogeniculooccipital (PGO) spikes. The tone of 3
the skeletal muscles in the neck is markedly reduced during 4
REM sleep.
Humans aroused during REM sleep often report that they 1 2 3 4 5 6 7
were dreaming, whereas individuals awakened from slow-
wave sleep do not. Thus, REM sleep and dreaming are closely Awake Young Adults
associated. Positron emission tomography (PET) scans
REM
of humans in REM sleep show increased activity in the pon-

Sleep stages
1
tine area, amygdala, and anterior cingulate gyrus, but decreased
2
activity in the prefrontal and parietal cortex. Activity in visual
association areas is increased, but there is a decrease in the 3
primary visual cortex. This is consistent with increased emo- 4
tion and operation of a closed neural system cut off from the
areas that relate brain activity to the external world. 1 2 3 4 5 6 7

Elderly
DISTRIBUTION OF SLEEP STAGES Awake
REM
Sleep stages

In a typical night of sleep, a young adult first enters NREM sleep, 1

passes through stages 1 and 2, and spends 70–100 minutes in 2
stages 3 and 4. Sleep then lightens, and a REM period follows. 3
This cycle is repeated at intervals of about 90 minutes through- 4
out the night (Figure 20–3). The cycles are similar, though there
is less stage 3 and 4 sleep and more REM sleep toward morning. 1 2 3 4 5 6 7
Four to six REM periods occur per night. Hours of sleep
If humans are awakened every time they show REM sleep
and then permitted to sleep without interruption, they show a FIGURE 20–3 Normal sleep cycles at various ages. REM sleep
great deal more than the normal amount of REM sleep for a is indicated by the darker-colored areas. (Reproduced with permission from
few subsequent nights. Various studies imply that sleep is Kales AM, Kales JD. Sleep disorders. Recent findings in the diagnosis and treatment
needed to maintain metabolic–caloric balance, thermal equi- of disturbed sleep. N Engl J Med. 1974; 290:487.)

librium, and immune competence.

SLEEP DISORDERS
Narcolepsy is a chronic neurological disorder caused by the
brain’s inability to regulate sleep–wake cycles normally. There
is a sudden loss of voluntary muscle tone (cataplexy), an
eventual irresistible urge to sleep during daytime, and some-
times brief episodes of total paralysis at the beginning or end
of sleep. Narcolepsy is characterized by a sudden onset of
REM sleep, unlike normal sleep that begins with NREM,
slow-wave sleep. Brains from humans with narcolepsy often
contain fewer hypocretin (orexin)-producing neurons in the
hypothalamus. An immune attack on these neurons can lead
to their degeneration. Obstructive sleep apnea (OSA) is a
common sleep disorder that involves periodic cessation of air
flow during sleep and causes abnormal sleep architecture and
daytime hypersomnolence. Central sleep apnea is a rare
sleep disorder that occurs when the brain temporarily stops
sending signals to the phrenic motor neurons controlling the
diaphragm.
Sleepwalking (somnambulism), bed-wetting (nocturnal
enuresis), and night terrors are referred to as parasomnias,
which are sleep disorders associated with arousal from NREM
and REM sleep. Episodes of sleepwalking are more common
in children than in adults, occur predominantly in males, and
may last several minutes. Somnambulists walk with their eyes
open and avoid obstacles, but when awakened, they cannot
recall the episodes.
CIRCADIAN RHYTHMS AND
THE SLEEP–WAKE CYCLE
Most, if not all, living cells in plants and animals have rhyth-
mic fluctuations in their function on a circadian cycle.
Normally, they become entrained (synchronized) to the day–
night light cycle in the environment. If they are not entrained,
the cycles become progressively more out of phase with the
light–dark cycle because they are longer or shorter than
24 hours. The entrainment process in most cases is dependent
188 SECTION IV CNS/Neural Physiology
Day
Inhibition
Night
Stimulation
FIGURE 20–4 Secretion of melatonin. Retinohypothalamic fibers synapse in the suprachiasmatic nuclei (SCN), and there are connections
from the SCN to sympathetic preganglionic neurons in the spinal cord that project to the superior cervical ganglion. Postganglionic neurons
project from this ganglion to the pineal gland that secretes melatonin. The cyclic activity of SCN sets up a circadian rhythm for melatonin release.
This rhythm is entrained to light/dark cycles by neurons in the retina. (Reproduced with permission from Fox SI: Human Physiology. McGraw-Hill, 2008.)
on the suprachiasmatic nuclei (SCN) that are located above
the optic chiasm (Figure 20–4). The SCN receives information
about the light–dark cycle via a special neural pathway, the
retinohypothalamic tract. Efferents from the SCN initiate
neural and humoral signals that entrain a wide variety of cir-
cadian rhythms including the sleep–wake cycle and the secre-
tion of the pineal hormone melatonin.
The exposure to bright light can advance, delay, or have no
effect on the sleep–wake cycle depending on the time of day
when it is experienced. During the usual daytime it has no
effect, but just after dark it delays the onset of the sleep period,
and just before dawn it accelerates the onset of the next sleep
period. Injections of melatonin have similar effects.
NEUROCHEMICAL MECHANISMS
PROMOTING SLEEP AND AROUSAL
Transitions between sleep and wakefulness manifest a circa-
dian rhythm consisting of an average of 8 hours of sleep and
16 hours of wakefulness. Nuclei in both the brain stem and
hypothalamus are critical for the transitions between these
states of consciousness. The brain stem reticular activating
Melatonin
H H H O
CH3O C C N C CH3
N H H
H
Pineal
gland
Sympathetic
neurons
Retinohypothalamic
tract
Superior cervical
Suprachiasmatic nucleus
ganglion
(the "biological clock")
system (RAS) is composed of several groups of neurons that
release norepinephrine, serotonin, or acetylcholine. In the
case of the forebrain neurons involved in control of the
sleep–wake cycles, preoptic neurons in the hypothalamus
release GABA and posterior hypothalamic neurons release
histamine.
One theory regarding the basis for transitions from sleep to
wakefulness involves alternating reciprocal activity of differ-
ent groups of RAS neurons. In this model (Figure 20–5), wake-
fulness and REM sleep are at opposite extremes. When the
activity of norepinephrine- and serotonin-containing neurons
(locus ceruleus and raphe nuclei) is dominant, there is a
reduced level of activity in acetylcholine-containing neurons
in the pontine reticular formation. This pattern of activity
contributes to the appearance of the awake state. The reverse
of this pattern leads to REM sleep. When there is a more even
balance in the activity of the aminergic and cholinergic neu-
rons, NREM sleep occurs.
In addition, an increased release of GABA and reduced
release of histamine increase the likelihood of NREM sleep via
deactivation of the thalamus and cortex. Wakefulness occurs
when GABA release is reduced and histamine release is
increased.
 CHAPTER 20 Electrical Activity of the Brain, Sleep–Wake States, and Circadian Rhythms 189

Brainstem nuclei that

melatonin secretion may function as a timing signal to coordi-
are part of the reticular nate events with the light–dark cycle in the environment.
activating system Melatonin synthesis and secretion are increased during the
dark period of the day and maintained at a low level dur-
ing daylight hours. This diurnal variation in secretion is
Norepinephrine Norepinephrine brought about by norepinephrine secreted by the postgangli-
and and
serotonin
onic sympathetic nerves that innervate the pineal gland
serotonin
(Figure 20–4). Norepinephrine acts via β-adrenergic receptors
to increase intracellular cAMP, and the cAMP in turn pro-
Acetylcholine Acetylcholine duces a marked increase in N-acetyltransferase activity. This
results in increased melatonin synthesis and secretion.
Circulating melatonin is rapidly metabolized in the liver by
6-hydroxylation followed by conjugation, and over 90% of the
Waking NREM sleep REM sleep
melatonin that appears in the urine is in the form of 6-hydroxy
conjugates and 6-sulfatoxymelatonin. The mechanism by
which the brain metabolizes melatonin may involve cleavage
Activation Activation of the indole nucleus.
of the thalamus of the thalamus The discharge of the sympathetic nerves to the pineal is
and cortex and cortex
entrained to the light–dark cycle in the environment via the
retinohypothalamic nerve fibers to the SCN. From the hypo-
Histamine Histamine thalamus, descending pathways converge onto preganglionic
sympathetic neurons that in turn innervate the superior cervi-
cal ganglion, the site of origin of the postganglionic neurons to
GABA GABA the pineal gland.

Hypothalamus with
circadian and
homeostatic centers
FIGURE 20–5 A model of how alternating activity of brain
stem and hypothalamic neurons may influence the different
states of consciousness. (Reproduced with permission from Widmaier EP, Raff
H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
MELATONIN AND THE
SLEEP–WAKE STATE
Melatonin release from the richly vascularized pineal gland
also plays a role in sleep mechanisms (Figure 20–4). The
pineal arises from the roof of the third ventricle in the dien-
cephalon and is encapsulated by the meninges. The pineal
stroma contains glia and pinealocytes with features suggest-
ing that they have a secretory function. Like other endocrine
glands, it has highly permeable fenestrated capillaries. In
infants, the pineal is large and the cells tend to be arranged in
alveoli. It begins to involute before puberty and small concre-
tions of calcium phosphate and carbonate (pineal sand)
appear in the tissue. Because the concretions are radiopaque,
the pineal is often visible on x-ray films of the skull in adults.
Displacement of a calcified pineal from its normal position
indicates the presence of a space-occupying lesion such as a
tumor in the brain.
Melatonin is synthesized by pinealocytes and secreted into
the blood and the cerebrospinal fluid. The diurnal change in
CLINICAL CORRELATION
A 47-year-old male research scientist at a biotechnology
institute has always been liked for his positive attitude and
high energy level. Recently, his colleagues have noticed
that he becomes agitated if things do not go well in the
laboratory, and he appears to be tired all of the time. His
wife has also been concerned about his being more
grumpy than normal. She accompanies him to his physi-
cian’s office for his annual physical. When the doctor
questions him about his sleep pattern, he insists there has
been no change. But his wife mentions that he has been
waking up suddenly at night and making very loud noises,
sounding somewhat like gasping. He is referred to a sleep
clinic where he undergoes a polysomnogram (PSG) that
records brain activity, eye movements, body movements,
breathing and heart rate, and blood oxygen saturation
over the course of a sleep cycle.
The results of PSG confirmed the doctor’s suspicion
that the scientist has obstructive sleep apnea OSA. OSA is
the most common cause of daytime sleepiness (hyper-
somnolence) due to fragmented sleep at night and affects
about 24% of middle-aged men and 9% of women in the
United States. Breathing ceases for more than 10 seconds
during frequent episodes of obstruction of the upper air-
way (especially the pharynx) due to reduction in upper
airway muscle tone despite continued activity of the
inspiratory muscles. The apnea causes brief arousals from
sleep in order to reestablish upper airway tone. Snoring is
190 SECTION IV CNS/Neural Physiology
a common patient complaint, and OSA is often associated
with obesity. There is actually not a reduction in total sleep
time, but individuals with OSA experience a much greater
time in stage 1 NREM sleep (from an average of 10% of
total sleep to 30–50%) and a marked reduction in slow-
wave sleep (stage 3 and 4 NREM sleep). The pathophysiol-
ogy of OSA includes both a reduction in neuromuscular
tone at the onset of sleep and a change in the central respi-
ratory drive. A common treatment of OSA is the use of a
continuous positive airway pressure (CPAP) mask during
sleep to prevent airway occlusions.
CHAPTER SUMMARY
■ The EEG is of some value in localizing pathologic processes,
and it is useful in characterizing different types of epilepsy.
■ The major rhythms in the EEG are alpha (8–13 Hz), beta
(13–30 Hz), theta (4–7 Hz), delta (0.5–4 Hz), and gamma
(30–80 Hz) oscillations.
■ Throughout NREM sleep, there is some activity of skeletal
muscle. A theta rhythm can be seen during stage 1 of sleep.
Stage 2 is marked by the appearance of sleep spindles and
occasional K complexes. In stage 3, a delta rhythm is dominant.
Maximum slowing with large slow waves is seen in stage 4.
■ REM sleep is characterized by low-voltage, high-frequency
EEG activity and rapid, roving movements of the eyes.
■ A young adult typically passes through stages 1 and 2, and
spends 70–100 minutes in stages 3 and 4. Sleep then lightens,
and a REM period follows. This cycle repeats at 90-minute
intervals throughout the night.
■ Transitions from sleep to wakefulness may involve alternating
reciprocal activity of different groups of RAS neurons. When
the activity of norepinephrine- and serotonin-containing
neurons is dominant, the activity in acetylcholine-containing
neurons is reduced, leading to the appearance of wakefulness.
The reverse of this pattern leads to REM sleep. Also, wakeful-
ness occurs when GABA release is reduced and histamine
release is increased.
■ The entrainment of biological processes to the light–dark cycle
is regulated by the SCN.
■ The diurnal change in melatonin secretion from serotonin in
the pineal gland may function as a timing signal to coordinate
events with the light–dark cycle, including the sleep–wake cycle.
STUDY QUESTIONS
1. In a healthy, alert adult sitting with the eyes closed, the dominant
EEG rhythm observed with electrodes over the occipital lobes is
A) delta (0.5–4 Hz).
B) theta (4–7 Hz).
C) alpha (8–13 Hz).
D) beta (18–30 Hz).
E) fast, irregular low-voltage activity.
2. Which of the following pattern of changes in central
neurotransmitters or neuromodulators is associated
with the transition from NREM to wakefulness?
A) decrease in norepinephrine, increase in serotonin,
increase in acetylcholine, decrease in histamine, and
decrease in GABA
B) decrease in norepinephrine, increase in serotonin,
increase in acetylcholine, decrease in histamine, and
increase in GABA
C) decrease in norepinephrine, decrease in serotonin,
increase in acetylcholine, increase in histamine, and
increase in GABA
D) increase in norepinephrine, increase in serotonin,
decrease in acetylcholine, increase in histamine, and
decrease in GABA
E) increase in norepinephrine, decrease in serotonin,
decrease in acetylcholine, increase in histamine, and
decrease in GABA
3. A gamma rhythm (30–80 Hz)
A) is characteristic of seizure activity.
B) is seen in an individual who is awake but not focused.
C) may be a mechanism to bind together sensory information
into a single percept and action.
D) is also called an alerting response.
E) is characteristic of obstructive sleep apnea.
4. Melatonin secretion would probably not be increased by
A) stimulation of the superior cervical ganglia.
B) a reduction in sunlight.
C) intravenous infusion of norepinephrine.
D) stimulation of the optic nerve.
E) an increase in N-acetyltransferase activity.
5. Absence seizures are a form of
A) nonconvulsive generalized seizures accompanied by
momentary loss of consciousness.
B) complex partial seizures accompanied by momentary
loss of consciousness.
C) nonconvulsive generalized seizures without loss of
consciousness.
D) simple partial seizures without loss of consciousness.
E) convulsive generalized seizures accompanied by momentary
loss of consciousness.
6. Narcolepsy is triggered by abnormalities in the
A) skeletal muscles.
B) medulla oblongata.
C) hypothalamus.
D) olfactory bulb.
E) neocortex.
 21
C H A P T E R

Learning, Memory,
Language, and Speech
Susan M. Barman

O B J E C T I V E S

■ Describe the various types of long-term memory.

■ Define synaptic plasticity, long-term potentiation, long-term depression,
habituation, and sensitization, and their roles in learning and memory.
■ List the parts of the brain that are involved in memory and their role in
memory processing and storage.
■ Describe the abnormalities of brain structure and function found in
Alzheimer disease.
■ Define the terms categorical hemisphere and representational hemisphere.
■ Explain the differences between fluent and nonfluent aphasia.

INTRODUCTION From a physiologic point of view, memory is divided into

explicit and implicit forms (Figure 21–2). Explicit or declara-
A revolution in our understanding of brain function has been tive memory is associated with consciousness (or at least
brought about by the development and widespread availabil- awareness) and is dependent on the hippocampus and other
ity of positron emission tomography (PET), functional parts of the medial temporal lobes of the brain for its reten-
magnetic resonance imaging (fMRI), and related tech- tion. Implicit or nondeclarative memory does not involve
niques. PET is often used to measure local glucose metabo- awareness, and its retention does not usually involve process-
lism, which is proportionate to neural activity, and fMRI is ing in the hippocampus.
used to measure local amounts of oxygenated blood. These
techniques make it possible to determine the activity in vari-
ous parts of the brain in healthy subjects and in those with
various diseases. They have been used to study not only sim-
ple responses, but also complex aspects of learning, memory,
and perception. An example of the use of PET scans to study
the functions of the cerebral cortex in processing words is
shown in Figure 21–1. Different portions of the cortex are
activated when a person is hearing, seeing, speaking, or gen-
erating words.

LEARNING AND MEMORY

Learning is acquisition of information that makes it possi-
ble to alter behavior on the basis of experience, and memory
is the retention and storage of that information. The two
are obviously closely related and should be considered
together.
FIGURE 21–1 Images of active areas of the brain in a male
(left) and female (right) during a language task. Note that males use
only one side of the brain whereas females use both sides of the
brain when language is being processed. (Reproduced with permission
from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. McGraw-Hill, 2008.)

191

Ch21_191-198.indd 191 11/26/10 4:42:30 PM

192 SECTION IV CNS/Neural Physiology
Explicit
(declarative)
Facts Events
(Semantic) (Episodic)
FIGURE 21–2 Forms of long-term
memory. (Modified with permission from Kandel
ER, Schwartz JH, Jessell TM [editors]: Principles of Medial temporal lobe
Neural Science, 4th ed. McGraw-Hill, 2000.) Hippocampus
Explicit memory is divided into episodic memory for events
and semantic memory for facts (e.g., words, rules, and lan-
guage). Explicit memories initially required for activities such
as riding a bicycle can become implicit once the task is thor-
oughly learned.
Implicit memory is subdivided into four types. Procedural
memory includes skills and habits, which, once acquired,
become unconscious and automatic. Priming is facilitation of
recognition of words or objects by prior exposure to them. An
example is improved recall of a word when presented with the
first few letters of it. In nonassociative learning, one learns
about a single stimulus. In associative learning, one learns
about the relation of one stimulus to another.
Explicit memory and many forms of implicit memory
involve (1) short-term memory, which lasts seconds to hours,
during which processing in the hippocampus and elsewhere
leads to long-term changes in synaptic strength; and (2) long-
term memory, which stores memories for years. During short-
term memory, the memory traces are subject to disruption by
trauma and various drugs, whereas long-term memory traces
are remarkably resistant to disruption. Working memory is a
form of short-term memory that keeps information available,
usually for very short periods, while the individual plans action
based on it.
SYNAPTIC PLASTICITY AND LEARNING
The key to memory is alteration in the strength of selected
synaptic connections. In all but the simplest of cases, the alter-
ation involves activation of genes and protein synthesis. This
occurs during the change from short-term working memory
to long-term memory. If an intervention occurs too soon after
a training session, acquisition of long-term memory is
impaired. This is exemplified by the loss of memory for the
events immediately preceding brain concussion or electro-
shock therapy (retrograde amnesia).
Short- and long-term changes in synaptic function can
occur as a result of the history of discharge at a synapse, that is,
Two forms of
long term memory
Implicit
(nondeclarative)
Priming Procedural Associative learning: Nonassociative learning:
(skills and classical and habituation and
habits) operant conditioning sensitization
Emotional Skeletal
responses musculature
Neocortex Striatum Amygdala Cerebellum Reflex
pathways
synaptic conduction can be strengthened or weakened on the
basis of past experience. These changes, which can be presyn-
aptic or postsynaptic, are of great interest because they repre-
sent forms of learning and memory.
One form of plastic change is post-tetanic potentiation, the
production of enhanced postsynaptic potentials in response to
stimulation. This enhancement lasts up to 60 seconds and
occurs after a brief (tetanizing) train of stimuli in a presynap-
tic neuron. The stimulation causes Ca2+ to accumulate in
the presynaptic neuron to such a degree that the intracellu-
lar binding sites that keep cytoplasmic Ca2+ low are over-
whelmed.
Habituation is a simple form of learning in which a neutral
stimulus is repeated many times. The first time it is applied it
is novel and evokes a reaction (the “what is it?” response);
however, it evokes less and less electrical response as it is
repeated. Eventually, the subject becomes habituated to the
stimulus and ignores it. This is associated with decreased
release of neurotransmitter from the presynaptic terminal
because of decreased intracellular Ca2+. The decrease in intra-
cellular Ca2+ is due to a gradual inactivation of Ca2+ channels.
It can be short-term, or it can be prolonged if exposure to the
benign stimulus is repeated many times. Habituation is a clas-
sic example of nonassociative learning.
Sensitization is the prolonged occurrence of augmented
postsynaptic responses after a stimulus to which one has
become habituated is paired once or several times with a nox-
ious stimulus. It is due to presynaptic facilitation and may
occur as a transient response. If it is reinforced by additional
pairings of the noxious stimulus and the initial stimulus, it can
exhibit features of short- or long-term memory. The short-
term prolongation of sensitization is due to a Ca2+-mediated
change in adenylyl cyclase that increases production of cAMP.
The long-term potentiation (LTP) involves protein synthesis
and growth of the presynaptic and postsynaptic neurons and
their connections.
LTP is a rapidly developing persistent enhancement of the
postsynaptic potential response to presynaptic stimulation
 CHAPTER 21 Learning, Memory, Language, and Speech
after a brief period of rapidly repeated stimulation of the pre-
synaptic neuron. It resembles post-tetanic potentiation but is
much more prolonged and can last for days. Unlike post-tetanic
potentiation, it is initiated by an increase in intracellular Ca2+
in the postsynaptic rather than the presynaptic neuron. It
occurs in many parts of the CNS but has been studied in great-
est detail in the hippocampus where there are two forms: mossy
fiber LTP, which is presynaptic and independent of N-methyl-
d-aspartate (NMDA) receptors, and Schaffer collateral LTP,
which is postsynaptic and NMDA receptor-dependent. The
hypothetical basis of the latter form is summarized in Figure
21–3. The basis of mossy fiber LTP appears to include cAMP
and Ih, a hyperpolarization-activated cation channel.
Long-term depression (LTD) is found throughout the brain
in the same fibers as LTP. It is characterized by a decrease in
synaptic strength. It is produced by slower stimulation of pre-
synaptic neurons and is associated with a smaller rise in intra-
cellular Ca2+ than occurs in LTP.
Ca2+ Glu Na+
Mg2+
PS
NMDA AMPA
P short period, all memory of what they were doing and what
Ca2+ AMPA
CaM CaM kII
FIGURE 21–3 Production of long-term potentiation (LTP)
in Schaffer collaterals in the hippocampus. Glutamate (Glu)
released from the presynaptic neuron binds to α-amino-3-hydroxyl-5-
methyl-4-isoxazole-propionate (AMPA) and N-methyl-d-aspartate
(NMDA) receptors in the membrane of the postsynaptic neuron. The
depolarization triggered by activation of the AMPA receptors relieves
the Mg2+ block in the NMDA receptor channel, and Ca2+ enters the
neuron with Na+. The increase in cytoplasmic Ca2+ activates calmodulin
(CaM), which in turn activates Ca2+/calmodulin kinase II (CaM kII).
The kinase phosphorylates the AMPA receptors (P), increasing their
conductance, and moves more AMPA receptors into the synaptic cell
membrane from cytoplasmic storage sites. In addition, a chemical
signal (PS) may pass to the presynaptic neuron, producing a long-term
increase in the quantal release of glutamate. (Courtesy of R. Nicoll)
193
Prefrontal
cortex
Parahippocampal cortex Hippocampus
FIGURE 21–4 Areas concerned with encoding explicit
memories. The prefrontal cortex and the parahippocampal cortex
of the brain are active during the encoding of memories. (Adapted
with permission from Rugg Russ MD. Memories are made of this. Science.
1998;281(5380):1151–1152.)
WORKING MEMORY
Working memory areas are connected to the hippocampus
and the adjacent parahippocampal portions of the medial
temporal cortex (Figure 21–4). Bilateral destruction of
the ventral hippocampus, or Alzheimer disease (described
below) and similar disease processes that destroy its CA1
neurons, causes striking defects in short-term memory.
Individuals with such destruction have intact working mem-
ory and remote memory. Their implicit memory processes
are generally intact. They perform adequately in terms of
conscious memory as long as they concentrate on what they
are doing. However, if they are distracted for even a very
they proposed to do is lost. They are thus capable of new
learning and retain old prelesion memories, but they cannot
form new long-term memories.
The hippocampus is closely associated with the overlying
parahippocampal cortex in the medial frontal lobe (Figure
21–4). When subjects recall words, activity in their left frontal
lobe and their left parahippocampal cortex increases, but when
they recall pictures or scenes, activity takes place in their right
frontal lobe and the parahippocampal cortex on both sides.
The connections of the hippocampus to the diencephalon
are also involved in memory. Some people with alcoholism-
related brain damage develop impairment of recent memory,
and the memory loss correlates well with the presence of
pathologic changes in the mamillary bodies, which have
extensive efferent connections to the hippocampus via the
fornix. The mamillary bodies project to the anterior thala-
mus via the mamillothalamic tract. From the thalamus, the
fibers concerned with memory project to the prefrontal cortex
and from there to the basal forebrain. From the basal fore-
brain, a diffuse cholinergic projection goes to all of the neo-
cortex, the amygdala, and the hippocampus from the nucleus
194 SECTION IV CNS/Neural Physiology
basalis of Meynert. Severe loss of these fibers occurs in
Alzheimer disease.
The amygdala is closely associated with the hippocampus
and is concerned with encoding and recalling emotionally
charged memories. During retrieval of fearful memories, the
theta rhythms of the amygdala and the hippocampus become
synchronized. In healthy subjects, events associated with
strong emotions are remembered better than events without
an emotional charge, but in patients with bilateral lesions of
the amygdala, this difference is absent.
LONG-TERM MEMORY
While the encoding process for short-term explicit mem-
ory involves the hippocampus, long-term memories are
stored in various parts of the neocortex. Various parts of the
memories—visual, olfactory, auditory, etc.—are located in
the cortical regions concerned with these functions, and the
pieces are tied together by long-term changes in the strength
of transmission at relevant synaptic junctions so that all the
components are brought to consciousness when the memory
is recalled.
Once long-term memories have been established, they can
be recalled or accessed by many different associations. For
example, the memory of a vivid scene can be evoked not
only by a similar scene, but also by a sound or smell associ-
ated with the scene. Thus, each stored memory must have
multiple routes, and many memories have an emotional
component.
A Normal
B Alzheimer disease
Neuropil
threads
Neurofibrillary
tangles
FIGURE 21–5 Comparison of a normal neuron (A) and one with abnormalities associated with Alzheimer disease (B). (Reproduced with
permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)
ALZHEIMER DISEASE AND
SENILE DEMENTIA
Alzheimer disease is the most common age-related neurode-
generative disorder. Memory decline initially manifests as a
loss of episodic memory, which impedes recollection of recent
events. Loss of short-term memory is followed by general loss
of cognitive and other brain functions, the need for constant
care, and, eventually, death. The cytopathologic hallmarks of
the disease are intracellular neurofibrillary tangles, made up
in part of hyperphosphorylated forms of the tau protein that
normally binds to microtubules, and extracellular senile
plaques, which have a core of β-amyloid peptides (Aβ)
surrounded by altered nerve fibers and reactive glial cells.
Figure 21–5 compares a normal nerve cell to one showing
abnormalities associated with Alzheimer disease.
The Aβ peptides are products of a normal protein, amyloid
precursor protein (APP), a transmembrane protein that proj-
ects into the extracellular fluid (ECF) from all nerve cells. This
protein is hydrolyzed at three different sites by α-, β-, and
γ-secretase, respectively. When APP is hydrolyzed by α-secretase,
nontoxic peptide products are produced. However, when it is
hydrolyzed by β- and γ-secretase, polypeptides with 40–42
amino acids are produced; the actual length varies because of
variation in the site at which γ-secretase cuts the protein chain.
These polypeptides are toxic, the most toxic being Aβσ1–42. The
polypeptides form extracellular aggregates, which can stick to
α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate
(AMPA) receptors and Ca2+ ion channels, increasing Ca2+ influx.
Nerve
terminals
Aβ Paired helical
(fibrillar) filaments
Abnormal
membranous
organelles
Neurites
Senile plaque
 CHAPTER 21 Learning, Memory, Language, and Speech
They also initiate an inflammatory response, with production of
intracellular tangles. The damaged cells eventually die.
An interesting finding that may have broad physiologic
implications is that frequent effortful mental activities, such as
doing difficult crossword puzzles and playing board games,
slow the onset of cognitive dementia due to Alzheimer disease
and vascular disease. The explanation for this “use it or lose it”
phenomenon is as yet unknown, but it certainly suggests that
the hippocampus and its connections have plasticity like other
parts of the brain.
LANGUAGE AND SPEECH
Memory and learning are functions of large parts of the brain,
but the centers controlling some of the other “higher functions
of the nervous system,” particularly the mechanisms related to
language, are more or less localized to the neocortex.
Human language functions depend more on one cerebral
hemisphere than on the other. This is called the dominant
hemisphere and is concerned with categorization and sym-
bolization. The other hemisphere is not less developed or
“nondominant”; instead, it is specialized in the area of spa-
tiotemporal relations. It is this hemisphere that is concerned,
for example, with the identification of objects by their form
and plays a primary role in the recognition of faces. This con-
tributes to the concept of complementary specialization of the
hemispheres, one for sequential-analytic processes (the cate-
gorical hemisphere) and one for visuospatial relations (the
representational hemisphere). The categorical hemisphere is
concerned with language functions. Lesions in the categorical
hemisphere produce language disorders. In contrast, lesions in
the representational hemisphere lead to astereognosis, the
inability to identify objects by feeling them.
Hemispheric specialization is related to handedness. In 96%
of right-handed individuals, who constitute 91% of the human
population, the left hemisphere is the dominant or categorical
hemisphere, and in the other 4%, the right hemisphere is dom-
inant. In 70% of left-handers, the left hemisphere is also the
categorical hemisphere; in 15%, the right hemisphere is the
categorical hemisphere; and in 15%, there is no clear lateral-
ization. Learning disabilities such as dyslexia (an impaired
ability to learn to read) are 12 times as common in left-handers
as they are in right-handers, possibly because some funda-
mental abnormality in the left hemisphere led to a switch in
handedness early in development. The spatial talents of left-
handers may be well above average as a disproportionately
large number of artists, musicians, and mathematicians are
left-handed.
Some anatomic differences between the two hemispheres
may correlate with the functional differences. The planum
temporale, an area of the superior temporal gyrus that is
involved in language-related auditory processing, is regularly
larger on the left side than the right. Imaging studies show that
other portions of the upper surface of the left temporal lobe
are larger in right-handed individuals, the right frontal lobe is
195
normally thicker than the left, and the left occipital lobe is
wider and protrudes across the midline.
In patients with schizophrenia, a disorder characterized by
a distorted sense of reality, MRI studies show reduced volumes
of gray matter on the left side in the anterior hippocampus,
amygdala, parahippocampal gyrus, and posterior superior
temporal gyrus. The degree of reduction in the left superior
temporal gyrus correlates with the degree of disordered think-
ing in the disease. There are also apparent abnormalities of
dopaminergic systems and cerebral blood flow in this disease.
PHYSIOLOGY OF LANGUAGE
The primary brain areas concerned with language are located
along and near the Sylvian fissure (lateral cerebral sulcus) of
the categorical hemisphere. A region at the posterior end of the
superior temporal gyrus called Wernicke’s area (Figure 21–6) is
concerned with comprehension of auditory and visual informa-
tion. It projects via the arcuate fasciculus to Broca’s area (area 44)
in the frontal lobe immediately in front of the inferior end of the
motor cortex. Broca’s area processes the information received
from Wernicke’s area into a detailed and coordinated pattern for
vocalization and then projects the pattern via a speech articula-
tion area in the insula to the motor cortex, which initiates the
appropriate movements of the lips, tongue, and larynx to pro-
duce speech. The probable sequence of events that occurs when
a subject names a visual object is shown in Figure 21–7. The
angular gyrus behind Wernicke’s area processes information
from words that are read in such a way that they can be con-
verted into the auditory forms of the words in Wernicke’s area.
In individuals who learn a second language in adulthood,
fMRI reveals that the portion of Broca’s area concerned with it
is adjacent to but separate from the area concerned with the
native language. However, in children who learn two languages
early in life, only a single area is involved with both. It is well
known, of course, that children acquire fluency in a second
language more easily than adults.
Arcuate
fasciculus
Broca’s
area Angular gyrus
Wernicke’s area
FIGURE 21–6 Location of some of the areas in the categorical
hemisphere that are concerned with language functions.
(Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H:
Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
196 SECTION IV CNS/Neural Physiology
Left Right
Broca’s area
Facial area of
motor cortex
(area 4) 6 Arcuate
fasciculus
Wernicke’s 5 and reproduce them. They can recognize people by their voices,
area From lateral
(area 22) geniculate nucleus
4
1 identify the familiar faces they see.
Angular gyrus
3
(area 39) 2
Higher order visual
cortical areas
(area 18) Primary visual cortex
(area 17)
FIGURE 21–7 Path taken by impulses when a subject names
a visual object projected on a horizontal section of the human
brain. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks
H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
LANGUAGE DISORDERS
Aphasias are abnormalities of language functions that are not
due to defects of vision or hearing or to motor paralysis. They
are caused by lesions in the categorical hemisphere. The most
common cause is embolism or thrombosis of a cerebral blood
vessel. A convenient classification divides them into fluent,
nonfluent, and anomic aphasias.
In one form of fluent aphasia, the lesion is in Wernicke’s area.
Speech itself is normal, and sometimes the patients talk exces-
sively; however, what they say is full of jargon and neologisms that
make little sense. The patient also fails to comprehend the mean-
ing of spoken or written words, so other aspects of the use of lan-
guage are compromised. Another form of fluent aphasia is a
condition in which patients can speak relatively well and have
good auditory comprehension but cannot put parts of words
together or conjure up words. It appears to be due to lesions in and
around the auditory cortex (Brodmann’s areas 40, 41, and 42).
In nonfluent aphasia, the lesion is in Broca’s area. Speech is
slow, and words are hard to come by. Patients with severe dam-
age to this area are limited to two or three words with which to
express the whole range of meaning and emotion. Sometimes
the words retained are those that were being spoken at the time
of the injury or vascular accident that caused the aphasia.
When a lesion damages the angular gyrus in the categorical
hemisphere without affecting Wernicke’s or Broca’s area, there
is no difficulty with speech or the understanding of auditory
information; instead, there is trouble understanding written
language or pictures, because visual information is not pro-
cessed and transmitted to Wernicke’s area. The result is a con-
dition called anomic aphasia.
RECOGNITION OF FACES
An important part of the visual input goes to the inferior tem-
poral lobe, where representations of objects, particularly faces,
are stored. Faces are particularly important in distinguishing
friends from foes and the emotional state of those seen. Storage
and recognition of faces is more strongly represented in the
right inferior temporal lobe in right-handed individuals.
Lesions in this area cause prosopagnosia, the inability to recog-
nize faces. Patients with this abnormality can recognize forms
and many of them show autonomic responses when they see
familiar as opposed to unfamiliar faces. However, they cannot
CLINICAL CORRELATION
A 9-year-old boy began to have epileptic seizures follow-
ing a bicycle accident. An electroencephalogram (EEG)
showed that the seizures originated in the temporal lobes
bilaterally. He had numerous partial seizures and several
tonic–clonic seizures by the age of 16. The frequent occur-
rence of seizures and lapses in consciousness made com-
pleting high school very difficult, despite his intellectual
abilities. He was also unable to hold down a job as an
assembly worker. At the age of 27, he underwent experi-
mental brain surgery to remove the amygdala, large por-
tions of the hippocampal formation, and portions of the
association area of the temporal cortex. The seizures were
better controlled after surgery, reduced to only about one
major seizure a year. However, the surgery led to devastat-
ing memory deficits. He has maintained long-term mem-
ory for events that occurred before surgery, but he suffers
from anterograde amnesia. His short-term memory is
intact, but he is unable to commit new events to long-
term memory. He has normal procedural memory, and he
can learn new puzzles and motor tasks.
This is an actual patient who underwent the experi-
mental brain surgery in 1953. This case has been studied
by many scientists and has led to a greater understanding
of the link between the temporal lobe and declarative
memory. His case is the first to bring attention to the crit-
ical role of temporal lobes in formation of long-term
memories and to implicate this region in the conversion of
short- to long-term memories. Later work showed that the
hippocampus is the primary structure within the tempo-
ral lobe involved in this conversion. Because he retained
memories from before surgery, his case also shows that
the hippocampus is not involved in the storage of declara-
tive memory. A fascinating audio recording by National
Public Radio from the 1990s of the patient talking to
scientists was released in 2007 and is available at http://
www.npr.org/templates/story/story.php?storyId=7584970.
 CHAPTER 21 Learning, Memory, Language, and Speech
CHAPTER SUMMARY
■ Long-term memory is divided into explicit (declarative) and
implicit (nondeclarative). Explicit is further subdivided into
semantic and episodic. Implicit is further subdivided into
priming, procedural, associative learning, and nonassociative
learning.
■ Synaptic plasticity is the ability of neural tissue to change as
reflected by LTP (an increased effectiveness of synaptic
activity) or LTD (a reduced effectiveness of synaptic activity)
after continued use.
■ Hippocampal and other temporal lobe structures and associa-
tion cortex are involved in declarative memory.
■ Alzheimer disease is characterized by progressive loss of
short-term memory followed by general loss of cognitive
function. The cytopathologic hallmarks of Alzheimer disease
are intracellular neurofibrillary tangles and extracellular senile
plaques.
■ Categorical and representational hemispheres are for sequen-
tial-analytic processes and visuospatial relations, respectively.
Lesions in the categorical hemisphere produce language
disorders, whereas lesions in the representational hemisphere
produce astereognosis.
■ Aphasias are abnormalities of language functions and are
caused by lesions in the categorical hemisphere. They are
classified as fluent (Wernicke’s area; auditory cortex), nonfluent
(Broca’s area), and anomic (angular gyrus) based on the
location of brain lesions.
STUDY QUESTIONS
1. The representational hemisphere
A) is the right cerebral hemisphere in most right-handed
individuals.
B) is the left cerebral hemisphere in most left-handed
individuals.
C) includes the part of the brain concerned with language
functions.
D) is the site of lesions in most patients with aphasia.
E) is morphologically identical to the opposite
nonrepresentational hemisphere.
197
2. The effects of bilateral loss of hippocampal function include
A) disappearance of remote memories.
B) loss of working memory.
C) loss of the ability to encode events of the recent past
in long-term memory.
D) loss of the ability to recall faces and forms but not the ability
to recall printed or spoken words.
E) production of inappropriate emotional responses when
recalling events of the recent past.
3. Which of the following are incorrectly paired?
A) lesion of the parietal lobe of the representational
hemisphere:unilateral inattention and neglect
B) loss of cholinergic neurons in the nucleus basalis of
Meynert and related areas of the forebrain:loss of
recent memory
C) lesions of mamillary bodies:loss of recent memory
D) lesion of the angular gyrus in the categorical
hemisphere:nonfluent aphasia
E) lesion of Broca’s area in the categorical hemisphere:slow
speech
4. The representational hemisphere is better than the categorical
hemisphere at
A) language functions.
B) recognition of objects by their form.
C) understanding printed words.
D) understanding spoken words.
E) mathematical calculations.
5. A lesion of Wernicke’s area (the posterior end of the superior
temporal gyrus) in the categorical hemisphere causes patients to
A) lose short-term memory.
B) speak in a slow, halting voice.
C) experience déjà vu.
D) talk rapidly but make little sense.
E) lose the ability to recognize faces.
6. Which of the following is most likely not to be involved in
production of LTP?
A) cAMP
B) Ca2+
C) NMDA receptors
D) membrane hyperpolarization
E) membrane depolarization
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 SECTION V CARDIOVASCULAR PHYSIOLOGY

22
C H A P T E R

Overview of the
Cardiovascular System
Lois Jane Heller and David E. Mohrman

O B J E C T I V E S

■ Define the role of the cardiovascular system in overall body homeostasis.

■ Identify the major body fluid compartments and state the approximate
volume of each.
■ Diagram the blood flow pathways between the heart and other major body
organs.
■ State the relationship among blood flow, blood pressure, and vascular
resistance.
■ Predict the relative changes in flow through a tube caused by changes in
tube length, tube radius, fluid viscosity, and pressure difference.
■ Identify the chambers and valves of the heart and describe the pathway of
blood flow through the heart.
■ Define cardiac output.
■ Describe the pathway of action potential propagation in the heart.
■ List five factors essential to proper ventricular pumping action.
■ State the relationship between ventricular filling and cardiac output
(Starling’s law of the heart) and describe its importance in the control of
cardiac output.
■ Identify the distribution of sympathetic and parasympathetic nerves in the
heart and list the basic effects of these nerves on the cardiac function.
■ List the major different types of vessels in a vascular bed and describe the
morphological differences among them.
■ Describe the basic anatomical features and functions of the different vessel
types.
■ Identify the major mechanisms in vascular control and blood flow
distribution.
■ Describe the basic composition of the fluid and cellular portions of blood and
list the events associated with blood clotting.

199

Ch22_199-210.indd 199 11/26/10 9:58:03 AM

200 SECTION V Cardiovascular Physiology
HOMEOSTATIC ROLE OF THE
CARDIOVASCULAR SYSTEM
Three compartments of watery fluids, known collectively as
the total body water, account for about 60% of body weight.
This water is distributed among the intracellular, interstitial,
and plasma compartments, as indicated in Figure 22-1. Note
that about two thirds of our body water is contained within
cells and communicates with the interstitial fluid across the
plasma membranes of cells. Of the fluid that is outside cells
(i.e., extracellular fluid), only a small amount, the plasma vol-
ume, circulates within the cardiovascular system. Blood is
composed of plasma and roughly an equal volume of formed
elements (primarily red cells). The circulating plasma fluid
communicates with the interstitial fluid across the walls of
small capillary vessels within organs.
The interstitial fluid is the immediate environment of indi-
vidual cells. The cells must draw their nutrients from and
release their products into the interstitial fluid. The interstitial
fluid cannot, however, be considered a large reservoir for
nutrients or a large sink for metabolic products since its vol-
ume is less than half that of the cells that it serves.
LUNGS
RIGHT
HEART
BODY ORGANS
CAPILLARIES
CELLS
Interstitial compartment
(internal environment)
≈12 L
FIGURE 22–1 Major body fluid compartments with average volumes indicated for a 70-kg human. Total body water is about 60% of
body weight. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
The well-being of individual cells therefore depends heavily
on the homeostatic mechanisms that regulate the composition
of the interstitial fluid. This task is accomplished by continu-
ously exposing the interstitial fluid to “fresh” circulating
plasma fluid.
As blood passes through capillaries, solutes exchange
between plasma and interstitial fluid by the process of diffu-
sion. The net result of transcapillary diffusion is always that
interstitial fluid tends to take on the composition of the incom-
ing blood. If, for example, potassium ion concentration in the
interstitium of a particular skeletal muscle were higher than
that in the plasma entering the muscle, potassium would dif-
fuse into the blood as it passed through the muscle’s capillar-
ies. Since this removes potassium from the interstitial fluid,
interstitial potassium ion concentration would decrease. It
would stop decreasing when net movement of potassium into
capillaries no longer occurred, that is, when interstitial con-
centration reached that of incoming plasma.
Three conditions are essential for this circulatory mecha-
nism to effectively control the composition of interstitial
fluid: (1) there must be adequate blood flow through the tis-
sue capillaries, (2) the chemical composition of the incom-
ing (or arterial) blood must be controlled to be that which is
LEFT
HEART
Circulating plasma compartment
≈3 L
Intracellular compartment
≈30 L
 CHAPTER 22 Overview of the Cardiovascular System
100%
LUNGS
RIGHT HEART PUMP
100%
HEART MUSCLE
BRAIN
SKELETAL MUSCLE
BONE
VEINS
GASTROINTESTINAL SYSTEM, SPLEEN
LIVER
KIDNEY
SKIN
OTHER
FIGURE 22–2 Cardiovascular circuitry indicating the percentage distribution of cardiac output to various organ systems in a
resting individual. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
optimal in the interstitial fluid, and (3) diffusion distances
must be short. Figure 22–1 shows how the cardiovascular
transport system operates to accomplish these tasks. As
discussed above, substances are transported between cells
and plasma in capillary vessels within organs by the process
of diffusion. This transport occurs over extremely small dis-
tances because almost no cell in the body is located farther
than about 10 μm from a capillary. Over such microscopic
distances, diffusion is a very rapid process; however, it is a
very poor mechanism by which to move substances from the
capillaries of one organ, such as the lungs, to the capillaries
of another organ that may be 1 m or more distant. Conse-
quently, substances are transported between organs by the
process of convection, by which the substances move along
with blood flow simply because they are dissolved or other-
wise contained within blood. The relative distances involved
in cardiovascular transport are not well illustrated in
Figure 22–1. If the figure were drawn to scale with 1 inch
representing the distance from capillaries to cells within a
calf muscle, the capillaries in the lungs would have to be
located about 1.5 miles away!
201
LEFT HEART PUMP
100%
3%
14%
15%
5%
ARTERIES
21%
6%
22%
6%
8%
The overall functional arrangement of the cardiovascular
system is illustrated in Figure 22–2. Since a functional rather
than an anatomical viewpoint is expressed in this figure, the
heart appears in three places: as the right heart pump, as the
left heart pump, and as the heart muscle tissue. It is common
practice to view the cardiovascular system as (1) the pulmo-
nary circulation, composed of the right heart pump and the
lungs, and (2) the systemic circulation, in which the left heart
pump supplies blood to the systemic organs (all structures
except the gas exchange portion of the lungs). The pulmonary
and systemic circulations are arranged in series, that is, one
after the other. Consequently, the right and left hearts must
each pump the same volume of blood each minute. This
amount is called the cardiac output. A cardiac output of
5–6 L/min is normal for a resting individual.
As indicated in Figure 22–2, the systemic organs are gen-
erally arranged in parallel (i.e., side by side) within the car-
diovascular system. There are two important consequences
of this parallel arrangement. First, nearly all systemic organs
receive blood of identical composition—that which has just
left the lungs and is known as arterial blood. Second, the
202 SECTION V Cardiovascular Physiology
flow through any one of the systemic organs can be con-
trolled independently of the flow through the other organs.
Thus, for example, the cardiovascular response to whole
body exercise can involve increased blood flow through
some organs, but decreased or unchanged blood flow
through others.
Many of the organs in the body help perform the task of
continuously reconditioning the blood circulating in the car-
diovascular system. Organs that communicate with the exter-
nal environment, such as the lungs, play key roles. As is evident
from the arrangement shown in Figure 22–2, blood that has
just passed through a systemic organ returns to the right heart
and is pumped through the lungs, where oxygen and carbon
dioxide are exchanged. Thus, the blood’s gas composition is
always reconditioned immediately after leaving a systemic
organ.
Like the lungs, many of the systemic organs also serve to
recondition the composition of blood, although the flow cir-
cuitry precludes their doing so each time the blood completes
one circuit. The kidneys, for example, adjust the electrolyte
composition of the blood passing through them. Because the
blood conditioned by the kidneys mixes freely with all the cir-
culating blood and because electrolytes and water freely pass
through most capillary walls, the kidneys control the electro-
lyte balance of the entire internal environment. To achieve
this, it is necessary that a given unit of blood pass often through
the kidneys. In fact, the kidneys (under resting conditions)
normally receive about one fifth of the cardiac output. This
greatly exceeds the amount of flow that is necessary to supply
the nutrient needs of the renal tissue. This situation is com-
mon to organs that have a blood-conditioning function.
Blood-conditioning organs can also withstand, at least tem-
porarily, severe reductions of blood flow. Skin, for example,
can easily tolerate a large reduction in blood flow when it is
necessary to conserve body heat (see Chapter 70). Most of the
large abdominal organs also fall into this category. The reason
is simply that because of their blood-conditioning functions,
their normal blood flow is far in excess of that necessary to
maintain their basal metabolic needs.
The brain, heart muscle, and skeletal muscles typify organs
in which blood flows primarily to supply the metabolic needs
of the tissue. They do not recondition blood for the benefit of
any other organ. Flow to brain and heart muscle is normally
Radius (r )
Pi
Inlet
pressure
FIGURE 22–3 Factors influencing fluid flow through a tube. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology,
6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
only slightly greater than that required for their metabolism,
and they do not tolerate blood flow interruptions well. Uncon-
sciousness can occur within a few seconds after stoppage of
cerebral flow, and permanent brain damage can occur in as
little as 4 minutes without flow. Similarly, the heart muscle
(myocardium) normally consumes about 75% of the oxygen
supplied to it, and the heart’s pumping ability begins to dete-
riorate within beats of a coronary flow interruption. As we
shall see later, the task of providing adequate blood flow to the
brain and the heart muscle receives a high priority in the over-
all operation of the cardiovascular system.
THE BASIC PHYSICS
OF BLOOD FLOW
As outlined above, the task of maintaining interstitial
homeostasis requires that an adequate quantity of blood
flow continuously through the millions of capillaries in the
body. In a resting individual, this adds up to a cardiac output
of about 5 L/min (about 80 gal/h). As people go about their
daily lives, the metabolic rates and therefore the blood flow
requirements in different organs and regions throughout the
body change from moment to moment. Thus, the cardiovas-
cular system must continuously adjust both the magnitude
of cardiac output and how that cardiac output is distributed
to different parts of the body. One of the most important
keys to comprehending how the cardiovascular system oper-
ates is a thorough understanding of the relationship among
the physical factors that determine the rate of fluid flow
through a tube.
The tube depicted in Figure 22–3 might represent a segment
of any blood vessel in the body. It has a certain length (L) and
a certain internal radius (r) through which blood flows. Fluid
flows through the tube only when the pressures in the fluid at
the inlet and outlet ends (Pi and Po) are unequal, that is, when
there is a pressure difference (ΔP) between the ends. Pressure
differences supply the driving force for flow. Because friction
develops between moving fluid and the stationary walls of a
tube, vessels tend to resist fluid movement through them. This
vascular resistance is a measure of how difficult it is to make
fluid flow through the tube, that is, how much of a pressure
Length (L)
P0
·
Flow (Q )
ΔP = Pi − P0 Outlet
pressure
 CHAPTER 22 Overview of the Cardiovascular System
difference it takes to cause a certain flow. The all-important
relation among flow, pressure difference, and resistance is
described by the basic flow equation as follows:
Flow = Pressure difference
______________
Resistance
(1)
Q· = ___
ΔP
R in systemic veins approaches 0 mm Hg.
where Q· is the flow (volume/time), ΔP the pressure difference
(mm Hg), and R the resistance to flow (mm Hg × time/vol-
ume).
The basic flow equation may be applied not only to a single
tube, but also to complex networks of tubes, for example, to
the vascular bed of an organ or to the entire systemic circula-
tion. The blood flow through the brain, for example, is deter-
mined by the difference in pressure between cerebral arteries
and veins divided by the overall resistance to flow through the
vessels in the cerebral vascular bed. It should be evident from
the basic flow equation that there are only two ways in which
blood flow through any organ can be changed: (1) by changing
the pressure difference across its vascular bed or (2) by chang-
ing its vascular resistance. Most often, it is the change in an
organ’s vascular resistance that causes the flow through the
organ to change.
The resistance to flow through a cylindrical tube depends
on several factors, including the radius and length of the tube
and the viscosity of the fluid flowing through it. These factors
influence resistance to flow as follows:
8 Lη
R = ____
πr4
(2)
where r is the inside radius of the tube, L the tube length, and
η the fluid viscosity.
Note that resistance is inversely proportional to the internal
radius of the tube to the fourth power. Thus, even small
changes in the internal radius of a tube have a very large influ-
ence on its resistance to flow. For example, halving the inside
radius of a tube will increase its resistance to flow by 16-fold.
Equations (1) and (2) may be combined into one expression
known as the Poiseuille equation (equation (3)), which
includes all the terms that influence flow through a cylindrical
vessel:
Q· = ΔP ____
π r4
8 Lη
(3)
Again note that flow occurs only when a pressure difference
exists. It is not surprising then that arterial blood pressure is an
extremely important and carefully regulated cardiovascular
variable. Also note once again that, for any given pressure dif-
ference, tube radius has a very large influence on the flow
through a tube. It is logical, therefore, that organ blood flows
are regulated primarily through changes in the radius of blood
vessels within organs. Whereas vessel length and blood viscos-
ity are factors that influence vascular resistance, they are not
variables that can be easily manipulated for the purpose of
moment-to-moment control of blood flow.
In regard to the overall cardiovascular system as depicted in
Figures 22–1 and 22–2, one can conclude that blood flows
203
through the vessels within an organ only because a pressure
difference exists between the blood in the arteries supplying
the organ and the veins draining it. The primary job of the
heart pump is to keep the pressure within arteries higher than
that within veins. Normally, the average pressure in systemic
arteries is approximately 100 mm Hg, and the average pressure
Therefore, because the pressure difference (ΔP) is identical
across all systemic organs, cardiac output is distributed among
the various systemic organs solely on the basis of their indi-
vidual resistances to flow. Because blood flows along the path
of least resistance, organs with relatively low resistance receive
relatively high flow.
THE HEART
PUMPING ACTION
The heart lies in the center of the thoracic cavity suspended by
its attachments to the great vessels within a thin fibrous sac
called the pericardium. A small amount of fluid in the sac
lubricates the surface of the heart and allows it to move freely
during contraction and relaxation. Blood flow through all
organs is passive and occurs only because arterial pressure is
kept higher than venous pressure by the pumping action of the
heart. The right heart pump provides the energy necessary to
move blood through the pulmonary vessels, and the left heart
pump provides the energy to move blood through the systemic
organs.
The amount of blood from each ventricle pumped per min-
ute (the cardiac output, CO) depends on the volume of blood
ejected per beat (the stroke volume, SV) and the number of
heart beats per minute (the heart rate, HR) as follows:
CO[volume/minute] = SV[volume/beat] × HR[beats/min] (4)
It should be evident from the above relationship that all
influences on cardiac output must act by changing either the
heart rate or the stroke volume. These influences will be
described in detail in subsequent chapters.
The pathway of blood flow through the chambers of the
heart is indicated in Figure 22–4. Venous blood returns from
the systemic organs to the right atrium via the superior and
inferior venae cavae. It passes through the tricuspid valve into
the right ventricle and from there is pumped through the pul-
monic valve into the pulmonary circulation via the pulmo-
nary arteries. Oxygenated pulmonary venous blood flows in
pulmonary veins to the left atrium and passes through the
mitral valve into the left ventricle. From there it is pumped
through the aortic valve into the aorta to be distributed to the
systemic organs.
Although the gross anatomy of the right heart pump is
somewhat different than the left heart pump, the pumping
principles are identical. Each pump consists of a ventricle,
which is a closed chamber surrounded by a muscular wall, as
204 SECTION V Cardiovascular Physiology

by rhythmic and synchronized contraction and relaxation of

the individual cardiac muscle cells that lie in a circumferential
Superior Aorta
vena cava orientation within the ventricular wall.
When the ventricular muscle cells are contracting, they gen-
Pulmonary erate a circumferential tension in the ventricular walls that
artery
causes the pressure within the chamber to increase. As soon as
Right
Pulmonary the ventricular pressure exceeds the pressure in the pulmo-
atrium nary artery (right pump) or aorta (left pump), blood is forced
veins
Pulmonic out of the chamber through the outlet valve (pulmonic or aor-
valve Left tic) as shown in Figure 22–5. This phase of the cardiac cycle
atrium during which the ventricular muscle cells are contracting is
called systole. Because the pressure is higher in the ventricle
Aortic
valve
than in the atrium during systole, the inlet or atrioventricular
(AV) valve (tricuspid or mitral) is closed. When the ventricu-
Mitral
valve
lar muscle cells relax, the pressure in the ventricle decreases
Tricuspid
valve below that in the atrium, the AV valve opens, and the ventricle
Left refills with blood as shown on the right of Figure 22–5. This
ventricle portion of the cardiac cycle is called diastole. The outlet valve
Inferior
vena cava is closed during diastole because arterial pressure is greater
than intraventricular pressure. After the period of diastolic
Right filling, the systolic phase of a new cardiac cycle is initiated.
ventricle

FIGURE 22–4 Pathway of blood flow through the heart.

(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology,
6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
illustrated in Figure 22–5. The valves are structurally designed
to allow flow in only one direction and passively open and
close in response to the direction of the pressure differences
across them. Ventricular pumping action occurs because the
volume of the intraventricular chamber is cyclically changed
EXCITATION
Efficient pumping action of the heart requires a precise coor-
dination of the contraction of millions of individual cardiac
muscle cells. Contraction of each cell is triggered when an
electrical excitatory impulse (action potential) sweeps over its
membrane. Proper coordination of the contractile activity of
the individual cardiac muscle cells is achieved primarily by the
conduction of action potentials from one cell to the next via

VENTRICULAR SYSTOLE VENTRICULAR DIASTOLE

Atrium Outlet
valve

Inlet
valve

Ventricular wall Intraventricular chamber

FIGURE 22–5 Ventricular pumping action. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange
Medical Books/McGraw-Hill, 2006.)
 CHAPTER 22 Overview of the Cardiovascular System
Sinoatrial
node
Atrioventricular
node
Atrial
muscle
Cartilage
Bundle
of His
Left bundle
branch
Right bundle
branch
Ventricular
muscle
FIGURE 22–6 Electrical conduction system of the heart.
(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology,
6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
gap junctions that connect all cells of the heart into a func-
tional syncytium (i.e., acting as one synchronous unit). In
addition, muscle cells in certain areas of the heart are specifi-
cally adapted to control the frequency of cardiac excitation,
the pathway of conduction, and the rate of the impulse propa-
gation through various regions of the heart. The major com-
ponents of this specialized excitation and conduction system
are shown in Figure 22–6. They include the sinoatrial node
(SA node), the atrioventricular (AV) node, the bundle of
His, and the right and left bundle branches made up of spe-
cialized cells called Purkinje fibers.
The SA node contains specialized cells that normally func-
tion as the heart’s pacemaker and initiate the action potential
that is conducted through the heart. The AV node contains
slowly conducting cells that normally function to create a
slight delay between atrial contraction and ventricular con-
traction. The Purkinje fibers are specialized for rapid conduc-
tion and assure that all ventricular cells contract at nearly the
same instant.
REQUIREMENTS FOR EFFECTIVE
OPERATION
For effective efficient ventricular pumping action, the heart
must be functioning properly in five basic respects:
1. The contractions of individual cardiac muscle cells must
occur at regular intervals and be synchronized (not
arrhythmic).
2. The valves must open fully (not stenotic).
205
3. The valves must not leak (not insufficient or regurgitant).
4. The muscle contractions must be forceful (not failing).
5. The ventricles must fill adequately during diastole.
In the subsequent chapters, we will study in detail how the
above-mentioned requirements are met in the normal heart.
CONTROL OF THE HEART AND
CARDIAC OUTPUT
Diastolic Filling
As cardiac filling increases during diastole, the volume ejected
during systole also increases. As a consequence, and as illus-
trated in Figure 22–7, with other factors equal, stroke volume
increases as cardiac end-diastolic volume increases. This phe-
nomenon (Starling’s law of the heart) is an intrinsic property
of the cardiac muscle and is one of the primary regulators of
cardiac output. The mechanisms responsible for this phenom-
enon depend largely on the cardiac muscle cell’s length–tension
relationship and will be described in detail in subsequent
chapters.
Autonomic Neural Influences
While the heart can inherently beat on its own, cardiac func-
tion can be influenced profoundly by neural inputs from both
the sympathetic and parasympathetic divisions of the auto-
nomic nervous system. These inputs allow us to modify car-
diac pumping as appropriate to meet changing homeostatic
needs of the body. All portions of the heart are richly inner-
vated by adrenergic sympathetic fibers. When active, these
sympathetic nerves release norepinephrine (noradrenalin) on
cardiac cells. Norepinephrine interacts with β1-adrenergic
receptors on cardiac muscle cells to increase heart rate, increase
action potential conduction velocity, and increase force of con-
Stroke volume
Ventricular end-diastolic volume
FIGURE 22–7 Starling’s law of the heart. (Reproduced with
permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York:
Lange Medical Books/McGraw-Hill, 2006.)
206 SECTION V Cardiovascular Physiology

traction and rates of contraction and relaxation. Overall, sym-
pathetic activation acts to increase cardiac pumping.
Cholinergic parasympathetic nerve fibers travel to the
heart via the vagus nerve and innervate the SA node, the AV
node, and atrial muscle. When active, these parasympathetic
nerves release acetylcholine on cardiac muscle cells. Acetyl-
choline interacts with muscarinic receptors on cardiac muscle
cells to decrease heart rate (SA node) and decrease action
potential conduction velocity (AV node). Parasympathetic
nerves may also act to decrease the force of contraction of
atrial (not ventricular) muscle cells. Overall, parasympathetic
activation acts to decrease cardiac pumping. Usually an
increase in parasympathetic nerve activity is accompanied by
a decrease in sympathetic nerve activity, and vice versa.
THE VASCULATURE
Blood that is ejected into the aorta by the left heart passes con-
secutively through many different types of vessels before it
returns to the right heart. As diagrammed in Figure 22–8, the
major vessel classifications are arteries, arterioles, capillaries,
venules, and veins. These consecutive vascular segments are
distinguished from one another by differences in physical
dimensions, morphological characteristics, and function. One
thing that blood vessels have in common is that they are lined
with a contiguous single layer of endothelial cells. In fact, this
is true for the entire circulatory system including the heart
chambers and even the valve leaflets.
Some representative physical characteristics are shown in
Figure 22–8 for each of the major vessel types. It should be
realized, however, that the vascular bed is a continuum and
that the transition from one type of vascular segment to
another does not occur abruptly. The total cross-sectional area
through which blood flows at any particular level in the vascu-
lar system is equal to the sum of the cross-sectional areas of all
the individual vessels arranged in parallel at that level. The
number and total cross-sectional area values presented in
Figure 22–8 are estimates for the entire systemic circulation.
Arteries are thick-walled vessels that contain, in addition to
some smooth muscle, a large component of elastin and colla-
gen fibers. Primarily because of the elastin fibers, which can
stretch to twice their unloaded length, arteries can expand to
accept and temporarily store some of the blood ejected by the
heart during systole and then, by passive recoil, supply this
blood to the organs downstream during diastole. The aorta is

ARTERIES ARTERIOLES CAPILLARIES VENULES VEINS

One-way
valves

Venae
Aorta cavae
Internal
2.5 cm 0.4 cm 30 mm 5 mm 70 mm 0.5 cm 3 cm
diameter
Wall
2 mm 1 mm 20 mm 1 mm 7 mm 0.5 mm 1.5 mm
thickness
Number 1 160 5 = 107 1010 108 200 2
Total
cross-
4.5 cm2 20 cm2 400 cm2 4500 cm2 4000 cm2 40 cm2 18 cm2
sectional
area

FIGURE 22–8 Structural characteristics of the peripheral vascular system. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular
Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
 CHAPTER 22 Overview of the Cardiovascular System
the largest artery and has an inside (luminal) diameter of about
25 mm. Arterial diameter decreases with each consecutive
branching, and the smallest arteries have diameters of approx-
imately 0.1 mm. The consecutive arterial branching pattern
causes an exponential increase in arterial numbers. Thus,
while individual vessels get progressively smaller, the total
cross-sectional area available for blood flow within the arterial
system increases to several-fold that in the aorta. Arteries are
often referred to as conduit vessels because they have rela-
tively low and unchanging resistance to flow.
Arterioles are smaller and structured differently than arter-
ies. In proportion to lumen size, arterioles have much thicker
walls with more smooth muscle and less elastic material than
arteries. Because arterioles are so muscular, their diameters
can be actively changed to regulate the blood flow through
peripheral organs. Despite their minute size, arterioles are so
numerous that in parallel their collective cross-sectional area
is much larger than that at any level in arteries. Arterioles are
often referred to as resistance vessels because of their high
and changeable resistance, which regulates peripheral blood
flow through individual organs.
Capillaries are the smallest vessels in the vasculature. In
fact, red blood cells with diameters of about 7 μm must
deform to pass through them. The capillary wall consists of a
single layer of endothelial cells, which separate the blood
from the interstitial fluid by only about 1 μm. Capillaries con-
tain no smooth muscle and thus lack the ability to change
their diameters actively. They are so numerous that the total
collective cross-sectional area of all the capillaries in systemic
organs is more than 1,000 times that of the root of the aorta.
Given that capillaries are about 0.5 mm in length, the total
surface area available for exchange of material between blood
and interstitial fluid can be calculated; it exceeds 100 m2. For
obvious reasons, capillaries are viewed as the exchange ves-
sels of the cardiovascular system. In addition to the transcap-
illary diffusion of solutes that occurs across these vessel walls,
there can sometimes be net movements of fluid (volume) into
and/or out of capillaries. For example, tissue swelling (edema)
is a result of net fluid movement from plasma into the inter-
stitial space.
After leaving capillaries, blood is collected in venules and
veins and returned to the heart. Venous vessels have very thin
walls in proportion to their diameters. Their walls contain
smooth muscle and the diameters of venous vessels can actively
change. Because of their thin walls, venous vessels are quite
distensible. Therefore, their diameters change passively in
response to small changes in transmural distending pressure
(i.e., the difference between the internal and external pressures
across the vessel wall). Venous vessels, especially the larger
ones, also have one-way valves that prevent reverse flow. As
will be discussed later, these valves are especially important in
the cardiovascular system’s operation during standing and
during exercise. It turns out that peripheral venules and veins
normally contain more than 50% of the total blood volume.
Consequently, they are commonly thought of as the capaci-
tance vessels. More importantly, changes in venous volume
207
greatly influence cardiac filling and therefore cardiac pump-
ing. Thus, peripheral veins actually play an extremely impor-
tant role in controlling cardiac output.
CONTROL OF BLOOD VESSELS
Blood flow through individual vascular beds is profoundly
influenced by changes in activity of sympathetic nerves inner-
vating arterioles. These nerves release norepinephrine from
their endings that interacts with α-adrenergic receptors on
the smooth muscle cells to cause contraction and thus arterio-
lar constriction. The reduction in arteriolar diameter increases
vascular resistance and decreases blood flow. These neural
fibers provide the most important means of reflex control of
vascular resistance and organ blood flow.
Arteriolar smooth muscle is also very responsive to changes
in the local chemical conditions within an organ that accom-
pany changes in the metabolic rate of the organ. For reasons to
be discussed later, increased tissue metabolic rate leads to arte-
riolar dilation and increased tissue blood flow.
Venules and veins are also richly innervated by sympathetic
nerves and constrict when these nerves are activated. The
mechanism is the same as that involved with arterioles. Thus,
increased sympathetic nerve activity is accompanied by
decreased venous volume. The importance of this phenome-
non is that venous constriction tends to increase cardiac filling
and therefore cardiac output via Starling’s law of the heart.
There is no important neural or local metabolic control of
either the arterial or capillary vessels.
BLOOD
Blood is a complex fluid that serves as the medium for
transporting substances between the tissues of the body and
it performs a host of other functions as well. Normally about
40% of the volume of whole blood is occupied by blood cells
that are suspended in the plasma, which accounts for the
rest of the volume. The fraction of blood volume occupied
by cells is a clinically important parameter termed the
hematocrit:
cell volume
Hematocrit = ______________ (5)
total blood volume
BLOOD CELLS
Blood contains three general types of “formed elements”:
red cells, white cells, and platelets (Table 22–1). All are
formed in bone marrow from a common stem cell. Red cells
(erythrocytes) are by far the most abundant. They are spe-
cialized to carry oxygen from the lungs to other tissues by
binding oxygen to hemoglobin, an iron-containing heme
protein concentrated within red blood cells. Because of the
presence of hemoglobin, blood can transport 50–60 times the
208 SECTION V Cardiovascular Physiology
TABLE 22–1 Normal values of erythrocytes, leukocytes, and platelets in adult human blood.a
Erythrocytes
Platelets
Leukocytes
Type of Leukocyte
Polymorphonuclear granulocytes
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes
a
Normal reference ranges vary somewhat with age, gender, and race. They also may vary from laboratory to laboratory. To confuse the issue further, various unit measurements
are used to report blood values, so caution must be used in interpreting data.
amount of oxygen that plasma alone could carry. In addition,
the hydrogen ion buffering capacity of hemoglobin is vitally
important to the blood’s capacity to transport carbon dioxide.
A small but important fraction of the cells in blood is white
cells or leukocytes. Leukocytes are involved in immune pro-
cesses and have specific roles as indicated in Table 22–1.
Platelets are small cell fragments that are important in the
blood clotting process.
PLASMA
Plasma is the liquid component of blood and, as indicated in
Table 22–2, is a complex solution of electrolytes and proteins.
Serum is the fluid obtained from a blood sample after it has
been allowed to clot. For all practical purposes, the composi-
tion of serum is very similar to that of plasma except that it
contains none of the clotting proteins.
Inorganic electrolytes (ions such as sodium, potassium,
chloride, and bicarbonate) are the most concentrated solutes
in plasma. Of these, sodium and chloride are by far the most
abundant and, therefore, are primarily responsible for plasma’s
normal osmolarity of about 300 mOsm/L. To a first approxi-
mation, plasma is a 150-mM solution of sodium chloride.
Such a solution is called isotonic saline and has many clinical
uses as a fluid that is compatible with cells.
Plasma normally contains many different proteins. Most
plasma proteins can be classified as albumins, globulins, or
fibrinogen on the basis of different physical and chemical
characteristics used to separate them. More than 100 distinct
plasma proteins have been identified and each presumably
serves some specific function. Many plasma proteins are
involved in blood clotting or immune/defense reactions. Many
others are important carrier proteins for a variety of substances
including fatty acids, iron, copper, and certain hormones.
4.0–5.5 million/μL of blood
130,000–400,000/μL of blood
4,000–10,000/μL of blood
Percent Total Leukocytes Primary Role
50–70 Phagocytosis
1–4 Allergic hypersensitivity reactions
0–0.75 Allergic hypersensitivity reaction
2–8 Phagocytosis and antibody
production
15–40 Antibody production and cell-
mediated immunity
Proteins do not readily cross capillary walls and, in gen-
eral, their plasma concentrations are much greater than their
concentrations in the interstitial fluid. As will be dis-
cussed, plasma proteins play an important osmotic role in
transcapillary fluid movement and thus the distribution of
extracellular volume between the plasma and interstitial
compartments. Albumin plays an especially important role
in this regard simply because it is by far the most abundant of
the plasma proteins.
Plasma also serves as the vehicle for transporting nutrients
and waste products. Thus, a plasma sample contains many
small organic molecules such as glucose, amino acids, urea,
creatinine, and uric acid whose measured values are useful in
clinical diagnosis.
HEMOSTASIS
Whenever damage occurs to a blood vessel, a variety of pro-
cesses are initiated that are aimed at preventing or stopping
blood from exiting the vascular space. The three primary pro-
cesses are summarized in the following outlines:
1. Platelet aggregation and plug formation: occur as a re-
sult of the following steps:
A. vessel injury with endothelial damage and collagen
exposure;
B. platelet adherence to collagen (mediated by von
Willebrand factor);
C. platelet shape change (from disks to spiny spheres);
D. platelet degranulation with release of the following:
(i) adenosine diphosphate, which causes platelet ag-
gregation to “plug” the hole,
(ii) thromboxane, causing vasoconstriction, and
platelet adhesion and aggregation.
 CHAPTER 22 Overview of the Cardiovascular System 209

TABLE 22–2 Normal constituents of adult human plasma.

Class Constituent Normal Concentration Range
+
Cations Sodium (Na ) 136–145 mEq/L
+
Potassium (K ) 3.5–5.0 mEq/L
2+
Calcium (Ca ) 4.3–5.2 mEq/L
2+
Magnesium (Mg ) 1.2–1.8 mEq/L
3+
Iron (Fe ) 60–160 μg/dL
+
Hydrogen (H ) 35–45 nmol/L (pH 7.35–7.45)
–
Anions Chloride (Cl ) 98–106 mEq/L
–
Bicarbonate (HCO3 ) 23–28 mEq/L

Lactate 0.67–1.8 mEq/L

2–
Phosphate (HPO4 mostly) 3.0–4.5 mg/dL

Proteins Total (7% of plasma weight) 6–8 g/dL

Albumin 3.4–5.0 g/dL

Globulins 2.2–4.0 g/dL

Fibrinogen 0.3 g/dL

(Note: Aspirin and other cyclooxygenase inhibi-
tors are anticoagulants because they prevent the
formation of thromboxane.)
2. Local vasoconstriction: mediated largely by thrombox-
ane but also may be induced by local release of other
chemical signals that constrict local vessels and reduce
blood flow.
3. Blood clotting: the formation of a solid gel made up of
the protein, fibrin, platelets, and trapped blood cells.
The critical step in blood clotting is the formation of
thrombin from prothrombin, which then catalyzes the
conversion of fibrinogen to fibrin. The final clot is stabi-
lized by covalent cross-linkages between fibrin strands cata-
lyzed by factor XIIIa (the formation of which is catalyzed
by thrombin).
The cascade of reactions that leads from vessel injury to the
formation of thrombin is as follows:
(1) Vessel injury or tissue damage with blood exposure to
subendothelial cells that release thromboplastin (“tissue
factor”).
(2) The plasma protein factor VII binds to the tissue factor,
which converts it to an activated form, factor VIIa.
(3) VIIa catalyzes conversion of both factors IX and X to ac-
tivated forms, IXa and Xa, respectively.
(4) IXa also helps convert factor X to Xa (Stuart factor).
(5) Xa converts prothrombin to thrombin.
(6) Thrombin:
(a) activates platelets (makes them sticky, induces de-
granulation, promotes attachment of various factors
that participate in clotting);
(b) converts fibrinogen to fibrin;
(c) recruits the “intrinsic pathway,” which amplifies fur-
ther formation of factor Xa and facilitates the conver-
sion of prothrombin to thrombin by promoting the
following reactions:
(i) conversion of factor XI to its activated form, XIa,
which then converts factor IX to IXa, which then
attaches to activated platelets and converts factor
X to Xa,
(ii) conversion of factor VIII (missing in people with
hemophilia) to its activated form, VIIIa, which
attaches to activated platelets and accelerates con-
version of factor X to Xa,
(iii) conversion of factor V to its activated form, Va,
which attaches to activated platelets and acceler-
ates conversion of prothrombin to thrombin.
Several agents clinically used as anticoagulants interfere
with various steps in this clotting process. Dicoumarol and
coumadin block the activity of vitamin K, which is neces-
sary for synthesis of many of the clotting factors by the liver.
Heparin activates a plasma protein called antithrombin
III, which, in turn, inactivates thrombin and several of the
other clotting factors. Because calcium is an important clot-
ting cofactor, calcium chelators such as EDTA, oxalate,
and citrate are used to prevent stored blood from clotting.
Various thrombolytic agents modeled after the endogenous
tissue plasminogen activator (tPA) are also available that
promote dissolution of the fibrin clot after it is formed.
These agents promote the formation of plasmin from plas-
minogen that enzymatically attacks the clot, turning it into
soluble peptides.
210 SECTION V Cardiovascular Physiology

■ Blood flow through individual organs is regulated by changes

CLINICAL CORRELATION in the diameters of their arterioles.
■ Changes in arteriolar diameter can be accomplished by
A 45-year-old investment banker passed out at the mall. alterations in sympathetic nerve activity and by variations in
He was conscious by the time the paramedics arrived a local conditions.
few minutes later but was brought to the emergency room ■ Blood is a complex suspension of red cells, white cells, and
for evaluation. He reported that he had been very busy platelets in plasma that is ideally suited to carry gases, salts,
and somewhat stressed lately but otherwise was healthy. nutrients, and waste molecules throughout the system.
He looked pale and felt somewhat nauseated and dizzy ■ Hemostasis involves platelet aggregation, local vasoconstric-
just before the episode, but did not remember falling or tion, and blood clotting.
anything else until the paramedic was leaning over him
on the floor. Physical findings included: weight = 90 kg,
height = 5΄10˝, arterial blood pressure = 130/85 mm Hg, STUDY QUESTIONS
heart rate = 85 b/min, normal heart and breath sounds, 1. You need to determine the correct dose of an i.v. drug that distributes
normal reflexes, and normal cognition. An electrocardio- only within the extracellular space. Which of the following values
gram was obtained and found to be normal. Blood sam- would be the closest estimate of the extracellular fluid volume of a
ples were obtained for markers of myocardial infarction healthy young adult male weighing 100 kg (220 lb)?
and heart failure, and also found to be normal. He was A) 3 L
admitted to the hospital and ECG was monitored over- B) 5 L
night with no significant findings. C) 8 L
Unexplained syncopal (fainting) episodes may be a D) 10 L
result of either a neural problem (seizure) or a significant E) 20 L
decrease in blood flow to the brain. The latter may be 2. You have transfused a liter of blood into your dehydrated patient.
caused by either a failure of the heart to maintain suffi- At any instant, most of this blood will be found in which segment
cient cardiac output (due to an arrhythmia, valve failure, of the systemic vascular bed?
or infarction affecting significant myocardial mass) or a A) arteries
failure within the systemic vasculature either to maintain B) arterioles
C) capillaries
sufficient contractile activity (due to a withdrawal of sym-
D) veins
pathetic neural influences as in vasovagal syncope) or to
E) right atrium
provide sufficient arterial blood supply to the brain (due
3. Which of the following will produce the greatest increase in
to severe, often transient, carotid artery occlusions pro-
blood flow through exercising muscles?
voking a transient ischemic attack [TIA]). Diagnostic
A) halve the length of the capillaries
testing was performed to evaluate these possibilities. The
B) halve the viscosity of the blood
man was outfitted with a Holter monitor that recorded his C) double the radius of the venules
ECG for a 24-hour period, and found to be normal. By D) double the blood pressure difference across the bed
process of elimination, he was given the diagnosis of vaso- E) double the radius of the arterioles
vagal syncope that is usually due to an increase in efferent 4. An individual has had the “flu” for 3 days with severe vomiting
vagal (parasympathetic) input to the heart that will be dis- and diarrhea without increasing his fluid intake. How is this
cussed in Chapters 23 and 29. In most cases of vasovagal likely to influence his hematocrit?
syncope, no treatment is necessary. A) no effect
B) higher than normal
C) lower than normal
D) cannot predict
CHAPTER SUMMARY E) eliminate it
5. Calculate the cardiac output from the following data: pulmonary
■ The primary role of the cardiovascular system is to maintain
arterial pressure = 20 mm Hg; left atrial pressure = 5 mm Hg;
homeostasis of the interstitial fluid.
pulmonary vascular resistance = 3 mm Hg per L/min.
■ The physical law that governs cardiovascular operation is that
A) 3 L/min
flow through any segment is equal to pressure difference across
· B) 5 L/min
that segment divided by its resistance to flow, that is, Q = ΔP/R.
C) 4 L/min
■ The heart pumps blood by rhythmically filling with and D) 15 L/min
ejecting blood from the ventricular chambers that are served by E) 60 mm Hg
passive one-way inlet and outlet valves.
■ Changes in heart rate and stroke volume (and therefore cardiac
output) can be accomplished by alterations in ventricular filling
and by alterations in autonomic nerve activity to the heart.
 23
C H A P T E R

Cardiac Muscle Cells

Lois Jane Heller and David E. Mohrman

O B J E C T I V E S

■ Describe the characteristics of cardiac resting potentials and “fast” and “slow”
response cardiac action potentials.
■ Identify the refractory periods of the cardiac cell electrical cycle.
■ Define threshold potential and describe the interaction between ion channel
conditions and membrane potential during the depolarization phase of the
action potential.
■ Define pacemaker potential and describe the basis for rhythmic electrical
activity of cardiac cells.
■ List the phases of the cardiac cell electrical cycle and state the membrane
permeability alterations responsible for each phase.
■ Describe gap junctions and their role in cardiac excitation.
■ Describe the normal pathway of action potential conduction through the heart.
■ Indicate the timing of electrical excitation of various areas of the heart and
identify the characteristic action potential shapes and conduction velocities
in each major part of the conduction system.
■ State the relationship between electrical events of cardiac excitation and the P,
QRS, and T waves, the PR interval, and the ST segment of the electrocardiogram.
■ State how diastolic potentials of pacemaker cells can be altered to produce
changes in heart rate.
■ Describe how cardiac sympathetic and parasympathetic nerves alter heart
rate and conduction of cardiac action potentials.
■ Define the terms chronotropic and dromotropic.
■ Define and describe the excitation–contraction process in cardiac muscle.
■ Define isometric, isotonic, and afterloaded contractions of cardiac muscle.
■ Identify the influence of altered preload on the tension-producing and
shortening capabilities of cardiac muscle.
■ Describe the influence of altered afterload on the shortening capabilities
of cardiac muscle.
■ Define the terms contractility and inotropic state and describe the influence
of altered contractility on the tension-producing and shortening capabilities
of cardiac muscle.
■ Describe the effect of altered sympathetic neural activity on cardiac
inotropic state.
■ State the relationships between ventricular volume and muscle length, and
between intraventricular pressure and muscle tension; explain the law of Laplace.

211

Ch23_211-222.indd 211 11/26/10 10:00:01 AM

212 SECTION V Cardiovascular Physiology
CHARACTERISTICS OF
CARDIAC MUSCLE CELLS
Coordination of the activity of cardiac muscle cells (myocytes)
depends on an electrical stimulus that is regularly initiated at
an appropriate rate and reliably conducted through the entire
heart. Mechanical pumping action depends on a robust con-
traction of the muscle cells that results in repeating cycles of
tension development, shortening, and relaxation. In addition,
mechanisms to adjust the excitation and contraction charac-
teristics must be available to meet changing demands on the
circulatory system.
ELECTRICAL PROPERTIES
Contraction of cardiac myocytes is triggered by action poten-
tials that occur on the cell membrane. Cardiac action poten-
tials differ sharply from those of skeletal muscle in three
important ways that promote synchronous rhythmic excita-
tion of the heart: (1) they can be self-generating; (2) they can
be conducted directly from cell to cell; and (3) they have long
durations, which preclude fusion of individual twitch contrac-
tions. To understand these special electrical properties of car-
diac muscle and how cardiac function depends on them, the
basic electrical properties of excitable cell membranes
described in Chapters 3 and 6 should be carefully reviewed.
SUMMARY OF CARDIAC CELL
MEMBRANE POTENTIALS
At rest, cardiac cell membranes are more permeable to potas-
sium than to any other ion. Because the potassium concentra-
tion inside the cells is significantly higher than that of the
interstitial fluid (150 mM vs. 4 mM, respectively), the outward
diffusion of potassium down its concentration gradient is bal-
anced by the generation of a membrane potential (i.e., the
potassium equilibrium potential). Both the electrical and the
concentration gradients favor Na+ and Ca2+ entry into the rest-
ing cells. However, the very low permeability of the resting
membrane to Na+ and Ca2+, in combination with an energy-
requiring sodium pump that extrudes Na+ from the cell, pre-
vents Na+ and Ca2+ from gradually accumulating inside the
resting cell. The steep sodium gradient promotes Ca2+ removal
from the cytoplasm via the sodium/calcium exchanger.
Action potentials of cells from different regions of the heart
are not identical but have varying characteristics that depend
on differences in the patterns of changes in their ion permea-
bilities. Some cardiac cells have the ability to act as pacemakers
and to spontaneously initiate action potentials, whereas ordi-
nary cardiac muscle cells do not (except under unusual
conditions). Basic membrane electrical features of an ordinary
cardiac muscle cell and a cardiac pacemaker-type cell are
shown in Figure 23–1. Action potentials from these cell types
are referred to as “fast response” and “slow response” action
potentials, respectively. As shown in panel A of this figure, fast
response action potentials are characterized by a rapid
depolarization (phase 0) with a substantial overshoot (positive
inside voltage), a rapid reversal of the overshoot potential
(phase 1), a long plateau (phase 2), and a repolarization
(phase 3) to a stable, high (i.e., large negative) resting mem-
brane potential (phase 4). In comparison, the slow response
action potentials are characterized by a slower initial depolar-
ization phase (phase 0), a lower amplitude overshoot, a shorter
and less stable plateau phase (phase 2), and a repolarization
(phase 3) to an unstable, slowly depolarizing “resting” poten-
tial (phase 4) (Figure 23–1B). The unstable resting potential
seen in pacemaker cells with slow response action potentials is
variously referred to as the phase 4 depolarization, diastolic
depolarization, or pacemaker potential. Such cells are usu-
ally found in the sinoatrial (SA) and atrioventricular (AV)
nodes.
As indicated at the bottom of Figure 23–1A, cells are in an
absolute refractory state during most of the action potential
(i.e., they cannot be stimulated to fire another action poten-
tial). Near the end of the action potential, the membrane is
relatively refractory and can be re-excited only by a larger-
than-normal stimulus. Immediately after the action potential,
the membrane is transiently hyperexcitable and is said to be in
a “vulnerable” or “supranormal” period. Similar alterations in
membrane excitability occur during slow action potentials but
at present are not well characterized.
Recall that the membrane potential of any cell at any given
instant depends on the relative permeability of the cell mem-
brane to specific ions. As in all excitable cells, cardiac cell
action potentials are the result of transient changes in the ionic
permeability of the cell membrane that are triggered by an ini-
tial depolarization. Panels C and D of Figure 23–1 indicate the
changes in membrane permeabilities to K+, Na+, and Ca2+ that
produce the various phases of the fast and slow response action
potentials.
Note that during the resting phase, the membranes of both
types of cells are dominated by a higher permeability to K+
than to Na+ or Ca2+. Therefore, the membrane potentials are
closer to the potassium equilibrium potential during this
period than to the equilibrium potential of any other ion. In
the pacemaker-type cells, at least three mechanisms are
thought to contribute to the slow depolarization of the mem-
brane observed during the diastolic interval: (1) there is a pro-
gressive slow decrease in the membrane permeability to K+,
(2) there is a slow increase in permeability to Na+, and (3) there
is a slight increase in the permeability of the membrane to
calcium ions.
When the membrane potential depolarizes to the threshold
potential in either type of cell, major rapid alterations in the
permeability of the membrane to specific ions are triggered.
Once initiated, these permeability changes cannot be stopped
and they proceed to completion.
The characteristic rapid rising phase of the fast response
action potential is a result of a sudden increase in Na+
permeability. As indicated in panel C of Figure 23–1, this

A Fast-response action
potentials
Transmembrane potential (mV)
Phase
0 2
Phase 0
–50
Phase 4
–100
Absolute refractory period
Relative refractory period
Supranormal period
C D
10.0
Na+
Relative membrane permeability
Ca2+
K+
1.0
0.1
0 0.15
Time (s)
FIGURE 23–1 Time course of membrane potential and ion permeability changes that occur during “fast response” (A and C) and
“slow response” (B and D) action potentials. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical
Books/McGraw-Hill, 2006.)
period of very high sodium permeability (phase 0) is short-
lived and is followed by a very brief increase in potassium per-
meability (not shown in Figure 23–1C). This brief current
accounts for the very early repolarization that immediately
follows the initial rising phase of the action potential (phase 1).
Development and maintenance of a depolarized plateau state
(phase 2) depends on: (1) a sustained reduction in K+ perme-
ability, (2) a slowly developed and sustained increase in the
membrane permeability to Ca2+, and (3) electrogenic action of
an Na+/Ca2+ exchanger in which three Na+ ions move into the
cell in exchange for a single Ca2+ moving out of the cell. In cells
with the slow response action potential, the initial fast inward
current is small (or even absent). The slow rising phase of
these action potentials is therefore primarily a result of an
inward movement of Ca2+ ions. In both types of cells, the
membrane is repolarized (phase 3) to its original resting
potential as the K+ permeability increases and the Ca2+ and
Na+ permeabilities return to their low resting values.
Recall that the smoothly graded permeability changes that
produce action potentials are the net result of alterations in
each of the many individual ion channels within the plasma
CHAPTER 23 Cardiac Muscle Cells 213
B Slow-response action
potentials
Phas
e3
se 4
Pha
Ca2+
K+
Na+
0.30 0 0.15 0.30
Time (s)
membrane of a single cell as discussed in Chapter 6. Table 23–1
summarizes some of the major currents and channel types
(both voltage- and ligand-gated) involved in cardiac cell elec-
trical activity.
Some of the voltage-gated channels respond to a sudden-
onset, sustained change in membrane potential with only a
brief period of activation. However, changes in membrane
potential of slower onset but the same magnitude may fail to
activate these channels at all. To explain such behavior, it is
postulated that these channels have two independently
operating “gates”—an activation gate and an inactivation
gate—both of which must be open for the channel as a whole
to be open. Both of these gates respond to changes in mem-
brane potential but do so with different voltage sensitivities
and time courses. With an abrupt depolarization to threshold,
sodium channel activation gates open and within a few milli-
seconds their inactivation gates close. In pacemaker cells with
slow diastolic depolarization, the inactivation gates of the
sodium channels are closed before the activation gates have a
chance to open. When threshold is reached, only the calcium
channel is available to open, thus accounting for the initial
214 SECTION V Cardiovascular Physiology

TABLE 23–1 Characteristics of important cardiac ion channels in order of their participation in an action potential.
Gating
Current Channel Mechanism Functional Role

iK1 Kir+ channel (inward rectifier) Voltage Maintains high K+ permeability during phase 4
Its decay contributes to diastolic depolarization
Its suppression during phases 0–2 contributes to plateau
+
iNa Na channel (fast) Voltage Accounts for phase 0 of action potential
Inactivation may contribute to phase 1 of action potential
+
Ito K channel (transient outward) Voltage Contributes to phase 1 of action potential
2+
iCa Ca channel (slow inward, Both Contributes to phase 2 of action potential
L channels) Inactivation may contribute to phase 3 of action potential
Is enhanced by sympathetic stimulation and β-adrenergic agents
+
iK K channel (delayed rectifier) Voltage Causes phase 3 of action potential
Is enhanced by increased intracellular Ca2+

iKATP K+ channel (ATP-sensitive) Ligand Increases K+ permeability when [ATP] is low

iKACh K+ channel Ligand Responsible for effects of vagal stimulation

(acetylcholine-activated)
+
if (“funny”) Nạ (pacemaker current)
Decreases diastolic depolarization (and heart rate)
Hyperpolarizes resting membrane potential
Shortens phase 2 of the action potential
Both Is activated by hyperpolarization and contributes to the diastolic depolarization
Is enhanced by sympathetic stimulation and β-adrenergic agents
Is suppressed by vagal stimulation

slow rising phase of the action potentials in pacemaker cells.
Calcium channel inactivation gate closing is delayed for more
than 100 milliseconds until near the end of the plateau phase.
Inactivation gates on the sodium and calcium channels remain
closed until the membrane repolarizes. This accounts for the
long cardiac muscle cell refractory period.
Multiple factors influence the operation of K+ channels,
some of which are summarized in Table 23–1. For example,
high intracellular Ca2+ concentration contributes to activation
of some K+ channels during repolarization.
Although cells in certain areas of the heart typically have
fast-type action potentials and cells in other areas normally
have slow-type action potentials, it is important to recognize
that all cardiac cells are potentially capable of having either
type of action potential depending on their resting membrane
potentials and how fast they depolarize to the threshold poten-
tial. Rapid depolarization to the threshold potential is usually
an event forced on a cell by the occurrence of an action poten-
tial in an adjacent cell. Slow depolarization to threshold occurs
when a cell itself spontaneously and gradually loses its resting
polarization, which normally happens only in the SA node. A
chronic moderate depolarization of the resting membrane
(caused, e.g., by moderately high extracellular K+ concentra-
tion) can inactivate the fast sodium channels (i.e., prevent
them from opening) without inactivating the slow calcium
channels. Under these conditions, all cardiac cell action poten-
tials will be of the slow type. Large sustained depolarizations,
however, can inactivate both the fast and slow channels and
thus make the cardiac muscle cells completely unexcitable.
CONDUCTION OF CARDIAC
ACTION POTENTIALS
Action potentials are conducted over the surface of individual
cells because active depolarization in any one area of the mem-
brane produces local currents in the intracellular and extracel-
lular fluids that passively depolarize immediately adjacent
areas of the membrane to their voltage threshold for active
depolarization.
In the heart, cardiac muscle cells are connected end-to-end
by structures called intercalated disks. These disks contain
the following: (1) firm mechanical attachments between
adjacent cell membranes by proteins called adherins in struc-
tures called desmosomes and (2) low-resistance electrical
connections between adjacent cells through channels formed
by a protein called connexin in structures called gap junc-
tions. Figure 23–2 shows schematically how these gap junc-
tions allow action potential propagation from cell to cell.
Cells B, C, and D are shown in the resting phase with more
negative charges on the inside than the outside. Cell A is shown
in the plateau phase of an action potential and has more positive
charges inside than out. Because of the gap junctions, electro-
static attraction can cause a local current flow (ion movement)
 CHAPTER 23 Cardiac Muscle Cells 215

+ + + + + + + + +
+ – – – – – – – – –
+ + –
+ + + – – Resting cell C
– – – – – – – – + – –
– – – – – – – – –
+ + + + + + + + – –+ + + + + + + +
+
Cell A with action potential Resting cell B ++ + + + + –

–
+ + + +
+ + + + + + + + – – – – – – – – – –
– – – – – – – – – – – –
+ + + – – – – Resting cell D – –+ +
+ – – –
+ + + – – – – –
+ +
+ + + – – – –
+ + +
+
Gap junction (nexus)

FIGURE 23–2 Local currents and cell-to-cell conduction of cardiac muscle cell action potentials. (Modified with permission from Mohrman
DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

between the depolarized membrane of active cell A and the
polarized membrane of resting cell B, as indicated by the arrows
in the figure. This ion movement depolarizes the membrane of
cell B. Once the local currents from active cell A depolarize the
membrane of cell B near the gap junction to the threshold level,
an action potential will be triggered at that site and will be con-
ducted over cell B. Because cell B branches (a common morpho-
logical characteristic of cardiac muscle fibers), its action
potential will evoke action potentials on cells C and D. This pro-
cess is continued through the entire myocardium. Thus, an
action potential initiated at any site in the myocardium will be
conducted from cell to cell throughout the entire myocardium.
The speed at which an action potential propagates through
a region of cardiac tissue is called the conduction velocity.
The conduction velocity varies considerably in different areas
in the heart and is determined by three variables:
1. Conduction velocity is directly dependent on the diame-
ter of the muscle fiber involved. Thus, conduction over
small-diameter cells in the AV node is significantly slower
than conduction over large-diameter cells in the ventricu-
lar Purkinje system.
2. Conduction velocity is also directly dependent on the
intensity of the local depolarizing currents, which are in
turn directly determined by the rate of rise of the action
potential. Rapid depolarization favors rapid conduction.
3. Conduction velocity is dependent on the capacitive and/
or resistive properties of the cell membranes, gap junc-
tions, and cytoplasm. Electrical characteristics of gap
junctions can be influenced by external conditions that
promote phosphorylation/dephosphorylation of the con-
nexin proteins.
Details of the overall consequences of the cardiac conduc-
tion system are shown in Figure 23–3. As noted earlier, the
specific electrical adaptations of various cells in the heart are
reflected in the characteristic shape of their action potentials
that are shown in the right half of Figure 23–3. Note that the

SA node A
mV

–100
Atrial muscle B

Atrial muscle C

AV node D

Purkinje fiber E
Ventricular muscle
F
Ventricular muscle
G

P wave T wave
ECG
Q S
PR Interval ST segment

QT Interval
1.0 second
FIGURE 23–3 Electrical activity of the heart: single-cell voltage recordings (traces A–G) and lead II electrocardiogram. (Modified with
permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
216 SECTION V Cardiovascular Physiology
action potentials shown in Figure 23–3 have been positioned
to indicate the time at which the electrical impulse that origi-
nates in the SA node reaches other areas of the heart. Cells of
the SA node act as the heart’s normal pacemaker and deter-
mine the heart rate. This is because the spontaneous diastolic
depolarization of the resting membrane is most rapid in SA
nodal cells, and they reach their threshold potential before
cells elsewhere in the heart.
The action potential initiated by an SA nodal cell first spreads
progressively through the atrial wall. Action potentials from
cells in two different regions of the atria are shown in Figure 23–3:
one close to the SA node and one more distant from the SA
node. Both cells have similarly shaped action potentials, but
their temporal displacement reflects the fact that it takes some
time for the impulse to spread over the atria. Action potential
conduction is greatly slowed as it passes through the AV node.
This is because of the small size of the AV nodal cells and
the slow rate of rise of their action potentials. Since the AV node
delays the transfer of the cardiac excitation from the atria to the
ventricles, atrial contraction can contribute to ventricular filling
just before the ventricles contract. Note also that AV nodal cells
have a faster spontaneous depolarization during the resting
period than other cells of the heart except those of the SA node.
The AV node is sometimes referred to as a latent pacemaker,
and in many pathological situations it (rather than the SA node)
controls the heart rhythm.
Because of sharply rising action potentials and other factors,
such as large cell diameters, electrical conduction is extremely
rapid in Purkinje fibers. This allows the Purkinje system to
transfer the cardiac impulse to cells in many areas of the ven-
tricle nearly in unison. Action potentials from muscle cells
in two areas of the ventricle are shown in Figure 23–3. Because
of the high conduction velocity in ventricular tissue, there is
only a small discrepancy in their time of onset. Note that the
ventricular cells that are the last to depolarize have
shorter-duration action potentials and thus are the first to
repolarize. The physiological importance of this unexpected
behavior is not clear but it does have an influence on the elec-
trocardiograms that will be discussed in Chapter 25.
ELECTROCARDIOGRAMS
Fields of electrical potential caused by the electrical activity of
the heart extend through the extracellular fluid of the body
and can be measured with electrodes placed on the body sur-
face. Electrocardiography provides a record of how the volt-
age difference between two points on the body surface changes
with time as a result of the electrical events of the cardiac cycle.
At any instant of the cardiac cycle, the electrocardiogram indi-
cates the net electrical field that is the summation of many
weak electrical fields being produced by voltage changes
occurring on individual cardiac cells. When a large number of
cells are simultaneously depolarizing or repolarizing, large
voltages are observed on the electrocardiogram. Since the
electrical impulse spreads through the heart tissue in a consis-
tent pathway, the temporal pattern of voltage change recorded
between two points on the body surface is also consistent and
will repeat itself with each heart cycle.
The lower trace of Figure 23–3 represents a typical record-
ing of the voltage changes normally measured between the
right arm and the left leg as the heart goes through two cycles
of electrical excitation; this record is called a lead II electrocar-
diogram. The major features of an electrocardiogram are the
P wave, the QRS complex, and the T wave. The P wave
corresponds to atrial depolarization, the QRS complex to
ventricular depolarization, and the T wave to ventricular
repolarization.
CONTROL OF HEART RATE
Normal rhythmic contractions of the heart occur because of
spontaneous electrical pacemaker activity (automaticity) of
cells in the SA node. The interval between heartbeats (and
thus the heart rate) is determined by how long it takes the
membranes of these pacemaker cells to spontaneously depo-
larize to the threshold level. The SA nodal cells fire at a spon-
taneous or intrinsic rate (≈100 beats/min) in the absence of
any outside influences.
The two most important outside influences on automaticity
of SA nodal cells come from the autonomic nervous system
(see Chapter 19). Fibers from both the sympathetic and para-
sympathetic divisions of the autonomic system terminate on
cells in the SA node and these fibers can modify the intrinsic
heart rate. Activation of the cardiac sympathetic nerves
(increasing cardiac sympathetic tone) increases the heart rate.
Increasing cardiac parasympathetic tone decreases the heart
rate. As shown in Figure 23–4, the parasympathetic and sym-
pathetic nerves both influence heart rate by altering the course
of spontaneous depolarization of the resting potential in SA
pacemaker cells.
Cardiac parasympathetic fibers, which travel to the heart
through the vagus nerves, release the transmitter substance
acetylcholine on SA nodal cells. Acetylcholine increases the
permeability of the resting membrane to K+ and decreases the
diastolic permeability to Na+. The signaling process involves
acetylcholine interaction with muscarinic receptors on the SA
nodal cell membrane that in turn are linked to inhibitory G
proteins, Gi. The activation of Gi has two effects: (1) an
increase in K+ permeability resulting from an increased
opening of the KAch channels and (2) a suppression of adeny-
late cyclase leading to a decrease in intracellular cyclic ade-
nosine monophosphate (cAMP) concentration that reduces
the inward-going pacemaker current carried by Na+ (if). As
indicated in Figure 23–4, these permeability changes have
two effects on the resting potential of cardiac pacemaker cells:
(1) they cause an initial hyperpolarization of the resting mem-
brane potential by bringing it closer to the K+ equilibrium
potential and (2) they slow the rate of spontaneous depolar-
ization of the resting membrane. Both of these effects increase
the time between beats by prolonging the time required for

Sympathetic tone
–10
tone
Membrane potential (mV)
pathetic
Intrinsic
–30
Parasym
–50
–70
Threshold potential
–90
Time
FIGURE 23–4 Effect of sympathetic and parasympathetic
tones on pacemaker potential. (Modified with permission from Mohrman
DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/
McGraw-Hill, 2006.)
the resting membrane to depolarize to the threshold level.
Since there is normally some continuous tonic activity of car-
diac parasympathetic nerves, the normal resting heart rate is
approximately 70 beats/min.
Sympathetic nerves release the transmitter substance nor-
epinephrine on cardiac cells. In addition to other effects dis-
cussed later, norepinephrine increases the inward currents
carried by Na+ (if ) and by Ca2+ during the diastolic interval.
The signaling process involves norepinephrine interaction
with β1-adrenergic receptors on the SA nodal cell membrane
that in turn are linked to stimulatory G proteins, Gs. The acti-
vation of Gs increases adenylate cyclase, leading to an increase
in intracellular cyclic AMP that increases the open-state prob-
ability of the pacemaker Na+ current channel (if ). These
changes increase heart rate by increasing the rate of diastolic
depolarization as shown in Figure 23–4.
In addition to sympathetic and parasympathetic nerves,
there are many (usually less important) factors that can alter
heart rate. These include a number of ions and circulating hor-
mones, as well as physical influences such as temperature and
atrial wall stretch. All act by altering the time required for the
resting membrane to depolarize to the threshold potential. An
abnormally high concentration of Ca2+ in the extracellular
fluid, for example, tends to decrease heart rate by shifting the
threshold potential. Factors that increase heart rate are said to
have a positive chronotropic effect. Those that decrease heart
rate have a negative chronotropic effect.
An increase in sympathetic activity also increases action
potential conduction velocity (has a positive dromotropic
effect), whereas an increase in parasympathetic activity
CHAPTER 23 Cardiac Muscle Cells 217
decreases conduction velocity (has a negative dromotropic
effect). These effects are most notable at the AV node and
can influence the time between the P and R waves (the PR
interval).
MECHANICAL PROPERTIES
Contraction of the cardiac muscle cell is initiated by the action
potential acting on intracellular organelles to evoke tension
generation and/or shortening of the cell. The reader is encour-
aged to carefully review the materials presented in Chapters 9
and 10 for specific cellular details describing contraction of
skeletal and cardiac muscle.
EXCITATION–CONTRACTION COUPLING
The major event in excitation–contraction coupling in car-
diac muscle is a dramatic rise in the intracellular free Ca2+ con-
centration from less than 0.1 μM to as much as 100 μM. When
the wave of depolarization passes over the muscle cell mem-
brane, Ca2+ is released from the sarcoplasmic reticulum (SR)
into the intracellular fluid. The specific trigger is a small local-
ized increase in calcium concentration triggering a massive
release of calcium from the SR. Although the amount of Ca2+
that enters the cell during a single action potential is quite
small compared with that released from the SR, it is not only
essential for triggering the SR calcium release, but also essen-
tial for maintaining adequate levels of Ca2+ in the intracellular
stores over the long run.
The contractile process initiated by the increase in intracel-
lular calcium concentration has been described in Chapters 9
and 10. Recall that excitation–contraction coupling in cardiac
muscle differs from that in skeletal muscle in that it may be
modulated; different intensities of actin–myosin interaction
(contraction) can result from a single action potential trigger
in cardiac muscle. The mechanism for this is largely depen-
dent on variations in the amount of Ca2+ reaching the myofila-
ments and therefore the number of cross-bridges activated
during the twitch. This ability of cardiac muscle to vary its
contractile strength—that is, change its contractility—is
extremely important to cardiac function, as will be discussed
later in this chapter.
RELAXATION
The processes that participate in the reduction of intracellular
Ca2+ that terminates the contraction include (1) active uptake
of ~80% of the calcium back into the SR by the action of
Ca2+-ATPase pumps, (2) active extrusion of ~5% of the cal-
cium from the cell via sarcolemmal Ca2+-ATPase pumps, and
(3) passive exchange of ~15% of the calcium with extracellular
sodium via the Na+–Ca2+ exchanger located in the sarcolemma.
The Na+–Ca2+ exchanger is powered by the sodium gradient
218 SECTION V Cardiovascular Physiology

across the sarcolemma that in turn is maintained by the Na+/
K+-ATPase. This exchanger is electrogenic in that three Na+
ions move into the cell in exchange for each Ca2+ ion that
moves out. This net inward movement of positive charge may
contribute to the maintenance of the plateau phase of the
action potential. The cardiac glycoside, digitalis, slows down
the Na+/K+ pump and thus reduces the sodium gradient,
resulting in an increase in intracellular Ca2+ that gets seques-
tered into the SR. This mechanism contributes importantly to
the positive effect of cardiac glycosides on the contractile force
of the failing heart.
The duration of the cardiac muscle cell contraction is
approximately the same as that of its action potential. There-
fore, the electrical refractory period of a cardiac muscle cell is
not over until the mechanical response is completed. Mechan-
ical relaxation accompanies electrical repolarization. As a con-
sequence, heart muscle cells cannot be activated rapidly
enough to cause a fused (tetanic) state of prolonged contrac-
tion. This is fortunate because intermittent contraction and
relaxation are essential for the heart’s pumping action.
CARDIAC MUSCLE CELL MECHANICS
As has been described in Chapters 9 and 10, the cross-bridge
interaction that occurs after a muscle is activated to contract
gives the muscle the potential to develop force and/or
shorten. Whether it does one, the other, or some combina-
tion of the two depends primarily on what is allowed to hap-
pen by the external constraints placed on the muscle during
the contraction. Muscle cells in the ventricular wall operate
under different constraints during different phases of each
cardiac cycle and undergo both isometric and isotonic con-
tractions.
ISOMETRIC CONTRACTIONS:
LENGTH–TENSION RELATIONSHIPS
Recall that the cardiac muscle maximum isometric contractile
force is strongly influenced by the initial length of the mus-
cle as is indicated in Figure 23–5. The top panel shows the

sarcomere

1 2
3 4
Resting Contracting 5 6
Resting Contracting
Resting Contracting

4 6
Muscle tension

2
Active tension
5 5

3 3
1 1
Stimulus Resting tension

Time

4
Peak isometric tension
Muscle tension

2 Active tension
FIGURE 23–5 Isometric contractions and
the effect of muscle length on resting tension Resting tension
and active tension development. (Modified with 3
permission from Mohrman DE, Heller LJ: Cardiovascular 1 Lmax
Physiology, 6th ed. New York: Lange Medical Books/
McGraw-Hill, 2006.) Muscle length
 CHAPTER 23 Cardiac Muscle Cells 219

experimental arrangement for measuring muscle force at rest
and during contraction at three different lengths. The middle
panel shows time records of muscle tensions recorded at each
of the three lengths in response to an external stimulus, and
the bottom panel shows a graph of the resting and peak ten-
sion results plotted against muscle length.
The length-dependent influence on the resting tension of
cardiac muscle is represented by the lower curve in the graph
in Figure 23–5. When a muscle is stimulated to contract while
its length is held constant (i.e., isometric contraction), it devel-
ops active tension. The total tension exerted by a muscle dur-
ing contraction is the sum of the active and resting tensions
and is represented by the upper curve in Figure 23–5. Active
tension development is shown to be maximal at some interme-
diate length referred to as Lmax. Normally, cardiac muscle oper-
ates at lengths well below Lmax, so that increasing muscle length
increases the tension developed during an isometric contrac-
tion. The mechanisms involved in the relationship between
cardiac muscle length and developed tension are discussed in
Chapter 10. The important point is that the dependence of
active tension development and shortening on muscle length
is a fundamental property of cardiac muscle that has extremely
powerful effects on heart function.
ISOTONIC & AFTERLOADED
CONTRACTIONS
During an isotonic (“fixed load”) contraction, muscle short-
ens against a constant load as shown in Figure 23–6. When a
1-g weight is suspended from a resting muscle, it will result in
some specific resting muscle length, which is determined by
the muscle’s resting length–tension curve. If the muscle were
to contract isometrically at this length, it would be capable of
generating a certain amount of tension, for example, 4.5 g as
indicated by the dashed line in the graph of Figure 23–6. How-
ever, a contractile tension of 4.5 g will not be generated when
lifting a 1-g weight. When a muscle has contractile potential in
excess of the tension it is actually developing, it shortens. Thus,
in an isotonic contraction, muscle length decreases at constant
tension, as illustrated by the horizontal arrow from point 1 to
point 3 in Figure 23–6. As the muscle shortens, however, its
contractile potential inherently decreases, as indicated by the
downward slope of the peak isometric tension curve in Figure
23–6. There exists some short length at which the muscle is
capable of generating only 1 g of tension, and when this length
is reached, shortening must cease. Thus, the curve on the car-
diac muscle length–tension diagram that indicates how much

Isotonic contraction Afterloaded contraction

Isometric Isotonic

3
5
2 1g 3-g total
1 4
1 1g 1g load
2-g 1g
1g 1g
afterload 2g
Resting Contracting 2g 2g

Resting
Contracting

5 Peak isometric tension

Muscle tension (g)

5
3 4

2 Resting tension

3 2
1
1

Muscle length

FIGURE 23–6 Relationship of isotonic and afterloaded contractions to the cardiac muscle length–tension diagram. (Modified with
permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
220 SECTION V Cardiovascular Physiology

isometric tension a muscle can develop at various lengths also A Isometric contraction
establishes the limit on how far muscle shortening can pro-
ceed with different loads. NE Peak isometric tension
ith
Figure 23–6 also shows an afterloaded isotonic contrac- W
5
tion, in which the load on the muscle at rest (the preload) and

Muscle tension (g)

the load on the muscle during contraction (the total load) are 4

NE
different. In the example of Figure 23–6, the preload is equal to

t
ou
3

it h
1 g, and because an additional 2-g weight (the afterload) is

E
engaged during contraction, the total load equals 3 g.

N
2
ut Resting tension
Since preload determines the resting muscle length, both i t ho
1 or w
isotonic contractions shown in Figure 23–6 begin from the With
same length. Because of the different loading arrangement,
however, the afterloaded muscle must increase its total ten- Muscle length
sion to 3 g before it can shorten. This initial tension will be
developed isometrically and can be represented as going
B Afterloaded contraction
from point 1 to point 4 on the length–tension diagram. Once
the muscle generates enough tension to equal the total load, Peak isometric tension
its tension output is fixed at 3 g and it will now shorten iso- NE
5 ith E
tonically because its contractile potential still exceeds its ten- W tN
ou
Muscle tension (g)
sion output. This isotonic shortening is represented as a 4 ith
W
horizontal movement on the length–tension diagram along
the line from point 4 to point 5. As in any isotonic contrac- 3
More shortening with NE Resting tension
tion, shortening must cease when the muscle’s tension-pro-

E
2 N
ducing potential is decreased sufficiently by the length ut
it ho
change to be equal to the load on the muscle. Note that the 1 or w
With
afterloaded muscle shortens less than the non-afterloaded
muscle even though both muscles began contracting at the
Muscle length
same initial length. Increases in afterload will further
decrease the shortening of the muscle. The factors that affect FIGURE 23–7 Effect of norepinephrine (NE) on isometric
the extent of cardiac muscle shortening during an afterloaded (A) and afterloaded (B) contractions of cardiac muscle. (Modified
with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New
contraction are of special interest because stroke volume is
York: Lange Medical Books/McGraw-Hill, 2006.)
determined by how far cardiac muscle shortens under these
conditions.

it enhances the forcefulness of muscle contraction even when

CARDIAC MUSCLE CONTRACTILITY
A number of factors in addition to initial muscle length can
affect the tension-generating potential of cardiac muscle. Any
intervention that increases the peak isometric tension that a
muscle can develop at a fixed length is said to increase cardiac
muscle contractility. Such an agent is said to have a positive
inotropic effect on the heart.
The most important physiological regulator of cardiac mus-
cle contractility is norepinephrine. When norepinephrine is
released on cardiac muscle cells from sympathetic nerves, it
has not only the chronotropic effect on heart rate discussed
earlier, but also a pronounced positive inotropic effect that
causes cardiac muscle cells to contract more rapidly and
forcefully.
The positive effect of norepinephrine on the isometric ten-
sion-generating potential is illustrated in Figure 23–7A. When
norepinephrine is present, cardiac muscle will, at every length,
develop more isometric tension, thus raising the peak isomet-
ric tension curve on the cardiac muscle length–tension graph.
Norepinephrine increases cardiac muscle contractility because
length is constant. Changes in contractility and initial length
can occur simultaneously, but by definition, a change in con-
tractility must involve a shift from one peak isometric length–
tension curve to another.
Figure 23–7B shows how raising the peak isometric length–
tension curve with norepinephrine increases the amount of
shortening in afterloaded contractions of cardiac muscle. With
preload and total load constant, more shortening occurs in the
presence of norepinephrine than in its absence. This is because
when contractility is increased, the tension-generating poten-
tial is equal to the total load at a shorter muscle length. Note
that norepinephrine has no effect on the resting length–tension
relationship of cardiac muscle. Thus, norepinephrine causes
increased shortening by changing the final but not the initial
muscle length associated with afterloaded contractions.
The cellular mechanism of the norepinephrine effect on
contractility is mediated by its interaction with a β1-adrenergic
receptor. The signaling pathway involves an activation of the
Gs protein–cAMP–protein kinase A, which then phosphory-
lates the Ca2+ channel, increasing the inward calcium current
during the plateau of the action potential. This increase in
 CHAPTER 23 Cardiac Muscle Cells 221

calcium influx not only contributes to the magnitude of the the length of the individual cardiac muscle cells. Thus, the
increase in intracellular Ca2+ for a given beat, but also loads the extent of diastolic filling of the ventricle determines the
internal calcium stores, which allows more to be released “preload.”
during subsequent depolarizations. This increase in free Ca2+ 2. At any given ventricular volume, an increase in the ten-
during activation allows more cross-bridges to be formed, sion of individual cardiac muscle cells in the wall causes
increases the speed of cross-bridge turnover, and allows greater an increase in intraventricular pressure.
tension to be developed at a faster rate. 3. As ventricular volume decreases (i.e., as the ventricular
Because norepinephrine also causes phosphorylation of the radius decreases), a lesser total (collective) force is re-
regulatory protein, phospholamban, on the sarcoplasmic quired by the muscle cells in the ventricular walls to pro-
reticular Ca2+-ATPase pump, the rate of calcium retrapping duce any given intraventricular pressure.
into the SR is enhanced and the rate of relaxation is also
The last point is a reflection of the law of Laplace that states
increased. This is called a positive lusitropic effect. In addi-
the physical relationship that must exist between total wall
tion to more rapid calcium retrapping by the SR, there is also a
tension and internal pressure in any hollow vessel with circu-
norepinephrine-induced decrease in the action potential dura-
lar containing walls. Regardless of whether the ventricle is
tion. This effect is achieved by a potassium channel alteration,
envisioned as a hollow cylinder or a hollow sphere, the law of
occurring in response to the elevated intracellular [Ca2+] that
Laplace says that the total wall tension (T) depends on both
increases potassium permeability, terminates the plateau phase
intraventricular pressure (P) and its internal radius (r) as fol-
of the action potential, and contributes to the early relaxation.
lows: T = P × r.
(Such shortening of the systolic interval is helpful in the pres-
One implication of the law of Laplace is that the muscle
ence of elevated heart rates that might otherwise significantly
cells in the ventricular wall have a somewhat easier job of
compromise diastolic filling time.)
producing internal pressure at the end of systole (when the
Enhanced parasympathetic activity has been shown to have
radius is small) than at the beginning of systole (when the
a small negative inotropic effect on the heart. In the atria,
radius is large). More importantly, the law of Laplace has
where this effect is most pronounced, the negative inotropic
significant clinical relevance in some pathological
effect is thought to be due to a decrease in the duration of the
situations.
action potential and a decrease in the amount of Ca2+ that
enters the cell during the action potential.
Changes in heart rate also influence cardiac contractility.
Recall that a small amount of extracellular Ca2+ enters the cell
during the plateau phase of each action potential. As the heart CLINICAL CORRELATION
rate increases, more Ca2+ enters the cells per minute. There is a
buildup of intracellular Ca2+ and a greater amount of Ca2+ is An elderly man is brought to the emergency room by his
released into the sarcoplasm with each action potential. Thus, daughter. She reports that he has recently complained of
a sudden increase in beating rate is followed by a progressive severe weakness, fatigue, some dizziness, and seems to be
increase in contractile force to a higher plateau (the force– a bit confused. This condition appeared only a few days
frequency relationship). ago and does not seem to be getting better or worse. He
has been healthy otherwise and usually likes to square
dance. The patient is alert and responsive but very weak
and pale. His blood pressure on admission is 100/60 mm Hg
RELATING CARDIAC and his heart rate is 41 beats/min. An electrocardiogram
taken at the time of admission verifies the bradycardia
MUSCLE CELL MECHANICS (slow heart rate) with a ventricular rate of 41 beats/min
TO VENTRICULAR FUNCTION and atrial rate at 95 beats/min. There are no ECG signs of
cardiac ischemia or infarction but the occurrence of
Certain geometric factors dictate how the length–tension rela- P waves is very rapid and not correlated with slow occur-
tionships of cardiac muscle fibers in the ventricular wall deter- rence of QRS waves.
mine the volume and pressure relationships of the ventricular This patient has a third degree (total) AV nodal heart
chamber. The actual relationships are complex because the block in which the normal conduction of action potentials
shape of the ventricle is complex. The ventricle is often mod- originating in the SA node is not conducted through the
eled as either a cylinder or a sphere, although its actual shape AV node to the ventricles. The ventricles are being driven
lies somewhere between the two. Because cardiac muscle cells at an "escape" rhythm established by a pacemaker located
are oriented circumferentially in the ventricular wall, either below the AV node firing at a rate that is significantly
model can be used to illustrate three important functional slower than that of SA nodal pacemaker cells. The atria
points: are beating much faster due to sympathetic activation
1. An increase in ventricular volume causes an increase in (triggered by the low blood pressure) but the signals are
ventricular circumference and therefore an increase in
222 SECTION V Cardiovascular Physiology
not conducted through the AV nodal block. His symp-
toms of weakness, fatigue, dizziness, and confusion are a
result of his low blood pressure that, in turn, is a result of
his low ventricular rate and reduced cardiac output.
Causes include drug toxicities (i.e., β-adrenergic blockers,
calcium channel blockers), metabolic disturbances (i.e.,
hyperkalemia), anterior wall myocardial infarctions
(i.e., septal ischemia), and cardiomyopathy (i.e., from a
viral infection). Diagnostic tests will be conducted to
determine what might be responsible for his condition.
His treatment will involve implantation of a cardiac
pacemaker. This is a subcutaneously implanted battery
pack that sends repetitive stimuli through wire electrodes
positioned in both the right atrium and right ventricle via
the vena cava. This dual-chamber pacemaker will syn-
chronize his atrial and ventricular beating rate at a more
normal rate and rhythm and perhaps restore circulatory
status and his activity levels back to normal.
CHAPTER SUMMARY
■ Cardiac myocyte membrane potentials are a result of the
relative permeability of the membrane to various ions and their
concentration differences across the membrane.
■ Action potentials of cardiac myocytes are a result of changes in
the membrane permeability to various ions.
■ Action potentials of cardiac myocytes have long plateau phases
that generate long refractory periods and preclude summated
or tetanic contractions.
■ Action potentials are spontaneously generated by pacemaker
cells in the SA node and are conducted from cell to cell via gap
junctions throughout the entire heart.
■ The rate of spontaneous diastolic depolarization of the SA
nodal cells (and thus the heart rate) is modulated by the
autonomic nervous system.
■ Excitation of the cardiac myocyte initiates contraction by
increasing the cytostolic calcium concentration that activates
the contractile apparatus.
■ Mechanical response of the myocyte depends on preload
(determined by the initial resting length), afterload (deter-
mined by the tension that must be developed), and contractility
(the degree of activation of the contractile apparatus dependent
on the amount of calcium released on activation).
■ The cardiac myocyte length–tension relationships are
correlated with changes in volume and pressure in the
intact ventricle.
STUDY QUESTIONS
1. A drug that promotes early activation of the “delayed rectifier”
K+ channel (Ik) in cardiac muscle will do which of the following?
A) The resting potential will be increased (hyperpolarized).
B) The action potential’s duration will be decreased.
C) The action potential’s peak amplitude will be decreased.
D) The action potential conduction velocity will be increased.
E) The absolute refractory period will be prolonged.
2. Action potential conduction velocity in cardiac muscle tissue
is influenced by all of the following except
A) cell diameter.
B) resting membrane potential.
C) extracellular potassium concentration.
D) rate of rise (phase 0) of the action potential.
E) duration of the plateau phase (phase 2) of the action
potential.
3. The primary route of removal of [Ca2+] from the sarcoplasm
during relaxation of a cardiac muscle cell is by
A) active transport out of the cell.
B) passive exchange with extracellular sodium.
C) active transport into the sarcoplasmic reticulum.
D) trapping of calcium by troponin in the myofilaments.
E) passive movement out of the cell via L-type calcium
channels.
4. A therapeutic strategy to improve the amount of active
shortening of cardiac muscle might include which one of
the following?
A) decrease preload
B) decrease afterload
C) decrease contractility
D) give a negative chronotropic agent
E) give a negative inotropic agent
5. Your patient has accidentally been given a large bolus injection
of potassium chloride and dies. Why?
A) Cardiac muscle is depolarized and his heart has stopped
in diastole.
B) Cardiac muscle is depolarized and his heart has stopped
in systole.
C) Cardiac muscle is hyperpolarized and his heart has stopped
in diastole.
D) Action potential conduction is sped up and heart
is fibrillating.
E) Gap junctions between cardiac muscle cells are disrupted.
 24
C H A P T E R

The Heart Pump

Lois Jane Heller and David E. Mohrman

O B J E C T I V E S

■ Correlate the electrocardiographic events with the mechanical events during

the cardiac cycle.
■ List the major distinct phases of the cardiac cycle as delineated by valve
opening and closure.
■ Describe the pressure and volume changes in the atria, the ventricles, and the
aorta during each phase of the cardiac cycle.
■ Define and state normal values for (1) ventricular end-diastolic volume,
end-systolic volume, stroke volume, diastolic pressure, and peak systolic
pressure, and (2) aortic diastolic pressure, systolic pressure, and pulse
pressure.
■ State similarities and differences between mechanical events in the left and
right heart pumps.
■ State the origin of the heart sounds.
■ Diagram the relationship between left ventricular pressure and volume
during the cardiac cycle.
■ Define cardiac output and cardiac index.
■ State the relationship between cardiac output, heart rate, and stroke volume.
■ Identify the major determinants of stroke volume.
■ State Starling’s law of the heart.
■ Predict the effect of altered ventricular preload on stroke volume and the
ventricular pressure–volume relationship.
■ Predict the effect of altered ventricular afterload on stroke volume and the
ventricular pressure–volume relationship.
■ Predict the effect of altered ventricular contractility (inotropic state) on stroke
volume and the ventricular pressure–volume relationship.
■ Draw a family of cardiac function curves describing the relationship
between filling pressure and cardiac output under various levels of
sympathetic tone.
■ Summarize the effect of sympathetic neural stimulation on cardiac
function.
■ List the determinants of myocardial oxygen consumption.

223

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224 SECTION V Cardiovascular Physiology

This chapter describes (1) the basic mechanical features of
the cardiac pump, (2) the factors that influence and/or regu-
late cardiac output, and (3) the sources of energy and the
energy costs required for myocardial activity.
CARDIAC CYCLE
LEFT PUMP
The mechanical function of the heart can be described by the
pressure, volume, and flow changes that occur within it during
one cardiac cycle. A cardiac cycle is defined as one complete
sequence of contraction and relaxation. The normal mechani-
cal events of a cycle of the left heart pump are correlated in
Figure 24–1. This important figure summarizes a great deal of
information and should be studied carefully.
VENTRICULAR DIASTOLE
The diastolic phase of the cardiac cycle begins with the open-
ing of the atrioventricular (AV) valves. (Unless otherwise
noted, systole and diastole denote phases of ventricular
operation.) As shown in Figure 24–1, the mitral valve opens
when left ventricular pressure decreases below left atrial pres-
sure and the period of ventricle filling begins. Blood that had
previously accumulated in the atrium behind the closed mitral
valve empties rapidly into the ventricle and this causes an ini-
tial decrease in atrial pressure. Later, the pressures in both
chambers slowly increase together as the atrium and ventricle
continue passively filling with blood returning to the heart
through the veins.
Atrial contraction is initiated near the end of ventricular
diastole by the depolarization of the atrial muscle cells, which
causes the P wave of the electrocardiogram. As the atrial

A B
Cardiac cycle C D E
phase

R
Lead II P T
electrocardiogram

Atrial
Muscle contraction
Ventricular
Incisura
Systolic pressure
120 Aortic
pressure
Pulse pressure

80 Diastolic pressure
Pressure (mm Hg)
Left ventricular pressure
40 Left atrial
pressure

Closed Closed
Aortic valve Open
Closed Open
Mitral valve Open
S3 S4 S1 S2 S3
Heart sounds

120
End-diastolic volume Stroke
Left ventricular volume volume
(mL)
End-systolic volume
60
FIGURE 24–1 Cardiac cycle—left heart.
Cardiac cycle phases: A) diastole; B) systole that is
divided into three periods; C) isovolumetric Outflow
contraction; D) ejection, and E) isovolumetric Aortic flow 0 Inflow
relaxation. (Modified with permission from Mohrman DE,
Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange 0 0.2 0.4 0.6 0.8
Medical Books/McGraw-Hill, 2006.) Time (s)

muscle cells develop tension and shorten, atrial pressure rises
and an additional amount of blood is forced into the ventricle.
At normal heart rates, atrial contraction is not essential for
adequate ventricular filling. This is evident in Figure 24–1
showing that the ventricle has nearly reached its maximum
(end-diastolic volume) before atrial contraction begins. Atrial
contraction plays an increasingly significant role in ventricu-
lar filling as heart rate increases because the time interval
between beats for passive filling becomes progressively shorter.
Note that throughout diastole, atrial and ventricular pressures
are almost the same. This is because a normal open mitral
valve has very little resistance to flow and thus only a very
small atrial–ventricular pressure difference is necessary to
produce ventricular filling.
VENTRICULAR SYSTOLE
Ventricular systole begins when the action potential breaks
through the AV node and sweeps over the ventricular muscle
resulting in the QRS complex of the electrocardiogram. Con-
traction of the ventricular muscle cells causes intraventricular
pressure to increase above that in the atrium, which causes
abrupt closure of the AV valve.
Pressure in the left ventricle continues to increase sharply as
the ventricular contraction intensifies. When the left ventricu-
lar pressure exceeds that in the aorta, the aortic valve opens.
The period of time between mitral valve closure and aortic
valve opening is referred to as the isovolumetric contraction
phase because, during this interval, the ventricle is a closed
chamber with a fixed volume. Ventricular ejection begins with
the opening of the aortic valve. In early ejection, blood enters
the aorta rapidly and causes the pressure there to rise. Pressure
builds simultaneously in both the ventricle and the aorta as
the ventricular muscle cells continue to contract in early sys-
tole. This interval is often called the rapid ejection period.
Left ventricular and aortic pressures ultimately reach a max-
imum called peak systolic pressure. At this point, the strength
of ventricular muscle contraction begins to wane. Muscle
shortening and ejection continue, but at a reduced rate. Aortic
pressure begins to decrease because blood is leaving the aorta
and large arteries faster than blood is entering from the left
ventricle. Throughout ejection, there are very small pressure
differences between the left ventricle and the aorta because the
aortic valve orifice is so large that it presents very little resis-
tance to flow.
Eventually, the strength of the ventricular contraction
diminishes to the point where intraventricular pressure
decreases below aortic pressure. This causes abrupt closure of
the aortic valve. A dip, called the incisura or dicrotic notch,
appears in the aortic pressure trace because a small volume of
aortic blood must flow backward to fill the aortic valve leaf-
lets as they close. After aortic valve closure, intraventricular
pressure decreases rapidly as the ventricular muscle relaxes.
For a brief interval, called the isovolumetric relaxation phase,
the mitral valve is also closed. Ultimately, intraventricular
CHAPTER 24 The Heart Pump 225
pressure decreases below atrial pressure, the AV valve opens,
and a new cardiac cycle begins.
Note that atrial pressure progressively increases during ven-
tricular systole because blood continues to return to the heart
and fill the atrium. The increased atrial pressure at the end of
systole promotes rapid ventricular filling once the AV valve
opens to begin the next heart cycle.
The ventricle has reached its minimum (end-systolic
volume) at the time of aortic valve closure. The amount of
blood ejected from the ventricle during a single beat, the
stroke volume, is equal to ventricular end-diastolic volume
minus ventricular end-systolic volume.
During the early, most rapid phase of systolic ejection, the
aorta distends because more blood is being put into it from the
left heart than is leaving it to the systemic organs. That disten-
sion is caused by the increasing pressure within the aorta.
During the later, weakening phase of cardiac ejection,
the opposite is true. The overall result is that the aortic pres-
sure reaches a maximum value (systolic pressure) near the
middle of ventricular systole. During diastole, the arterial
pressure is maintained by the elastic recoil of walls of the aorta
and other large arteries. Nonetheless, aortic pressure gradually
decreases during diastole as the aorta supplies blood to the
systemic vascular beds. The lowest aortic pressure, reached at
the end of diastole, is called diastolic pressure. The difference
between diastolic and peak systolic pressure in the aorta is
called the arterial pulse pressure. Typical values for systolic
and diastolic pressures in the aorta are 120 and 80 mm Hg,
respectively, with a pulse pressure of 40 mm Hg.
At a normal resting heart rate of about 70 beats/min, the
heart spends approximately two thirds of the cardiac cycle in
diastole and one third in systole. When increases in heart rate
occur, both diastolic and systolic intervals become shorter.
Action potential durations are shortened and conduction
velocity is increased. Contraction and relaxation rates are also
enhanced. This shortening of the systolic interval tends to
blunt the potential adverse effects of increases in heart rate on
diastolic filling time.
RIGHT PUMP
Because the entire heart is served by a single electrical excita-
tion system, similar mechanical events occur almost simulta-
neously in both the left heart and the right heart. Both ventricles
have synchronous systolic and diastolic periods and the valves
of the right and left heart normally open and close nearly in
unison. Because the two sides of the heart are arranged in
series in the circulation, they must pump the same amount of
blood and therefore must have the same cardiac output.
The major difference between the right and left pumps is in
the magnitude of the peak systolic pressure. The pressures
developed by the right heart as shown in Figure 24–2 are
considerably lower than those for the left heart (Figure 24–1).
This is because the pulmonary vessels provide considerably
less resistance to blood flow than that offered collectively by
226 SECTION V Cardiovascular Physiology
Lead II electrocardiogram
25
Pressure (mm Hg)
20
15
10
Right atrial a pressure
5 pressure c v
0 physiological splitting of the second heart sound. The dis-
0.0 0.2 0.4 0.6
Time (s)
FIGURE 24–2 Cardiac cycle—right heart. (Modified with
permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York:
Lange Medical Books/McGraw-Hill, 2006.)
those of the systemic organs. Therefore, less arterial pressure is
required to drive the cardiac output through the lungs than
through the systemic organs. Typical pulmonary artery sys-
tolic and diastolic pressures are 25 and 8 mm Hg, respectively.
The pressure pulsations that occur in the right atrium are
transmitted in retrograde fashion to the large veins near the
heart. These pulsations, shown on the atrial pressure trace of
Figure 24–2, can be visualized in the neck over the jugular
veins in a recumbent individual. They are collectively referred
to as the jugular venous pulse, and can provide clinically use-
ful information about the heart. Atrial contraction produces
the first pressure peak, called the a wave. The c wave, which
follows shortly thereafter, coincides with the onset of ventricu-
lar systole and is caused by an initial bulging of the tricuspid
valve into the right atrium. Right atrial pressure decreases after
the c wave because of atrial relaxation and a downward dis-
placement of the tricuspid valve during ventricular emptying.
Right atrial pressure then begins to increase toward a third
peak, the v wave, as the central veins and right atrium fill
behind a closed tricuspid valve with blood returning to the
heart from the peripheral organs. With the opening of the tri-
cuspid valve at the conclusion of ventricular systole, right
atrial pressure again decreases as blood moves into the relaxed
right ventricle. Shortly afterward, right atrial pressure begins
to increase once more toward the next a wave as returning
blood fills the central veins, the right atrium, and right ven-
tricle together during diastole.
HEART SOUNDS
A record of the heart sounds, which occur in the cardiac cycle,
is included in Figure 24–1. These sounds are normally heard
by auscultation with a stethoscope placed on the chest. The
first heart sound, S1, occurs at the beginning of systole because
of the abrupt closure of the AV valves, which produces
vibrations of the cardiac structures and the blood in the
ventricular chambers. S1 can be heard most clearly by placing
the stethoscope over the apex of the heart. Note that this
sound occurs immediately after the QRS complex of the
electrocardiogram.
Pulmonary
artery The second heart sound, S2, arises from the closure of the
aortic and pulmonic valves at the beginning of the period of
pressure
isovolumetric relaxation. This sound is heard at about the time
of the T wave in the electrocardiogram. The pulmonic valve
Right
ventricular usually closes slightly after the aortic valve. Because this dis-
crepancy is enhanced during the inspiratory phase of the
respiratory cycle, inspiration causes what is referred to as the
crepancy in valve closure during inspiration may range from
0.8 1.0
30 to 60 milliseconds. One of the factors that leads to pro-
longed ejection of the right ventricle during inspiration is that
the decreased intrathoracic pressure that accompanies
inspiration transiently enhances venous return and diastolic
filling of the right heart. For reasons that will be detailed later
in this chapter, this extra filling volume will be ejected but a
little extra time is required.
The third and fourth heart sounds, shown in Figure 24–1,
are not normally present. When they are present, however,
they, along with S1 and S2, produce what are called gallop
rhythms (resembling the sound of a galloping horse). When
present, the third heart sound occurs shortly after S2 during
the period of rapid passive ventricular filling and, in
combination with heart sounds S1 and S2, produces what is
called ventricular gallop rhythm. Although S3 may sometimes
be detected in normal children, it is heard more commonly in
patients with left ventricular failure. The fourth heart sound,
which occasionally is heard shortly before S1, is associated
with atrial contraction and rapid active filling of the ventricle.
Thus, the combination of S1, S2, and S4 sounds produces what
is called an atrial gallop rhythm. The presence of S4 often
indicates an increased ventricular diastolic stiffness, which
can occur with several cardiac disease states.
CARDIAC CYCLE PRESSURE–VOLUME
& LENGTH–TENSION RELATIONSHIPS
Intraventricular pressure and volume are intimately linked to
the tension and length of the cardiac muscle cells in the ven-
tricular wall. Figure 24–3A and B shows the correspondence
between a ventricular pressure–volume loop and a cardiac
muscle length–tension loop during one cardiac cycle. It is clear
that cardiac muscle length–tension behavior is the underlying
basis for ventricular function. Each major phase of the ventric-
ular cardiac cycle has a corresponding phase of cardiac muscle
length and tension change. During diastolic ventricular filling,
for example, the progressive increase in ventricular pressure
stretches the resting cardiac muscle to greater lengths along its
resting length-tension curve and causes a corresponding
increase in muscle tension. End-diastolic ventricular pressure
is referred to as ventricular preload because it sets the end-
 CHAPTER 24 The Heart Pump 227

A
120 Ejection
Intraventricular pressure (mm Hg)

Reaches end-
systolic volume

80 Aortic valve opens

Systole

Isovolumetric
relaxation Isovolumetric contraction

Mitral valve
opens Diastolic filling
Reaches end-diastolic volume

60 130
Stroke volume
Intraventricular volume (mL)

Shortening
Muscle tension

Reaches end-
systolic length
Active Isometric tension development

Isometric relaxation
Passive stretch Reaches end-diastolic length FIGURE 24–3 Ventricular pressure–volume
cycle (A), and corresponding cardiac muscle
length–tension cycle (B). (Modified with permission
from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th
Muscle length ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

diastolic ventricular volume and therefore the resting length of against which they are shortening. Once shortening ceases
the cardiac muscle fibers at the end of diastole. and the output valve closes, the cardiac muscle cells relax
At the onset of systole, the ventricular muscle cells develop isometrically. Ventricular wall tension and intraventricular
tension isometrically (during the isovolumetric contraction pressure decrease in unison during isovolumetric relaxation.
phase) and intraventricular pressure increases accordingly.
After the intraventricular pressure increases sufficiently to
open the outlet valve, ventricular ejection begins as a conse- DETERMINANTS OF
quence of ventricular muscle shortening. Systemic arterial CARDIAC OUTPUT
pressure is often referred to as the ventricular afterload
because it determines the tension that must be developed by The cardiac output (liters of blood pumped by each of the
cardiac muscle fibers before they can shorten. It should be ventricles per minute) is an extremely important cardiovascu-
noted that other factors that influence the actual wall tension lar variable that is continuously adjusted so that the cardiovas-
required to eject blood from the ventricle (such as end-diastolic cular system operates to meet the body’s moment-to-moment
volume, velocity of contraction, viscosity of the blood) do con- circulatory needs. In going from rest to strenuous exercise, for
tribute to ventricular afterload but we choose to ignore them example, the cardiac output of an average person will increase
at this point. from approximately 5.5 to perhaps 15 L/min. The extra car-
During cardiac ejection, cardiac muscle is simultaneously diac output provides the exercising skeletal muscles with the
generating active tension and shortening (i.e., an afterloaded additional nutritional supply needed to sustain an increased
isotonic contraction). The stroke volume is determined by metabolic rate. To understand the cardiovascular system’s
how far ventricular muscle cells are able to shorten during response not only to exercise, but also to all other physiologi-
contraction. This, as already discussed, depends on the length– cal or pathological demands placed on it, we must understand
tension relationship of the cardiac muscle cells and the load what determines, and therefore controls, cardiac output.
228 SECTION V Cardiovascular Physiology

As stated in Chapter 22, cardiac output is the product of A

heart rate and stroke volume (CO = HR × SV). Therefore, all
5
changes in cardiac output must be produced by changes in

Muscle tension (g)

Peak isometric
heart rate and/or stroke volume. 4 tension
Factors influencing heart rate do so by altering the charac-
3
teristics of the diastolic depolarization of the pacemaker cells More shortening
as discussed in Chapter 23 (see Figure 23–4). Recall that varia- 2
tions in activity of the sympathetic and parasympathetic nerves Resting
tension
leading to cells of the sinoatrial (SA) node constitute the most 1
Larger preload
important regulators of heart rate. Increases in sympathetic
activity increase heart rate, whereas increases in parasympa- Muscle length
thetic activity decrease heart rate. These neural inputs have
immediate effects (within one beat) and therefore can cause B
very rapid adjustments in cardiac output. 120

LV pressure (mm Hg)

INFLUENCES ON STROKE VOLUME 80
More
EFFECT OF CHANGES IN 40
stroke volume

VENTRICULAR PRELOAD: Larger

STARLING’S LAW OF THE HEART ventricular
preload

The volume of blood that the heart ejects with each beat can
vary significantly. One of the most important factors respon-
sible for these variations in stroke volume is the extent of car-
diac filling during diastole. This concept was introduced in
Chapter 22 (Figure 22–7) and is known as Starling’s law of the
heart. To review (and to reemphasize its importance), this law
states that, with other factors equal, stroke volume increases as
60 120
LV volume (mL)
FIGURE 24–4 Effect of changes in preload on cardiac
muscle shortening during afterloaded contractions (A) and
on ventricular stroke volume (B). (Modified with permission from
Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange
Medical Books/McGraw-Hill, 2006.)

cardiac filling increases. As shown below, this phenomenon is

based on the intrinsic mechanical properties of myocardial
muscle.
Figure 24–4A illustrates how increasing muscle preload will
increase the extent of shortening during a subsequent contrac-
tion with a fixed total load. Recall from the nature of the rest-
ing length–tension relationship that an increased preload is
necessarily accompanied by increased initial muscle fiber
length. As was described in Chapter 23, when a muscle starts
from a greater length, it has more distance to shorten before it
reaches the length at which its tension-generating capability is
no longer greater than the load upon it. Cardiac muscle cells
exhibit the same behavior when they are operating in the ven-
tricular wall. Increases in ventricular preload increase both
end-diastolic volume and stroke volume almost equally, as
illustrated in Figure 24–4B.
The precise relationship between cardiac preload (cardiac
filling pressure) and end-diastolic volume has especially
important physiological and clinical consequences. Although
the relationship is somewhat curvilinear, especially at very
high filling pressures, it is nearly linear over the normal oper-
ating range of the heart. The low slope of this relationship
indicates the incredible distensibility of the normal ventricle
during diastole. (For example, a change in filling pressure of
only 1 mm Hg normally will change end-diastolic volume by
about 25 mL!)
One form of heart failure is called diastolic failure and is
characterized by an abnormally stiff ventricle and a distur-
bance in the relationship between cardiac filling pressure and
end-diastolic volume. In this situation, diastolic filling is lim-
ited, stroke volume is reduced, cardiac output is inadequate,
and function of the cardiovascular system is compromised.
It should be noted in Figure 24–4A that increasing preload
increases initial muscle length without significantly changing
the final length to which the muscle shortens against a con-
stant total load. Thus, increasing ventricular filling pressure
increases stroke volume primarily by increasing end-diastolic
volume. As shown in Figure 24–4B, this is not accompanied by
a significant alteration in end-systolic volume.
EFFECT OF CHANGES IN
VENTRICULAR AFTERLOAD
Figure 24–5A shows how increased afterload, at constant pre-
load, has a negative effect on cardiac muscle shortening
because muscle cannot shorten beyond the length at which its
peak isometric tension-generating potential equals the total
load upon it. Thus, shortening must stop at a greater muscle
length when afterload is increased.
 CHAPTER 24 The Heart Pump 229

A EFFECT OF CHANGES IN CARDIAC

Peak isometric
MUSCLE CONTRACTILITY
5
Muscle tension (g)

tension
4 Less shortening Recall that activation of the sympathetic nervous system
results in release of norepinephrine from cardiac sympathetic
3 nerves, which increases contractility of the individual cardiac
Resting
tension
muscle cells. This results in an upward shift of the peak iso-
2
Larger total load metric length–tension curve. As shown in Figure 24–6A, such
1 a shift will result in an increase in the shortening of a muscle
contracting with constant preload and total load. Thus, as
shown in Figure 24–6B, the norepinephrine released by sym-
Muscle length
pathetic nerve stimulation will increase ventricular stroke vol-
ume by decreasing the end-systolic volume without directly
B influencing the end-diastolic volume.
120 In addition to these changes in the extent of myocyte short-
ening, an increase in contractility will also cause an increase in
LV pressure (mm Hg)

the rates of myocyte tension development and of shortening.

80 This will result in an increase in the rate of isovolumetric pres-
Lower Larger sure development (dP/dt) and the rate of ejection during
stroke volume ventricular systole.
40 afterload Systolic failure is characterized by a severely depressed abil-
ity of the cardiac muscle cells to produce tension and shorten.
In this situation, systolic contraction is limited, stroke volume

60 120
LV volume (mL) A Afterloaded contraction
FIGURE 24–5 Effect of changes in afterload on cardiac Peak isometric
muscle shortening during afterloaded contractions (A) and on NE tension
h
ventricular stroke volume (B). Dashed line shows how stroke 5 NE
it
t
Muscle tension (g)

ou
volume is decreased by an increase in afterload. Dotted line shows ith
4
W

the relationship between end-systolic pressure and end-systolic

volume obtained at a constant preload but different afterloads. 3
(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, More shortening N
E Resting tension
6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.) 2 ut
wi th o
1 or
With
Normally, mean ventricular afterload is nearly constant,
because mean arterial pressure is held within tight limits by Muscle length
the cardiovascular control mechanisms described in
B
Chapter 29. In many pathological situations such as hyperten-
Wi
sion (high blood pressure) and aortic valve obstruction, ven- th
120 NE
tricular function is adversely influenced by abnormally high
LV pressure (mm Hg)

With
o ut
ventricular afterload. When this occurs, stroke volume may be N E
decreased as shown by the changes in the pressure–volume
80
loop indicated by the dashed line in Figure 24–5B. Under these Increased
conditions, note that stroke volume is decreased because end- stroke volume
systolic volume is increased. 40
The relationship between end-systolic pressure and
end-systolic volume obtained at a constant preload but different
afterloads is indicated by the dotted line in Figure 24–5B. In a
normally functioning heart, the effect of changes in afterload 60 120
on end-systolic volume (and therefore stroke volume) is quite LV volume (mL)
small (about 0.5 mL/mm Hg). However, in systolic cardiac FIGURE 24–6 Effect of norepinephrine (NE) on afterloaded
failure, the end-systolic pressure-volume line is shifted down- contractions on cardiac muscle (A) and on ventricular stroke
ward and is flattened so that the effect of afterload on end- volume (B). (Modified with permission from Mohrman DE, Heller LJ:
systolic volume is greatly exaggerated. Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
230 SECTION V Cardiovascular Physiology

Negative chronotropic
CARDIAC PARASYMPATHETIC NERVE ACTIVITY LEVEL –
HEART RATE
+
Positive chronotropic

CARDIAC SYMPATHETIC NERVE ACTIVITY LEVEL

+
CARDIAC OUTPUT
Contractility (positive inotropic) +

ARTERIAL PRESSURE

FIGURE 24–7 Influences on cardiac

Afterload
– STROKE VOLUME
FILLING PRESSURE
output. (Modified with permission from Mohrman DE,
Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Preload
+
Medical Books/McGraw-Hill, 2006.) (Starling’s law)

is reduced, cardiac output is inadequate, and function of the CARDIAC FUNCTION CURVES
cardiovascular system is compromised.
One very useful way to summarize the influences on cardiac
function and the interactions between them is by cardiac
SUMMARY OF DETERMINANTS function curves such as those shown in Figure 24–8. Cardiac
filling pressure (“cardiac preload”) is plotted as the independent
OF CARDIAC OUTPUT variable on the horizontal axis in this figure and cardiac out-
put as the dependent variable on the vertical axis. Each curve
The major influences on cardiac output are summarized in
in this figure shows the effect of changes in cardiac preload on
Figure 24–7. Heart rate is controlled by chronotropic influ-
ences on the spontaneous electrical activity of SA nodal cells.
Cardiac parasympathetic nerves have a negative chronotro-
pic effect, and sympathetic nerves have a positive chronotro-
Activity levels of
pic effect on the SA node. Stroke volume is controlled by cardiac sympathetic nerves
influences on the contractile performance of ventricular car- Greatly increased
diac muscle—in particular its degree of shortening in the
afterloaded situation. The three distinct influences on stroke
volume are contractility, preload, and afterload. Increased car- 10.0 Moderately increased
diac sympathetic nerve activity tends to increase stroke vol-
Cardiac output (L /min)

ume by increasing the contractility of cardiac muscle (a

8.0 Normal
positive inotropic effect). Increased arterial pressure tends to
decrease stroke volume by increasing the afterload on cardiac C B
muscle fibers. Increased ventricular filling pressure increases 6.0
end-diastolic volume, which tends to increase stroke volume Decreased
through Starling’s law of the heart. A
It is important to recognize at this point that both heart 4.0
rate and stroke volume are subject to more than one influ-
ence. Thus, the fact that increased contractility tends to
increase stroke volume should not be taken to mean that, in 2.0
the intact cardiovascular system, stroke volume is always high
when contractility is high. Following blood loss caused by
hemorrhage, for example, stroke volume may be low in spite 0 2.0 4.0 6.0
of a high level of sympathetic nerve activity and increased Cardiac filling pressure (mm Hg)
contractility. Because arterial pressure is normal or low fol- FIGURE 24–8 Influence of cardiac sympathetic nerves on
lowing hemorrhage, the low stroke volume associated with cardiac function curves. (Modified with permission from Mohrman DE,
severe blood loss must be (and is) the result of low cardiac Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/
filling pressure. McGraw-Hill, 2006.)

cardiac output at one constant level of cardiac sympathetic
nerve activity. Different curves are used for different levels of
cardiac sympathetic nerve activity. Thus, Figure 24–8 shows
how the cardiac filling pressure and the activity level of cardiac
sympathetic nerves interact to determine cardiac output.
When cardiac filling pressure is 2 mm Hg and the activity of
cardiac sympathetic nerves is normal, the heart will operate at
point A and will have a cardiac output of 5 L/min. Each single
curve in Figure 24–8 shows how cardiac output would be
changed by changes in cardiac filling pressure if cardiac sym-
pathetic nerve activity were held at a fixed level. For example,
if cardiac sympathetic nerve activity remained normal, increas-
ing cardiac filling pressure from 2 to 4 mm Hg would cause the
heart to shift its operation from point A to point B on the car-
diac function diagram. In this case, cardiac output would
increase from 5 to 7 L/min solely as a result of the increased
filling pressure (Starling’s law). If, on the other hand, cardiac
filling pressure were fixed at 2 mm Hg while the activity of
cardiac sympathetic nerves was moderately increased from
normal, the heart would change from operating at point A to
operating at point C. Cardiac output would again increase
from 5 to 7 L/min. In this instance, however, cardiac output
does not increase through the length-dependent mechanism
because cardiac filling pressure did not change. Cardiac out-
put increases at constant filling pressure with an increase in
cardiac sympathetic activity for two reasons. First, increased
cardiac sympathetic nerve activity increases heart rate. Second,
but just as importantly, increased sympathetic nerve activity
increases stroke volume by increasing cardiac contractility.
Cardiac function graphs thus consolidate knowledge of
many mechanisms of cardiac control, and are most helpful in
describing how the heart interacts with other elements in the
cardiovascular system. Furthermore, these graphs reempha-
size the important point that a change in cardiac filling pres-
sure alone will have a very potent effect on cardiac output at
any level of sympathetic activity.
SUMMARY OF SYMPATHETIC
NEURAL INFLUENCES ON
CARDIAC FUNCTION
The effects of the sympathetic nervous system on the electrical
and mechanical properties of cardiac muscle, and thus on car-
diac pumping ability, are initiated by the interaction of norepi-
nephrine with β1-adrenergic receptors on cardiac muscle
cells. This results in a cascade of events involving the Gs acti-
vation of adenylate cyclase, formation of cAMP, and activa-
tion of protein kinase A with subsequent phosphorylation of
many molecules that play key regulatory roles in intracellular
processes. These cellular events combine to evoke the follow-
ing improvements in pumping capabilities of the heart:
1. an increase in heart rate (positive chronotropic effect) by
activating the inward-going sodium if current in SA
nodal cells;
CHAPTER 24 The Heart Pump 231
2. a decrease in cardiac action potential duration by early
activation of the delayed iK current in cardiac myocytes,
which minimizes the detrimental effect of high heart rates
on diastolic filling time;
3. an increase in the rate of action potential conduction,
particularly evident in the AV node (positive dromotropic
effect), by altering conductivity of gap junctions;
4. an increase in cardiac contractility (positive inotropic ef-
fect) by activating the iCa2+ current and increasing Ca2+
release from the sarcoplasmic reticulum, which increas-
es the contractile ability of cardiac muscle at any given
preload; and
5. an increase in rate of cardiac relaxation (positive lusitropic
effect) by increasing Ca2+ uptake by the sarcoplasmic
reticulum, which also helps minimize the detrimental
effect of high heart rates on diastolic filling time.
Most catecholamine influences on the heart are a result
of increases in sympathetic neural activity. Although circulat-
ing catecholamines of adrenal origin can potentially evoke
similar effects, their concentrations are normally so low that
their contributions are negligible. Specific drugs called
β1-adrenergic receptor blockers (antagonists) can block all of
the effects of catecholamines from whatever source on cardiac
muscle. These drugs may be useful in the treatment of coro-
nary artery disease to thwart increased metabolic demands
placed on the heart by activity of sympathetic nerves.
As we will see in subsequent chapters, increases in sympa-
thetic activity can also have indirect influences on cardiac
function that are a consequence of sympathetic-induced alter-
ations in arteriolar and venous tone (i.e., alterations in after-
load and preload, respectively).
DETERMINANTS OF MYOCARDIAL
OXYGEN CONSUMPTION
In many pathological situations, such as severe coronary
atherosclerosis, oxygen requirements of myocardial tissue
may exceed the capacity of coronary blood flow to deliver
oxygen to the heart muscle. This mismatch can result in
severe chest pain or discomfort called angina pectoris. It is
important to understand what factors determine energy
costs, and therefore the myocardial oxygen consumption,
because reduction of oxygen demand may be of significant
clinical benefit to the patient.
Because the heart derives its energy almost entirely from
aerobic metabolism, myocardial oxygen consumption is
directly related to myocardial ATP use. The basal metabo-
lism of the heart tissue (the energy consumed in cellular pro-
cesses other than contraction such as energy-dependent ion
pumping) normally accounts for about 25% of myocardial
ATP use and therefore myocardial oxygen consumption in a
resting individual. The processes associated with muscle
contraction account for about 75% of myocardial energy
use. Primarily, this reflects ATP splitting associated with
232 SECTION V Cardiovascular Physiology
cross-bridge cycling during the isovolumetric contraction
and ejection phases of the cardiac cycle. Some ATP is also
used for Ca2+ sequestration at the termination of each
contraction.
The energy expended during the isovolumetric contraction
phase of the cardiac cycle accounts for the largest portion
(~50%) of total myocardial oxygen consumption despite
the fact that the heart does no external work during this
period. The energy needed for isovolumetric contraction is
mainly dependent on the intraventricular pressure that must
develop during this time, that is, on the cardiac afterload.
Cardiac afterload then is a major determinant of myocardial
oxygen consumption. Reductions in cardiac afterload can pro-
duce clinically significant reductions in myocardial energy
requirements and therefore myocardial oxygen consumption.
Energy utilization during isovolumetric contraction is actu-
ally more directly related to isometric wall tension develop-
ment than to intraventricular pressure development. Recall
that wall tension is related to intraventricular pressure and to
ventricular radius through the law of Laplace (T = P × r).
Consequently, reductions in cardiac preload (i.e., end-diastolic
volume, radius) will also tend to reduce the energy required
for isovolumetric contraction.
It is during the ejection phase of the cardiac cycle that the
heart actually performs external work and the energy the
heart expends during ejection depends on how much exter-
nal work it is doing. In a fluid system, work (force × dis-
tance) is equal to pressure (force/distance2) × volume
(distance3). The external physical work done by the left ven-
tricle in one beat, that is, the stroke work, is equal to the area
enclosed by the left ventricular pressure–volume loop
(see Figure 24–3A). Stroke work is increased either by an
increase in stroke volume (increased “volume” work) or by
an increase in afterload (increased “pressure” work). In terms
of ATP utilization and oxygen consumption, increases in the
pressure work of the heart are more costly than increases in
volume work. Thus, reductions in afterload are especially
helpful in reducing the myocardial oxygen requirements for
doing external work.
Changes in myocardial contractility can have important
consequences on the oxygen requirement for basal metabo-
lism, isovolumic wall tension generation, and external work.
Heart muscle cells use more energy in rapidly developing a
given tension and shortening by a given amount than in doing
the same thing more slowly. Also, with increased contractility,
more energy is expended in active Ca2+ transport. The net
result of these influences is often referred to as the “energy-
wasting” effect of increased contractility.
Heart rate is one of the most important determinants
of myocardial oxygen consumption because the energy
costs per minute must equal the energy cost per beat
times the number of beats per minute. In general, it has been
found that it is more efficient (i.e., less oxygen is required) to
achieve a given cardiac output with low heart rate and high
stroke volume than with high heart rate and low stroke vol-
ume. This again appears to be related to the relatively high
energy cost of the isovolumetric pressure development phase
of the cardiac cycle. The less pressure (wall tension) devel-
oped and the less often pressure development occurs, the less
energy used.
CLINICAL CORRELATION
A 40-year-old woman comes to the emergency room
because of the sudden onset of weakness and dizziness
about an hour earlier. In addition, she reports a sense of
fluttering in her chest and throat. Examination reveals
her heart rate to be rapid (165 beats/min; tachycardia)
and regular and her blood pressure to be on the low side
at 80/60 mm Hg. Her ECG shows a tachycardia associ-
ated with a narrow QRS complex. After attempts
to restore normal rates by massaging the neck at the
location of the carotid sinuses, and by putting a cold
compress on her face, she was given an intravenous injec-
tion of adenosine that converted her heart rate to
80 beats/min and her blood pressure to 130/85 mm Hg.
The primary complaint of weakness and dizziness
suggests a decrease in systemic blood flow including
the cerebral circulation caused by the low arterial pres-
sure. This could be caused by a decrease either in car-
diac output or in total peripheral resistance. In our
patient, the very fast heart rate severely shortened the
duration of diastole and, as a result, cardiac filling was
significantly compromised. Because of Starling’s law of
the heart relating end-diastolic volume with stroke vol-
ume, the decrease in filling results in a decrease in
stroke volume. In spite of the rapid heart rate, the low
stroke volume produces a significant decrease in car-
diac output. The therapeutic strategy involves attempts
to decrease heart rate.
The ECG suggests a supraventricular tachycardia
with either an atrial ectopic focus firing rapidly or a
reentrant AV nodal circuit rapidly exciting the normal
ventricular conduction system. (See Chapter 25 for more
details.) Mechanical ways to interrupt these processes
include strategies to increase vagal firing to the atrial tis-
sue by (1) massage of neck at the region of the carotid
sinus (carotid massage), stretching the arterial barore-
ceptors, and tricking the medullary cardiovascular cen-
ters to think arterial pressure is elevated (see Chapter
29) or (2) instituting the diving reflex with a cold com-
press on the face in which bradycardia is induced by
activation of the trigeminal nerve afferents to the brain
(see Chapter 71). The primary pharmacological strategy
used in the emergency room involved intravenous injec-
tion of a bolus of adenosine. This can have a transient
influence on supraventricular conduction within the
heart and can often interrupt the abnormal reentrant
pathway. Adenosine was effective in our patient. If it had

not been, drugs such as β-adrenergic receptor blockers
or calcium channel blockers can be effective. She was
referred to a cardiologist who will perform extensive
testing of her cardiac function to try to identify the ana-
tomical source of her abnormal cardiac rhythm.
CHAPTER SUMMARY
■ Effective cardiac pumping of blood requires coordinated filling
of the chambers, excitation and contraction of the cardiac
muscle cells, pressure generation within the chambers, opening
and closing of cardiac valves, and one-way movement of blood
through the chambers into the aorta or pulmonary artery.
■ Except for lower ejection pressures, events of the right side of
the heart are identical to those of the left side.
■ Heart sounds associated with valve movements and detected
on auscultation can be used to identify the beginnings of
diastolic and systolic phases of the cardiac cycle.
■ The events of a single ventricular cardiac cycle can be displayed
as records of electrical, mechanical, pressure, sound, or flow
changes against time or as a record of volume against pressure.
■ Cardiac output is defined as the amount of blood pumped by
either of the ventricles per minute and is determined by the
product of heart rate and stroke volume.
■ Stroke volume can be altered by changes in ventricular preload
(filling), ventricular afterload (arterial pressure), and/or cardiac
muscle contractility.
■ A cardiac function curve describes the relationship between
ventricular filling and cardiac output and can be shifted up
(left) or down (right) by changes in sympathetic activity to the
heart or by changes in cardiac muscle contractility.
■ Energy for cardiac muscle contraction is derived primarily
from aerobic metabolic pathways such that cardiac work is
tightly related to myocardial oxygen consumption.
STUDY QUESTIONS
1. You are listening to your patient’s heart sounds and have
identified the systolic and diastolic intervals. Four of the
conditions listed below exist during the same phase of
the cardiac cycle and one does not. Which one is the odd one?
A) The mitral valve is open.
B) The ST segment of the ECG is occurring.
C) The “v” wave of the jugular venous pulse has just occurred.
D) Ventricular volume is rapidly increasing.
E) Aortic pressure is decreasing.
CHAPTER 24 The Heart Pump 233
2. Your patient has coronary artery disease with significant
occlusion of the left anterior descending coronary artery.
Although all of the following will increase cardiac work,
which of the following will be most likely to result in an attack
of angina pectoris?
A) high heart rates
B) elevated arterial blood pressures
C) increased end-diastolic volume
D) low arterial blood pressure
E) increased cardiac contractility
3. A drug is given that blocks cardiac β1-adrenergic receptors.
What will be the direct consequences of this drug on
the heart?
A) Heart rate will increase.
B) The PR interval of the ECG will shorten.
C) Metabolic demands will be reduced.
D) Coronary flow rate will increase.
E) Cardiac contractility will increase.
4. A cannula is placed in the pulmonary artery (PA) of a normal
healthy individual and pressure is reported to be 25/8 mm Hg.
Which of the following can be surmised from these values?
A) RV systolic pressure is 25 mm Hg; PA diastolic pressure
is 8 mm Hg.
B) RV systolic pressure is 25 mm Hg; left atrial pressure
is 8 mm Hg.
C) RV systolic pressure must be significantly higher
than 25 mm Hg.
D) RV diastolic pressure must be significantly higher
than 8 mm Hg.
E) Pulmonary capillary pressure is 8 mm Hg.
5. An individual has an autonomic nervous system dysfunction
in which cardiac parasympathetic nerve activity abruptly
increases while cardiac sympathetic activity decreases.
Which of the following situations is most likely
to occur?
A) LV end-diastolic volume will increase.
B) Cardiac output will increase.
C) Heart rate will increase.
D) LV end-systolic volume will decrease.
E) Coronary blood flow will increase.
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 25
C H A P T E R

Cardiac Function
Assessments
Lois Jane Heller and David E. Mohrman

O B J E C T I V E S

■ State the relationship between electrical events of cardiac excitation and

the P, QRS, and T waves, the PR and QT intervals, and the ST segment of the
electrocardiogram.
■ State Einthoven’s basic electrocardiographic conventions and, given data,
determine the mean electrical axis of the heart.
■ Describe the standard 12-lead electrocardiogram.
■ Detect common cardiac arrhythmias from the electrocardiogram, identify
their physiological bases, and describe their physiological consequences.
■ Calculate cardiac output using the Fick principle.
■ Recognize echocardiographic images obtained during the cardiac cycle.
■ Define ejection fraction and identify visualization methods used to determine it.
■ Describe the end-systolic pressure–volume relationship.
■ List stenotic and regurgitant valve abnormalities for the left heart and
describe their consequences in terms of intracardiac and arterial pressures,
flow patterns, and heart sounds that accompany them.

TECHNIQUES FOR ASSESSING MEASUREMENT OF CARDIAC

CARDIAC FUNCTION
There are a variety of methods available to assess cardiac
function. Some of these are noninvasive (e.g., electrocardiog-
raphy to evaluate electrical characteristics, auscultation of the
chest to evaluate valve function, and echocardiography to
visualize mechanical pumping action) and others require vari-
ous types of invasive instrumentation. This chapter will pro-
vide a brief overview of some of these commonly used clinical
tools and an introduction to some of the common cardiac
functional abnormalities.
EXCITATION—THE
ELECTROCARDIOGRAM
The electrocardiogram is a powerful clinical tool that is used to
evaluate cardiac beating rate, rhythm, and the conduction char-
acteristics of cardiac tissue. As briefly described in Chapter 23,
the electrocardiogram is the result of currents propagated
through the extracellular fluid that are generated by the spread
of the wave of excitation throughout the heart. Electrodes
placed on the surface of the body record the small potential dif-
ferences between various recording sites that vary over the time
course of the cardiac cycle.

235

Ch25_235-250.indd 235 11/26/10 10:00:28 AM

236 SECTION V Cardiovascular Physiology
R cells have already returned to the resting phase, whereas ven-
1 mV
0.5
Voltage
T
P again appears on the body surface and is measured as the
0 T wave of the electrocardiogram. The T wave is wider and not
Q S
−0.5 PR ST
QRS
segment segment
interval
PR
interval QT interval
Time
FIGURE 25–1 Typical electrocardiogram. (Modified with
permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York:
Lange Medical Books/McGraw-Hill, 2006.)
A typical electrocardiographic record of voltages recorded
on the surface of the body between the left leg and the right
arm (called “lead II”) is indicated in Figure 25–1. The major
features of the electrocardiogram are the P, QRS, and T waves
that are caused by atrial depolarization, ventricular depolar-
ization, and ventricular repolarization, respectively. The
period of time from the initiation of the P wave to the begin-
ning of QRS complex is designated as the PR interval and
indicates the time it takes for an action potential to spread
through the atria and the atrioventricular (AV) node. During
the latter portion of the PR interval (PR segment), no voltages
are detected on the body surface. This is because atrial muscle
cells are depolarized (in the plateau phase of their action
potentials), ventricular cells are still resting, and the electrical
field set up by the action potential progressing through the
small AV node is not intense enough to be detected. The dura-
tion of the normal PR interval ranges from 120 to 200 millisec-
onds. Shortly after the cardiac impulse breaks out of the AV
node and into the rapidly conducting Purkinje system, all the
ventricular muscle cells depolarize rapidly and cause the QRS
complex. The R wave is the largest event in the electrocardio-
gram because ventricular muscle cells are so numerous and
because they depolarize nearly in unison. The normal QRS
complex lasts between 60 and 100 milliseconds. (The repolar-
ization of atrial cells is also occurring during the time period
in which ventricular depolarization generates the QRS com-
plex on the electrocardiogram [see Figure 23–3]. Atrial repo-
larization is not evident on the electrocardiogram because it is
a poorly synchronized event in a relatively small mass of heart
tissue and is completely overshadowed by the major electrical
events occurring in the ventricles at this time.)
The QRS complex is followed by the ST segment. Normally,
no electrical potentials are measured on the body surface dur-
ing the ST segment because no rapid changes in membrane
potential are occurring in any of the cells of the heart; atrial
tricular muscle cells are in the plateau phase of their action
potentials. (Myocardial injury or inadequate blood flow, how-
ever, can produce elevations or depressions in the ST segment.)
When ventricular cells begin to repolarize, a voltage once
as large as the R wave because ventricular repolarization is less
synchronous than depolarization. At the conclusion of the
T wave, all the cells in the heart are in the resting state. The QT
interval roughly approximates the duration of the ventricular
myocyte depolarization and thus the period of ventricular sys-
tole. At a normal heart rate of 60 beats/min, the QT interval is
normally less than 380 milliseconds. No body surface poten-
tial is measured until the next impulse is generated by the
sinoatrial (SA) node.
The operation of the specialized conduction system is a pri-
mary factor in determining the normal electrocardiographic
pattern. For example, the AV nodal transmission time deter-
mines the PR interval. Also, the effectiveness of the ventricular
Purkinje system in synchronizing ventricular depolarization
is reflected in the large magnitude and short duration of the
QRS complex. Remember that nearly every heart muscle cell is
inherently capable of rhythmicity and that all cardiac cells are
electrically interconnected through gap junctions. Thus, a
functional heart rhythm can and often does occur without the
involvement of part or all of the specialized conduction sys-
tem. Such a situation is, however, abnormal, and the existence
of abnormal conduction pathways produces an abnormal elec-
trocardiogram.
BASIC ELECTROCARDIOGRAPHIC
CONVENTIONS
Recording electrocardiograms is a routine diagnostic proce-
dure standardized by universal application of certain conven-
tions. The conventions for recording and analysis of
electrocardiograms from the three standard bipolar limb leads
are briefly described here and summarized in Figure 25–2.
Recording electrodes are placed on both arms and the left leg—
usually at the wrists and ankle. The arms and legs act as con-
ductive extensions from the body, and voltage measurements
are actually between points that form an equilateral triangle
over the thorax. This is called Einthoven’s triangle in honor of
the Dutch physiologist who devised it at the turn of the 19th
century. Any single electrocardiographic trace is a recording of
the voltage difference measured between any two vertices of
Einthoven’s triangle. An example of the lead II electrocardio-
gram measured between the right arm and the left leg
has already been shown in Figure 25–2. Similarly, lead I and
lead III electrocardiograms represent voltage measurements
taken along the other two sides of Einthoven’s triangle, as
indicated in Figure 25–2. The + and – symbols in Figure 25–2
indicate polarity conventions that have been universally adopted.
For example, an upward deflection in a lead II electrocardiogram
 CHAPTER 25 Cardiac Function Assessments 237

Right arm − Lead I + Left arm

−
−

III
Le

ad
ad

Le
II
Lead selector

+
Chart recorder and amplifier

+
Left leg

FIGURE 25–2 Einthoven’s

Voltage scale Paper speed electrocardiographic conventions. (Modified
10 mm 25 mm = 1 s
= +1 mV with permission from Mohrman DE, Heller LJ: Cardiovascular
upward Physiology, 6th ed. New York: Lange Medical Books/
McGraw-Hill, 2006.)

(as normally occurs during the P, R, and T waves) indicates that
an electrical polarity exists at that instant between the left leg
and the right shoulder electrodes, with the left leg electrode
being positive. Conversely, a downward deflection in a lead
II record indicates that an electrical polarity exists between this
pair of electrodes but this time the electrode on the left leg is
recording negative charges instead of positive charges. Similar
polarity conventions have been established for lead I and lead
III recordings and are indicated by the + and – symbols in
Figure 25–2. In addition, electrocardiographic recording equip-
ment is usually standardized so that a 1-cm deflection on the
vertical axis always represents a potential difference of 1 mV,
and that a 25-mm segment of the horizontal tracing of any elec-
trocardiographic record represents 1 second. Most electrocar-
diographic records contain calibration signals so that abnormal
rates and wave amplitudes can be easily detected.
As shown in the subsequent section, many cardiac electrical
abnormalities can be detected in recordings from a single elec-
trocardiographic lead. However, certain clinically useful infor-
mation can only be derived by combining the information
obtained from two electrocardiographic leads. To understand
these more complex electrocardiographic analyses, the way
voltages appear on the body surface as a result of the cardiac
electrical activity must be examined.
CARDIAC DIPOLES AND
ELECTROCARDIOGRAPHIC
RECORDS
Einthoven’s conceptualization of how cardiac electrical activ-
ity causes potential differences on the surface of the body is
illustrated in Figure 25–3. In this example, the heart is shown
at one instant in the atrial depolarization phase. The cardiac
impulse, after having arisen in the SA node, is spreading as a
wavefront of depolarization through the atrial tissue. At each
point along this wavefront of electrical activity, a small charge
separation exists in the extracellular fluid between polarized
membranes (positive outside) and depolarized membranes
(negative outside). Thus, the wavefront may be thought of as
a series of individual electrical dipoles (regions of charge
separation). Each individual dipole is oriented in the direction
of local wavefront movement. The large black arrow in

Depolarized − I
RA LA
cells − −
SA Wavefront of
node −
− electrical activity
−
−
− −− Net dipole
II III
Atria
FIGURE 25–3 Net cardiac dipole during atrial
depolarization and its components on the limb
Ventricles leads. (Modified with permission from Mohrman DE, Heller LJ:
Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/
LL
McGraw-Hill, 2006.)
238 SECTION V Cardiovascular Physiology
Figure 25–3 represents the total net dipole created by the
summed contributions of all the individual dipoles distributed
along the wavefront of atrial depolarization. The salty extra-
cellular fluid acts as an excellent conductor, allowing these
instantaneous net dipoles generated on the surface of the heart
muscle to be recorded by electrodes on the surface of the
body.
The net dipole that exists at any instant is oriented (i.e.,
points) in the general direction of wavefront movement at that
instant. The magnitude or strength of the dipole (represented
here by the arrow length) is determined by: (1) how extensive
the wavefront is (i.e., how many cells are simultaneously depo-
larizing at the instant in question) and (2) the consistency of
orientation between individual dipoles at different points in
the wavefront (dipoles with the same orientation reinforce
each other; dipoles with opposite orientation cancel each
other).
The net dipole in the example of Figure 25–3 causes the
lower left portion of the body to be generally positive with
respect to the upper right portion. This particular dipole will
cause positive voltages to exist on all three of the electrocar-
diogram limb leads. As shown in the right half of Figure 25–3,
this can be deduced from Einthoven’s triangle by observing
that the net dipole has some component that points in the
positive direction of leads I, II, and III. As illustrated in
Figure 25–3, the component that a cardiac dipole has on a
given electrocardiogram lead is found by drawing perpendic-
ular lines from the appropriate side of Einthoven’s triangle to
the tip and tail of the dipole. (It may be helpful to think of the
component on each lead as the “shadow” cast by the dipole on
that lead as a result of a “sun” located far beyond the corner of
Einthoven’s triangle that is opposite the lead.) Note that the
dipole in this example is most parallel to lead II and therefore
has a large component in the lead II direction. Thus, it will
create a larger voltage on lead II than on leads I or III. This
dipole has a rather small component on lead III because it is
oriented nearly perpendicular to lead III.
The limb lead configuration may be thought of as a way to
view the heart’s electrical activity from three different perspec-
tives (or axes). The vector representing the heart’s instanta-
neous dipole strength and orientation is the object under
observation, and its appearance depends on the position from
which it is viewed. The instantaneous voltage measured on the
axis of lead I, for example, indicates how the dipole being gen-
erated by the heart’s electrical activity at that instant appears
when viewed from directly above. A cardiac dipole that is ori-
ented horizontally appears large on lead I, whereas a vertically
oriented cardiac dipole, however large, produces no voltage on
lead I. Thus, it is necessary to have views from two directions
to establish the magnitude and orientation of the heart’s dipole.
A vertically oriented dipole would be invisible on lead I but
would be readily apparent if viewed from the perspective of
lead II or lead III.
It is important to recognize that the example of Figure 25–3
pertains only to one instant during atrial depolarization. The
net cardiac dipole continuously changes in magnitude and
orientation during the course of atrial depolarization. The
nature of these changes will determine the shape of the P wave
on each of the electrocardiogram leads.
The P wave terminates when the wave of depolarization
reaches the nonmuscular border between the atria and the
ventricles and the number of individual dipoles becomes very
small. At this time, the cardiac impulse is still being slowly
transmitted toward the ventricles through the AV node. How-
ever, the electrical activity in the AV node involves so few cells
that it generates no detectable net cardiac dipole. Thus, no
voltages are measured on the surface of the body for a brief
period following the P wave. A net cardiac dipole reappears
only when the depolarization completes its passage through
the AV node, enters the Purkinje system, and begins its rapid
passage over the ventricular muscle cells. Because the Purkinje
fibers terminate in the intraventricular septum and in the
endocardial layers at the apex of the ventricles, ventricular
depolarization occurs first in these areas and then proceeds
outward and upward through the ventricular myocardium.
VENTRICULAR DEPOLARIZATION
AND THE QRS COMPLEX
It is the rapid and large changes in the magnitude and direction
of the net cardiac dipoles that exist during ventricular depolar-
ization that are responsible for the QRS complex of the electro-
cardiogram. The normal process is illustrated in Figure 25–4.
The initial ventricular depolarization usually occurs on the left
side of the intraventricular septum as diagrammed in the upper
panel of the figure. Analysis of the cardiac dipole formed by
this initial ventricular depolarization with the aid of Einthoven’s
triangle shows that this dipole has a negative component on
lead I, a small negative component on lead II, and a positive
component on lead III. The upper right panel shows the actual
deflections on each of the electrocardiographic limb leads that
will be produced by this dipole. Note that it is possible for a
given cardiac dipole to produce opposite deflections on differ-
ent leads. For example, in Figure 25–4, Q waves appear on leads
I and II but not on lead III.
The second row of panels in Figure 25–4 shows the ventri-
cles during the instant in ventricular depolarization when the
number of individual dipoles is greatest and/or their orienta-
tion is most similar. This phase generates the large net cardiac
dipole, which is responsible for the R wave of the electrocar-
diogram. In Figure 25–4, this net cardiac dipole is nearly par-
allel to lead II. As indicated, such a dipole produces large
positive R waves on all three limbs leads.
The third row of diagrams in Figure 25–4 shows the situa-
tion near the end of the spread of depolarization through the
ventricles and indicates how the small net cardiac dipole pres-
ent at this time produces the S wave. Note that an S wave does
not necessarily appear on all electrocardiogram leads (as in
lead I of this example).
The bottom row of diagrams in Figure 25–4 shows that
during the ST segment, all ventricular muscle cells are in a

− I
− −
Q II III
wave
− I
− −
II III
R
wave
− I
− −
II III
S
wave
− I
− −
ST II III
segment
depolarized state. There are no waves of electrical activity
moving through the heart tissue. Consequently, no net cardiac
dipole exists at this time and no voltage differences exist
between points on the body surface. All electrocardiographic
traces will be flat at the isoelectric (zero voltage) level.
VENTRICULAR REPOLARIZATION
AND THE T WAVE
As illustrated in Figure 25–1, the T wave is normally positive
on lead II as is the R wave. This indicates that the net cardiac
dipole generated during ventricular repolarization is oriented
in the same general direction as that which exists during ven-
tricular depolarization. This may be somewhat surprising.
However, recall from Figure 24–3 that the last ventricular cells
to depolarize are the first to repolarize. The reasons for this are
not well understood but the result is that the wavefront of elec-
trical activity during ventricular repolarization tends to
retrace, in reverse direction, the course followed during ven-
tricular depolarization. Therefore, the dipole formed during
repolarization has the same polarity as that during depolariza-
tion. This reversed wavefront propagation pathway during
CHAPTER 25 Cardiac Function Assessments 239
I
II
III
I
II
III
I
II
III
I
II FIGURE 25–4 Ventricular depolarization
and the generation of the QRS complex.
(Modified with permission from Mohrman DE, Heller LJ:
III Cardiovascular Physiology, 6th ed. New York: Lange Medical
Books/McGraw-Hill, 2006.)
ventricular repolarization results in a positive T wave recorded,
for example, on lead II. The T wave is broader and smaller
than the R wave because the repolarization of ventricular mus-
cle cells is less well synchronized than is their depolarization.
MEAN ELECTRICAL AXIS
AND AXIS DEVIATIONS
The orientation of the cardiac dipole during the most intense
phase of ventricular depolarization (i.e., at the instant the R wave
reaches its peak) is called the mean electrical axis of the heart. It
is used clinically as an indicator of whether or not ventricular
depolarization is proceeding over normal pathways. The mean
electrical axis is reported in degrees according to the convention
indicated in Figure 25–5. Note that the downward direction is
designated as plus 90° in this polar coordinate system describing
axis orientation in the frontal plane (a vertical plane that divides
the body into anterior and posterior sections.) As indicated, a
mean electrical axis that lies anywhere in the patient’s lower left-
hand quadrant is considered normal (between 0° and 90°). A
left axis deviation exists when the mean electrical axis falls in
240 SECTION V Cardiovascular Physiology
RA LA
−90 degrees
Left axis
deviation
180 0 < 0 degrees
degrees degrees
Right axis Range of normal
deviation 0 to +90 degrees
> +90 degrees +90 degrees
LL
FIGURE 25–5 Mean electrical axis and axis deviations.
(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology,
6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
the patient’s upper left-hand quadrant and may indicate any of
the several conditions such as a physical displacement of the
heart to the left, left ventricular hypertrophy, or loss of electrical
activity in part of the right ventricle (e.g., after an infarct). A
right axis deviation exists when the mean electrical axis falls in
the patient’s lower right-hand quadrant and may indicate, among
several conditions, a physical displacement of the heart to the
right, right ventricular hypertrophy, or loss of electrical activity
in part of the left ventricle.
The mean electrical axis of the heart can be determined from
the electrocardiogram. The process involves determining what
single net dipole orientation will produce the R-wave ampli-
tudes recorded on any two leads. For example, if the R waves on
leads II and III are both positive (upright) and of equal magni-
tude, the mean electrical axis must be +90°. As should be obvi-
ous, in this case, the amplitude of the R wave on lead I will be
zero. Alternatively, one can scan the electrocardiographic
records for the lead tracing with the largest R waves and then
deduce that the mean electrical axis must be nearly parallel to
that lead. In Figure 25–4, for example, the largest R wave occurs
on lead II. Lead II has an orientation of +60°, which is very
close to the actual mean electrical axis in this example.
THE STANDARD 12-LEAD
ELECTROCARDIOGRAM
The standard clinical electrocardiogram involves voltage mea-
surements recorded from 12 different leads. Three of these are
the bipolar limb leads I, II, and III, which have already been
discussed. The other nine leads are unipolar leads. Three of
these leads are generated by using the limb electrodes. Two of
the electrodes are electrically connected to form an indifferent
electrode while the third limb electrode is made the positive
pole of the pair. Recordings made from these electrodes are
called augmented unipolar limb leads. The voltage record
obtained between the electrode at the right arm and the indif-
ferent electrode is called a lead aVR electrocardiogram. Simi-
larly, lead aVL is recorded from the electrode on the left arm
and lead aVF is recorded from the electrode on the left leg.
The standard limb leads (I, II, and III) and the augmented uni-
polar limb leads (aVR, aVL, and aVF) record the electrical activity
of the heart as it appears from six different “perspectives.” As
shown in Figure 25–6A, the axes for leads I, II, and III are those
of the sides of Einthoven’s triangle, while those for aVR, aVL, and
aVF are specified by lines drawn from the center of Einthoven’s
triangle to each of its vertices. As indicated in Figure 25–6B,
these six limb leads can be thought of as a hexaxial reference
system for observing the cardiac vectors in the frontal plane.
The other six leads of the standard 12-lead electrocardio-
gram are also unipolar leads that “look” at the electrical vector
projections in the transverse plane (a horizontal plane that
divides the body into superior and inferior segments). These
potentials are obtained by placing an additional (exploring)
electrode in six specified positions on the chest wall as shown
in Figure 25–6C. The indifferent electrode in this case is
formed by electrically connecting the limb electrodes. These
leads are identified as precordial or chest leads and are desig-
nated as V1–V6. As shown in this figure, the wave of ventricu-
lar excitation sweeps away from V1, resulting in a downward
deflection. The wave of ventricular excitation sweeps toward
V6, resulting in an upward deflection.
In summary, the electrocardiogram is a powerful tool for
evaluating cardiac excitation characteristics. It must be recog-
nized, however, that the ECG does not provide direct evidence
of mechanical pumping effectiveness. For example, a leaky
heart valve will usually have no direct electrocardiographic
consequences but may adversely influence pumping ability of
the heart.
ABNORMAL CARDIAC
EXCITATION AND RHYTHMICITY
The material presented here is an introduction to the more
common abnormalities in cardiac rate and rhythm with an
emphasis on the primary physiological consequences of these
abnormal situations. Many cardiac excitation problems can be
diagnosed from the information in a single lead of an electro-
cardiogram. The lead II electrocardiogram trace at the top of
Figure 25–7 is identified as normal sinus rhythm based on the
following characteristics: (1) the frequency of QRS complexes is
~1/s, indicating a normal beating rate of 60 beats/min; (2) the
shape of the QRS complex is normal for lead II and its duration
is less than 120 milliseconds, indicating rapid depolarization of
the ventricles via normal conduction pathways; (3) each QRS
complex is preceded by a P wave of proper configuration, indi-
cating SA nodal origin of the excitation; (4) the PR interval is
less than 200 milliseconds, indicating proper conduction delay
of the impulse propagation through the AV node; (5) the QT
interval is less than half of the R-to-R interval, indicating nor-
mal ventricular repolarization; and (6) there are no extra P
waves, indicating that no AV nodal conduction block is present.
The subsequent electrocardiographic tracings in Figures 25–7
and 25–9 represent irregularities commonly found in clinical
practice. Examination of each of these traces with the above
characteristics in mind will aid in the differential diagnosis.
 CHAPTER 25 Cardiac Function Assessments 241

A B − C
RA − I + LA − −
aVR aVL
− aV − + +
+ R aV L +
−
− − − + I
aVF

II III
− −
+ V6
V1
+ + V2
+ + III + II
LL aVF
V5
V3 V4

FIGURE 25–6. The standard 12-lead electrocardiogram. A and B) Leads in the frontal plane. C) Electrode positions for precordial leads in the
transverse plane. D) A 12 lead ECG. The bottom line is a rhythm strip taken from lead V1 (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular
Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006. Fig. 25–6D courtesy of Dr. David Gutterman)

The physiological consequences of abnormal excitation and
conduction in the heart depend on whether the electrical
abnormality evokes a tachycardia, which will limit the time
for cardiac filling between beats; evokes a bradycardia, which
is inadequate to support sufficient cardiac output; or decreases
the coordination of myocyte contraction, which will reduce
stroke volume (SV).
SUPRAVENTRICULAR ABNORMALITIES
Traces 2–6 below the normal trace in Figure 25–7 represent
typical supraventricular arrhythmias (i.e., originating in the
atria or AV node). Supraventricular tachycardia (shown in
trace 2 of Figure 25–7 and sometimes called paroxysmal atrial
tachycardia) occurs when the atria are abnormally excited
and drive the ventricles at a very rapid rate. These paroxysms
may begin abruptly, last for a few minutes to a few hours, and
then, just as abruptly, disappear and heart rate reverts to
normal. QRS complexes appear normal (albeit frequent) with
simple paroxysmal atrial tachycardia because the ventricular
conduction pathways operate normally. The P and T waves
may be superimposed because of the high heart rate. Low
blood pressure and dizziness may accompany bouts of this
arrhythmia because the extremely high heart rate does not
allow sufficient diastolic time for ventricular filling.
There are two mechanisms that may account for supraven-
tricular tachycardia. First, an atrial region, usually outside
the SA node, may become irritable (perhaps because of local
interruption in blood flow) and begin to fire rapidly to take
over the pacemaker function for the entire heart. Such an
abnormal pacemaker region is called an ectopic focus. Alter-
natively, atrial conduction may become altered so that a
single wave of excitation does not die out but continually
travels around some abnormal atrial conduction loop. In
this case, the continual activity in the conduction loop may
drive the atria and AV node at a very high frequency. This
self-sustaining process is called a reentry phenomenon and
is diagrammed in Figure 25–8. This situation may develop
as a result of abnormal repolarization and altered refractory
periods in local areas of the myocardium. Atrial flutter is a
special form of tachycardia of atrial origin in which a large
reentrant pathway drives the atria at very fast rates (250–300
beats/min) and normal refractory periods of AV nodal tis-
sue are overwhelmed. Thus, ventricular rate is often some
fixed ratio of the atrial rate (2:1, 4:1) with frequencies often
150–220 beats/min.
242 SECTION V Cardiovascular Physiology

1. Normal sinus rhythm

2. Supraventricular
tachycardia

3. First-degree block

2:1 4:1
4. Second-degree block

5. Third-degree block
FIGURE 25–7 Supraventricular
arrhythmias. (Reproduced with permission from 6. Atrial fibrillation
Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. 1 mV
New York: Lange Medical Books/McGraw-Hill, 2006.) 1s

Conduction blocks occur at the AV node and generally rep- node from the atria at unpredictable times. Fibrillation is a self-
resent impaired conduction through this tissue. In first-degree sustaining process. The mechanisms behind it are not well
heart block (trace 3 of Figure 25–7), the only electrical understood, but impulses are thought to progress repeatedly
abnormality is unusually slow conduction through the AV around irregular conduction pathways (sometimes called circus
node. This condition is detected by an abnormally long PR pathways, which imply a reentry phenomenon as described ear-
interval (>0.2 second). Otherwise, the electrocardiogram may lier and in Figure 25–8). However, because atrial contraction
be normal. At normal heart rates, the physiological effects of a usually plays a negligible role in ventricular filling, atrial fibrilla-
first-degree block are usually inconsequential. The danger, tion may be well tolerated by most patients as long as ventricular
however, is that the slow conduction may deteriorate to an rate is sufficient to maintain the cardiac output. The real danger
actual interruption of conduction. with atrial fibrillation lies in the tendency for blood to form clots
A second-degree heart block (trace 4 of Figure 25–7) is said in the atria in the absence of the normal vigorous, coordinated
to exist when some but not all atrial impulses are transmitted atrial contraction. These clots can fragment and move out of the
through the AV node to the ventricle. Impulses are blocked in heart to lodge in small arteries throughout the systemic or pul-
the AV node if the cells of the region are still in a refractory monary circulation. These emboli can have devastating effects
period from a previous excitation. The situation is aggravated on function of critical organs. Consequently, anticoagulant ther-
by high atrial rates and slower-than-normal conduction apy is used as prophylaxis for patients in atrial fibrillation.
through the AV nodal region. In second-degree block, some
but not all P waves are accompanied by corresponding QRS
complexes and T waves. Atrial rate is often faster than ven- VENTRICULAR ABNORMALITIES
tricular rate by a certain ratio (e.g., 2:1, 3:1, 4:1). This condi-
Traces 2–6 below the normal trace in Figure 25–9 show typical
tion may not represent a serious clinical problem as long as the
ventricular electrical abnormalities. Conduction blocks called
ventricular rate is adequate to meet the pumping needs.
bundle branch blocks or hemiblocks (trace 2 of Figure 25–9)
In third-degree heart block (trace 5 of Figure 25–7), no
impulses are transmitted through the AV node. In this event,
some area in the ventricles—often in the common bundle or
bundle branches near the exit of the AV node—assumes the
pacemaker role for the ventricular tissue. Atrial rate and ven-
tricular rate are completely independent, and P waves and QRS
complexes are totally dissociated in the electrocardiogram.
Ventricular rate is likely to be slower than normal (bradycardia)
and sometimes is slow enough to impair cardiac output.
Atrial fibrillation (trace 6 of Figure 25–8) is characterized by
a complete loss of the normally close synchrony of the excitation
and resting phases between individual atrial cells. Cells in differ-
ent areas of the atria depolarize, repolarize, and are excited again Normal Reentrant
randomly. Consequently, no P waves appear in the electrocar- pathway pathway
diogram although there may be rapid irregular small waves FIGURE 25–8 Normal and reentrant (circus) cardiac excitation
apparent throughout diastole. The ventricular rate is often very pathways. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular
irregular in atrial fibrillation because impulses enter the AV Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

1. Normal sinus rhythm
2. Bundle branch block
3. Premature ventricular
contraction
4. Ventricular tachycardia
5. Long QT syndrome with
torsades des pointes
6. Ventricular fibrillation
can occur in either of the branches of the Purkinje system of
the intraventricular septum often as a result of a myocardial
infarction. Ventricular depolarization is less synchronous than
normal in the half of the heart with the nonfunctional Purkinje
system. This results in a widening of the QRS complex (>0.12
second) because a longer time is required for cell-to-cell ven-
tricular depolarization of the blocked side to be completed.
The direct physiological effects of bundle branch blocks are
usually inconsequential.
Premature ventricular contractions (PVCs; trace 3 of Figure
25–9) are caused by action potentials initiated by and propa-
gated away from an ectopic focus in the ventricle. As a result,
the ventricle depolarizes and contracts before it normally
would. A PVC is often followed by a missed beat (called a com-
pensatory pause) because the ventricular cells are still refrac-
tory when the next normal impulse emerges from the SA node.
The highly abnormal ventricular depolarization pattern of a
PVC produces the large-amplitude, long-duration deflections
on the electrocardiogram. The shapes of the electrocardio-
graphic records of these extra beats are highly variable and
depend on the ectopic site of their origin and the depolariza-
tion pathways involved. The volume of blood ejected by the
premature beat itself is smaller than normal (if a volume is
ejected at all), whereas the stroke volume of the beat following
the compensatory pause is larger than normal. This is partly
due to the differences in filling times and partly to an inherent
phenomenon of cardiac muscle called postextrasystolic poten-
tiation. Single PVCs occur occasionally in most individuals
and, although sometimes alarming to the individual experi-
encing them, are not dangerous. Frequent occurrence of PVCs,
however, may be a signal of possible myocardial damage or
perfusion problems and can lead to ventricular tachycardia
and even ventricular fibrillation (discussed below).
Ventricular tachycardia (trace 4 of Figure 25–9) occurs
when the ventricles are driven at high rates, usually by impulses
originating from a ventricular ectopic focus. Ventricular
tachycardia is a very serious condition. Not only is diastolic
CHAPTER 25 Cardiac Function Assessments 243
FIGURE 25–9 Ventricular arrhythmias.
(Modified with permission from Mohrman DE, Heller LJ:
1 mV Cardiovascular Physiology, 6th ed. New York: Lange Medical
1s Books/McGraw-Hill, 2006.)
filling time limited by the rapid rate, but also the abnormal
excitation pathways make ventricular contraction less syn-
chronous and therefore less effective than normal. In addition,
ventricular tachycardia often precedes ventricular fibrillation.
Prolonged QT intervals (left side of trace 5 in Figure 25–9)
are a result of delayed ventricular myocyte repolarization,
which may be due to inappropriate opening of sodium chan-
nels or prolonged closure of potassium channels during the
action potential plateau phase. Although the normal QT inter-
val varies with heart rate, it is normally less than 40% of the
cardiac cycle length (except at very high heart rates). Long QT
syndrome is identified when the QT interval is greater than
50% of the cycle duration. It may be genetic in origin (muta-
tions influencing various ion channels involved with cardiac
excitability), may be acquired from several electrolyte distur-
bances (low blood levels of Ca2+, Mg2+, or K+), or may be
induced by several pharmacological agents (including some
antiarrhythmic drugs). The prolongation of the myocyte
refractory period, which accompanies the long QT syndrome,
extends the vulnerable period during which extra stimuli can
evoke tachycardia or fibrillation. Patients with long QT syn-
drome are predisposed to a particularly dangerous type of
ventricular tachycardia called torsades de pointes (“twisting of
points” as shown on the right side of trace 5 in Figure 25–9).
This differs from the ordinary ventricular tachycardia in
that the ventricular electrical complexes cyclically vary in
amplitude around the baseline and can deteriorate rapidly into
ventricular fibrillation.
In ventricular fibrillation (trace 6 of Figure 25–9), various
areas of the ventricle are excited and contract asynchronously.
The mechanisms are similar to those in atrial fibrillation. The
ventricle is especially susceptible to fibrillation whenever a
premature excitation occurs at the end of the T wave of the
previous excitation, that is, when most ventricular cells are in
the “hyperexcitable” or “vulnerable” period of their electrical
cycle. In addition, because some cells are repolarized and some
are still refractory, circus pathways can be triggered easily at
244 SECTION V Cardiovascular Physiology

A niques. One of the most accurate methods of measuring car-

Increased Normal diac output by invasive means makes use of the Fick principle,
contractility contractility which is discussed in more detail in Chapter 26. Briefly, this
principle states that the amount of a substance consumed by
120 the tissues, Xtc, is equal to what goes in minus what goes out
LV pressure (mm Hg)

Increased (which is the arterial–venous concentration difference in the

afterload substance ([X]a – [X]v) times the blood flow rate, Q̇). This
80
relationship can be algebraically arranged to solve for blood
flow as follows:
Ẋtc
Q̇ = ________
[X] _ [X] (1)
Increased a v
40 preload
A common method of determining cardiac output is to use
the Fick principle to calculate the collective flow through the
systemic organs from (1) the whole body oxygen consumption
60 120 rate (Ẋ tc), (2) the oxygen content of the arterial blood ([X]a),
LV volume (mL) and (3) the concentration of oxygen in mixed venous blood
([X]v). Of the values required for this calculation, the oxygen
B Normal Cardiac failure content of mixed venous blood is the most difficult to obtain.
individual patient
Generally, the sample for venous blood oxygen measurement
d
se must be taken from a venous catheter positioned in the pul-
LV pressure (mm Hg)

120 r es tility
p c
y
ntr rmal

De ntra monary artery to ensure that it is a mixed sample of venous

tilit

co
ac

blood from all systemic organs.

No

Untreated
80 The calculation of cardiac output from the Fick principle
co

is best illustrated by an example. Suppose a patient is con-

40
60 120
LV volume (mL)
FIGURE 25-10 Left ventricular end systolic pressure-
volume relationships. A) The effect of increased contractility shifts
the line upward and to the left. B) The effect of systolic cardiac failure
shifts the line downward and to the right. (Modified with permission from
Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical
Books/McGraw-Hill, 2006.)
this time. Since no pumping action occurs with ventricular
fibrillation, the situation is fatal unless quickly corrected by
cardiac conversion (commonly referred to as external electri-
cal defibrillation or cardioversion). During this procedure,
the artificial application of large currents to the entire heart
(via paddle electrodes applied across the chest) may be effec-
tive in depolarizing all heart cells simultaneously and thus
allowing a normal excitation pathway to be reestablished.
Cardiopulmonary resuscitation (CPR) must be administered
until a defibrillation is achieved.
MEASUREMENT OF
CARDIAC OUTPUT
Fick Principle: Measurement of cardiac output is not a simple
task and usually involves either some invasive maneuver or
some significant assumptions based on noninvasive tech-
Treated with
afterload suming 250 mL of O2/min when systemic arterial blood
reducer contains 200 mL of O2/L and the right ventricular blood
contains 150 mL of O2/L. This means that, on the average,
each liter of blood loses 50 mL of O2 as it passes through the
180
systemic organs. In order for 250 mL of O2 to be consumed
per minute, 5 L of blood must pass through the systemic cir-
culation each minute:
250[mL O2/min]
Q̇ = __________________
200–150[mL O /L blood]
= 5[L blood/min] (2)
2
Although use of the Fick Principle as described above pro-
vides the gold standard for cardiac output determination,
there are several other techniques that give good estimates
of cardiac output. Indicator dilution techniques involve
injection of a known quantity of indicator (dye or a thermal
bolus) into blood entering the right heart and appropriate
detectors are arranged to continuously record the concen-
tration of the indicator in blood as it leaves the left heart.
The dilution of the indicator is proportional to the cardiac
output. Other techniques for imaging the heart (echocar-
diography, ventricular angiography, radionuclide ventricu-
lography) can be used to estimate stroke volume, cardiac
output and other indices of ventricular function as are
described below.
Cardiac index is the cardiac output corrected for the indi-
vidual’s size. For example, the cardiac output of a 50-kg woman
will be significantly lower than that of a 90-kg man. It has been
found, however, that cardiac output correlates better with body
surface area than with body weight. Therefore, it is common to
express the cardiac output per square meter of surface area.
Under resting conditions, the cardiac index is normally
approximately 3 (L/min)/m2.

CARDIAC CONTRACTILITY
ESTIMATIONS
It is often important to assess an individual’s cardiac function
without using major invasive procedures. Advances in several
techniques have made it possible to obtain two- and three-
dimensional images of the heart throughout the cardiac cycle.
Visual or computer-aided analysis of such images provides
information useful in clinically evaluating cardiac function.
Echocardiography is the most widely used of the several
imaging techniques currently available. This noninvasive
technique is based on the fact that sound waves reflect back
toward the source when encountering abrupt changes in the
density of the medium through which they travel. A trans-
ducer, placed at specified locations on the chest, generates
pulses of ultrasonic waves and detects waves reflected from
the cardiac tissue interfaces. The longer the time between the
transmission of the wave and the arrival of the reflection, the
deeper the structure is in the thorax. Such information can be
reconstructed by computer in various ways to produce a con-
tinuous image of the heart and its chambers throughout the
cardiac cycle.
Echocardiography is especially well suited for detecting
abnormal operation of cardiac valves or contractile function
in portions of the heart walls. It also can provide estimates of
heart chamber volumes at different times in the cardiac cycle
that are used in a number of ways to assess cardiac function.
Ejection fraction (EF) is an extremely useful clinical mea-
surement that can be calculated from an echocardiogram. It is
defined as the ratio of stroke volume (SV) to end-diastolic
volume (EDV):
SV
EF = ____ (3)
EDV
Estimates of end-diastolic and -systolic volumes can be
made from the images and SV calculated. EF is commonly
expressed as a percentage and normally ranges from 55% to
80% (mean 67%) under resting conditions. EFs of less than
55% indicate depressed myocardial contractility.
The end-systolic pressure–volume relationship is another
useful clinical technique to assess cardiac contractility. End-
systolic volume for a given cardiac cycle is estimated by one of
the imaging techniques described above while end-systolic
pressure for that cardiac cycle can obtained from the arterial
pressure recorded at the point of the closure of the aortic valve
(the incisura). Values for several different cardiac cycles may
be obtained during infusion of a vasoconstrictor (which
increases afterload), and the data plotted as in Figure 25–10 in
the context of overall ventricular pressure–volume loops. As
shown, increases in myocardial contractility are associated
with a leftward rotation in the end-systolic pressure–volume
relationship. This method of assessing cardiac function is par-
ticularly important because it provides an estimate of contrac-
tility that is independent of the EDV (preload). (Recall from
Figure 24–4 that increases in preload cause increases in SV
without changing the end-systolic volume. Thus, only altera-
CHAPTER 25 Cardiac Function Assessments 245
tions in contractility will cause shifts in the end-systolic
pressure–volume relationship.)
Note in Figure 25–10A that both the “normal” and “increased
contractility” end-systolic pressure–volume lines nearly proj-
ect to the origin at zero pressure, zero volume. Thus, it is pos-
sible to get a reasonable clinical estimate of the slope of the
end-systolic pressure–volume relationship (read “myocardial
contractility”) from a single measurement of end-systolic pres-
sure and volume. This avoids the need to do multiple expen-
sive tests with vasodilator or vasoconstrictor infusions.
A decrease in contractility (as may be caused by heart dis-
ease) is associated with a downward shift of the end-systolic
pressure–volume relationship and is known as systolic heart
failure. In this situation, increases in sympathetic drive have
limited influence on cardiac output. Part of the compensatory
process involves a significant increase in body fluid retention
that results in an increase in circulating blood volume and
ventricular EDV (see Chapter 29). A left ventricular pressure–
volume loop describing the events of a cardiac cycle from a
failing heart (shown in Figure 25–10B) is displaced far to the
right of that of a normal heart. The untreated patient described
in this figure is in serious trouble with a reduced SV and EF
and high filling pressure with possible pulmonary vascular
congestion. Furthermore, the slope of the line describing the
end-systolic pressure–volume relationship is shifted down-
ward and is less steep, indicating the reduced contractility of
the cardiac muscle. However, because of this flatter relation-
ship, small reductions in cardiac afterload (i.e., arterial blood
pressure) will produce substantial increases in EF and SV that
will significantly help this patient.
ABNORMAL CARDIAC
VALVE FUNCTION
Pumping action of the heart is impaired when the valves do
not function properly. A number of techniques, ranging from
simple auscultation (listening to the heart sounds) to echocar-
diography or cardiac catheterization, are used to obtain infor-
mation about the nature and extent of these valve malfunctions.
Often, abnormal heart sounds called murmurs accompany
cardiac valve defects. These sounds are caused by abnormal
pressure gradients and turbulent blood flow patterns that
occur during the cardiac cycle.
In general, when a valve does not open fully (i.e., is stenotic),
the chamber upstream of the valve has to develop more pres-
sure during its systolic phase to achieve a given flow through
the valve. This increase in “pressure” work will induce hypertro-
phy of cardiac muscle cells and thickening of the walls of that
chamber. (This is analogous to the hypertrophied skeletal mus-
cles of the weightlifter doing isometric or high-tension work.)
When a valve does not close completely (i.e., is insufficient,
regurgitant, or incompetent), the regurgitant blood flow repre-
sents an additional volume that must be ejected in order to get
sufficient forward flow out of the ventricle into the tissues. This
increase in “volume” work often leads to chamber dilation but
246 SECTION V Cardiovascular Physiology

not to an increase in wall thickness. (This is analogous to the
nonhypertrophied but well-toned skeletal muscles of the long-
distance runner doing isotonic or shortening work.)
A second generality about valve abnormalities is that when-
ever there is an increase in the atrial pressure as a result of AV
valve stenosis or regurgitation, this will result in higher pres-
sures in the upstream capillary beds. If capillary hydrostatic
pressures are increased, tissue edema will ensue with substan-
tial negative consequences on the function of those upstream
organs.
A brief overview of four of the common valve defects influ-
encing left ventricular function is given in Figure 25–11. The
reader should note that similar stenotic and regurgitant abnor-
malities can occur in right ventricular valves with similar con-
sequences on right ventricular function.
AORTIC STENOSIS
Some characteristics of aortic stenosis are shown in
Figure 25–11A. Normally, the aortic valve opens widely and
offers a pathway of very low resistance through which blood
leaves the left ventricle. If this opening is narrowed
(stenotic), resistance to flow through the valve increases. A
significant pressure difference between the left ventricle
and the aorta may be required to eject blood through a

A B

150

Aortic pressure
100

Left ventricular
pressure

Left atrial
50
pressure

ECG

Phonocardiogram

C D

Aortic pressure
100
Left ventricular
pressure

Left atrial
pressure
50

ECG

Phonocardiogram

FIGURE 25–11 Common valve abnormalities. A) Aortic stenosis. B) Mitral stenosis. C) Aortic regurgitation (insufficiency).
D) Mitral insufficiency. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

stenotic aortic valve. As shown in Figure 25–11A, intraven-
tricular pressures may rise to very high levels during systole
while aortic pressure rises more slowly than normal to a
systolic value that is subnormal. Pulse pressure is usually
low with aortic stenosis. High intraventricular pressure
development is a strong stimulus for cardiac muscle cell
hypertrophy, and an increase in left ventricular muscle mass
invariably accompanies aortic stenosis. This tends to pro-
duce a leftward deviation of the electrical axis. (The mean
electrical axis will fall in the upper right-hand quadrant of
Figure 25–5.) Blood being ejected through the narrowed
orifice may reach very high velocities, and turbulent flow
may occur as blood enters the aorta. This abnormal turbu-
lent flow can be heard as a systolic (or ejection) murmur
with a properly placed stethoscope. The primary physiolog-
ical consequence of aortic stenosis is a high ventricular
afterload that is caused by restriction of the outflow tract.
This imposes an increased pressure workload on the left
ventricle.
MITRAL STENOSIS
Some characteristics of mitral stenosis are shown in
Figure 25–11B. A pressure difference of more than a few mil-
limeters of mercury across the mitral valve during diastole is
distinctly abnormal and indicates that this valve is stenotic.
The high resistance mandates an increased pressure difference
to achieve normal flow across the valve (Q̇ = ΔP/R). Conse-
quently, as shown in Figure 25–11B, left atrial pressure is
increased with mitral stenosis. The high left atrial workload
may induce hypertrophy of the left atrial muscle. Increased left
atrial pressure is reflected back into the pulmonary bed and, if
high enough, causes pulmonary edema and pulmonary vascu-
lar congestion. A diastolic murmur associated with turbulent
flow through the stenotic mitral valve can often be heard. The
primary physiological consequences of mitral stenosis are
increases in left atrial pressure and pulmonary capillary pres-
sure. The latter can cause interference with normal gas exchange
in the lungs, leading to dyspnea (shortness of breath).
AORTIC INSUFFICIENCY
Typical characteristics of aortic regurgitation (insufficiency,
incompetence) are shown in Figure 25–11C. When the leaflets
of the aortic valve do not provide an adequate seal, blood
regurgitates from the aorta back into the left ventricle during
the diastolic period. Aortic pressure falls faster and further
than normal during diastole, which causes a low diastolic pres-
sure and a large pulse pressure. In addition, ventricular EDV
and pressure are higher than normal because of the extra blood
that reenters the chamber through the incompetent aortic
valve during diastole. Turbulent flow of the blood reentering
the left ventricle during early diastole produces a characteris-
tic diastolic murmur. Often the aortic valve is altered so that it
is both stenotic and insufficient. In these instances, both a sys-
CHAPTER 25 Cardiac Function Assessments 247
tolic and a diastolic murmur are present. The primary physi-
ological consequences of aortic insufficiency are a reduction
in forward flow out to the tissues (if the insufficiency is severe)
and an increase in the volume workload of the left ventricle.
MITRAL REGURGITATION
Typical characteristics of mitral regurgitation (insufficiency,
incompetence) are shown in Figure 25–11D. When the mitral
valve is insufficient, some blood regurgitates from the left ven-
tricle into the left atrium during systole. A systolic murmur
may accompany this abnormal flow pattern. Left atrial pressure
is increased to abnormally high levels, and left ventricular EDV
and pressure increase. Mitral valve prolapse is a common form
of mitral insufficiency in which the valve leaflets evert into the
left atrium during systole. The primary physiological conse-
quences of mitral regurgitation are somewhat similar to aortic
insufficiency in that forward flow out of the left ventricle into
the aorta may be compromised (if the insufficiency is severe)
and there is an increase in the volume workload of the left ven-
tricle. In addition, the elevated left atrial pressure can also lead
to pulmonary effects with shortness of breath.
CLINICAL CORRELATION
A 72-year-old man comes to the doctor’s office with com-
plaints of diminished exercise tolerance. He has had dys-
pnea (shortness of breath) on exertion for several years
but it has gotten worse lately. He now experiences chest
pain and some dizziness with only mild exertion and, the
day before his appointment, he fainted when getting out
of bed. His heart rate is 75 beats/min and his blood pres-
sure is 113/90 mm Hg. A loud systolic murmur is heard
using a stethoscope placed above the aorta, and a slowly
rising pulse is detected in his radial artery. An ECG reveals
normal rate and rhythm but significant left ventricular
hypertrophy (positive R wave in lead I, negative R wave in
lead AVF , and large R-wave amplitudes in leads aVl, V5,
and V6). Echocardiography indicated significant left ven-
tricular wall thickening and significant narrowing of the
aortic valve opening during systole.
This man’s symptoms can all be a result of an increasing
severity of aortic valve stenosis. Because of the elevated
resistance to outflow (essentially an increased afterload),
the left ventricular muscles must develop more force to
generate sufficient pressure to eject blood during systole.
Left ventricular pressure during systole will be much
higher than aortic pressure during systole, thereby pro-
ducing a significant pressure gradient. Over time, this
increased workload induces hypertrophy of the left ven-
tricular muscle that accounts for the leftward shift in the
mean electrical axis. The dyspnea on exertion is a result of
an exercise-induced imbalance in SV from the normal
248 SECTION V Cardiovascular Physiology
right side and the abnormal left side of the heart and
blood backing up into the pulmonary circulation.
Fainting may be a common symptom in patients with
aortic stenosis and, although it certainly reflects a decrease
in brain blood flow, the specific causes are not entirely
clear. A popular theory is that because the left ventricular
SV (and therefore cardiac output) is nearly fixed and not
able to adjust to the many cardiovascular challenges asso-
ciated with even mild exertion, arterial pressure decreases
as a result of the unopposed decrease in peripheral vascu-
lar resistance. Other possibilities include a hypertrophy-
induced predisposition to arrhythmias or a vasodilator
reflex evoked by high left ventricular pressures.
The chest pain (angina pectoris) is a result of inade-
quate coronary blood flow to meet the myocardial meta-
bolic demands. Ischemia can be a result of either an
impediment to coronary flow (as might occur with coro-
nary artery disease or atherosclerosis) or an increase in
metabolic demands. In this case, the increase in myocar-
dial work because of the aortic stenosis plus the accomp-
anying hypertrophy outstrips the ability of the coronary
bed to provide sufficient flow. (Eventually, there will be
ischemia even at rest and ECG signs of ventricular strain
and subendocardial ischemia will appear. These signs
include ST-segment depression and T-wave inversion.)
The treatment for aortic stenosis is surgical replace-
ment of the aortic valve.
CHAPTER SUMMARY
■ The electrocardiogram is a record of the voltage changes
that occur on the surface of the body as a result of the
propagation of the action potential through the heart during
a cardiac cycle.
■ There are standardized conventions used for recording
electrocardiograms.
■ The magnitude and direction of the net dipole formed by the
wavefront of the action potential at any instant in time can be
deduced from the magnitude and orientation of the electrocar-
diographic deflections.
■ The mean electrical axis describes the orientation of the net
dipole at the instant of maximum wavefront propagation
during ventricular depolarization and normally falls between
0° and +90° on a polar coordinate system.
■ The standard 12-lead electrocardiogram is widely used to
evaluate cardiac electrical activity and consists of a combina-
tion of bipolar and unipolar records from limb electrodes and
chest electrodes.
■ Cardiac arrhythmias can often be detected and diagnosed from
a single electrocardiographic lead.
■ Physiological consequences of abnormal excitation and
conduction in the heart depend on whether the electrical
abnormality limits the time for adequate cardiac filling or
decreases the coordination of myocyte contractions resulting in
inadequate pressure development and ejection.
■ Supraventricular arrhythmias are a result of abnormal action
potential initiation at the SA node or altered propagation
characteristics through the atrial tissue and the AV node.
■ Tachycardias may originate either in the atria or ventricles and
are a result of increased pacemaker automaticity or of continu-
ously circling pathways setting up a reentrant circuit.
■ Abnormal conduction through the AV node results in
conduction blocks.
■ Abnormal conduction pathways in the Purkinje system or in
the ventricular tissue result in significant QRS alterations.
■ Ventricular tachycardia and ventricular fibrillation represent
severe abnormalities that are incompatible with effective
cardiac pumping.
■ A variety of methods are available for measuring various
aspects of cardiac mechanical function. These methods are
based on the Fick principle and various imaging techniques
including echocardiography.
■ The ejection fraction (which is the stroke volume divided by
the end-diastolic volume) and the ventricular end-systolic
pressure–volume relationship are very useful indices of cardiac
contractility.
■ Failure of cardiac valves to open fully (stenosis) can result in
elevated upstream chamber pressure and abnormal pressure
gradients, congestion in upstream vascular beds, chamber wall
hypertrophy, turbulent forward flow across the valve, and
murmurs during systole or diastole.
■ Failure of cardiac valves to close completely (insufficiency,
incompetence, regurgitation) can result in large stroke
volumes, abnormal pressure pulses, congestion in upstream
vascular beds, turbulent backward flow across the valve, and
murmurs during systole or diastole.
STUDY QUESTIONS
1. Your 75-year-old male patient is alert with complaints of general
fatigue. His heart rate = 90 beats/min and arterial pressure =
140/50 mm Hg. A diastolic murmur is present. There are no ECG
abnormalities identified and mean electrical axis = 10°. Cardiac
catheterization indicate that LV pressure = 140/20 mm Hg and
left atrial pressure = 10/3 mm Hg (as peak systolic/end diastolic).
Which of the following is most consistent with these findings?
A) aortic stenosis
B) aortic insufficiency
C) mitral stenosis
D) mitral insufficiency
E) right ventricular hypertrophy
2. Evaluation of your patient’s electrocardiogram shows that P
waves occur at a regular rate of 90/min and QRS complexes occur
at a regular rate of 37/min. Which of the following is the most
likely diagnosis?
A) supraventricular tachycardia
B) first-degree heart block
C) second-degree heart block
D) third-degree heart block
E) bundle branch block
 CHAPTER 25 Cardiac Function Assessments 249

3. Given the following information, calculate cardiac output and 5. Your patient’s ECG shows that R-wave amplitude on leads I
determine whether this would be a normal value for a healthy and aVF is upright and equally large. Which of the following
70 kg young adult: systemic arterial blood oxygen concentration, statements is true?
[O2]SA = 200 mL/L; pulmonary arterial blood oxygen A) This indicates a significant left electrical axis deviation.
concentration, [O2]PA = 140 mL/L; total body oxygen B) The mean electrical axis is +90°.
consumption, VO2 = 600 mL/min. C) The R-wave amplitude will be smallest on lead aVL.
A) 10 L/min that is normal for mild exercise D) The R-wave amplitude will be positive on lead aVR.
B) 10 L/min that is abnormally low at rest E) The left ventricle is hypertrophied.
C) 6 L/min that is close to a normal resting value
D) 0.6 L/min that is abnormally low at rest
E) 60 L/min that is impossible for normal individuals
4. Your patient takes a drug that decreases AV nodal action potential
conduction velocity. The direct effect of this drug will be seen on
the ECG as
A) a decrease in QRS-wave frequency.
B) an increase in P-wave amplitude.
C) an increase in the PR interval.
D) a widening of the QRS interval.
E) an increase in the ST-segment duration.
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 26
C H A P T E R

Peripheral Vascular
System
David E. Mohrman and Lois Jane Heller

O B J E C T I V E S

■ Define convective transport and diffusion and list the factors that determine
the rate of each.
■ Given data, use the Fick principle to calculate the rate of removal of a solute
from blood as it passes through an organ.
■ Describe how capillary wall permeability to a solute is related to the size and
lipid solubility of the solute.
■ List the factors that influence transcapillary fluid movement and, given data,
predict the direction of transcapillary fluid movement.
■ Describe the lymphatic vessel system and its role in preventing fluid
accumulation in the interstitial space.
■ Given data, calculate the vascular resistances of networks of vessels arranged
in parallel and in series.
■ Describe differences in the blood flow velocity in the various segments and
how these differences are related to their total cross-sectional area.
■ Describe laminar and turbulent flow patterns and the origin of flow sounds in
the cardiovascular system.
■ Identify the approximate percentage of the total blood volume that is
contained in the various vascular segments in the systemic circulation.
■ Define peripheral venous pool and central venous pool.
■ Describe the pressure changes that occur as blood flows through a vascular
bed and relate them to the vascular resistance of the various vascular
segments.
■ State how the resistance of each consecutive vascular segment contributes to
an organ’s overall vascular resistance and, given data, calculate the overall
resistance.
■ Define total peripheral resistance (systemic vascular resistance) and
state the relationship between it and the vascular resistance of each
systemic organ.
■ Define vascular compliance and state how the volume–pressure curves for
arteries and veins differ.
■ Predict what will happen to venous volume when venous smooth muscle
contracts or when venous transmural pressure increases.
■ Describe the role of arterial compliance in storing energy for blood
circulation.
(Continued)

251

Ch26_251-262.indd 251 11/26/10 11:50:20 AM

252 SECTION V Cardiovascular Physiology

O B J E C T I V E S (Continued)

■ Describe the auscultation technique of determining arterial systolic and

diastolic pressures.
■ Identify the physical bases of the Korotkoff sounds.
■ Indicate the relationship between arterial pressure, cardiac output, and
total peripheral resistance and predict how arterial pressure will be
altered when cardiac output and/or total peripheral resistance change.
■ Given arterial systolic and diastolic pressures, estimate mean arterial
pressure.
■ Indicate the relationship between pulse pressure, stroke volume, and arterial
compliance and predict how pulse pressure will be changed by changes in
stroke volume, or arterial compliance.
■ Describe how arterial compliance changes with age and how this affects
arterial pulse pressure.

OVERVIEW OF THE PERIPHERAL CARDIOVASCULAR TRANSPORT

VASCULAR SYSTEM
Homeostasis implies that each and every cell in the body is
continuously bathed in a local environment of constant com-
position that is optimal for cell function. In essence, the
peripheral vascular system is a sophisticated irrigation system.
Blood flow is continuously delivering nutrients to and remov-
ing waste products from the local interstitial environment
throughout the body.
The heart supplies the pumping power required to create
flow through the system. Because of the heart’s action, pres-
sure at the inlet (the aorta) of the vascular network is higher
than that at its outlets (the vena cavae). Everywhere within the
vascular system, blood always flows from higher pressure to
lower pressure according to well-known physical rules. Like
water flowing downhill, blood seeks to travel along the path of
least resistance. Consequently, the peripheral vascular system
changes the resistance of its various pathways to direct blood
flow to where it is needed.
This chapter begins with a description of the mechanisms
responsible for the transport of dissolved substances through
the vascular system and the movement of these substances
and fluid from capillaries to and from the interstitial space.
Next, the basic equation for flow though a single vessel (Q =
ΔP/R, presented in Chapter 22) is applied to the complex
network of branching vessels that actually exists in the car-
diovascular system. Then, the consequences of the elastic
properties of the large diameter arteries and veins on overall
cardiovascular system operation are considered. Finally, the
principles of the routine clinical measurement of arterial
blood pressure are presented along with the conclusions
about overall cardiovascular function that can be made from
the information.
THE FICK PRINCIPLE
Substances are carried between organs within the cardiovas-
cular system by the process of convective transport, the sim-
ple process of being swept along with the flow of the blood in
which they are contained. The rate at which a substance (X) is
transported by this process depends solely on the concentra-
tion of the substance in the blood and the blood flow:
Transport rate = Flow × Concentration
or
. .
X = Q [X] (1)
. .
where X is the rate of transport of X (mass/time), Q is the
blood flow (volume/time), and [X] is the concentration of X in
blood (mass/volume).
It is evident from the preceding equation that only two
methods are available for altering the rate at which a substance
is carried to an organ: (1) a change in the blood flow through
the organ or (2) a change in the arterial blood concentration of
the substance. The preceding equation might be used, for
example, to calculate how much oxygen is carried to a certain
skeletal muscle each minute. Note, however, that this calcula-
tion would not indicate whether the muscle actually used the
oxygen carried to it.
One can extend the convective transport principle to determine
a tissue’s rate of utilization (or production) of a substance by
simultaneously considering the transport rate of the substance to
and from the tissue. The relationship that results is referred to as
the Fick principle and may be formally stated as follows:
. .
Xtc= Q ([X]a − [X]v) (2)

. .
where X tc is the transcapillary efflux rate of X (mass/time), Q
the blood flow (volume/time), and [X]a,v the arterial and
venous concentrations of X.
The Fick principle demonstrates that the amount of a. sub-
stance that goes into an organ in a given
. period of time (Q[X]a)
minus the amount that comes out (Q [X]v) must equal the tis-
sue utilization rate of that substance. (If the tissue is producing
substance X, then the above equation will yield a negative uti-
lization rate.)
Recall that one method for determining cardiac output
(CO) described in Chapter 25 used the Fick principle to calcu-
late the blood flow through the systemic circulation. In that
case, the known variables included the systemic tissue oxygen
consumption rate and the concentrations of oxygen in arterial
blood and mixed venous blood and the. above equation was
rearranged to solve for the blood flow (Q ).
TRANSCAPILLARY SOLUTE DIFFUSION
Capillaries act as efficient exchange sites where most substances
cross the capillary walls by passively diffusing from regions of
high concentration to regions of low concentration (see Chap-
ter 1). There are four factors that determine the diffusion rate
of a substance between the blood and the interstitial fluid: (1)
the concentration difference, Δ[X], (2) the surface area for
exchange, A, (3) the diffusion distance, ΔL, and (4) the perme-
ability of the capillary wall to the diffusing substance repre-
sented as the diffusion coefficient, D. These factors are
combined in an equation (Fick’s first law of diffusion) that
. and carbon dioxide, cross the capillary wall easily. Because the
describes the diffusion (X d) of a substance X across a barrier:
. Δ[X]
Xd= DA ____
ΔL
(3)
Interstitium
Endothelial cell
Water-filled
channels
1 μ m thick
Plasma
40 Å
O2, CO2,
Na+, K+
ethanol
Cl– , H2O,
glucose
Proteins
Small
water-soluble
substances
CHAPTER 26 Peripheral Vascular System 253
Capillary beds allow huge amounts of materials to enter
and leave blood because they maximize the area across
which exchange can occur while minimizing the distance
over which the diffusing substances must travel. Capillaries
are extremely fine vessels with a lumen (inner) diameter of
about 5 μm, a wall thickness of approximately 1 μm, and an
average length of perhaps 0.5 mm. (For comparison, a
human hair is roughly 100 μm in diameter.) Capillaries are
distributed in incredible numbers in organs and communi-
cate intimately with all regions of the interstitial space. It is
estimated that there are about 1010 capillaries in the systemic
organs with a collective surface area of about 100 m2. That is
roughly the area of one player’s side of a singles tennis court.
Recall from Chapter 22 that most cells are no more than
about 10 μm (less than one tenth the thickness of paper)
from a capillary. Diffusion is a tremendously powerful
mechanism for material exchange when operating over such
a short distance and through such a large area. We are far
from being able to duplicate—in an artificial lung or kidney,
for example—the favorable geometry for diffusional
exchange that exists in our own tissues.
As diagrammed in Figure 26–1, the capillary wall itself con-
sists of only a single thickness of endothelial cells joined to
form a tube. The ease with which a particular solute crosses
the capillary wall is expressed in a parameter called its capil-
lary permeability. Permeability takes into account all the fac-
tors (diffusion coefficient, diffusion distance, and surface
area)—except concentration difference—that affect the rate at
which a solute crosses the capillary wall.
Two fundamentally distinct pathways exist for transcapillary
exchange. Lipid-soluble substances, such as the gases oxygen
lipid endothelial cell plasma membranes are not a significant
diffusion barrier for lipid-soluble substances, transcapillary
Cytoplasm
Plasma
membranes
Lipid-soluble
substances
FIGURE 26–1 Pathways for transcapillary
solute diffusion. (Modified with permission from
Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed.
New York: Lange Medical Books/McGraw-Hill, 2006.)
254 SECTION V Cardiovascular Physiology
movement of these substances can occur through the entire
capillary surface area.
The capillary permeability to small polar particles such as
sodium and potassium ions is about 10,000-fold less than that
for oxygen. Nevertheless, the capillary permeability to small
ions is several orders of magnitude higher than the permeabil-
ity that would be expected if the ions were forced to move
through the lipid plasma membranes. It is therefore postulated
that capillaries are somehow perforated at intervals with water-
filled channels or pores (which may actually be clefts between
the endothelial cells). Calculations from diffusion data indi-
cate that the collective cross-sectional area of the pores relative
to the total capillary surface area varies greatly between capil-
laries in different organs. Brain capillaries appear to be very
tight (have few pores), whereas capillaries in the kidney and
fluid-producing glands are much more leaky. On the average,
however, pores constitute only a very small fraction of total
capillary surface area—perhaps 0.01%. This area is, neverthe-
less, sufficient to allow very rapid equilibration of small water-
soluble substances between the plasma and interstitial fluids of
most organs. Thus, the concentrations of inorganic ions mea-
sured in a plasma sample can be taken to indicate their con-
centrations throughout the entire extracellular space.
In general, albumin and other large plasma proteins cannot
easily cross capillary walls. The precise mechanism for the low
capillary permeability to proteins is in dispute. One hypothesis
is that capillary pores are just physically smaller than the diam-
eter of plasma protein molecules. Whatever the mechanism(s),
the result is that much higher protein concentrations normally
exist in blood plasma than in interstitial fluid.
ENDOTHELIAL CELLS
In addition to forming capillaries, a layer of endothelial cells
lines the entire cardiovascular system—including the heart
chambers and valves. Because of their ubiquitous and intimate
contact with blood, endothelial cells have evolved to serve
many functions in addition to acting as a barrier to transcapil-
lary solute and water exchange. For example, endothelial cell
membranes contain specific enzymes that convert some circu-
lating hormones from inactive to active forms. Endothelial
cells are also intimately involved in producing substances that
lead to blood clot formation and the stemming of bleeding in
the event of tissue injury. Moreover, and as will be discussed in
the next chapter, the endothelial cells lining muscular vessels
such as arterioles can produce vasoactive substances that act
on the smooth muscle cells that surround them to influence
arteriolar diameter.
TRANSCAPILLARY FLUID MOVEMENT
In addition to providing a diffusion pathway for polar mole-
cules, the water-filled channels that traverse capillary walls
permit fluid flow through the capillary wall. Net shifts of fluid
between the capillary and interstitial compartments are
important for a host of physiological functions, including the
maintenance of circulating blood volume, intestinal fluid
absorption, tissue edema formation, and saliva, sweat, and
urine production. Net fluid movement out of capillaries is
referred to as filtration, and fluid movement into capillaries is
called reabsorption.
Fluid flows through transcapillary channels in response to
pressure differences between the interstitial and intracapillary
fluids according to the basic flow equation. However, both
hydrostatic and osmotic pressures influence transcapillary
fluid movement. How hydrostatic pressure provides the driv-
ing force for causing blood flow along vessels has been dis-
cussed previously. The hydrostatic pressure inside capillaries,
Pc, is about 25 mm Hg and is the driving force that causes blood
to return to the right heart from the capillaries of systemic
organs. In addition, however, the 25-mm Hg hydrostatic intra-
capillary pressure tends to cause fluid to flow through the tran-
scapillary pores into the interstitium where the hydrostatic
pressure (Pi) is near 0 mm Hg. Thus, there is normally a large
hydrostatic pressure difference favoring fluid filtration across
the capillary wall. Our entire plasma volume would soon be in
the interstitium if there were not some counteracting force
tending to draw fluid into the capillaries. The balancing force is
an osmotic pressure that arises from the fact that plasma has a
higher protein concentration than interstitial fluid.
Recall that water always tends to move from regions of low
to regions of high total solute concentration in establishing
osmotic equilibrium. Also recall that the driving force for
osmotic water movement between one solution and another
can be expressed as an osmotic pressure difference between the
two. The osmotic pressure difference is directly related to the
difference in total solute concentration in the two solutions in
question. Because plasma and interstitial fluid are essentially
identical except for their protein concentrations, plasma pro-
teins are primarily responsible for the net osmotic pressure
difference across capillary walls. The component of total
osmotic pressure due to proteins has been given the special
name, oncotic pressure (or colloid osmotic pressure).
Because of plasma proteins, the oncotic pressure of plasma
(πc) is about 25 mm Hg. Due to the absence of proteins, the
oncotic pressure of the interstitial fluid (πi) is near 0 mm Hg.
Thus, there is normally a large osmotic force for fluid reab-
sorption into capillaries. The forces that influence transcap-
illary fluid movement are summarized on the left side of
Figure 26–2.
The relationship among the factors that influence transcap-
illary fluid movement, known as the Starling hypothesis, can
be expressed by the following equation:
Net filtration rate = k[(Pc − Pi) − (πc − πi)] (4)
where Pc is the hydrostatic pressure of intracapillary fluid,
πc the oncotic pressure of intracapillary fluid, Pi and πi the
hydrostatic and oncotic pressures for interstitial fluid,
respectively, and k a constant expressing how readily fluid can
move across capillaries (essentially the reciprocal of the resis-
tance to fluid flow through the capillary wall).

Interstitium
Endothelial cell
Net fluid
Plasma filtration
Pc – Pi > πc – πi
Hydrostatic
Pi Pc
No net
movement
Osmotic Pc – Pi = πc – πi
πi πc
Net fluid
reabsorption
Pc – Pi < πc – πi
FIGURE 26–2 Factors influencing transcapillary fluid
movement. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular
Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
Fluid balance within a tissue (the absence of net transcapil-
lary water movement) occurs when the bracketed term in this
equation is zero. This equilibrium may be upset by alterations
in any of the four pressure terms. The pressure imbalances that
cause capillary filtration and reabsorption are indicated on the
right side of Figure 26–2.
In most tissues, rapid net filtration of fluid is abnormal and
causes tissue swelling as a result of excess fluid in the intersti-
tial space (edema). For example, a substance called histamine
is often released in damaged tissue. One of the actions of his-
tamine is to increase capillary permeability to the extent that
proteins leak into the interstitium. Net filtration and edema
accompany histamine release, in part because the oncotic
pressure difference (πc – πi) is reduced below normal.
Transcapillary fluid filtration is not always detrimental.
Indeed, fluid-producing organs such as salivary glands and
kidneys utilize high intracapillary hydrostatic pressure to pro-
duce continuous net filtration. Moreover, in certain abnormal
situations, such as severe loss of blood volume through hem-
orrhage, the net fluid reabsorption accompanying diminished
intracapillary hydrostatic pressure helps restore the volume of
circulating fluid.
LYMPHATIC SYSTEM
Despite the extremely low capillary permeability to proteins, these
molecules as well as other large particles such as long-chain fatty
acids and bacteria find their way into the interstitial space. If such
particles are allowed to accumulate in the interstitial space, filtration
forces will ultimately exceed reabsorption forces and edema will
result. The lymphatic system represents a pathway by which large
molecules reenter the circulating blood.
CHAPTER 26 Peripheral Vascular System 255
The lymphatic system begins in the tissues with blind-end
lymphatic capillaries that are roughly equivalent in size to but
less numerous than regular capillaries. These capillaries are
very porous and easily collect large particles accompanied by
interstitial fluid. This fluid, called lymph, moves through the
converging lymphatic vessels, is filtered through lymph nodes
where bacteria and particulate matter are removed, and reen-
ters the circulatory system through the thoracic duct near the
point where the blood enters the right heart.
Flow of lymph from the tissues toward the entry point into
the circulatory system is promoted by (1) increases in tissue
interstitial pressure (due to fluid accumulation or to move-
ment of surrounding tissue), (2) contractions of the lymphatic
vessels, and (3) valves located in these vessels to prevent back-
ward flow.
Roughly 2.5 L of lymphatic fluid enters the cardiovascular
system each day. In the steady state, this indicates a total body
net transcapillary fluid filtration rate of 2.5 L per day. When
compared with the total amount of blood that circulates each
day (about 7,000 L), this may seem like an insignificant amount
of net capillary fluid leakage. However, lymphatic blockage is a
very serious problem and is accompanied by severe swelling
(lymphedema). Thus, the lymphatics play a critical role in
keeping the interstitial protein concentration low and in
removing excess capillary filtrate from the tissues.
BASIC VASCULAR FUNCTION
RESISTANCE AND FLOW IN
NETWORKS OF VESSELS
In. Chapter 22, it was asserted that the basic flow equation
(Q =ΔP/R) may be applied to networks of tubes as well as to
individual tubes. The reason is that any network of resis-
tances, however complex, can always be reduced to a single
“equivalent” resistor that relates the total flow through the
network to the pressure difference across the network. To do
so, one must make use of the two equations below for series
(one after another) and parallel (side-by-side) networks of
individual vessels. When vessels with individual resistances
R1, R2, …, Rn are connected in series, the overall resistance of
the network is given by the following formula:
Rs = R1 + R2 + … + Rn (5)
Figure 26–3A shows an example of three vessels connected
in series between some region where the pressure is Pi and
another region with a lower pressure Po, so that the total pres-
sure difference across the network, ΔP, is equal to Pi – Po. By
the series resistance equation, the total resistance across this
network (Rs) is equal to R1 + R2 + R3. By
. the basic flow equa-
tion, the flow through the network. (Q ) is equal to ΔP/Rs. It
should be intuitively obvious that Q is also the flow (volume/
time) through each of the elements in the series as indicated
in Figure 26–3B. (Fluid particles may move with different
256 SECTION V Cardiovascular Physiology

velocities [distance/time] in different elements of a series net- A

R1
R3
work, but the volume that passes through each element in a R2
minute must be identical.) Pi Q P0
As shown in Figure 26–3C, a portion of the total pressure a b
c d
decrease across the network occurs within each element of the
series. The pressure decrease across any element in the series Rs = R1 + R2 + R3
can be calculated by applying . the basic flow equation to that ele- ΔP• = Pi − P0
ment, for example, ΔP1 = Q R1. Note that the largest portion of Q = ΔP/Rs
the overall pressure decrease will occur across the element in the B
series with the largest resistance to flow (R2 in Figure 26–3). Q
•

As indicated in Figure 26–4, when several tubes with indi-

Flow
vidual resistances R1, R2, …, Rn are brought together to form a
parallel network of vessels, one can calculate a single overall
resistance for the parallel network Rp according to the follow- a b c d
ing formula: Position along network
70
1 __ C
__ = 1 + __
Rp R1 R2
1 1
+ … + __
Rn
(6) Pi
•
ΔP1 =Q ·R1
The total flow through a parallel network is determined by
ΔP/Rp. As the preceding equation implies, the overall resis- •
ΔP2 =Q ·R2 ΔP
Pressure
tance of any parallel network will always be less than that of
•
any of the elements in the network. (In the special case where ΔP3 =Q ·R3
the individual elements that form the network have identical
resistances Rx, the overall resistance of the network is equal P0
to the resistance of an individual element divided by the
number (n) of parallel elements in the network: Rp = Rx/n.) In a b c d
general, the more parallel elements that occur in the net- Position along network
work, the lower the overall resistance of the network. Thus, FIGURE 26–3 A–C) Series resistance network. (Modified with
for example, a capillary bed that consists of many individual permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York:
capillary vessels in parallel can have a very low overall resis- Lange Medical Books/McGraw-Hill, 2006.)
tance to flow even though the resistance of a single capillary
is relatively high.
As indicated in Figure 26–4, the basic flow equation may be PERIPHERAL BLOOD FLOW VELOCITIES
applied to any single element in the network or to the network
as a whole. For example,
. the flow through
. only the first element It is important to make the distinction between blood flow
of the network (Q 1) is given by Q 1 = ΔP/R1 , whereas
. the flow (volume/time) and blood flow velocity (distance/time) in the
through the entire parallel network is given by Qp = ΔP/Rp . peripheral vascular system. Linear velocity of flow at any point

•
R1 Q1 = ΔP/R1

Pi • P0
R2 Q2 = ΔP/R2

•
R3 Q3 = ΔP/R3

1 1 1 1
= + +
Rp R1 R2 R3

ΔP = Pi − P0
• • • •
Qtotal = Q1 + Q2 + Q3
•
Qtotal = ΔP/Rp
FIGURE 26–4 Parallel resistance network. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange
Medical Books/McGraw-Hill, 2006.)

is equal to the flow divided by the cross-sectional area. Con-
sider the analogy of a stream whose water moves with greater
velocity through shallow rapids than it does through an adja-
cent deep pool. The volume of water passing through the pool
in a day (volume/time = flow), however, must equal that pass-
ing through the rapids in the same day. In such a series arrange-
ment, the flow is the same at all points along the channel but
the flow velocity varies inversely with the local cross-sectional
area. The situation is the same in the peripheral vasculature,
where blood flows most rapidly in the region with the smallest
total cross-sectional area (the aorta) and most slowly in the
region with the largest total cross-sectional area (the capillary
beds). Regardless of the differences in velocity, when the CO
(flow into the aorta) is 5 L/min, the flow through the systemic
capillaries (or arterioles, or venules) is also 5 L/min. The
changes in flow velocity that occur as blood passes through
the peripheral vascular system are shown in the top trace of
Figure 26–5.
The important consequence of this slow flow through the cap-
illaries is that it allows sufficient time for adequate solute and fluid
exchange between the vascular and interstitial compartments.
Blood normally flows through all vessels in the cardiovascu-
lar system in an orderly streamlined manner called laminar
flow. With laminar flow, there is a parabolic velocity profile
Arteries Arterioles
500 mm/s
Flow velocity
Blood
volume
2%
12%
Systolic
Mean 100 mm Hg
Diastolic
blood pressure
Vascular
resistance
FIGURE 26–5 Flow velocities, blood volumes, blood pressures, and vascular resistances in the peripheral vasculature from aorta to
right atrium. Approximately 20% of the total volume is contained in the pulmonary system and the heart chambers and is not accounted for in
this figure. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
CHAPTER 26 Peripheral Vascular System 257
across the tube as shown on the left side of Figure 26–6. Veloc-
ity is fastest along the central axis of the tube and falls to zero
at the wall. The concentric layers of fluid with different veloci-
ties slip smoothly over one another. Little mixing occurs
between fluid layers so that individual particles move in
straight streamlines parallel to the axis of the flow. Laminar
flow is very efficient because little energy is wasted on any-
thing but producing forward fluid motion.
Because blood is a viscous fluid, its movement through a ves-
sel exerts a shear stress on the walls of the vessel. This is a force
that wants to drag the inside surface (the endothelial cell layer)
of the vessel along with the flow. The endothelial cells that line
a vessel are able to sense (and possibly respond to) changes in
the rate of blood flow through the vessel by detecting changes
in the shear stress on them. Shear stress may also be an impor-
tant factor in certain pathological situations. For example, ath-
erosclerotic plaques tend to form preferentially near branches
of large arteries where, for complex hemodynamic reasons
beyond the scope of this text, high shear stresses exist.
When blood is forced to move with too high a velocity
through a narrow opening, the normal laminar flow pattern
may break down into the turbulent flow pattern shown on the
right side of Figure 26–6. With turbulent flow, there is much
internal mixing and friction. When the flow within a vessel is
Capillaries Venules and veins
0.5 mm/s
60%
5%
25 mm Hg
258 SECTION V Cardiovascular Physiology
Streamlines
FIGURE 26–6 Laminar and turbulent flow patterns.
(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular
Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
turbulent, the resistance to flow is significantly higher than that
predicted from the Poiseuille equation given in Chapter 22.
Turbulent flow also generates sound, which can be heard with
the aid of a stethoscope. Cardiac murmurs, for example, are
manifestations of turbulent flow patterns generated by cardiac
valve abnormalities. Detection of sounds from peripheral
arteries (bruits) is abnormal and usually indicates a pathologi-
cal reduction of a large vessel’s cross-sectional area or an abnor-
mally high blood flow through an organ.
PERIPHERAL BLOOD VOLUMES
The second trace in Figure 26–5 shows the approximate per-
centage of the total circulating blood volume that is contained
in the different vascular regions of the systemic organs at any
instant.
Note that most of the circulating blood is contained within
the veins of the systemic organs. This diffuse but large blood
reservoir is often referred to as the peripheral venous pool. A
second but smaller reservoir of venous blood, called the central
venous pool, is contained in the great veins of the thorax and
the right atrium. When peripheral veins constrict, blood is dis-
placed from the peripheral venous pool and enters the central
pool. An increase in the central venous volume, and thus pres-
sure, enhances cardiac filling, which in turn augments stroke
volume (SV) according to the Starling law of the heart. This is
an extremely important mechanism of cardiovascular regula-
tion and will be discussed in greater detail in Chapter 28.
PERIPHERAL BLOOD PRESSURES
Blood pressure decreases in the consecutive segments with the
pattern shown in the third trace of Figure 26–5. Recall from
Figure 24–1 that aortic pressure fluctuates between a systolic
and a diastolic value with each heartbeat, and the same is true
throughout the arterial system. The average pressure in the
arch of the aorta, however, is about 100 mm Hg, and this mean
arterial pressure decreases by only a small amount within the
arterial system.
As indicated in Figure 26–5, arterial pulse pressure actually
increases with distance from the heart, a phenomenon referred
to as peripheral peaking of pulse pressure. The hemodynamic
reasons for this are very complex but involve the positive addi-
tion of primary pressure waves produced by the heart (that
travel much faster than blood flow does) and reflected pressure
Velocity profile
Turbulent flow
Laminar flow
waves (traveling back toward the heart) caused by discontinui-
ties such as branching points in the arterial system.
A large pressure drop occurs in the arterioles, where the pul-
satile nature of the pressure also nearly disappears. The aver-
age capillary pressure is approximately 25 mm Hg. Pressure
continues to decrease in the venules and veins as blood returns
to the right heart. The central venous pressure (which is the
filling pressure for the right heart) is normally very close to
0 mm Hg.
PERIPHERAL VASCULAR RESISTANCES
The bottom trace in Figure 26–5 indicates the relative resistance
to flow that exists in each of the consecutive vascular regions.
Because arterioles have such a large vascular resistance in com-
parison to the other vascular segments, the overall vascular
resistance of any organ is determined to a very large extent by
the resistance of its arterioles. Arteriolar resistance is strongly
influenced by arteriolar radius (R is proportional to 1/r4). Thus,
the blood flow through an organ is primarily regulated by
adjustments in the internal diameter of arterioles caused by
contraction or relaxation of their muscular arteriolar walls.
When the arterioles of an organ change diameter, not only
does the flow to the organ change, but the manner in which
the pressures decrease within the organ is also modified. The
effects of arteriolar dilation and constriction on the pressure
profile within a vascular bed are illustrated in Figure 26–7.
Arteriolar constriction causes a greater decrease in pressure
across the arterioles, and this tends to increase the arterial
pressure while it decreases the pressure in capillaries and veins.
Conversely, increased organ blood flow caused by arteriolar
dilation is accompanied by decreased arterial pressure and
increased capillary pressure. Because of the changes in capil-
lary hydrostatic pressure, arteriolar constriction tends to cause
transcapillary fluid reabsorption, whereas arteriolar dilation
tends to promote transcapillary fluid filtration.
TOTAL PERIPHERAL RESISTANCE
The overall resistance to flow through the entire systemic circu-
lation is called the total peripheral resistance (TPR; sometimes
called the systemic vascular resistance [SVR]). Because the
systemic organs are generally arranged in parallel (see Figure
22–2), the vascular resistance of each organ contributes to the
TPR according to the parallel resistance equation (6).

Blood pressure
Arteriolar
dilation
Normal
Arteriolar
constriction
Arteries Arterioles Capillaries Veins
FIGURE 26–7 Effect of changes in arteriolar resistance on
vascular pressures. (Modified with permission from Mohrman DE, Heller LJ:
Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
ELASTIC PROPERTIES OF
ARTERIES AND VEINS
Arteries and veins contribute only a small portion to the overall
resistance to flow through a vascular bed. Therefore, changes in
their diameters have no significant effect on the blood flow through
systemic organs. The elastic behavior of arteries and veins is, how-
ever, very important to overall cardiovascular function because
they can act as reservoirs and substantial amounts of blood can be
stored in them. Arteries or veins behave more like balloons with
one pressure throughout rather than as resistive pipes with a flow-
related pressure difference from end-to-end. Thus, think of an
“arterial compartment” and a “venous compartment,” each with
an internal pressure that is related to the volume of blood within it
at any instant and how easily its walls can be stretched.
This is characterized by a parameter called compliance (C;
see Chapter 1) given as follows that describes how much its
volume changes (ΔV) in response to a given change in distend-
ing pressure (ΔP), which is the difference between the internal
and external pressures on the vascular walls:
ΔV
C = ___
ΔP
(7)
Volume–pressure curves for the systemic arterial and venous
compartments are shown in Figure 26–8. It is apparent from the
disparate slopes of the curves in this figure that the elastic proper-
ties of arteries and veins are very different. For the arterial com-
partment, the ΔV/ΔP measured near a normal operating pressure
of 100 mm Hg indicates a compliance of about 2 mL/mm Hg. By
contrast, the venous pool has a compliance of over 100 mL/mm
Hg near its normal operating pressure of 5–10 mm Hg.
Because veins are so compliant, even small changes in periph-
eral venous pressure can cause a significant amount of the circu-
lating blood volume to shift into or out of the peripheral venous
pool. Standing upright, for example, increases venous pressure
in the lower extremities and promotes blood accumulation
CHAPTER 26 Peripheral Vascular System 259
Arterial
compartment
Distending pressure (mm Hg)
100 ΔP
ΔV
50
Venous
compartment
C B
D
d ΔP
tricte
Cons A ΔV
l
0 Norma
Volume
FIGURE 26–8 Volume–pressure curves of arterial and venous
compartments. (Modified with permission from Mohrman DE, Heller LJ:
Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
(pooling) in these vessels as might be represented by a shift from
point A to point B in Figure 26–8. Fortunately, this process can
be counteracted by active venous constriction. The dashed line
in Figure 26–8 shows the venous volume–pressure relationship
that exists when veins are constricted by activation of venous
smooth muscle. In constricted veins, volume may be normal
(point C) or even below normal (point D) despite greater-than-
normal venous pressure. Peripheral venous constriction tends
to increase peripheral venous pressure and shift blood out of the
peripheral venous compartment.
The elasticity of arteries allows them to act as a reservoir on a
beat-to-beat basis. Arteries play an important role in converting
the pulsatile flow output of the heart into a steady flow through
the vascular beds of systemic organs. During the early rapid
phase of cardiac ejection, the arterial volume increases because
blood is entering the aorta more rapidly than it is passing into
systemic arterioles. Thus, part of the work the heart does in
ejecting blood goes to stretching the elastic walls of arteries.
Toward the end of systole and throughout diastole, arterial vol-
ume decreases because the flow out of arteries exceeds flow into
the aorta. Previously stretched arterial walls recoil to shorter
lengths, and in the process give up their stored potential energy.
This reconverted energy is what actually does the work of pro-
pelling blood through the peripheral vascular beds during dias-
tole. If arteries were rigid tubes that could not store energy by
expanding elastically, arterial pressure would fall immediately
to zero with the termination of each cardiac ejection.
MEASUREMENT OF
ARTERIAL PRESSURE
Recall that the systemic arterial pressure fluctuates with each
heart cycle between a diastolic value (PD) and a higher systolic
value (PS). Obtaining estimates of an individual’s systolic and
260 SECTION V Cardiovascular Physiology
diastolic pressures is one of the most routine diagnostic tech-
niques available to the clinician. The basic principles of the
auscultation technique used to measure blood pressure are
described as follows with the aid of Figure 26–9:
1. An inflatable cuff is wrapped around the upper arm, with a
recording device attached to monitor the pressure within the
cuff. The cuff is initially inflated with air to a pressure (usually
175–200 mm Hg) that is well above normal systolic values.
This pressure collapses all blood vessels under the cuff.
2. After initial inflation, air is gradually “bled” from the cuff
so that the pressure within it decreases slowly and steadily
through the range of arterial pressure fluctuations.
3. The moment cuff pressure decreases below peak systolic ar-
terial pressure, some blood is able to pass beneath the cuff
during the systolic phase of the cycle. Because the flow
through these partially compressed vessels is intermittent
and turbulent, tapping sounds can be detected with a stetho-
scope placed over the radial artery at the elbow. As indicated
in Figure 26–9, sounds of varying character, known collec-
tively as Korotkoff sounds, are heard whenever the cuff
pressure is between the systolic and diastolic arterial pres-
sures. The highest cuff pressure at which tapping sounds are
heard is taken as the systolic arterial pressure.
4. When the cuff pressure decreases below the diastolic pres-
sure, blood flows through the vessels beneath the cuff
without periodic interruption and again no sound is de-
tected over the radial artery. The cuff pressure at which the
sounds become muffled or disappear is taken as the dia-
stolic arterial pressure.
DETERMINANTS OF
ARTERIAL PRESSURE
MEAN ARTERIAL PRESSURE
Mean arterial pressure is a critically important cardiovascular
variable because it is the average effective pressure that drives
Cuff pressure
120
mm Hg
80
FIGURE 26–9 Blood pressure measurement by
auscultation. Point A indicates systolic pressure and
point B indicates diastolic pressure. (Modified with
permission from Mohrman DE, Heller LJ: Cardiovascular Physiology,
6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
blood through the systemic organs. One of the most fundamen-
tal equations of cardiovascular physiology is that which indi-
–
cates how mean arterial pressure (Pa) is related to CO and TPR:
–
Pa = CO × TPR (8)
The above equation
. is simply a rearrangement of the basic
flow equation Q = ΔP /R applied to the entire systemic circula-
tion with the single assumption that central venous pressure is
–
approximately zero so that ΔP = Pa . Note that mean arterial
pressure is influenced both by the heart (via CO) and by the
peripheral vasculature (via TPR). All changes in mean arterial
pressure result from changes in either CO or TPR.
Calculating the true value of mean arterial pressure requires
mathematically averaging the arterial pressure waveform over
one or more complete heart cycles. Most often, however, we
know from auscultation only the systolic and diastolic pres-
sures, yet wish to make some estimate of the mean arterial
pressure. Mean arterial pressure necessarily falls between the
systolic and diastolic pressures. A useful rule of thumb is that
–
mean arterial pressure (Pa) is approximately equal to diastolic
pressure (PD) plus one third of the difference between systolic and
diastolic pressures (PS – PD).
ARTERIAL PULSE PRESSURE
The arterial pulse pressure (Pp) is defined simply as systolic
pressure minus diastolic pressure (PS – PD). To be able to use
pulse pressure to deduce something about how the cardiovascu-
lar system is operating, one must do more than just define it. It
is important to understand what determines pulse pressure, that
is, what causes it to be what it is and what can cause it to change.
In a previous section of this chapter, there was a brief discussion
about how, as a consequence of the compliance of the arterial
vessels, arterial pressure increases as arterial blood volume is
expanded during cardiac ejection. The magnitude of the pres-
sure increase (ΔP) caused by an increase in arterial volume
depends on how large the volume change (ΔV) is and on how
compliant (Ca) the arterial compartment is: ΔP = ΔV/Ca. If, for
the moment, the fact that some blood leaves the arterial com-
Arterial pressure
A
Lou
der fter
So
No sound Korotkoff sounds No sound

partment during cardiac ejection is neglected, then the increase
in arterial volume during each heartbeat is equal to the SV.
Thus, pulse pressure is, to a first approximation, equal to SV
divided by arterial compliance:
SV
Pp ∼ ___
− C
Arterial pulse pressure is about 40 mm Hg in a normal resting
young adult because SV is about 80 mL and arterial compliance
is about 2 mL/mm Hg. Pulse pressure tends to increase with age
in adults because of a decrease in arterial compliance (and
increase in arterial stiffness also referred to as “hardening of the
arteries” or arteriosclerosis. This differs from atherosclerosis
which involves deposition of fat in the vessel wall). Arterial vol-
ume–pressure curves for a 20- and a 70-year-old are shown in
Figure 26–10. The increase in arterial stiffness with age is indi-
cated by the steeper curve for the 70-year-old (more ΔP for a
given ΔV) than for the 20-year-old. Thus, a 70-year-old will nec-
essarily have a larger pulse pressure for a given SV than a
20-year-old. As indicated in Figure 26–10, the increase in arte-
rial stiffness is sufficient to cause increased pulse pressure even
though SV tends to decrease with age (Also see Figure 73–1).
Figure 26–10 also illustrates the fact that arterial blood vol-
ume and mean arterial pressure tend to increase with age. The
increase in mean arterial pressure is not caused by the decreased
arterial compliance, however, because compliance changes do
not directly influence either CO or TPR, which are the sole
–
determinants of Pa. Mean arterial pressure tends to increase
with age because of an age-dependent increase in TPR that is
controlled primarily by arterioles, not arteries.
Arterial compliance also decreases with increasing mean
arterial pressure as evidenced by the curvature of the volume–
pressure relationships shown in Figure 26–10. Otherwise,
arterial compliance is a relatively stable parameter. Thus, most
acute changes in arterial pulse pressure are the result of changes
200
20-year-old
Arterial pressure (mm Hg)
100
0
FIGURE 26–10 Effect of age on systemic arterial volumes and pressures and arterial stiffness. (Modified with permission from Mohrman DE,
Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
CHAPTER 26 Peripheral Vascular System 261
in SV. Changes in TPR, however, have little or no effect on pulse
pressure, because a change in TPR causes parallel changes in
both systolic and diastolic pressures.
A common misconception in cardiovascular physiology is
that the systolic pressure alone or the diastolic pressure alone
(9) indicates the status of a specific cardiovascular variable. The
reader should not attempt to interpret systolic and diastolic
pressure values independently. Interpretation is much more
straightforward when the focus is on mean arterial pressure
–
(Pa = CO × TPR) and arterial pulse pressure (Pp ∼ − SV/Ca).
CLINICAL CORRELATION
A 27-year-old woman comes to the clinic because of the
overnight onset of a pain in her left leg and swelling in her
left ankle and foot. She describes the pain as a cramping
sort of deep ache. She had returned to the United States
yesterday on a 12-hour flight from Brazil where she had
spent several weeks on an expedition to the rain forests.
She takes no drugs except birth control pills containing
estrogen (see Chapter 68). She is 1.73-m tall and weighs
93 kg. Vital signs are all within normal ranges. On exami-
nation, it is noted that her left lower leg is sensitive to
touch and her left foot feels warmer than her right.
Furthermore, there is edema with her left ankle and foot
significantly swollen compared to her right.
The symptoms suggest that there is an imbalance between
filtration and absorptive forces at work in the capillaries of
the lower left leg. Because these symptoms are restricted to
one leg and not both, overall circulatory abnormalities that
might cause ankle edema can be eliminated (e.g., decreased
70-year-old
ΔP
ΔP
ΔV
ΔV
Arterial volume
262 SECTION V Cardiovascular Physiology

■ Turbulent blood flow is usually abnormal and makes noise

plasma proteins which would decrease plasma oncotic (murmurs and bruits).
pressure; or right-sided heart failure, liver or kidney disease ■ Veins contain most of the total blood volume.
which would increase fluid retention and peripheral venous ■ Arterioles contribute most to the resistance to flow through
pressure). Local factors that might cause fluid to accumu- organs.
late in the interstitial space could include situations that ■ Arteriolar constriction tends to reduce flow through an
either prevent lymphatic drainage of this space (i.e., organ, reduce capillary hydrostatic pressure, and promote
lymphedema from tropical pathogenic filarial parasites) or transcapillary fluid reabsorption within the organ.
increase hydrostatic pressure in the veins draining the tis- ■ Venous constriction is important for cardiac filling and the
sue. Because of the rapid onset and symptoms, it is much ability to cope with blood loss.
more likely that a clot has formed in one of the large veins ■ Because arteries and arterioles are elastic, the intermittent
draining her left leg (deep vein thrombosis [DVT]) that has flow from the heart is converted to continuous flow through
increased the upstream capillary hydrostatic pressure, and capillaries.
caused the pain, filtration of fluid out of the vascular space, ■ Mean systemic arterial pressure is determined by the product
and edema of the tissue. of CO and TPR.
Being overweight and taking birth control pills contain- ■ Changes in arterial pulse pressure reflect changes in SV and/or
ing estrogens are risk factors that predispose this woman the compliance of the arterial space.
toward the development of such a clot. In addition, a long
period of time spent in a sitting position without moving
her legs (as might have occurred on her long airplane ride) STUDY QUESTIONS
allows blood to pool in these lower extremities and is an 1. Determine the rate of glucose uptake by an exercising skeletal
added risk factor for DVT or inflammation of the more muscle from the following data: arterial blood (glucose) = 50 mg
superficial veins (thrombophlebitis). In addition to the per 100 mL blood; muscle venous blood (glucose) = 30 mg per
localized discomfort, there is the real danger that these 100 mL blood; muscle blood flow = 60 mL/min.
clots can become dislodged from their anchorage in the A) 3,000 mg/min
leg vein, travel to the heart as an embolus, and become B) 1,200 mg/min
lodged in the lungs (pulmonary embolism). This can be a C) 30 mg/min
life-threatening event and requires immediate treatment. D) 20 mL/mg
E) 12 mg/min
Doppler ultrasonic examination of the patient’s leg
revealed the presence of DVT and she was treated with an 2. Which of the following conditions favor net absorption of
fluid out of the interstitial space and into the capillary bed
anticoagulant (heparin at first and then warfarin) as well
within an organ?
as drugs that can help dissolve clots. It is also possible that
A) increased interstitial protein concentration
this patient has an increased tendency to form clots (i.e.,
B) venous clot
she is hypercoagulable) in part due to being overweight.
C) decreased plasma protein concentration
There are some inherited forms of hypercoagulability that D) increased capillary pore size
she and her blood relatives can be tested for. It is possible E) arteriolar constriction
that she will require lifelong treatment with anticlotting 3. Which of the following is consistent with a normal mean arterial
drugs. Finally, she will be encouraged to switch to a differ- pressure but an abnormally high arterial pulse pressure?
ent birth control method, as estrogens can increase the A) low stroke volume
tendency to form clots. B) high heart rate
C) decreased total peripheral resistance
D) increased arterial stiffness
E) aortic valve stenosis
CHAPTER SUMMARY 4. Which of the following substances is likely to move most easily
■ Within the cardiovascular system, convection is used to across a skeletal muscle capillary wall?
transport substances between capillary beds and diffusion
A) potassium
is used to transport substances between blood and tissue.
B) glucose
■ Water may move out of (filtration) or into (reabsorption) C) oxygen
capillaries depending on the net balance of hydrostatic and D) water
osmotic forces across capillary walls. E) albumin
■ Plasma proteins are responsible for the major osmotic force 5. In which of the following vessels do red cells move with the
across capillary walls. fastest speed (distance/time)?
■ Lymphatic vessels serve to remove excess filtrate from tissues A) arteries
and keep interstitial protein concentration low. B) arterioles
■ The velocity of blood flow is indirectly proportional to the total C) capillaries
cross-sectional area of the vascular segment and is slowest in D) venules
capillaries. E) veins
 27
C H A P T E R

Vascular Control
David E. Mohrman and Lois Jane Heller

O B J E C T I V E S

■ Define basal tone.

■ List several substances potentially involved in local metabolic control
of vascular tone.
■ State the local metabolic vasodilator hypothesis.
■ Describe how vascular tone is influenced by locally produced
endothelial factors and chemicals such as prostaglandins, histamine,
and bradykinin.
■ Describe the myogenic response of blood vessels.
■ Define active and reactive hyperemia and indicate a possible mechanism
for each.
■ Define autoregulation of blood flow and briefly describe the metabolic,
myogenic, and tissue pressure theories of autoregulation.
■ Define neurogenic tone and describe how sympathetic
(and parasympathetic) neural influences can alter it.
■ Describe how vascular tone is influenced by circulating catecholamines,
vasopressin, and angiotensin II.
■ List the major influences on the diameter of veins.
■ Describe in general how control of blood flow differs between organs with
strong local metabolic control of arteriolar tone and organs with strong
neurogenic control of arteriolar tone.
■ State the relative importance of local metabolic and neural control of
coronary blood flow.
■ Define systolic compression and indicate its relative importance to
blood flow in the endocardial and epicardial regions of the right and left
ventricular walls.
■ Describe the major mechanisms of blood flow control in skeletal muscle
and brain.

VASCULAR SMOOTH MUSCLE
The cardiovascular system must adjust the diameter of its vessels
to efficiently distribute the cardiac output among tissues with
different current needs (the job of arterioles), and to regulate the
distribution of blood volume and cardiac filling (the job of veins).
Vascular diameter adjustments are made by regulating the con-
tractile activity of vascular smooth muscle cells, which are pres-
ent in the walls of all vessels except capillaries. Vascular smooth
muscle is unique because it must maintain its vessel diameter in
the face of the continuous distending pressure of the blood within
it, and therefore sustain active tension for prolonged periods.
The basics of smooth muscle operation were presented in
Chapter 11. Here the focus is on the functional consequences of

263

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264 SECTION V Cardiovascular Physiology
influences on vascular smooth muscle that have particular rel-
evance to the operation of the cardiovascular system. In general,
these influences on vascular smooth muscle can be separated
into those that originate locally (and therefore have only local
consequences) and those that have global influences on vessels
throughout the body. Examples of the latter are general changes
in autonomic nerve activity and changes in the blood concen-
trations of hormones that affect vascular smooth muscle. Such
influences have much different functional consequences on
arterioles than on veins. Consequently, the operations of arteri-
oles and veins are described separately in this chapter.
VASCULAR TONE
Vascular tone is a term commonly used to characterize the
general contractile state of a vessel or a vascular region. The
“vascular tone” of a region can be taken as an indication of
the “level of activation” of the individual smooth muscle cells
in that region. An increase in arteriolar tone is automatically
taken to imply a decrease in arteriolar vessel diameter, the
functional consequences of which are an increase in arteriolar
resistance and a decrease in flow. The primary functional con-
sequence of an increase in venous tone is a decrease in venous
volume and thus a peripheral-to-central shift of blood volume
that increases cardiac filling.
CONTROL OF ARTERIOLAR TONE
As described in Chapter 26, the blood flow through any organ
is determined largely by its vascular resistance, which is depen-
dent primarily on the diameter of its arterioles. Consequently,
an organ’s flow is controlled by factors that influence the arte-
riolar smooth muscle tone.
BASAL TONE
The arterioles in a healthy individual at rest have a certain level
of basal tone that lies somewhere between complete relaxation
and maximum possible constriction. A myriad of influences
on arteriolar smooth muscle contribute collectively to the
establishment of this basal tone. One important consequence
Release proportional to tissue metabolism
FIGURE 27–1 Local metabolic vasodilator Blood flow
hypothesis. (Modified with permission from Mohrman
DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York:
Lange Medical Books/McGraw-Hill, 2006.)
of basal tone is that it serves as a baseline from which arterio-
lar tone can be regulated, either increased or decreased as nec-
essary to meet the needs of changing situations. Another
important consequence is that the basal tone of arterioles
throughout the body collectively contributes directly to the
total peripheral resistance (TPR) and thus to arterial blood
pressure in a resting individual.
LOCAL INFLUENCES ON ARTERIOLES
Local Metabolic Influences
The arterioles that control flow through a given organ lie within
the organ tissue itself. Thus, arterioles and the smooth muscle
in their walls are exposed to the chemical composition of the
interstitial fluid of the organ they serve. The interstitial concen-
trations of many substances reflect the balance between the
metabolic activity of the tissue and its blood supply. Interstitial
oxygen levels, for example, decrease when cells are using oxy-
gen faster than it is being supplied to the tissue by blood flow.
Conversely, interstitial oxygen levels increase whenever more
oxygen is delivered than is used by a tissue. In nearly all vascu-
lar beds, exposure to low oxygen reduces arteriolar tone and
causes vasodilation, whereas high oxygen levels cause arterio-
lar vasoconstriction. Thus, a local feedback mechanism exists
that automatically operates on arterioles to regulate blood flow
to a tissue in accordance with its metabolic needs.
Many substances in addition to oxygen are present within
tissues and can affect the tone of vascular smooth muscle.
When the metabolic rate of skeletal muscle is increased by
exercise, for example, tissue levels of carbon dioxide, H+, and
K+ increase. These chemical alterations cause arteriolar dila-
tion. In addition, with increased metabolic activity or oxygen
deprivation, cells in many tissues may release adenosine,
which is a potent vasodilator agent.
At present, it is not known which of these (or possibly other)
metabolically related chemical alterations within tissues are
most important in the local metabolic control of blood flow. It
is likely that arteriolar tone depends on the combined action of
many factors.
Figure 27–1 summarizes current understanding of local
metabolic control. Vasodilator factors enter the interstitial
Tissue cells
Removal rate proportional to blood flow
Vasodilator factors
Arterioles Capillaries Veins

space from the tissue cells at a rate proportional to tissue
metabolism. These vasodilatory factors are removed from
the tissue at a rate proportional to blood flow. Whenever tis-
sue metabolism is at a rate for which the blood flow is inade-
quate, the interstitial vasodilator concentrations build up and
cause the arterioles to dilate and blood flow to increase. The
process continues until blood flow has increased sufficiently to
appropriately match the tissue metabolic rate and prevent fur-
ther accumulation of vasodilator factors. The same system also
operates to reduce blood flow when it is greater than required
by the tissue metabolic activity because the interstitial concen-
trations of metabolic vasodilator factors are decreased.
Local metabolic mechanisms are usually the most important
means of local blood flow control in most tissues. Individual
organs are therefore able to regulate their own blood flow in
accordance with their metabolic needs. As indicated below,
there are several other types of local influences on blood ves-
sels. However, many of these represent fine-tuning mecha-
nisms and may be important only in certain, usually
pathological, situations.
Local Nonmetabolic Influences
An ever-increasing number of local factors unrelated to tissue
metabolism have been shown to influence arterioles within an
organ. Table 27–1 contains a list of some of these more impor-
tant factors and summarizes some of the information about
their actions.
Many of these factors exert their vascular effects by action on
endothelial cells. Thus, endothelial cells can actively participate
in the control of arteriolar diameter by producing local chemi-
cals that affect the tone of the surrounding smooth muscle cells.
The vasodilatory influence produced by endothelial cells is
mediated by nitric oxide (NO). NO is produced within
endothelial cells from the amino acid, l-arginine, by the action
of an enzyme, NO synthase, that is activated by an increase in
the intracellular level of Ca2+. NO is a small lipid-soluble mol-
ecule that, once formed, easily diffuses into adjacent smooth
muscle cells where it causes relaxation by stimulating cGMP
production as mentioned in Chapter 11. Acetylcholine and
several other agents (including bradykinin, vasoactive intesti-
nal peptide, and substance P) stimulate endothelial cell NO
production because their receptors on endothelial cells are
linked to receptor-operated Ca2+ channels. Blood flow–related
shear stresses on endothelial cells stimulate NO production
through stretch-sensitive channels for Ca2+. This phenomenon
may explain why exercise and increased blood flow through
muscles of the lower leg can cause dilation of the blood-
supplying femoral artery at points far upstream from the exer-
cising muscle itself.
Transmural Pressure
The passive elastic mechanical properties of arteries and veins
and how changes in transmural pressure affect their diameters
were discussed in Chapter 26. The effect of transmural pres-
sure on arteriolar diameter is actually more complex because
arterioles respond both passively and actively to changes in
CHAPTER 27 Vascular Control 265
transmural pressure. For example, a sudden increase in the
internal pressure within an arteriole produces first an initial
slight passive mechanical distention (slight because arterioles
are relatively thick-walled and muscular), and second, an
active constriction that, within seconds, may completely
reverse the initial distention. A sudden decrease in transmural
pressure elicits essentially the opposite response, that is, an
immediate passive decrease in diameter followed shortly by a
decrease in active tone that returns the arteriolar diameter to
near that which existed before the pressure change. The active
phase of such behavior is referred to as a myogenic response,
because it seems to originate within the smooth muscle itself.
The mechanism of the myogenic response is not known for
certain, but stretch-sensitive ion channels on arteriolar vascu-
lar smooth muscle cells are likely candidates for involvement.
All arterioles have some normal distending pressure to
which they probably are actively responding. Therefore, the
myogenic mechanism is likely to be a fundamentally impor-
tant factor in determining the basal tone of arterioles every-
where. The myogenic response is potentially involved in the
vascular reaction to any cardiovascular disturbance that
involves a change in arteriolar transmural pressure, as will be
discussed in the next section.
FLOW RESPONSES CAUSED BY
LOCAL MECHANISMS
In organs with a highly variable metabolic rate, such as skeletal
and cardiac muscle, the blood flow closely follows the tissue
metabolic rate. For example, skeletal muscle blood flow increases
within seconds of the onset of muscle exercise and returns to
control values shortly after exercise ceases. This phenomenon,
which is illustrated in Figure 27–2A, is known as exercise or
active hyperemia (hyperemia means high flow). It should be
clear how active hyperemia could result from the local meta-
bolic vasodilator feedback on arteriolar smooth muscle. As
mentioned previously, once initiated by local metabolic influ-
ences on small resistance vessels, endothelial flow–dependent
mechanisms may assist in propagating the vasodilation to larger
vessels upstream, which helps promote the delivery of blood to
the exercising muscle.
Reactive or post-occlusion hyperemia is a greater-than-
normal blood flow that occurs transiently after the removal of
any restriction that has caused a period of lower-than-normal
blood flow. The phenomenon is illustrated in Figure 27–2B.
For example, flow through an extremity is greater than normal
for a period after a tourniquet is removed from the extremity.
Both local metabolic and myogenic mechanisms may be
involved in producing reactive hyperemia. The magnitude and
duration of reactive hyperemia depend on the duration and
severity of the occlusion as well as the metabolic rate of the tis-
sue. These findings are best explained by an interstitial accu-
mulation of metabolic vasodilator substances during the period
of flow restriction. However, unexpectedly large flow increases
can follow arterial occlusions lasting only 1 or 2 seconds. These
may be best explained by a myogenic dilation response to the
266 SECTION V Cardiovascular Physiology

TABLE 27–1 Local influences on vascular smooth muscle.

Substance Description Vascular Response Other Information

Nitric oxide (NO), From endothelial cells in response to: Vasodilation Basal release may reduce normal net
endothelial-derived acetylcholine, vasoactive intestinal resting tone of vascular smooth muscle
relaxing factor (EDRF) peptide, substance P, bradykinin, shear locally throughout the body
stress, others
Acetylcholine Neurotransmitter—normal dilation Vasodilation and/or Important local effects on GI circulation
mediated by NO vasoconstriction (from enteric plexus neurons)
-Constriction occurs when
endothelium is absent/
damaged
Vasoactive intestinal Neurotransmitter (also a peptide Vasodilation GI neurotransmitter from enteric plexus
peptide (VIP) hormone)—action is mediated by NO neuron, causes smooth muscle relaxation,
promotes secretion in the gut

Substance P Neurotransmitter—action is mediated Vasodilation Important local roles in pain nociception,

by NO GI function, vomiting, skin circulation

Bradykinin Polypeptide formed from plasma protein Vasodilation -Increases vascular permeability
by action of enzyme, kallikrein—action is -Involved in pain mechanisms
mediated by NO

Shear stress Action is mediated by NO Vasodilation Dependent on flow velocity

Endothelial-derived Unknown factor from endothelial cells Vasodilation May be K+, cANP, electrogenic spread of
hyperpolarizing hyperpolarization, other possible factors
factor (EDHF)

Endothelin Polypeptide from endothelial cells Vasoconstriction Basal release may reduce normal net
resting tone of vascular smooth muscle
locally in tissues throughout the body

Prostacyclin (PGI2) Arachidonic acid (AA) metabolite of the Vasodilation Inflammatory responses, blocked by
cyclooxygenase (CO) pathway cyclooxygenase inhibitors such as aspirin

Thromboxane AA metabolite of the CO pathway (made Vasoconstriction Important for platelet aggregation and
by platelets) blood clotting, also blocked by aspirin

Other prostaglandins AA metabolites of the CO pathway Vasoconstriction Actions vary with the specific organ and
and/or vasodilation local conditions

Leukotrienes AA metabolites of the lipoxygenase Vasoconstriction Increase vascular permeability during

pathway and/or vasodilation inflammatory responses

Histamine Secretory granules of tissue mast cells Vasodilation Leads to an increase in vascular
and circulating basophils permeability, edema formation
-Involved in inflammatory and immune
reactions

reduced intravascular pressure and decreased stretch of the
arteriolar walls during the period of occlusion.
Except when displaying active and reactive hyperemia,
nearly all organs tend to keep their blood flow constant despite
variations in arterial pressure—that is, they display autoregu-
lation of blood flow. As shown in Figure 27–3A, an abrupt
increase in arterial pressure is normally accompanied by an
initial abrupt increase in organ blood flow that then gradually
returns toward normal despite the sustained increase in arte-
rial pressure. The initial increase in flow with increased pres-
sure is expected from the basic flow equation (Q̇ = Δ P / R). The
subsequent return of flow toward the normal level is caused by
a gradual increase in active arteriolar tone and resistance to
blood flow. Ultimately, a new steady state is reached with only
slightly increased blood flow because the increased driving
pressure is counteracted by a greater-than-normal vascular
resistance. As with the phenomenon of reactive hyperemia,
blood flow autoregulation may be caused by both local meta-
bolic feedback mechanisms and myogenic mechanisms. The
arteriolar vasoconstriction responsible for the autoregulatory
response shown in Figure 27–3A, for example, may be partially
due to (1) a “washout” of metabolic vasodilator factors from
the interstitium by the excessive initial blood flow and (2) a
myogenic increase in arteriolar tone stimulated by the increase
in stretching forces that the increase in pressure imposes on
the vessel walls. There is also a tissue pressure hypothesis of
blood flow autoregulation for which it is assumed that an
abrupt increase in arterial pressure causes transcapillary fluid
 CHAPTER 27 Vascular Control 267

A A

Arterial pressure
Organ blood flow

Sustained pressure
Active hyperemia increase

Blood flow
Period of increased autoregulation

Organ blood flow

metabolic rate

B Steady state
Organ blood flow

Reactive hyperemia B

Autoregulatory
Steady-state Organ blood flow
range

Normal
Period of arrested blood flow

FIGURE 27–2 Organ blood flow responses caused by local

Normal
mechanisms: A) active and B) reactive hyperemia. (Modified with
permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York:
Lange Medical Books/McGraw-Hill, 2006.)

filtration and thus leads to a gradual increase in interstitial
fluid volume and pressure. Presumably the increase in extravas-
cular pressure would cause a decrease in vessel diameter by
simple compression. This mechanism might be especially
important in organs such as the kidney and brain whose vol-
umes are constrained by external structures.
Although not illustrated in Figure 27–3A, autoregulatory
mechanisms operate in the opposite direction in response to a
decrease in arterial pressure below the normal value. One
important general consequence of local autoregulatory mecha-
nisms is that the steady-state blood flow in many organs tends
to remain near the normal value over quite a wide range of arte-
rial pressure. This is illustrated in the graph of Figure 27–3B. As
will be discussed later, the inherent ability of certain organs to
maintain adequate blood flow despite lower-than-normal arte-
rial pressure is of considerable importance in situations such as
hypotension (low arterial pressure) from blood loss.
NEURAL INFLUENCES ON ARTERIOLES
Sympathetic Vasoconstrictor Nerves
These neural fibers innervate arterioles in all systemic organs
and provide by far the most important means of reflex control
100 200
Mean arterial pressure (mm Hg)
FIGURE 27–3 A and B) Autoregulation of organ blood flow.
(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology,
6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
of the vasculature. Sympathetic vasoconstrictor nerves are
the backbone of the system for controlling TPR and thus are
essential participants in global cardiovascular tasks such as
regulating arterial blood pressure.
Sympathetic vasoconstrictor nerves release norepinephrine
from their terminal structures in amounts generally propor-
tional to their electrical activity. Norepinephrine causes an
increase in the tone of arterioles after combining with an
α1-adrenergic receptor on smooth muscle cells.
Sympathetic vasoconstrictor nerves normally have a con-
tinuous or tonic firing activity. Thus, arterioles have a certain
level of neurogenic tone as a normal component of their nor-
mal baseline state of contraction. When the firing rate of sym-
pathetic vasoconstrictor nerves is increased above normal,
arterioles constrict and cause organ blood flow to fall below
normal. Conversely, vasodilation and increased organ blood
flow occurs when the normal tonic activity of sympathetic
vasoconstrictor nerves is reduced.
268 SECTION V Cardiovascular Physiology
Other Neural Influences
Most blood vessels do not receive innervation from the para-
sympathetic division of the autonomic nervous system and
systemic vascular resistance is not significantly influenced by
parasympathetic nerve activity. However, parasympathetic
vasodilator nerves, which release acetylcholine, are present
in vessels of the brain and heart but their influence on arterio-
lar tone in these organs appears to be inconsequential. Para-
sympathetic vasodilator nerves are also present in the vessels
of the salivary glands, pancreas, gastric mucosa, and external
genitalia (where they are responsible for the vasodilation of
inflow vessels responsible for erection).
HORMONAL INFLUENCES
ON ARTERIOLES
Circulating Catecholamines
During activation of the sympathetic nervous system, cate-
cholamines epinephrine and norepinephrine are released from
the adrenal medulla into the bloodstream (see Chapter 65).
Under normal circumstances, the concentrations of these agents
in the blood are probably not high enough to cause significant
cardiovascular effects. However, circulating catecholamines
may have cardiovascular effects in situations (such as vigorous
exercise or hemorrhagic shock) that involve increased activity of
the sympathetic nervous system. In general, the cardiovascular
effects of greatly increased levels of circulating catecholamines
parallel the direct effects of sympathetic activation that have
already been discussed; both epinephrine and norepinephrine
can activate cardiac β1-adrenergic receptors to increase heart
rate and myocardial contractility and can activate vascular
α1-receptors to cause vasoconstriction. Recall that in addition
to the α1-receptors that mediate vasoconstriction, arterioles in a
few organs also possess β2-adrenergic receptors that mediate
vasodilation. Because vascular β2-receptors are more sensitive
to epinephrine than are vascular α1-receptors, moderately
increased levels of circulating epinephrine can cause vasodila-
tion—whereas higher levels cause α1-receptor-mediated vaso-
constriction. Vascular β2-receptors are not innervated and
therefore are not activated by norepinephrine released directly
from sympathetic vasoconstrictor nerves. The physiological
importance of these vascular β2-receptors is unclear because
adrenal epinephrine release occurs during periods of increased
sympathetic activity when arterioles would simultaneously be
undergoing direct neurogenic vasoconstriction.
Vasopressin
The polypeptide hormone vasopressin (also known as antidi-
uretic hormone (ADH), plays an important role in extracel-
lular fluid homeostasis and is released into the bloodstream
from the posterior pituitary gland in response to low blood
volume and/or high extracellular fluid osmolarity (see
Chapter 45). Vasopressin acts on collecting ducts in the kid-
neys to decrease renal excretion of water. Its role in body fluid
balance has some very important indirect influences on car-
diovascular function, which will be discussed in more detail in
Chapter 29. Because it is such a potent vasoconstrictor agent,
even the normally low levels of circulating vasopressin are
likely to have some normal tonic effect on the basal tone of
arterioles throughout the body. Moreover, abnormally high
levels of vasopressin are clearly important in the intense arte-
riolar constriction that accompanies certain disturbances such
as severe blood loss through hemorrhage.
Angiotensin II
Angiotensin II is a circulating polypeptide that regulates aldos-
terone release from the adrenal cortex as part of the system for
controlling body sodium balance. This system, to be discussed in
greater detail in Chapter 29, is very important in blood volume
regulation. Angiotensin II is also a very potent vasoconstrictor
agent. Like vasopressin, even the normal low circulating level
of angiotensin II likely has a role in producing the normal
basal tone of arterioles throughout the body. In addition, an
abnormally high blood level of angiotensin II seems to be an
important contributing factor in certain forms of hypertension.
CONTROL OF VENOUS TONE
Recall that venules and veins are relatively large-diameter ves-
sels that have little resistance to flow but do contain relatively
large amounts of blood. Therefore, venous tone or diameter
has relatively little direct effect on the flow through organs.
However, venous diameter does have a large effect on the frac-
tion of total blood volume that is located in the periphery
versus centrally. Consequently, when one considers what
peripheral veins are doing, one should be thinking primarily
about what the effects will be on central venous pressure and
cardiac output.
Veins contain vascular smooth muscle that is influenced by
many of the same things that influence the vascular smooth
muscle of arterioles. Constriction of the veins (venoconstric-
tion) is largely mediated through activity of the sympathetic
nerves that innervate them. As in arterioles, these sympathetic
nerves release norepinephrine, which interacts with α1-receptors
and produces an increase in venous tone and a decrease in ves-
sel diameter. There are, however, several functionally impor-
tant differences between veins and arterioles. Compared with
arterioles, veins normally have little basal tone. Thus, veins are
normally in a dilated state. One important consequence of the
lack of basal venous tone is that vasodilator metabolites that
may accumulate in the tissue have little effect on veins.
Because of their thin walls, veins are much more susceptible
to physical influences than are arterioles. The large effect of
internal venous pressure on venous diameter was discussed in
Chapter 26 and is evident in the pooling of blood in the veins
of the lower extremities that occurs during prolonged standing
(as will be discussed further in Chapter 30).

External compression is an important determinant of venous
volume. This is especially true of veins in skeletal muscle. Very
high pressures are developed inside skeletal muscle tissue dur-
ing contraction and cause venous vessels to collapse. Because
veins and venules have one-way valves, the blood displaced
from veins during skeletal muscle contraction is forced in the
forward direction toward the right heart. In fact, rhythmic
skeletal muscle contractions can produce a considerable
pumping action, often called the skeletal muscle pump, which
helps return blood to the heart during exercise.
SUMMARY OF PRIMARY
VASCULAR CONTROL
MECHANISMS
Certain general factors dominate the primary control of the
peripheral vasculature when it is viewed from the standpoint
of overall cardiovascular system function; these influences are
summarized in Figure 27–4. Basal tone, local metabolic vaso-
dilator factors, and sympathetic vasoconstrictor nerves acting
through α1-receptors are the major factors controlling arterio-
lar tone and therefore the blood flow through peripheral
organs. Sympathetic vasoconstrictor nerves, internal pressure,
and external compression are the most important influences
on venous diameter and therefore on peripheral–central dis-
tribution of blood volume.
The flow in organs such as the brain, heart muscle, and skel-
etal muscle is very strongly regulated by local metabolic con-
trol, whereas the flow in the kidneys, skin, and splanchnic
Reflex influences Local influences
Basal tone
Sympathetic
constrictor NE α
nerves
Vasodilator
metabolites
Arterioles
Passive
distention
Sympathetic α P
constrictor NE
nerves
External
P
compression
Veins
FIGURE 27–4 Primary influences on arterioles and veins.
NE, norepinephrine; α, alpha-adrenergic receptor; P, pressure.
(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology,
6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
CHAPTER 27 Vascular Control 269
organs is very strongly regulated by sympathetic nerve activity.
Consequently, some organs are automatically forced to par-
ticipate in overall cardiovascular reflex responses to a greater
extent than are other organs. The overall plan seems to be that
in cardiovascular emergency, flow to the brain and heart will
be preserved at the expense of everything else.
VASCULAR CONTROL IN
SPECIFIC ORGANS
The details of vascular control in many specific organs are pre-
sented in several other sections of this book. Included below
are descriptions of vascular control in some important organs
that are not covered elsewhere.
VASCULAR CONTROL OF
CORONARY BLOOD FLOW
The major right and left coronary arteries that serve the heart
tissue are the first vessels to branch off the aorta. Thus, the driv-
ing force for myocardial blood flow is the systemic arterial pres-
sure, just as it is for other systemic organs. Most of the blood
that flows through the myocardial tissue returns to the right
atrium by way of a large cardiac vein called the coronary sinus.
Local Metabolic Control
As emphasized before, coronary blood flow is controlled pri-
marily by local metabolic mechanisms and thus it responds
rapidly and accurately to changes in myocardial oxygen con-
sumption. In a resting individual, the myocardium extracts
70–75% of the oxygen in the blood that passes through it, which
is more than any other organ does. Myocardial oxygen extrac-
tion cannot increase significantly from its resting value. Conse-
quently, increases in myocardial oxygen consumption must be
accompanied by appropriate increases in coronary blood flow.
The issue of which metabolic vasodilator factors play the
dominant role in modulating the tone of coronary arterioles is
unresolved. Many believe that adenosine, released from myo-
cardial muscle cells in response to increased metabolic rate, may
be an important local coronary metabolic vasodilator influence.
Regardless of the specific details, myocardial oxygen consump-
tion is the most important influence on coronary blood flow.
Systolic Compression
Large forces and/or pressures are generated within the myo-
cardial tissue during cardiac muscle contraction. Such
intramyocardial forces press on the outside of coronary vessels
and cause them to collapse during systole. Because of this sys-
tolic compression and the associated collapse of coronary
vessels, coronary vascular resistance is greatly increased dur-
ing systole. The result, at least for much of the left ventricular
myocardium, is that coronary flow is lower during systole than
270 SECTION V Cardiovascular Physiology
Aortic pressure
Left ventricular pressure
Left coronary flow
FIGURE 27–5 Phasic flows in the left and
right coronary arteries in relation to aortic
and left ventricular pressures. (Modified with
permission from Mohrman DE, Heller LJ: Cardiovascular Right coronary flow
Physiology, 6th ed. New York: Lange Medical Books/
McGraw-Hill, 2006.)
during diastole, even though systemic arterial pressure (i.e.,
coronary perfusion pressure) is highest during systole. This is
illustrated in the left coronary artery flow trace shown in Fig-
ure 27–5. Systolic compression has much less effect on flow
through the right ventricular myocardium. This is because the
peak systolic intraventricular pressure is much lower for the
right heart than for the left, and the systolic compressional
forces in the right ventricular wall are correspondingly less
than those in the left ventricular wall.
Because the endocardial surface of the left ventricle is exposed
to intraventricular pressure (∼120 mm Hg during systole), and
the epicardial surface is exposed only to intrathoracic pressure
(∼0 mm Hg), systolic compressional forces on coronary vessels
are greater in the endocardial layers of the left ventricular wall
than in the epicardial layers. Thus, the flow to the endocardial
layers of the left ventricle is impeded more than the flow to epi-
cardial layers by systolic compression. Normally, the endocardial
region of the myocardium can make up for the lack of flow dur-
ing systole by a high flow in the diastolic interval. However, when
coronary blood flow is limited—for example, by coronary dis-
ease and stenosis—the endocardial layers of the left ventricle are
often the first regions of the heart to have difficulty maintaining
a flow sufficient for their metabolic needs. Myocardial infarcts
(areas of tissue killed by lack of blood flow) occur most frequently
in the endocardial layers of the left ventricle.
Neural Influences on Coronary Flow
Coronary arterioles are densely innervated with sympathetic
vasoconstrictor fibers, yet when the activity of the sympathetic
nervous system increases, the coronary arterioles normally
vasodilate rather than vasoconstrict. This is because an
increase in sympathetic tone increases myocardial oxygen
0
0
consumption by increasing heart rate and contractility. The
increased local metabolic vasodilator influence outweighs the
concurrent neurogenic vasoconstrictor. Whether these coro-
nary vasoconstrictor fibers might be functionally important in
certain pathological situations is an open question.
VASCULAR CONTROL OF
SKELETAL MUSCLE BLOOD FLOW
Because of the large mass of skeletal muscle, blood flow
through it is an important factor in overall cardiovascular
hemodynamics. Collectively, the skeletal muscles constitute
40–45% of body weight—more than any other single body
organ. Even at rest, about 15% of the cardiac output goes to
skeletal muscle, and during strenuous exercise skeletal muscle
may receive more than 80% of the cardiac output. Resting
skeletal muscle has a high level of intrinsic vascular tone.
Because of this high tone of smooth muscle in resistance ves-
sels of resting skeletal muscles, the blood flow per gram of tis-
sue is low when compared with that of other organs such as
the kidneys. However, resting skeletal muscle blood flow is
still substantially above that required to sustain its metabolic
needs. Resting skeletal muscles normally extract only 25–30%
of the oxygen delivered to them in arterial blood. Thus,
changes in the activity of sympathetic vasoconstrictor fibers
can reduce resting muscle blood flow without compromising
resting tissue metabolic processes.
Local metabolic control of arteriolar tone is the most impor-
tant influence on blood flow through exercising muscle. A
particularly important characteristic of skeletal muscle is its
very wide range of metabolic rates. During strenuous exercise,
the oxygen consumption rate of and oxygen extraction by

skeletal muscle tissue can reach the high values typical of the
myocardium. In most respects, the factors that control blood
flow to exercising muscle are similar to those that control cor-
onary blood flow. Local metabolic control of arteriolar tone is
very strong in exercising skeletal muscle, and muscle oxygen
consumption is the most important determinant of its blood
flow. Blood flow in skeletal muscle can increase 20-fold during
a bout of strenuous exercise.
Alterations in sympathetic neural activity can alter nonex-
ercising skeletal muscle blood flow. For example, maximum
sympathetic discharge rates can decrease blood flow in a
resting muscle to less than one fourth its normal value, and,
conversely, if all neurogenic tone is removed, resting skeletal
muscle blood flow may double. This is a modest increase in
flow compared with what can occur in an exercising skeletal
muscle. Nonetheless, because of the large mass of tissue
involved, changes in the vascular resistance of resting skeletal
muscle brought about by changes in sympathetic activity are
very important in the overall reflex regulation of arterial
pressure.
Alterations in sympathetic neural activity can influence
exercising skeletal muscle blood flow. As will be discussed in
Chapter 72, the cardiovascular response to muscle exercise
involves a general increase in sympathetic activity. This
reduces flow to susceptible organs, which include nonexer-
cising muscles. In exercising muscles, the increased sympa-
thetic vasoconstrictor nerve activity is not evident as outright
vasoconstriction but does limit the degree of metabolic vaso-
dilation. One important function that this seemingly coun-
terproductive process may serve is preventing an excessive
reduction in TPR during exercise. Indeed, if arterioles in
most of the skeletal muscles in the body were allowed to
dilate to their maximum capacity simultaneously, TPR would
be so low that the heart could not possibly supply enough
cardiac output to maintain arterial pressure.
Rhythmic contractions can increase venous return from
exercising skeletal muscle. As in the heart, muscle contraction
produces large compressional forces within the tissue, which
can collapse vessels and impede blood flow. Strong, sustained
(tetanic) skeletal muscle contractions may actually stop mus-
cle blood flow. About 10% of the total blood volume is nor-
mally contained within the veins of skeletal muscle, and during
rhythmic exercise the skeletal muscle pump is very effective in
displacing blood from skeletal muscle veins. Valves in the
veins prevent reverse flow back into the muscles. Blood dis-
placed from skeletal muscle into the central venous pool is an
important factor in the hemodynamics of strenuous whole-
body exercise.
Veins in skeletal muscle can constrict in response to
increased sympathetic activity. However, they are sparsely
innervated with sympathetic vasoconstrictor fibers, and the
rather small volume of blood that can be mobilized from skel-
etal muscle by sympathetic nerve activation is probably not of
much significance to total body hemodynamics. This is
in sharp contrast to the large displacement of blood from exer-
cising muscle by the muscle pump mechanism. (This will be
CHAPTER 27 Vascular Control 271
discussed in more detail when postural reflexes are considered
in Chapter 30.)
VASCULAR CONTROL OF
CEREBRAL BLOOD FLOW
Interruption of cerebral blood flow for more than a few sec-
onds leads to unconsciousness. One rule of overall cardiovas-
cular system function is that, in all situations, measures are
taken that are appropriate to preserve adequate blood flow to
the brain. Cerebral blood flow is regulated almost entirely by
local mechanisms. The brain as a whole has a nearly constant
rate of metabolism that, on a per gram basis, is nearly as high
as that of myocardial tissue. Flow through the cerebrum is
autoregulated very strongly and is little affected by changes in
arterial pressure unless it falls below about 60 mm Hg. When
arterial pressure decreases below 60 mm Hg, brain blood flow
decreases proportionately. It is presently unresolved whether
metabolic mechanisms or myogenic mechanisms or both are
involved in the phenomenon of cerebral autoregulation.
Local changes in cerebral blood flow may be influenced by
local metabolic conditions. Presumably because the overall
average metabolic rate of brain tissue shows little variation,
total brain blood flow is remarkably constant in most situa-
tions. The cerebral activity in discrete locations within the
brain, however, changes from situation to situation. As a result,
blood flow to discrete regions is not constant but closely fol-
lows the local neuronal activity. The mechanisms responsible
for this strong local control of cerebral blood flow are as yet
undefined, but H+, K+, oxygen, and adenosine seem most
likely to be involved.
As in most organs, cerebral blood flow increases whenever
the partial pressure of carbon dioxide (Pco2) in arterial blood
increases and, conversely, cerebral blood flow decreases when-
ever Pco2 decreases below normal. This is the normal state of
affairs in most tissues but it has important nonvascular conse-
quences when it happens in the brain. For example, the dizzi-
ness, confusion, and even fainting that can occur when a
person hyperventilates (and “blows off ” CO2) are direct
results of cerebral vasoconstriction. It appears that cerebral
arterioles respond not to changes in Pco2 but to changes in the
extracellular H+ concentration (i.e., pH) caused by changes in
Pco2. Cerebral arterioles also dilate whenever the partial pres-
sure of oxygen (Po2) in arterial blood decreases significantly
below normal values. However, higher-than-normal arterial
blood Po2, such as that caused by pure oxygen inhalation, pro-
duces little decrease in cerebral blood flow.
Sympathetic and parasympathetic neural influences on cere-
bral blood flow are minimal. Although cerebral vessels receive
both sympathetic vasoconstrictor and parasympathetic vasodi-
lator fiber innervation, cerebral blood flow is influenced very
little by changes in the activity of either under normal circum-
stances. Sympathetic vasoconstrictor responses may, however, be
important in protecting cerebral vessels from excessive passive
distention following large, abrupt increases in arterial pressure.
272 SECTION V Cardiovascular Physiology
The blood–brain barrier refers to the tightly connected vas-
cular endothelial cells that severely restrict transcapillary move-
ment of all polar and many other substances. Because of this
blood–brain barrier, the extracellular space of the brain repre-
sents a special fluid compartment in which the chemical com-
position is regulated separately from that in the plasma and
general body extracellular fluid compartment. The extracellular
compartment of the brain encompasses both interstitial fluid
and cerebrospinal fluid (CSF) that surrounds the brain and
spinal cord and fills the brain ventricles. The CSF is formed
from plasma by selective secretion (not simple filtration) by spe-
cialized tissues, the choroid plexus, located within the cerebral
ventricles. These processes regulate the chemical composition
of the CSF. The interstitial fluid of the brain takes on the chemi-
cal composition of CSF through free diffusional exchange.
The blood–brain barrier serves to protect the cerebral cells
from ionic disturbances in the plasma because it is not very
permeable to charged substances. Also, by exclusion and/or
endothelial cell metabolism, it prevents many circulating hor-
mones (and drugs) from influencing the parenchymal cells of
the brain and the vascular smooth muscle cells in brain ves-
sels. Brain capillaries have a special carrier system for glucose
and present no barrier to oxygen and carbon dioxide diffu-
sion. Thus, the blood–brain barrier does not restrict nutrient
supply to the brain tissue.
VASCULAR INFLUENCES ON
PULMONARY BLOOD FLOW
See Chapter 34.
VASCULAR CONTROL OF RENAL
BLOOD FLOW
See Chapter 40.
VASCULAR CONTROL OF
SPLANCHNIC BLOOD FLOW
See Chapter 49.
VASCULAR CONTROL OF
CUTANEOUS BLOOD FLOW
See Chapter 70.
CLINICAL CORRELATION
A 58-year-old man comes to the emergency room com-
plaining of weakness and severe chest pain. He is a sales-
man in a high stress industry, has smoked two packs of
cigarettes a day for more than 25 years, and eats a high-fat,
high-salt diet. He is overweight, pale, and sweaty and is
clutching his chest. His heart rate is 110 beats/min and his
blood pressure is 110/90 mm Hg. His medical record
indicates that he has been treated with sublingual nitro-
glycerin for mild angina pectoris for several years and
had been instructed about lifestyle changes. The angina
has been getting more severe and required increasingly
more nitroglycerin to achieve relief. This time, the nitro-
glycerin has not worked. An ECG indicates that he has a
myocardial infarction in the anterior wall of the left ven-
tricle. He is taken immediately to the cardiac catheteriza-
tion laboratory and an angiogram reveals an almost
complete occlusion of his left anterior descending coro-
nary artery. A stent is placed in the artery and blood flow
is restored to the ischemic tissue.
The condition experienced by this man occurs when-
ever coronary blood flow decreases below that required to
meet the metabolic needs of the heart. The myocardium
becomes ischemic and pumping capability of the heart is
impaired. The most common cause of coronary artery
disease is atherosclerosis of the large coronary arteries
and this man had several of the known risk factors (smok-
ing, obesity, high stress, poor diet, high blood cholesterol).
Localized lipid deposits called plaques develop within the
arterial walls and with severe disease may become large
enough to permanently narrow the lumen of arteries. If
the coronary artery narrowing (stenosis) is not too severe,
local metabolic vasodilator mechanisms may reduce arte-
riolar resistance sufficiently to compensate for the abnor-
mally increased coronary arterial resistance.
Coronary artery disease can jeopardize cardiac func-
tion in several ways. (1) Ischemic muscle cells are electri-
cally irritable and the danger of fibrillation is enhanced
(see Chapter 25) because ectopic pacemaker foci may
develop. (2) Platelet aggregation and clotting function
may be abnormal in atherosclerotic coronary arteries
and the danger of thrombi or emboli formation is
enhanced (see Chapter 22). (3) Myocardial ischemia pro-
duces intense, debilitating chest pain called angina
pectoris. Anginal pain is often absent in individuals with
coronary artery disease when they are resting but is
induced during physical exertion or emotional excite-
ment when sympathetic activity is increased and myo-
cardial oxygen consumption is elevated.
Primary treatment of coronary artery disease includes
lifestyle alterations and attempts to lower blood lipids by
dietary and pharmacological techniques. Treatment of
angina that is a result of coronary artery disease may first
involve quick-acting vasodilator drugs such as nitroglyc-
erin to provide relief during an anginal attack. These
“nitrate” drugs are NO donors and directly vasodilate coro-
nary vessels to acutely increase coronary blood flow. In
addition to increasing myocardial oxygen delivery, nitrates

reduce myocardial oxygen demand by dilating systemic
veins (reducing preload) and by decreasing arterial resis-
tance (reducing afterload). Second, β-adrenergic blocking
agents such as propranolol may be used to block the effects
of cardiac sympathetic nerves on heart rate and contractility.
These agents limit myocardial oxygen consumption and
prevent it from increasing above the level that the compro-
mised coronary blood flow can sustain. Third, calcium
channel blockers such as verapamil may be used to dilate
coronary and systemic blood vessels, and to lower blood
pressure and heart rate. These drugs, which block entry of
calcium into the vascular smooth muscle cell, interfere
with normal excitation–contraction coupling.
Invasive or surgical interventions may be used to treat
coronary artery stenosis. Fluoroscopic techniques com-
bined with radio-opaque contrast injections can be used
to visualize the coronary arteries. A balloon-tipped cath-
eter can be threaded into the occluded region of the coro-
nary artery and rapidly inflated to squeeze the plaque
against the vessel wall and improve the patency of the ves-
sel. This technique, called coronary angioplasty, may also
be effective in opening occlusions produced by intravas-
cular clots associated with acute myocardial infarction. A
small, mesh tubular device called a stent is often implanted
inside the vessel at the angioplasty site. This rigid implant
has been shown to improve continued patency of the ves-
sel over a longer period than angioplasty alone. If angio-
plasty and stent placement is inappropriate or unsuccessful,
coronary bypass surgery may be performed. The stenotic
coronary artery segments are bypassed by implanting
parallel low-resistance pathways formed from either nat-
ural (e.g., saphenous vein or mammary artery) or artifi-
cial vessels.
CHAPTER SUMMARY
■ Continuous adjustments of vascular diameter are required to
properly distribute the cardiac output to the various systemic
tissues (the role of arterioles) and maintain adequate cardiac
filling (the role of veins).
■ Vascular adjustments are made by changes in the tone of
vascular smooth muscle.
■ Vascular smooth muscle has many properties that make it
sensitive to a wide array of local and reflex stimuli and capable
of maintaining tone for long periods of time.
■ The tone of arterioles, but not veins, can be strongly influenced
by local vasodilator factors produced by local tissue metabo-
lism.
■ In abnormal situations (such as tissue injury or severe blood
volume depletion), certain local factors such as histamine and
bradykinin, and hormonal factors such as vasopressin and
angiotensin have significant vascular influences.
CHAPTER 27 Vascular Control 273
■ Sympathetic vasoconstrictor nerves provide the primary reflex
mechanisms for regulating both arteriolar and venous tone.
■ Sympathetic vasoconstrictor nerves release norepinephrine,
which interacts with α1-adrenergic receptors on vascular
smooth muscle to induce vasoconstriction.
■ The relative importance of local metabolic versus reflex
sympathetic control of arteriolar tone (and therefore blood
flow) varies from organ to organ.
■ In many organs (such as brain, heart muscle, and exercising
skeletal muscle), blood flow normally closely follows metabolic
rate because of local metabolic influences on arterioles.
■ In other organs (such as skin and kidneys), blood flow is
normally regulated more by sympathetic nerves than by
local metabolic conditions.
STUDY QUESTIONS
1. Vascular smooth muscle differs from cardiac muscle in that it
A) contains no actin molecules.
B) can be directly activated in the absence of action potentials.
C) is unresponsive to changes in intracellular calcium levels.
D) is unresponsive to changes in membrane potentials.
E) is unresponsive to changes in muscle length.
2. Arteriolar constriction tends to do which of the following?
A) decrease total peripheral resistance
B) decrease mean arterial pressure
C) decrease capillary hydrostatic pressure
D) increase transcapillary fluid filtration
E) increase blood flow through the capillary bed
3. When an organ responds to an increase in metabolic activity
with a decrease in arteriolar resistance, this is known as
A) active hyperemia.
B) reactive hyperemia.
C) autoregulation of blood flow.
D) flow-dependent vasodilation.
E) metabolic vasoconstriction.
4. A particular vascular bed demonstrates the phenomenon
of autoregulation of blood flow. This means that
A) when flow increases, capillary pressure increases.
B) when metabolic activity increases, flow increases.
C) when arterial pressure increases, arteriolar resistance
increases.
D) when blood flow is interrupted, arteriolar resistance
decreases.
E) when arterial pressure falls, sympathetic vasoconstriction
occurs.
5. Which of the following is most likely to increase coronary
blood flow?
A) decreased arterial pressure
B) decreased heart rate
C) increased sympathetic neural activity
D) reduced left ventricular end-diastolic volume
E) reduced left ventricular ejection fraction
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 28
C H A P T E R

Venous Return and

Cardiac Output
David E. Mohrman and Lois Jane Heller

O B J E C T I V E S

■ Describe the overall arrangement of the systemic circulation

and identify the primary functional properties of each of its major
components.
■ Define mean circulatory filling pressure and state the primary factors
that determine it.
■ Define venous return and explain how it is distinguished from cardiac
output.
■ State why cardiac output and venous return must be equal in the
steady state.
■ List the factors that control venous return.
■ Describe the relationship between central venous pressure and venous
return and draw the normal venous return curve.
■ Define peripheral venous pressure.
■ List the factors that determine peripheral venous pressure.
■ Predict the shifts in the venous return curve that occur with altered blood
volume and altered venous tone.
■ Describe how the output of the left heart pump is matched to that of the
right heart pump.
■ Draw the normal venous return and cardiac output curves on a graph and
describe the significance of the point of curve intersection.
■ Predict how normal venous return, cardiac output, and central venous
pressure will be altered with any given combination of changes in cardiac
sympathetic tone, peripheral venous sympathetic tone, or circulating
blood volume.
■ Identify conditions that may result in abnormally high or low central venous
pressure.

venous side of this system is often conceptually separated into

INTERACTION OF
SYSTEM COMPONENTS
As illustrated in Figure 28–1, the systemic cardiovascular sys-
tem is a closed hydraulic circuit that includes the heart, arter-
ies, arterioles, capillaries, and veins. (Note: The pulmonary
circuit and lymphatics are not included because they do not
influence the major points to be made in this chapter.) The
two different compartments: (1) a large and diverse peripheral
section (the peripheral venous compartment) and (2) a
smaller intrathoracic section that includes the venae cavae and
the right atrium (the central venous compartment). Each of
the segments of this circuit has a distinctly different role to
play in the overall operation of the system because of inherent
differences in anatomical volume, resistance to blood flow,
and compliance that are summarized in Table 28–1.

275

Ch28_275-284.indd 275 11/26/10 11:51:25 AM

276 SECTION V Cardiovascular Physiology

Th Arteries
ora
x

Arterioles

Ventricle

Atrium Capillaries
Central venous compartment

FIGURE 28–1 Major functionally distinct

Peripheral venous compartment
components of the systemic cardiovascular
circuit. (Modified with permission from Mohrman DE, Heller
LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical
Books/McGraw-Hill, 2006.)

Note especially the surprisingly high ventricular diastolic
compliance of 24 mL/mm Hg in Table 28–1. This value indi-
cates how sensitive the ventricular end-diastolic volume (and
therefore stroke volume and cardiac output) is to small changes
in cardiac filling pressure (i.e., central venous pressure).
Cardiac filling pressure is a crucial factor that determines how
well the cardiovascular system functions.
MEAN CIRCULATORY
FILLING PRESSURE
Imagine the heart arrested in diastole with no flow around the
circuit shown in Figure 28–1. It will take a certain amount of
blood just to fill the anatomical space contained by the sys-
temic system without stretching any of its walls or developing
any internal pressure. In a 70-kg adult, this amount is 3.5 L, as
indicated by the total systemic circuit volume (V0) in Table
28–1. Normally, however, the systemic circuit contains about
4.5 L of blood and thus is somewhat inflated. From the total
systemic circuit compliance (C) given in Table 28–1, one can
see that an extra 1,000 mL of blood would result in an internal
pressure of about 7 mm Hg (i.e., 1,000 mL/140 mL/mm Hg).
This theoretical pressure is called the mean circulatory filling
pressure and is the pressure that would exist throughout the
system in the absence of flow.
The two major factors that affect mean circulatory filling
pressure are the circulating blood volume and the state of
the peripheral venous vessel tone. In the latter case, look at
Figure 28–1 and imagine how constriction of the vessels of the
large venous compartment (increasing venous tone) will sig-
nificantly increase pressure throughout the system. In con-

TABLE 28–1 Typical properties of the major components of the systemic cardiovascular circuit.a
Compartment V0 (mL) C (mL/mm Hg) R (mm Hg/(L/min))

Ventricle in diastole 30 24 0

Arteries 600 2 1

Arterioles 100 0 13

Capillaries 250 0 5

Peripheral venous compartment 2,500 110 1

Central venous compartment 80 4 0

Entire circuit 3,560 140 20

a
Values are for a normal, young, resting 70-kg adult. V0, anatomical volume of compartment at zero pressure: C, compliance of compartment; R, resistance to flow through
compartment.
Reproduced with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.

Venous return Central venous compartment
Great veins in thorax and right atrium
trast, squeezing on arterioles (increasing arteriolar tone) will
have a negligible effect on mean circulatory filling pressure
because arterioles contain so little blood in any state. The other
major components of the system (arteries and capillaries) do
not actively change their contained volume.
FLOW-INDUCED DISTRIBUTION OF
BLOOD VOLUME AND PRESSURE
The presence of flow around the circuit does not change the
total volume of blood in the system or the mean circulatory
filling pressure. The flow caused by cardiac pumping action
does, however, tend to shift some of the blood volume from
the venous side of the circuit to the arterial side. This causes
pressures on the arterial side to increase above the mean cir-
culatory pressure while pressures on the venous side
decrease below it. Because veins are about 50 times more
compliant than arteries (Table 28–1), the flow-induced
decrease in venous pressure is only about 1/50th as large as
the accompanying increase in arterial pressure. Thus,
flow or no flow, pressure in the peripheral venous compart-
ment is normally quite close to the mean circulatory filling
pressure.
CENTRAL VENOUS PRESSURE:
AN INDICATOR OF
CIRCULATORY STATUS
The cardiovascular system must continuously adjust to meet
changing metabolic demands of the body. Because the cardio-
vascular system is a closed hydraulic loop, adjustments in any
one part of the circuit will have pressure, flow, and volume
effects throughout the circuit. Because of the critical influence
of cardiac filling on cardiovascular function, the remainder of
this chapter will focus on the factors that determine the pres-
sure in the central venous compartment. In addition, the way
in which measures of central venous pressure can provide
CHAPTER 28 Venous Return and Cardiac Output 277
Cardiac output
FIGURE 28–2 Distinction between cardiac
output and venous return. (Modified with
permission from Mohrman DE, Heller LJ: Cardiovascular
Physiology, 6th ed. New York: Lange Medical Books/
McGraw-Hill, 2006.)
clinically useful information about the state of the circulatory
system will be discussed.
The central venous compartment corresponds roughly to
the volume enclosed by the right atrium and the great veins
in the thorax. Blood leaves the central venous compartment
by entering the right ventricle at a rate that is equal to the
cardiac output. Venous return, in contrast, is the rate at
which blood returns to the thorax from the peripheral
vascular beds and thus is the rate at which blood enters the
central venous compartment. The important distinction
between venous return to the central venous compartment
and cardiac output from the central venous compartment is
illustrated in Figure 28–2.
In any stable situation, venous return must equal cardiac
output or blood would gradually accumulate in either the cen-
tral venous compartment or the peripheral vasculature. How-
ever, there often are temporary differences between cardiac
output and venous return. Whenever such differences exist,
the volume of the central venous compartment must be chang-
ing. Because the central venous compartment is enclosed by
elastic tissues, any change in central venous volume produces
a change in central venous pressure.
As discussed in Chapter 24, the central venous pressure
(i.e., cardiac filling pressure) has an extremely important posi-
tive influence on cardiac output (Starling’s law of the heart).
As explained below, central venous pressure has an equally
important negative effect on venous return. Thus, central
venous pressure is always automatically driven to a value that
makes cardiac output equal to venous return.
INFLUENCE OF CENTRAL VENOUS
PRESSURE ON VENOUS RETURN
The important factors involved in the process of venous
return can be summarized as shown in Figure 28–3A. Ana-
tomically the peripheral venous compartment is scattered
throughout the systemic organs, but functionally it can be
viewed as a single vascular space that has a particular pressure
278 SECTION V Cardiovascular Physiology
A
From
P PV ≅
capillaries
7 mm Hg
Peripheral venous compartment
Venous resistance
8
Venous return (L/min)
6
Ve
nou
s
4 nc
2
0 2
Central venous pressure (mm Hg)
FIGURE 28–3 Venous Return A) Factors influencing venous return. B) The venous function curve. (Modified with permission from Mohrman DE,
Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
(PPV) at any instant. The normal operating pressure in the
peripheral venous compartment is usually very close to mean
circulatory filling pressure. Moreover, the same factors that
influence mean circulatory filling pressure have essentially
equal influences on peripheral venous pressure. Thus,
“peripheral venous pressure” can be viewed as essentially
equivalent to “mean circulatory filling pressure.” The blood
flow between the peripheral venous compartment and
the central venous compartment is governed by the basic flow
equation Q̇ = Δ P/R, where ΔP is the pressure decrease between
the peripheral and central venous compartments and R the
small resistance associated with the peripheral veins. In the
example in Figure 28–3, peripheral venous pressure is
assumed to be 7 mm Hg. Thus, there will be no venous return
when the central venous pressure (PCV) is also 7 mm Hg as
shown in Figure 28–3B.
If the peripheral venous pressure remains at 7 mm Hg,
decreasing central venous pressure will increase the pressure
difference across the venous pathway and consequently cause
an increase in venous return to the central venous pool. This
relationship is summarized by the venous function curve,
which shows how venous return increases as central venous
Thorax
Intrathoracic pressure ≅
0 mm Hg
P CV
Venous return Cardiac output
Central venous
compartment
fu
tio
n
cu
rv
e
4 6 8 10
pressure decreases. There are two minor additional points to
be made about this venous function curve. First, changes in
venous resistance can influence the slope of the venous func-
tion curve but, in the example given, venous return will be
0 L/min when PCV = 7 mm Hg at any level of venous vascular
resistance. Second, if central venous pressure reaches very low
values and decreases below the intrathoracic pressure, the
veins in the thorax collapse and tend to limit venous return. In
the example of Figure 28–3, intrathoracic pressure is taken
to be 0 mm Hg and the flat portion of the venous function
curve indicates that lowering central venous pressure below
0 mm Hg produces no additional increase in venous return.
Just as a cardiac function curve shows how central venous
pressure influences cardiac output, a venous function curve
shows how central venous pressure influences venous return.
(By convention, these relationships are plotted with the inde-
pendent variable on the horizontal axis and the dependent vari-
able on the vertical axis and they must be read in that sense.
For example, Figure 28–3B says that increasing central venous
pressure tends to cause decreased venous return. Figure 28–3B
does not imply that increasing venous return will tend to lower
central venous pressure.)
 CHAPTER 28 Venous Return and Cardiac Output 279

INFLUENCE OF PERIPHERAL
VENOUS PRESSURE ON VENOUS 10

RETURN In

Venous return (L/min)

8 cr
ea
As can be deduced from Figure 28–3A, it is the pressure dif- se
d
ference between the peripheral and central venous compart- bl
ood
6 Co
ments that determines venous return. Therefore, an increase nt vo
ro lum
in peripheral venous pressure can be just as effective in lv e
De en or
increasing venous return as a decrease in central venous 4 or cr ou ve
ve ea s no
pressure. no se f un us
us d b ct to
The two ways in which peripheral venous pressure can l
to oo
i o n ne
change were discussed in Chapter 26. First, because veins are 2 ne d cu
vo rv
lu e
elastic vessels, changes in the volume of blood contained within m
e
the peripheral veins alter the peripheral venous pressure.
0 2 4 6 8 10
Moreover, because the veins are much more compliant than
Central venous pressure (mm Hg)
any other vascular segment, changes in circulating blood vol-
ume produce larger changes in the volume of blood in the FIGURE 28–4 Effect of changes in blood volume and venous
veins than in any other vascular segment. For example, blood tone on venous function curves. (Modified with permission from Mohrman
DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/
loss by hemorrhage or loss of body fluids through severe
McGraw-Hill, 2006.)
sweating, vomiting, or diarrhea will decrease circulating blood
volume and significantly reduce the volume of blood con-
tained in the veins and thus decrease the peripheral venous
pressure. Conversely, transfusion, fluid retention by the kid-
ney, or transcapillary fluid reabsorption will increase circulat-
CENTRAL VENOUS PRESSURE
ing blood volume and venous blood volume. Whenever DETERMINES BOTH CARDIAC
circulating blood volume increases, so does peripheral venous
pressure. OUTPUT AND VENOUS RETURN
Recall from Chapter 27 that the second way that peripheral The significance of the fact that central venous pressure simul-
venous pressure can be altered is through changes in venous taneously affects both cardiac output and venous return can be
tone produced by increasing or decreasing the activity of sym- best seen by plotting the cardiac function curve (the Starling
pathetic vasoconstrictor nerves supplying the venous smooth curve) and the venous function curve on the same graph, as in
muscle. Peripheral venous pressure increases whenever the Figure 28–5.
activity of sympathetic vasoconstrictor fibers to veins increases.
In addition, an increase in any force compressing veins from
the outside has the same effect on the pressure inside veins as
an increase in venous tone. Thus, such things as muscle exer-
cise and wearing elastic stockings tend to increase peripheral
Cardiac output or Venous return (L/min)

venous pressure.
Whenever peripheral venous pressure is altered, the rela- 10
tionship between central venous pressure and venous return is
also altered. For example, whenever peripheral venous pres- 8
sure is increased by increases in blood volume or by sympa-
thetic stimulation, the venous function curve shifts upward Cardiac function curve
6
and to the right (Figure 28–4). This phenomenon can be most
easily understood by focusing first on the central venous pres-
sure at which there will be no venous return. When peripheral 4
venous pressure is 7 mm Hg, venous return is 0 L/min when Venous function curve
central venous pressure is 7 mm Hg. When peripheral venous 2
pressure is increased to 10 mm Hg, considerable venous return
occurs with a central venous pressure of 7 mm Hg, and venous
return stops only when central venous pressure is increased to 0 2 4 6 8 10
10 mm Hg. Thus, increasing peripheral venous pressure shifts Central venous pressure (mm Hg)
the whole venous function curve to the right. By similar logic, FIGURE 28–5 Interaction of cardiac output and venous
decreased peripheral venous pressure caused by blood loss or return through central venous pressure. (Modified with permission from
decreased sympathetic vasoconstriction of peripheral veins Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical
shifts the venous function curve to the left. Books/McGraw-Hill, 2006.)
280 SECTION V Cardiovascular Physiology
Central venous pressure, as defined earlier, is the filling
pressure of the right heart. Strictly speaking, this pressure
directly affects only the stroke volume and output of the right
heart pump. In most contexts, however, “cardiac output”
implies the output of the left heart pump. How is it then, as has
often been previously implied, that central venous pressure
(the filling pressure of the right heart) profoundly affects car-
diac output (the output of the left heart)? The short answer is
that in the steady state, the right and left hearts have equal
outputs. (Since the right and left hearts always beat with iden-
tical rates, this implies that their stroke volumes must be equal
in the steady state.) The detailed answer is that changes in cen-
tral venous pressure automatically cause essentially parallel
changes in the filling pressure of the left heart (i.e., in left atrial
pressure). Consider, for example, the following sequence of
consequences that a small step-wise increase in central venous
pressure has on a heart that previously was in a steady state:
(1) Increased central venous pressure → (2) increased right
ventricular stroke volume via Starling’s law → (3) increased
output of right heart → (4) right heart output temporarily
exceeds that of the left heart → (5) as long as this imbalance
exists, blood accumulates in the pulmonary vasculature and
raises pulmonary venous and left atrial pressure → (6)
increased left atrial pressure increases left ventricular stroke
volume via Starling’s law → (7) very quickly, a new steady state
will be reached when left atrial pressure has risen sufficiently
to make left ventricular stroke volume exactly equal to the
increased right ventricular stroke volume.
The major conclusion here is that left atrial pressure will
change in the correct direction to match left ventricular stroke
volume to the current right ventricular stroke volume. Conse-
quently, it is usually an acceptable simplification to say that
central venous pressure affects cardiac output as if the heart
consisted only of a single pump as is shown in Figure 28–1.
Note that in Figure 28–5, cardiac output and venous return
are equal (at 5 L/min) only when the central venous pressure is
2 mm Hg. If central venous pressure were to decrease
to 0 mm Hg, cardiac output would decrease (to 2 L/min) and
venous return would increase (to 7 L/min). With a venous
return of 7 L/min and a cardiac output of 2 L/min, the volume
of the central venous compartment would necessarily be
increasing and this would produce a progressively increasing
central venous pressure. In this manner, central venous pres-
sure would return to the original level (2 mm Hg) in a very
short time. Moreover, if central venous pressure were to
increase from 2 to 4 mm Hg, venous return would decrease (to
3 L/min) and cardiac output would increase (to 7 L/min). This
would quickly reduce the volume of blood in the central
venous pool, and the central venous pressure would soon fall
back to the original level. The cardiovascular system automat-
ically adjusts to operate at the point where the cardiac and
venous function curves intersect.
Central venous pressure is always inherently driven to the
value that makes cardiac output and venous return equal.
Cardiac output and venous return always stabilize at the level
where the cardiac function and venous function curves intersect.
Cardiac output or Venous return (L /min)
10
Normal cardiac function curve
8
6
4 N
or
Fu m
al
nc ve
tio n
2 n ou
cu s
rv
e
0 2 4 6 8 10
Central venous pressure (mm Hg)
FIGURE 28–6 Families of cardiac function and venous
function curves. Intersection points indicate equilibrium values
for cardiac output, venous return, and central venous pressure.
(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular
Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
Recall from Chapter 24 that cardiac output is affected by
more than just cardiac filling pressure and that at any moment,
the heart may be operating on any one of a number of cardiac
function curves, depending on the existing level of cardiac
sympathetic tone (see Figure 24–8). The family of possible
cardiac function curves may be plotted along with the family
of possible venous function curves, as shown in Figure 28–6.
At a particular moment, the existing influences on the heart
dictate the cardiac function curve on which it is operating, and
similarly, the existing influences on peripheral venous pres-
sure dictate the venous function curve that applies. Thus, the
influences on the heart and on the peripheral vasculature
determine where the cardiac and venous function curves
intersect and thus what the central venous pressure and car-
diac output (and venous return) are in the steady state. In the
intact cardiovascular system, cardiac output can rise only
when the point of intersection of the cardiac and venous func-
tion curves is raised. All changes in cardiac output are caused
by a shift in the cardiac function curve, a shift in the venous
function curve, or both.
The cardiac function and venous function curves are use-
ful for understanding the complex interactions that occur in
the intact cardiovascular system. With the help of Figure
28–7, let us consider, for example, what happens to the car-
diovascular system when there is a significant loss of blood
(hemorrhage). Assume that before the hemorrhage, sympa-
thetic activity to the heart and peripheral vessels is normal,
as is the blood volume. Therefore, cardiac output is related to
central venous pressure as indicated by the “normal” cardiac
function curve in Figure 28–7. In addition, venous return is
determined by central venous pressure as indicated by the

Cardiac output or Venous return (L /min)
Increased cardiac
10
sympathetic nerve activity
8 loss is increased activity of the sympathetic nerves leading
Normal cardiac function curve
6 curve. Therefore, increased sympathetic activity to veins
D
A tends to shift the venous function curve, originally decreased
Venous constriction
4 after hemorrhage
C increased peripheral venous tone and the shift to a more
B normal venous function curve, the cardiovascular operation
Normal venous
2
function curve
Hemorrhage
0 2 4 6 8 10
Central venous pressure (mm Hg)
FIGURE 28–7 Cardiovascular adjustments to hemorrhage.
(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology,
6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
“normal” venous function curve shown. The normal cardiac
and venous function curves intersect at point A, so cardiac
output is 5 L/min and central venous pressure is 2 mm Hg in
the normal state. When blood volume decreases due to hem-
orrhage, the peripheral venous pressure decreases and the
venous function curve is shifted to the left. In the absence of
any reflex responses, the cardiovascular system must switch
its operation to point B because this is now the point at which
the cardiac function curve and the new venous function
curve intersect. This automatically occurs because at the
moment of blood loss, the venous function curve is shifted
to the left and venous return decreases below cardiac output
at the central venous pressure of 2 mm Hg. This is what leads
to the decrease in the central venous compartment’s volume
and pressure that causes the shift in operation from point A
to point B. By comparing points A and B in Figure 28–7,
note that blood loss itself decreases cardiac output and cen-
tral venous pressure by shifting the venous function curve.
In going from point A to point B, cardiac output decreases
solely because of decreased filling pressure and Starling’s law
of the heart.
Subnormal cardiac output evokes a number of compensa-
tory mechanisms to bring cardiac output back to more normal
levels. One of these is an increase in the activity of cardiac
sympathetic nerves that, as discussed in Chapter 24, causes a
shift to a cardiac function curve that is higher than normal.
The effect of increasing cardiac sympathetic activity is illus-
trated by a shift in cardiovascular operation from point B to
point C. In itself, the increased cardiac sympathetic nerve
activity increases cardiac output (from 3 to 4 L/min) but causes
a further decrease in central venous pressure. This decrease in
central venous pressure occurs because points B and C lie on
CHAPTER 28 Venous Return and Cardiac Output 281
the same venous function curve. Cardiac sympathetic nerves
do not affect the venous function curve. Venous return is
higher at point C than at point B, but the venous function
curve has not shifted.
An additional compensatory mechanism evoked by blood
to veins. Recall that this increases peripheral venous pres-
sure and causes a rightward shift of the venous function
by blood loss, back toward normal. As a consequence of the
shifts from point C to point D in Figure 28–7. Thus, periph-
eral venous constriction raises cardiac output by increasing
central venous pressure and moving upward along a fixed
cardiac function curve. It must be pointed out that separat-
ing the response to hemorrhage into distinct, progressive
steps (i.e., A to B to C to D) is only a conceptualization for
appreciating the individual effects of the different processes
involved. In reality, the reflex venous and cardiac responses
occur simultaneously and so quickly that they will keep up
with the blood loss as it occurs. Thus, the actual response to
hemorrhage would follow nearly a straight line from point
A to point D.
In summary, point D illustrates that normal cardiac output
can be sustained in the face of blood loss by the combined
effect of peripheral and cardiac adjustments. Hemorrhage
is only one of the numerous potential disturbances to the car-
diovascular system. Plots such as those shown in Figure 28–7
are very useful for understanding the many disturbances to
the cardiovascular system and the ways by which they may
be compensated.
CLINICAL IMPLICATIONS OF
ABNORMAL CENTRAL VENOUS
PRESSURES
Although there is no way to actually determine the position of
either cardiac function or venous function curves, important
information about a patient’s circulatory status can be obtained
from measures of central venous pressure. From what has been
presented in this chapter, it is possible to conclude that a
patient with abnormally high central venous pressure must have
a depressed cardiac function curve, a right-shifted venous
function curve, or both. Very high central venous pressures
are a hallmark of patients with congestive heart failure because
they have the combination of dysfunctional heart muscle
(depressed cardiac function curve) and excessive fluid volume
(right-shifted venous function curve). Abnormally low central
venous pressures, on the other hand, could theoretically be
caused by either an increased cardiac function curve or a left-
shifted venous function curve. The clinical reality is that
abnormally low central venous pressures are invariably the
282 SECTION V Cardiovascular Physiology
result of a left shift of the venous function curve caused by
either low blood volume or lack of venous tone.
Rough estimates of a patient’s central venous pressure can
be obtained by observing the external jugular veins. Because
gravity keeps veins in the head and neck collapsed when a nor-
mal individual is upright, there is no distention (or retrograde
pulsations from atrial contractions) observed in these neck
veins. Conversely, when fully recumbent, neck veins are full
and pulsations are detected. If a normal individual is placed in
a semi-recumbent position so that external jugular veins are
positioned at 7 cm above the right atrium, the point between
the collapsed venous segment and the filled segment can often
be visualized. Abnormally high central venous pressure is
associated with neck vein distention at a higher level (perhaps
even when the patient is upright).
Because of its diagnostic value in critical care situations,
central venous pressure is often monitored continuously via
a catheter inserted in a peripheral vein and advanced cen-
trally until its tip is in the central venous compartment (i.e.,
near or in the right atrium). In some situations, it is desirable
to assess left atrial pressure, which is the filling pressure for
the left side of the heart. This is commonly done with a spe-
cialized, flow-directed venous catheter with a small inflat-
able balloon at its tip to drag it with the blood flow through
the right ventricle and pulmonic valve into the pulmonary
artery. The balloon is then deflated and the cannula is
advanced further until it wedges into a terminal branch of
the pulmonary vasculature. The pulmonary wedge pressure
recorded at this junction provides a useful estimate of left
atrial pressure because there are no valves between the left
atrium and the catheter tip.
CLINICAL CORRELATION
A 75-year-old woman visits her doctor complained of
increasing weakness and fatigue, shortness of breath on
minimal exertion, and a recent increase in body weight.
She often has to get up at night to urinate and has noticed
that her feet and ankles seem to be swollen. She reports
several episodes of waking up at night feeling like she could
not catch her breath until she got out of bed and stood at
her open window. She has been physically well until this
condition developed over the last few months. She does
not smoke or drink and takes no medicines except for an
occasional aspirin or antacid. She is 5′3″ (160 cm), 146 lb
(66 kg) with heart rate of 88 beats/min and blood pressure
165/95 mm Hg (normal values 120–140/80–90 mm Hg).
Auscultation of the chest with a stethoscope indicates nor-
mal heart sounds but abnormal breath sounds with fine
crackles heard over both lung bases late in expiration. An
ECG indicates mild left ventricular hypertrophy and her
chest x-ray shows an enlarged cardiac silhouette and pleu-
ral effusion, an accumulation of fluid between the visceral
pleura and parietal pleura. An echocardiogram revealed
dilated cardiac chambers, thickened left ventricular wall,
and a left ventricular ejection fraction of 0.35 (normal
value >0.55) (see Chapter 25).
She was diagnosed with chronic congestive heart failure
secondary to chronic hypertension. She was treated with
a diuretic to increase her urine output and relieve her
symptoms of congestion and an angiotensin converting
enzyme (ACE) inhibitor to reduce her high blood pres-
sure. Once her condition stabilizes, she will be treated
with beta-adrenergic receptor blockers at a low dose to
decrease sympathetic stimulation of the heart.
Chronic heart failure (CHF) exists whenever ventric-
ular function is depressed through conditions that
directly impair the mechanical performance of heart
muscle such as (1) progressive coronary artery disease,
(2) sustained increase in cardiac afterload as that which
accompanies arterial hypertension or aortic valve steno-
sis, (3) reduced functional muscle mass following myo-
cardial infarction, or (4) primary cardiomyopathy.
Regardless of the precipitating cause, most forms of
heart failure are associated ultimately with a reduced
myocyte function. Systolic heart failure is associated
with a left ventricular ejection fraction of less than 0.40.
This also implies that the heart is operating on a lower-
than-normal cardiac function curve, that is, a reduced
cardiac output at any given filling pressure. An example
of the progression of events leading to CHF is well illus-
trated by the cardiac output and venous function curves
shown in Figure 28–8. Initially, normal cardiac output
and normal venous function curves will intersect at
point A with cardiac output of 5 L/min at a central
venous pressure of less than 2 mm Hg. With an abrupt
heart failure as might accompany a myocardial infarc-
tion and severe damage to the ventricular muscle, the
heart’s operation will shift to a much lower-than-normal
cardiac output curve and the “equilibrium” will shift
from the normal point A to point B—that is, cardiac out-
put decreases below normal while central venous pres-
sure increases above normal. The decreased cardiac
output leads to decreased arterial pressure and reflex
activation of the cardiovascular sympathetic nerves.
Increased sympathetic nerve activity tends to (1) raise
the cardiac function curve toward normal and (2)
increase peripheral venous pressure through venous
constriction and thus raises the venous function curve
above normal. The heart’s operation will now shift from
point B to point C. Thus, the depressed cardiac output is
substantially improved by the immediate consequences
of increased sympathetic nerve activity. Note, however,
that the cardiac output at point C is still below normal.
The arterial pressure associated with cardiovascular
operation at point C is likely to be near normal, however,
because higher-than-normal total peripheral resistance
 CHAPTER 28 Venous Return and Cardiac Output 283

↑↑ Fluid retention
Normal heart

12
Normal sympathetic activity

Cardiac output or Venous return (L/min)

↑ Fluid retention
10

↑ Venous tone ↑↑ Sympathetic activity

8
Failing
↑ Sympathetic
heart
Normal activity
6
Normal
sympathetic
A C activity
D E
4

2 B

0 2 4 6 8 10
Central venous pressure (mm Hg)
FIGURE 28–8 Cardiovascular alterations with compensated chronic systolic heart failure. (Modified with permission from Mohrman DE, Heller
LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

will also accompany higher-than-normal sympathetic after reaching the compensated state even though sympa-
nerve activity. thetic activity may have returned to near-normal levels.
In the long term, cardiovascular operation cannot (Net fluid loss from this new steady state with expanded
remain at point C in Figure 28–8. Operation at point body fluid volume requires a period of less-than-normal
C involves higher-than-normal sympathetic activity, and sympathetic activity.)
this will inevitably cause a gradual increase in blood vol- Unfortunately, the consequences of fluid retention in
ume by mechanisms that will be described in Chapter 29. cardiac failure are not all beneficial. Note in Figure 28–8
Over several days, there is a progressive rise in the venous that fluid retention (C → D → E) will cause both periph-
function curve as a result of increased blood volume and, eral and central venous pressures to be much higher than
consequently, increased mean circulatory filling pressure. their normal values. Chronically high central venous
This will progressively shift the cardiovascular operating pressure causes chronically increased end-diastolic vol-
point from C to D to E. ume (cardiac dilation). Up to a point, cardiac performance
Note that increased fluid retention (C → D → E in is improved by increased cardiac filling volume through
Figure 28–8) causes a progressive increase in cardiac out- Starling’s law. Excessive cardiac dilation, however, can
put toward normal and simultaneously allows a reduction impair cardiac function because according to the law of
in sympathetic nerve activity toward the normal value. Laplace, increased total wall tension is required to gener-
Reduced sympathetic activity is beneficial for several rea- ate pressure within an enlarged ventricular chamber.
sons. First, decreased arteriolar constriction permits renal The high venous pressure associated with fluid retention
and splanchnic blood flow to return toward more normal also adversely affects organ function because high venous
values. Second, myocardial oxygen consumption may fall pressure produces transcapillary fluid filtration, edema for-
as sympathetic nerve activity falls, even though cardiac mation, and congestion (hence the commonly used term
output tends to increase. Recall that increased heart rate congestive heart failure). Left heart failure may lead to
and increased cardiac contractility greatly increase myo- pulmonary edema with dyspnea (shortness of breath) and
cardial oxygen consumption. Reduced myocardial oxygen respiratory crisis. Patients often complain of difficulty
consumption is especially beneficial in situations where breathing especially during the night (paroxysmal noctur-
inadequate coronary blood flow is the cause of the heart nal dyspnea). Being recumbent promotes a fluid shift from
failure. In any case, once a normal cardiac output has been the extremities into the central venous pool and lungs,
achieved, the individual is said to be in a “compensated” making the horizontal patient’s pulmonary problems worse.
state. The extracellular fluid volume remains expanded Such patients often sleep more comfortably when propped
284 SECTION V Cardiovascular Physiology
up. Right heart failure results in distended neck veins,
ankle edema, and fluid accumulation in the abdomen
(ascites) with liver congestion and dysfunction. Plasma
volume expansion combines with abnormal liver function
to reduce the concentration of plasma proteins by as much
as 30%. This reduction in plasma oncotic pressure further
contributes to the development of interstitial edema of con-
gestive heart failure.
In the example shown in Figure 28–8, the depression in
the cardiac output curve because of heart failure is only
moderately severe. Thus, it is possible, through moderate
fluid retention, to achieve a new steady state with a nor-
mal cardiac output and essentially normal sympathetic
activity (point E). The situation at point E is relatively
stable because the stimuli for further fluid retention have
been removed. If, however, the heart failure is more severe,
the cardiac output curve may be so depressed that normal
cardiac output cannot be achieved by any amount of fluid
retention. In these cases fluid retention is extremely
marked, as is the elevation in venous pressure, and the
complications of congestion are very serious problems.
CHAPTER SUMMARY
■ Mean circulatory filling pressure is a theoretical measure
of pressure in the systemic circuit when flow is stopped and
is influenced primarily by blood volume and peripheral
venous tone.
■ Central venous pressure has a negative influence on venous
return that can be illustrated graphically as a venous function
curve.
■ Peripheral venous pressure has a positive influence on venous
return and can be elevated by increased blood volume and/or
increased venous tone.
■ Because of its opposing influences on cardiac output and
venous return, central venous pressure automatically attains a
value that makes cardiac output and venous return equal.
■ Central venous pressure gives clinically relevant information
about circulatory status.
■ Central venous pressure can be estimated noninvasively
by noting the fullness of a patient’s jugular veins.
STUDY QUESTIONS
1. In a severely dehydrated patient, you would expect to find
A) a depressed cardiac function curve.
B) an increased mean circulatory filling pressure.
C) an increased central venous pressure.
D) distended jugular veins.
E) decreased cardiac output.
2. If you gave a blood transfusion to a patient who had recently
experienced a severe hemorrhage, you would expect
A) to expand arterial volume.
B) to expand venous volume.
C) to decrease central venous pressure.
D) to decrease the mean circulatory filling pressure.
E) to reduce cardiac output.
3. Which of the following would directly (by themselves in the
absence of any compensatory responses) tend to decrease
central venous (cardiac filling) pressure?
A) increased sympathetic nerve activity to only the heart
B) increased parasympathetic nerve activity to only the heart
C) increased blood volume
D) decreased total peripheral resistance
E) immersion in water up to the waist
4. Which of the following will decrease the mean circulatory
filling pressure?
A) increased circulating blood volume
B) increased cardiac output
C) decreased arteriolar tone
D) decreased venous tone
E) increased arterial stiffness
5. In a steady state, venous return will be greater than cardiac
output when
A) peripheral venous pressure is higher than normal.
B) blood volume is higher than normal.
C) heart rate is lower than normal.
D) cardiac contractility is lower than normal.
E) Never, because in a steady state venous return must
equal cardiac output.
 29
C H A P T E R

Arterial Pressure
Regulation
David E. Mohrman and Lois Jane Heller

O B J E C T I V E S

■ Identify the sensory receptors, afferent pathways, central integrating

centers, efferent pathways, and effector organs that participate in the
arterial baroreceptor reflex.
■ State the location of the arterial baroreceptors and describe their operation.
■ Describe how changes in the afferent input from arterial baroreceptors
influence the activity of the sympathetic and parasympathetic preganglionic
fibers.
■ Describe how the sympathetic and parasympathetic outputs from the
medullary cardiovascular centers change in response to changes in arterial
pressure.
■ Diagram the chain of events that are initiated by the arterial baroreceptor
reflex to compensate for a change in arterial pressure.
■ Describe how inputs to the medullary cardiovascular centers from
cardiopulmonary baroreceptors, and arterial and central chemoreceptors
influence sympathetic activity, parasympathetic activity, and mean arterial
pressure.
■ Describe and indicate the mechanisms involved in the cerebral
ischemic response, the Cushing reflex, the alerting reaction, blushing,
vasovagal syncope, and the cardiovascular responses to emotion
and pain.
■ Describe baroreceptor adaptation.
■ Describe the influence of changes in body fluid volume on arterial pressure
and diagram the steps involved in this process.
■ Describe how mean arterial pressure is adjusted in the long term to that
which causes fluid output rate to equal fluid intake rate.

puts unnecessary demands on the heart and vessels. Arterial

REGULATION OF
ARTERIAL PRESSURE
Appropriate systemic arterial pressure is the single most
important requirement for the proper function of the cardio-
vascular system. Without sufficient arterial pressure, the brain
and the heart do not receive adequate blood flow no matter
what adjustments are made in their vascular resistance by local
control mechanisms. In contrast, excessive arterial pressure
pressure is continuously monitored by sensors located within
the body. Whenever arterial pressure varies from normal,
multiple reflex responses are initiated that cause the adjust-
ments in cardiac output and total peripheral resistance neces-
sary to return arterial pressure to its normal value. In the short
term (seconds), these adjustments are brought about by
changes in the activity of the autonomic nerves leading to the
heart and peripheral vessels. In the long term (minutes to
days), other mechanisms such as changes in cardiac output

285

Ch29_285-294.indd 285 11/26/10 11:51:35 AM

286 SECTION V Cardiovascular Physiology

brought about by changes in blood volume play an increas-
ingly important role in the control of arterial pressure. The
short- and long-term regulations of arterial pressure will be
discussed in order in this chapter.
SHORT-TERM REGULATION
OF ARTERIAL PRESSURE
ARTERIAL BARORECEPTOR REFLEX
The arterial baroreceptor reflex is the single most impor-
tant mechanism providing short-term regulation of arte-
rial pressure. Recall that the usual components of a reflex
pathway include sensory receptors, afferent pathways, inte-
grating centers in the central nervous system, efferent path-
ways, and effector organs. As shown in Figure 29–1, the
efferent pathways of the arterial baroreceptor reflex are the
cardiovascular sympathetic and cardiac parasympathetic
nerves. The effector organs are the heart and peripheral
blood vessels.
Efferent Pathways
Previous chapters have discussed the many actions of the sym-
pathetic and parasympathetic nerves leading to the heart
and blood vessels. For both systems, postganglionic fibers,
whose cell bodies are in ganglia outside the central nervous
system, form the terminal link to the heart and vessels. The
influences of these postganglionic fibers on key cardiovascular
variables are summarized in Figure 29–1.
The activity of the terminal postganglionic fibers of the
autonomic nervous system is determined by the activity of
preganglionic fibers whose cell bodies lie within the central
nervous system (see Chapter 19). In the sympathetic pathways,
the cell bodies of the preganglionic fibers are located within
the spinal cord. These preganglionic neurons have spontane-
ous activity that is modulated by excitatory and inhibitory
inputs, which arise from centers in the brainstem and descend

Medulla
Spinal
cord rvlm
− ?? nts
+

− +
rn +
Sympathetic na
preganglionic
fibers
Parasympathetic
+
preganglionic
+ fibers
Ganglia

+
Ganglia

Arterial
+ + − baroreceptor
+
Pcv SV × HR = CO +
Central −
Pa = CO × TPR
venous Heart
pool

Systemic organs

Veins Arterioles
Ppv
TPR
+ +

FIGURE 29–1 Components of the arterial baroreceptor reflex pathway. nts, nucleus tractus solitarius; rvlm, rostral ventrolateral
medullary group; rn, raphe nucleus; na, nucleus ambiguus; ??, incompletely mapped integration pathways that may also involve structures
outside the medulla. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

in distinct excitatory and inhibitory spinal pathways. In the
parasympathetic system, the cell bodies of the preganglionic
fibers are located within the brainstem. Their spontaneous
activity is modulated by inputs from adjacent centers in the
brainstem.
Afferent Pathways
Sensory receptors, called arterial baroreceptors, are found in
abundance in the walls of the aorta and carotid arteries. Major
concentrations of these receptors are found near the arch of
the aorta (the aortic baroreceptors) and at the bifurcation of
the common carotid artery into the internal and external
carotid arteries on either side of the neck (the carotid sinus
baroreceptors). The receptors are mechanoreceptors that
sense arterial pressure indirectly from the degree of stretch of
the elastic arterial walls. In general, increased stretch causes an
increased action potential generation rate by the arterial barore-
ceptors. Baroreceptors actually sense not only absolute stretch,
but also the rate of change of stretch. For this reason, both the
mean arterial pressure and arterial pulse pressure affect barore-
ceptor firing rate as indicated in Figure 29–2. The dashed
curve shows how baroreceptor firing rate is affected by differ-
ent levels of a steady arterial pressure. The solid curve indi-
cates how baroreceptor firing rate is affected by the mean value
of a pulsatile arterial pressure. Note that the presence of pulsa-
tions increases the baroreceptor firing rate at any given level of
mean arterial pressure. Note also that changes in mean arterial
pressure near the normal value of 100 mm Hg produce the
largest changes in baroreceptor discharge rate and there is very
little output at low pressures.
If arterial pressure remains above normal over a period of
several days, the arterial baroreceptor firing rate will gradually
return toward normal. Thus, arterial baroreceptors are said to
adapt to long-term changes in arterial pressure. For this rea-
son, the arterial baroreceptor reflex does not serve as a mecha-
nism for the long-term regulation of arterial pressure.
Max
Baroreceptor nerve activity
Pulsatile
Steady
0 50 100 150
Mean arterial pressure (mm Hg)
FIGURE 29–2 Effect of mean arterial pressure on
baroreceptor nerve activity. (Modified with permission from Mohrman DE,
Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/
McGraw-Hill, 2006.)
CHAPTER 29 Arterial Pressure Regulation 287
Central Integration
Much of the central integration involved in reflex regulation of
the cardiovascular system occurs in the medulla oblongata in
what are traditionally referred to as the medullary cardiovas-
cular centers. The neural interconnections between the dif-
fuse structures in this area are complex and not completely
mapped. Moreover, these structures appear to serve multiple
functions including respiratory control. What is known with a
fair degree of certainty is where the cardiovascular afferent
and efferent pathways enter and leave the medulla. As indi-
cated in Figure 29–1, the afferent sensory information from
the arterial baroreceptors enters the medullary nucleus trac-
tus solitarius, where it is relayed via polysynaptic pathways to
other structures in the medulla (and higher brain centers, such
as the hypothalamus, as well). The cell bodies of the efferent
vagal parasympathetic cardiac nerves are located primarily in
the medullary nucleus ambiguus. The sympathetic autonomic
efferent information leaves the medulla predominantly from
the rostral ventrolateral medulla group of neurons (via an
excitatory spinal pathway) or the raphe nucleus (via an inhib-
itory spinal pathway). The intermediate processes involved in
the actual integration of the sensory information into appro-
priate sympathetic and parasympathetic responses are not well
understood. Much of this integration takes place within the
medulla, but higher centers such as the hypothalamus are
probably involved as well. In this context, knowing the details
of the integration process is not as important as appreciating
the overall effects that changes in arterial baroreceptor activity
have on the activities of parasympathetic and sympathetic car-
diovascular nerves.
Several functionally important points about the central con-
trol of the autonomic cardiovascular nerves are illustrated in
Figure 29–1. The major external influence on the cardiovascu-
lar centers comes from the arterial baroreceptors. Because the
arterial baroreceptors are active at normal arterial pressures,
they supply a tonic input to the central integration centers.
As indicated in Figure 29–1, the integration process is such
that increased input from the arterial baroreceptors tends to
simultaneously: (1) inhibit the activity of the spinal sympa-
thetic excitatory tract, (2) stimulate the activity of the spinal
sympathetic inhibitory tract, and (3) stimulate the activity of
parasympathetic preganglionic nerves. Thus, an increase in
the arterial baroreceptor discharge rate (caused by increased
arterial pressure) causes a decrease in the tonic activity of car-
diovascular sympathetic nerves and a simultaneous increase
in the tonic activity of cardiac parasympathetic nerves. Con-
versely, decreased arterial pressure causes increased sympa-
thetic and decreased parasympathetic activity.
200 OPERATION OF THE ARTERIAL
BARORECEPTOR REFLEX
The arterial baroreceptor reflex is a continuously operating
control system that automatically makes adjustments to pre-
vent disturbances in the heart and/or vessels from causing
288 SECTION V Cardiovascular Physiology

↓ Mean arterial pressure (primary disturbance)

29

↓ Baroreceptor discharge

29
29 29
Medullary cardiovascular centers

↑ Sympathetic activity ↓ Parasympathetic activity

27
27 24
↑ Arteriolar tone ↑ Venous tone ↑ Cardiac contractility
27
27

↑ Blood volume
↑ Peripheral venous pressure
23
28 23
27 28
Transcapillary fluid reabsorption
+ −
Central venous pressure
26 24

↓ Capillary pressure 24

↑ Vasoconstriction
26 ↑ Stroke volume ↑ Heart rate
24
26 24
↑ Total peripheral resistance ↑ Cardiac output

26 26
↑ Mean arterial pressure (counteracting response)

FIGURE 29–3 Immediate cardiovascular adjustments caused by a decrease in arterial blood pressure. Circled numbers indicate the
chapter in which each interaction is discussed. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange
Medical Books/McGraw-Hill, 2006.)

large changes in mean arterial pressure. The arterial barore-
ceptor reflex mechanism acts to regulate arterial pressure in a
negative feedback fashion as was described in Chapter 1.
Figure 29–3 shows many events in the arterial baroreceptor
reflex pathway that occur in response to a disturbance of
decreased mean arterial pressure. All of the events shown in
Figure 29–3 have already been discussed, and each should be
carefully examined (and reviewed if necessary) at this point
because a great many of the interactions that are essential to
understanding cardiovascular physiology are summarized in
this figure.
Note in Figure 29–3 that the overall response of the arterial
baroreceptor reflex to the disturbance of decreased mean arte-
rial pressure is to increase mean arterial pressure (i.e., the
response tends to counteract the disturbance). A disturbance
of increased mean arterial pressure would elicit events oppo-
site to those shown in Figure 29–3 and produce a decrease in
mean arterial pressure; again, the response tends to counteract
the disturbance. Recall that neural control of vessels is more
important in some areas such as the kidney, the skin, and the
splanchnic organs than in the brain and heart muscle. Thus,
the reflex response to a decrease in arterial pressure may, for
example, include a significant increase in renal vascular resis-
tance and a decrease in renal blood flow without changing the
cerebral vascular resistance or blood flow. The peripheral vas-
cular adjustments associated with the arterial baroreceptor
reflex take place primarily in organs with strong sympathetic
vascular control.
OTHER CARDIOVASCULAR
REFLEXES & RESPONSES
In spite of the arterial baroreceptor reflex mechanism, large
and rapid changes in mean arterial pressure occur in certain
physiological and pathological situations. These reactions are
caused by influences on the medullary cardiovascular centers
other than those from the arterial baroreceptors. As outlined

in the following sections, these inputs to the medullary cardio-
vascular centers arise from many types of peripheral and cen-
tral receptors as well as from “higher centers” in the central
nervous system such as the hypothalamus and the cortex.
An analogy was made between the arterial baroreceptor
reflex operating to control arterial pressure to a home heating
system acting to control room temperature (see Chapter 1).
The temperature setting on the thermostat determines the set
point for temperature regulation. Most of the influences that
are about to be discussed influence arterial pressure as if they
changed the arterial baroreceptor reflex’s set point for pressure
regulation. Consequently, the arterial baroreceptor reflex does
not resist most of these pressure disturbances but actually
assists in producing them.
REFLEXES FROM RECEPTORS
IN HEART & LUNGS
A host of mechanoreceptors and chemoreceptors that elicit
reflex cardiovascular responses have been identified in the atria,
ventricles, coronary vessels, and lungs. The role of these cardio-
pulmonary receptors in the control of the cardiovascular sys-
tem is, in most cases, incompletely understood, but they are
likely involved in many physiological and pathological states.
Cardiopulmonary baroreceptors (sometimes referred to as
low-pressure receptors) sense the pressure (or volume) in the
atria and central venous pool. Increased central venous pres-
sure (or volume) causes activation of these receptors by stretch,
and elicits a reflex decrease in sympathetic activity. Decreased
central venous pressure (or volume) produces the opposite
response. These cardiopulmonary baroreflexes normally exert a
tonic inhibitory influence on sympathetic activity. Alterations in
sympathetic activity evoked by increases or decreases in central
venous pressure not only have short-term influences on arterial
pressure, but also influence renal mechanisms that influence
blood volume and long-term regulation of arterial pressure.
CHEMORECEPTOR REFLEXES
Low Po2, low pH, and/or high Pco2 levels in the arterial blood
cause reflex increases in breathing and mean arterial pressure.
These responses appear to be a result of increased activity of
arterial chemoreceptors, located in the carotid arteries and
the arch of the aorta, and central chemoreceptors, located
within the central nervous system. Chemoreceptors probably
play little role in the normal regulation of arterial pressure
because arterial blood Po2 and Pco2 are normally held very nearly
constant by respiratory control mechanisms. See Chapter 38
for more details.
An extremely strong reaction called the cerebral ischemic
response is triggered by inadequate blood flow (ischemia) to
the brain and can produce a more intense sympathetic vaso-
constriction and cardiac stimulation than is elicited by any
other influence on the cardiovascular control centers. Presum-
CHAPTER 29 Arterial Pressure Regulation 289
ably the cerebral ischemic response is initiated by chemore-
ceptors located within the central nervous system. However, if
cerebral blood flow is severely inadequate for several minutes,
the cerebral ischemic response wanes and is replaced by
marked loss of sympathetic activity. This results when func-
tion of the nerve cells in the cardiovascular centers becomes
directly depressed by the unfavorable chemical conditions in
the cerebrospinal fluid.
Whenever intracranial pressure is increased—for example,
by increased cerebral spinal fluid (CSF) pressure or trauma-
induced bleeding within the rigid cranium—there is a parallel
increase in arterial pressure. This is called the Cushing reflex.
It can cause mean arterial pressures of more than 200 mm Hg
in severe cases of increased intracranial pressure. The benefit
of the Cushing reflex is that it prevents collapse of cranial ves-
sels and thus preserves adequate brain blood flow in the face of
large increases in intracranial pressure. The mechanisms
responsible for the Cushing reflex are not known but could
involve the central chemoreceptors. A hallmark of the Cush-
ing reflex is acutely increased arterial pressure in spite of
accompanying bradycardia. It seems as if the short-term arte-
rial baroreceptor reflex is attempting to counteract this distur-
bance by activating parasympathetic nerves to the SA node of
the heart.
CARDIOVASCULAR RESPONSES
ASSOCIATED WITH EMOTION
Cardiovascular responses are frequently associated with cer-
tain states of emotion. These responses originate in the cere-
bral cortex and reach the medullary cardiovascular centers
through corticohypothalamic pathways. The least compli-
cated of these responses is the blushing that is often detectable
in individuals with lightly pigmented skin during states of
embarrassment. The blushing response involves a loss of sym-
pathetic vasoconstrictor activity only to particular cutaneous
vessels, and this produces the blushing by allowing engorge-
ment of the cutaneous venous sinuses.
Excitement or a sense of danger often elicits a complex
behavioral pattern called the alerting reaction (also called the
“defense” or “fight-or-flight” response). The alerting reac-
tion involves a host of responses such as pupillary dilation and
increased skeletal muscle tenseness that are generally appro-
priate preparations for some form of intense physical activity.
The cardiovascular component of the alerting reaction is an
increase in blood pressure caused by a general increase in car-
diovascular sympathetic nervous activity and a decrease in
cardiac parasympathetic activity.
Some individuals respond to situations of extreme stress by
fainting, a situation referred to clinically as vasovagal syn-
cope. The loss of consciousness is due to decreased cerebral
blood flow that is itself produced by a sudden dramatic loss of
arterial blood pressure that occurs as a result of a sudden loss
of sympathetic tone and a simultaneous large increase in para-
sympathetic tone and decrease in heart rate.
290 SECTION V Cardiovascular Physiology
CENTRAL COMMAND
The term central command is used to imply an input from the
cerebral cortex to lower brain centers during voluntary muscle
exercise. The concept is that the same cortical drives that initi-
ate somatomotor (skeletal muscle) activity also simultaneously
initiate cardiovascular (and respiratory) adjustments appro-
priate to support that activity. In the absence of any other obvi-
ous causes, central command is at present the best explanation
as to why both mean arterial pressure and respiration increase
during voluntary exercise.
REFLEX RESPONSES TO PAIN
Pain can have either a positive or a negative influence on arte-
rial pressure. Generally, superficial or cutaneous pain causes
an increase in blood pressure in a manner similar to that asso-
ciated with the alerting response and perhaps over many of
the same pathways. Deep pain from receptors in the viscera or
joints, however, often causes a cardiovascular response similar
to that which accompanies vasovagal syncope, that is, decreased
sympathetic tone, increased parasympathetic tone, and a sig-
nificant decrease in blood pressure. This response may con-
tribute to the state of shock that often accompanies crushing
injuries and/or joint displacement.
SUMMARY
The influences on the medullary cardiovascular centers
that have been discussed in the preceding sections are sum-
marized in Figure 29–4. This figure is intended first to reem-
Sympathetic
output
FIGURE 29–4 Summary of the factors that
influence the set point of the arterial
baroreceptor reflex. (Modified with permission from
Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New
York: Lange Medical Books/McGraw-Hill, 2006.)
phasize that the arterial baroreceptors normally and
continuously supply the major input to the medullary cen-
ters. The arterial baroreceptor input is shown as inhibitory
because an increase in arterial baroreceptor firing rate results
in a decrease in sympathetic output. (Decreased sympathetic
output should be taken to imply also a simultaneous increase
in parasympathetic output that is not shown in this figure.)
As is indicated in Figure 29–4, the nonarterial baroreceptor
influences on the medullary cardiovascular centers fall into two
categories: (1) those that increase arterial pressure by raising the
set point for the arterial baroreceptor reflex and thus cause an
increase in sympathetic activity and (2) those that decrease arte-
rial pressure by lowering the set point for the arterial barorecep-
tor reflex and thus cause a decrease in sympathetic activity.
LONG-TERM REGULATION OF
ARTERIAL PRESSURE
Long-term regulation of arterial pressure is a topic of clinical
relevance because of the prevalence of hypertension (sustained
excessive arterial blood pressure) in our society. The most
long-standing and generally accepted theory of long-term
pressure regulation is that it crucially involves the kidneys,
their sodium handling, and ultimately the regulation of blood
volume. This theory is sometimes referred to as the “renal-
MAP set point” or “fluid balance” model of long-term arte-
rial blood pressure control. In essence, this theory asserts that
in the long term, mean arterial pressure is whatever it needs to
be to maintain an appropriate blood volume through arterial
pressure’s direct effects on renal function.
Response to exercise (central command)
Sense of danger (alerting/defense reaction)
Cerebral ischemic response
↑ Intracranial pressure (cushing reflex)
↓ PO2, ↑ PCO2 in arterial blood
↓ Central venous pressure (cardiopulmonary baroreflexes)
Cutaneous pain
Increase
set point
+
Arterial
Medullary baroreceptor
−
centers input
Lower
set point
Vasovagal syncope
Deep pain
↑ Central venous pressure (cardiopulmonary baroreflexes)

FLUID BALANCE &
ARTERIAL PRESSURE
Several key factors in the long-term regulation of arterial
blood pressure have already been considered. First is the fact
that the baroreceptor reflex, however well it counteracts tem-
porary disturbances in arterial pressure, cannot effectively
regulate arterial pressure in the long term for the simple rea-
son that the baroreceptor firing rate adapts to prolonged
changes in arterial pressure.
The second pertinent fact is that circulating blood volume
can influence arterial pressure because: ↑ blood volume →
↑ peripheral venous pressure → right shift of venous function
curve → ↑ central venous pressure → ↑ cardiac output →
↑ arterial pressure.
Arterial pressure has a profound influence on urinary out-
put rate and thus affects total body fluid volume. Because
blood volume is one of the components of the total body fluid,
blood volume alterations accompany changes in total body
fluid volume. The mechanisms are such that a decrease in
arterial pressure causes a decrease in urinary output rate and
thus an increase in blood volume. But, as outlined in the pre-
ceding sequence, increased blood volume tends to increase
arterial pressure. Thus, the complete sequence of events that
are initiated by a decrease in arterial pressure can be listed as
follows:
↓ Arterial pressure (disturbance) → ↓ urinary output rate
→ ↑ fluid volume → ↑ blood volume → ↑ cardiac output →
↑ arterial pressure (compensation).
As indicated in Figure 29–5, both the arterial baroreceptor
reflex and this fluid volume mechanism are negative feedback
loops that regulate arterial pressure. Whereas the arterial barore-
ceptor reflex is very quick to counteract disturbances in arterial
SHORT-TERM LONG-TERM
Baroreceptor reflex Fluid balance
Blood volume
− − +
TPR CO
+ +
Fluid Volume
Arterial pressure
Kidney
+ Urinary output rate
CHAPTER 29 Arterial Pressure Regulation 291
pressure, hours or even days may be required before a change in
urinary output rate produces a significant accumulation or loss
of total body fluid volume. What this fluid volume mechanism
lacks in speed, however, it more than makes up for in persis-
tence. As long as there is any inequality between the fluid intake
rate and the urinary output rate, body fluid volume is changing
and this fluid volume mechanism has not completed its adjust-
ment of arterial pressure. The fluid volume mechanism is in
equilibrium only when the urinary output rate equals the fluid
intake rate. (In the present discussion, assume that fluid intake
rate represents that in excess of the obligatory fluid losses that
normally occur in the feces and by transpiration from the skin
and structures in the respiratory tract. The processes that regu-
late thirst are not well understood but seem to involve many of
the same factors that influence urinary output.) In the long term,
the arterial pressure must be that which makes the urinary output
rate equal to the fluid intake rate.
The arterial baroreceptor reflex is, of course, essential for
counteracting rapid changes in arterial pressure. The fluid vol-
ume mechanism, however, determines the long-term level of
arterial pressure because it slowly overwhelms all other influ-
ences. Through adaptation, the baroreceptor mechanism
adjusts itself so that it operates to prevent acute changes in
blood pressure from the prevailing long-term level as deter-
mined through fluid balance.
EFFECT OF ARTERIAL PRESSURE
ON URINARY OUTPUT RATE
As discussed above, an increase in arterial pressure normally
leads to an increase in urine output rate. Many mechanisms
are involved in this phenomenon and are discussed in detail
Fluid intake rate
+
−
FIGURE 29–5 Mechanisms of short- and
long-term regulations of arterial pressure. TPR,
total peripheral resistance; CO, cardiac output.
(Modified with permission from Mohrman DE, Heller LJ:
Cardiovascular Physiology, 6th ed. New York: Lange Medical
Books/McGraw-Hill, 2006.)
292 SECTION V Cardiovascular Physiology
3 Heathy person
Urine output rate × normal
Hypertensive person
y
rap
2 daily for 1 week and to report his results to the doctor.
d
ate
he
ic t
tre
Un
ret
Normal fluid intake N Diu
1 mean systemic arterial pressure above 140/90 mm Hg. It is
A
C an extremely common cardiovascular problem, affecting
B Restricted fluid intake
50 100 150 200
Mean arterial pressure (mm Hg)
FIGURE 29–6 Renal function curves in a normal person and
in a hypertensive person with and without antihypertensive
therapy. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular
Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)
in Section 7. At this point, it is only important to recognize
that, because of many synergistic influences, arterial pressure
has a huge positive effect on renal urine output rate as is indi-
cated by the very steep slope of the relationship shown in
Figure 29–6. In a steady state, urine output (plus fluid lost
from the body by other means) is equal to fluid intake (point
N in this figure). At arterial pressures below point N, fluid
intake exceeds urinary output and bodily fluid volume will
necessarily be increasing. The opposite is true at arterial blood
pressure higher than that at point N. Thus, a healthy person
with a normal fluid intake rate will have, as a long-term aver-
age, the arterial pressure associated with point N in Figure
29–6. Because of the steepness of the curve shown in Figure
29–6, even marked changes in fluid intake rate have minor
influences on the arterial pressure of a normal individual.
CLINICAL CORRELATION
A 35-year-old African American male has come to the
doctor for a general physical exam. He has not been to see
a physician for at least 10 years. At present, he has no spe-
cific complaints about health conditions, but admits to not
getting as much exercise as he did while in his twenties. His
father had a mild heart attack at 50 years of age, received a
coronary artery stent, and has been treated for hyperten-
sion for the 15 years since that time. His mother has recently
been diagnosed with type 2 diabetes mellitus.
He is 5′11″ (180 cm), 240 lb (109 kg), and has a heart rate
of 64 beats/min and an arterial pressure of 150/92 mm Hg.
Chest sounds and heart sounds are normal. All other
aspects of the physical exam are within normal ranges. An
ECG shows left deviation of the ventricular mean electri-
cal axis (−35°) (see Chapter 25).
A tentative diagnosis of chronic hypertension is made.
He has access to blood pressure monitoring equipment at
home and was instructed to monitor his blood pressure
At that time, a decision about therapeutic strategies will
be made.
Systemic hypertension is defined as a chronic increase in
more than 20% of the adult population of the Western
world. It has been established that hypertension increases
the risk of coronary artery disease, myocardial infarction,
heart failure, stroke, and many other serious cardiovascular
problems. Moreover, it has been clearly demonstrated that
the risk of serious cardiovascular incidents is reduced by
proper treatment of hypertension.
In approximately 90% of cases, the primary abnor-
mality that produces high blood pressure is unknown.
(This condition is sometimes referred to as primary or
essential hypertension because the elevated level was
previously thought to be “essential” to drive the blood
through the systemic circulation, particularly the brain.)
Genetic factors contribute importantly to the develop-
ment of hypertension (generally being more common
in males than females and in blacks than whites) and
environmental factors such as obesity, high-salt diets,
diabetes mellitus, and/or certain forms of psychological
stress may either aggravate or precipitate hypertension
in susceptible individuals.
Structural changes in the left heart and arterial vessels
occur in response to hypertension. Early alterations
include hypertrophy of muscle cells and thickening of the
walls of the ventricle and resistance vessels. Late changes
associated with deterioration of function include increases
in connective tissue and increased tissue stiffness.
The established phase of hypertension is associated
with increased total peripheral resistance. Cardiac output
and/or blood volume may be increased during the early
developmental phase, but are usually normal after the
hypertension is established. The increased total periph-
eral resistance associated with established hypertension
may be due to microvessel rarefaction (decrease in den-
sity), pronounced structural adaptations of the peripheral
vascular bed, increased basal vascular smooth muscle
tone, increased sensitivity and reactivity of the vascular
smooth muscle cells to external vasoconstrictor stimuli,
and/or diminished production and/or effect of endoge-
nous vasodilator substances (e.g., nitric oxide).
Chronic hypertension is not due to a sustained increase
in sympathetic vasoconstrictor neural discharge nor is it
due to a sustained increase of any blood-borne vasocon-
strictive factor. (Both neural and hormonal influences,

however, may help initiate primary hypertension.) Blood
pressure–regulating reflexes (both the short-term arte-
rial and cardiopulmonary baroreceptor reflexes and the
long-term, renal-dependent, pressure-regulating reflexes)
become adapted or “reset” to regulate blood pressure at a
higher-than-normal level. Disturbances in renal function
contribute importantly to the development and mainte-
nance of primary hypertension. Recall that, in the long
term, arterial pressure can stabilize only at the level that
makes urinary output rate equal to fluid intake rate. As
shown by point N in Figure 29–6, this pressure is approx-
imately 100 mm Hg in a normal individual. All forms of
hypertension involve an alteration somewhere in
the chain of events by which changes in arterial pressure
produce changes in urinary output rate such that the
renal function curve is shifted rightward as indicated in
Figure 29–6. Higher-than-normal arterial pressure is
required to produce a normal urinary output rate in a
hypertensive individual.
The untreated hypertensive individual in Figure 29–6
would have a very low urinary output rate at the normal
mean arterial pressure of 100 mm Hg. With a normal
fluid intake rate, this untreated hypertensive patient
retains fluid to ultimately stabilize at point A (mean arte-
rial pressure = 150 mm Hg). Baroreceptors adapt within
days so that they will have a normal discharge rate at the
prevailing average arterial pressure. Thus, once the hyper-
tensive individual has been at point A for a week or more,
even the baroreceptor mechanism will begin resisting
acute changes from the 150-mm Hg pressure level. In
certain hypertensive individuals, dietary salt restriction
produces a substantial reduction in blood pressure
because of the reduced requirement for water retention
to osmotically balance the salt load. This effect is illus-
trated by a shift from point A to point B. The efficacy of
lowering salt intake to lower arterial pressure depends
heavily on the slope of the renal function curve in the
hypertensive individual. The arterial pressure of a nor-
mal individual, for example, is affected only slightly by
changes in salt intake because the normal renal function
curve is so steep. A second common treatment of hyper-
tension is diuretic therapy (see Chapters 44 and 46). The
net effect of diuretic therapy is that the urinary output
rate for a given arterial pressure is increased, that is,
diuretic therapy shifts the renal function curve upward.
The combined result of restricted fluid intake and diuretic
therapy for the hypertensive individual of Figure 29–6 is
illustrated by point C.
A variety of antihypertensive pharmacological
approaches are available that may include β-adrenergic
blockers, angiotensin-converting enzyme inhibitors,
angiotensin II receptor blockers, and calcium channel
blockers (see Section 7). Alterations in lifestyle, including
reduction of stress, decreases in caloric intake, limitation
CHAPTER 29 Arterial Pressure Regulation 293
of the amount of saturated fats in the diet, and establish-
ment of a regular exercise program, may also help reduce
blood pressure in certain individuals.
CHAPTER SUMMARY
■ Arterial pressure is closely regulated to ensure adequate blood
flow to the tissues.
■ The arterial baroreceptor reflex is responsible for regulating
arterial pressure in the short term on a second-to-second and
moment-to-moment basis.
■ The arterial baroreceptor reflex involves the following: pressure
sensing by stretch-sensitive baroreceptor nerve endings in the
walls of arteries, neural integrating centers in the brainstem
that adjust autonomic nerve activity in response to the pressure
information they receive from the arterial baroreceptors, and
responses of the heart and vessels to changes in autonomic
nerve activity.
■ Overall, the arterial baroreflex operates such that increases
in arterial pressure lead to an essentially immediate decrease
in sympathetic nerve activity and a simultaneous increase in
parasympathetic nerve activity (and vice versa).
■ The brainstem integrating centers also receive nonarterial
baroreceptor inputs that can raise or lower the set point for
short-term arterial pressure regulation.
■ In the long term, arterial pressure is regulated by changes in
blood volume that come about because arterial pressure has
a strong influence on urinary output rate by the kidney.
STUDY QUESTIONS
1. In the normal operation of the arterial baroreceptor reflex, a
cardiovascular disturbance that decreases mean arterial pressure
will evoke a decrease in
A) urine output rate.
B) sympathetic nerve activity.
C) heart rate.
D) total peripheral resistance.
E) myocardial contractility.
2. Which one of the following, after all reflex adjustments are
complete, will result in an increase in mean arterial pressure?
A) low carbon dioxide levels in arterial blood
B) increased intracranial pressure
C) decreased cardiac filling pressure
D) low blood volume
E) supraventricular tachycardia
3. An individual has higher-than-normal mean arterial pressure
and lower-than-normal pulse rate. Which of the following is
most likely to cause such a combination?
A) low oxygen levels in arterial blood
B) anxiety
C) exercise
D) significant blood loss
E) a drug that selectively stimulates alpha-adrenergic
receptors
294 SECTION V Cardiovascular Physiology

4. Which of the following best describes, first, the immediate direct 5. An increase in arterial baroreceptor firing rate will reflexly result in
effect and, second, the reflex cardiovascular consequences of A) an increase in vagal activity to the heart.
giving a normal person a drug that blocks beta1-adrenergic B) an increase in sympathetic activity to arterioles in the brain.
receptors? C) an increase in renal blood flow.
A) decreased heart rate, increased total peripheral resistance D) an increase in mean arterial pressure.
B) decreased ejection fraction, decreased total peripheral E) an increase in cardiac ejection fraction.
resistance
C) increased heart rate, increased urine production
D) increased cardiac output, decreased total peripheral
resistance
E) decreased end-diastolic volume, increased heart rate
 30
C H A P T E R

Cardiovascular Responses
to Physiological Stress
Lois Jane Heller and David E. Mohrman

O B J E C T I V E S

■ Identify the primary disturbance(s) that any given normal homeostatic

disturbance (such as changes in body position) places on the cardiovascular
system.
■ List how any such given primary disturbance changes the influence on
the medullary cardiovascular centers from (1) arterial baroreceptors and
(2) other sources.
■ State what immediate reflex compensatory changes will occur in sympathetic
and parasympathetic nerve activities as a result of the altered influences on
the medullary cardiovascular centers.
■ Indicate what immediate compensatory changes will occur to influence
mean arterial pressure in response to any given primary disturbance,
including changes in: heart rate, cardiac contractility, stroke volume, arteriolar
tone, venous tone, peripheral venous pressure, central venous pressure, total
peripheral resistance, resistance in any major organ, blood flow through any
major organ, cutaneous blood flow, transcapillary fluid movement, and
long-term renal adjustments in urine output and total body fluid balance.
■ State how gravity influences arterial, venous, and capillary pressures at any
height above or below the heart in a standing individual.
■ Describe and explain the changes in central venous pressure and the changes
in transcapillary fluid balance and venous volume in the lower extremities
caused by standing upright.
■ Describe the operation of the “skeletal muscle pump” and explain how it
simultaneously promotes venous return and decreases capillary hydrostatic
pressure in the muscle vascular beds.
■ Identify the primary disturbances and compensatory responses evoked by
acute changes in body position.
■ Describe the chronic effects of long-term bed rest on cardiovascular variables.
■ List the cardiovascular consequences of respiratory activity.
■ Identify the major maternal cardiovascular adjustments that occur
during pregnancy.
■ Follow the pathway of blood flow through the fetal heart and describe the
changes that occur at birth.
■ Indicate the normal changes that occur in cardiovascular variables during
childhood.
■ Identify age-dependent changes that occur in cardiovascular variables
■ Describe gender-dependent differences in cardiovascular variables.

295

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296 SECTION V Cardiovascular Physiology

CARDIOVASCULAR RESPONSES EFFECT OF GRAVITY

TO PHYSIOLOGICAL STRESSES
A wide variety of normal, everyday situations can disturb
homeostasis within the cardiovascular system and can evoke
an equally wide variety of reflex responses. The key to
understanding the cardiovascular adjustments in each situa-
tion is to recall that the arterial baroreceptor reflex and renal
fluid balance mechanisms always act to blunt changes in
arterial pressure. The overall result is that adequate blood
flow to the brain and the heart muscle is maintained in any
circumstance.
The cardiovascular alterations in the following example is
produced by the combined effects of (1) the primary, direct
influences of the disturbance on the cardiovascular variables
and (2) the reflex compensatory adjustments that are trig-
gered by the primary disturbances. As you will see in later
sections of this book, the general pattern of reflex adjustment
is similar in all situations. Rather than trying to memorize the
cardiovascular alterations that accompany each situation, the
reader should strive to understand each response in terms of
the primary disturbances and reflex compensatory reactions
involved.
RESPONSES TO CHANGES
IN BODY POSITION
Significant cardiovascular readjustments accompany changes in
body position because gravity has an effect on pressures within
the cardiovascular system. In the preceding chapters, the influ-
ence of gravity was ignored and pressure differences between
various points in the systemic circulation were related only to
flow and vascular resistance (Δ P = Q̇ R). As shown in Figure
30–1, this is approximately true only for a recumbent individual.
In a standing individual, additional cardiovascular pressure dif-
ferences exist between the heart and regions that are not at heart
level. This is most important in the lower legs and feet of a stand-
ing individual. As indicated in Figure 30–1B, intravascular pres-
sures in the feet may be increased by 90 mm Hg simply from the
weight of the blood in the arteries and veins leading to and from
the feet. Note by comparing Figure 30–1A and B that standing
upright does not in itself change the flow through the lower
extremities, since gravity has the same effect on arterial and
venous pressures and thus does not change the arteriovenous
pressure difference at any given level above or below the heart.

A RECUMBENT
P = 100 mm Hg Arteries P = 95 mm Hg

Arterioles
Heart Foot
Capillaries
Veins
P = 25 mm Hg

P = 0 mm Hg Valves P = 5 mm Hg

STANDING
Surface P = 100 mm Hg P = 0 mm Hg P =100 mm Hg
P = 0 mm Hg Heart level
P = 0 mm Hg
Lymphatics

Arteries
Veins

P = 95 mm Hg
1.5-m depth
P = 95 mm Hg P = 185 mm Hg P = 20 mm Hg P = 185 mm Hg
Foot level
P = 90 mm Hg Filtration P = 185 mm Hg P = 105 mm Hg P = 40 mm Hg
P = 115 mm Hg
Without compensation With sympathetic stimulation During skeletal muscle contraction Shortly after contraction
B C D E
FIGURE 30–1 Effect of gravity on vascular pressure (A and B) with compensatory influences of sympathetic stimulation (C) and
the skeletal muscle pump (D and E). (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/
McGraw-Hill, 2006.)
 CHAPTER 30 Cardiovascular Responses to Physiological Stress
There are, however, two major direct effects of the increased
pressure in the lower extremities that are shown in Figure 30–1B:
(1) the increase in venous transmural pressure distends the
compliant peripheral veins and greatly increases peripheral
venous volume by as much as 500 mL in a normal adult and
(2) the increase in capillary transmural hydrostatic pressure
causes a tremendously high transcapillary filtration rate.
For reasons to be described, reflex activation of sympathetic
nerves accompanies the transition from a recumbent to an
upright position. However, Figure 30–1C shows how vasocon-
striction from sympathetic activation is only marginally effec-
tive in ameliorating the adverse effects of gravity on the lower
extremities. Arteriolar constriction can cause a greater pressure
drop across arterioles, but this has only a limited effect on capil-
lary pressure because venous pressure remains extremely high.
Filtration will continue at a very high rate. In fact, the normal
cardiovascular reflex mechanisms alone are incapable of deal-
ing with upright posture without the aid of the skeletal muscle
pump. A person who remained upright without intermittent
contraction of the skeletal muscles in the legs would lose con-
sciousness in 10–20 minutes because of the decreased brain
blood flow that would stem from diminished central blood vol-
ume, stroke volume, cardiac output, and arterial pressure.
The effectiveness of the skeletal muscle pump in counteract-
ing venous blood pooling and edema formation in the lower
extremities during standing is illustrated in Figure 30–1D and E.
The compression of vessels during skeletal muscle contraction
expels both venous blood and lymphatic fluid from the lower
extremities (Figure 30–1D). Immediately after a skeletal muscle
contraction, both veins and lymphatic vessels are relatively
empty because their one-way valves prevent the backflow of
previously expelled fluid (Figure 30–1E). Most important, the
weight of the venous and lymphatic fluid columns is temporar-
ily supported by the closed one-way valve leaflets. Consequently,
venous pressure is drastically lowered immediately after skeletal
muscle contraction and rises only gradually as veins refill with
blood from the capillaries. Thus, capillary pressure and trans-
capillary fluid filtration rate are dramatically reduced for some
period after a skeletal muscle contraction. Some transcapillary
fluid filtration is still present, but the increased lymphatic flow
resulting from the skeletal muscle pump is normally sufficient
to prevent noticeable edema formation in the feet.
The actions of the skeletal muscle pump, however benefi-
cial, do not completely prevent an increase in the average
venous pressure and blood pooling in the lower extremities on
standing. Thus, assuming an upright position upsets the car-
diovascular system and elicits reflex cardiovascular adjust-
ments, as shown in Figure 30–2.
As with all cardiovascular responses, the key to understand-
ing the alterations associated with standing is to distinguish the
primary disturbances from the compensatory responses.
As shown in the top part of Figure 30–2, the immediate conse-
quence of standing is an increase in both arterial and venous
pressures in the lower extremities. The latter causes a major
redistribution of blood volume out of the central venous pool.
By the chain of events shown, the primary disturbances influ-
297
ence the cardiovascular centers by lessening the normal input
from both the arterial and the cardiopulmonary baroreceptors.
The result of a decreased baroreceptor input to the cardiovas-
cular centers will be reflex adjustments appropriate to increase
blood pressure—that is, decreased cardiac parasympathetic
nerve activity and increased activity of the cardiovascular sym-
pathetic nerves as shown in the bottom part of Figure 30–2.
Heart rate and cardiac contractility will increase, as will arterio-
lar and venous constriction in most systemic organs (brain and
heart excepted).
Heart rate and total peripheral resistance are greater when
an individual stands than when the individual is lying
down. Note that these particular cardiovascular variables are
not directly influenced by standing but are changed by the
compensatory responses. Stroke volume and cardiac output,
conversely, are usually decreased below their recumbent val-
ues during quiet standing despite the reflex adjustments that
tend to increase them. This is because the reflex adjustments
do not quite overcome the primary disturbance on these vari-
ables caused by standing. This is in keeping with the general
dictum that short-term cardiovascular compensations never
completely correct the initial disturbance.
Mean arterial pressure is often found to increase when a per-
son changes from the recumbent to the standing position. At first
glance, this is a violation of many rules of cardiovascular system
operation. How can a compensation be more than complete?
Moreover, how is increased sympathetic activity compatible with
higher-than-normal mean arterial pressure in the first place? In
the case of standing, there are many answers to these apparent
puzzles. First, the average arterial baroreceptor discharge rate
can actually decrease in spite of a small increase in mean arterial
pressure if there is simultaneously a sufficiently large decrease in
pulse pressure. Second, the influence on the medullary cardio-
vascular centers from cardiopulmonary receptors is interpreted
as a decrease in blood volume and may increase arterial pressure
by mechanisms that increase the set point. Third, mean arterial
pressure determined by sphygmomanometry from the arm of a
standing individual overestimates the mean arterial pressure
actually being sensed by the baroreceptors in the carotid sinus
region of the neck because of gravitational effects.
The kidney is especially susceptible to changes in sympathetic
nerve activity (as will be discussed in Section 7). Consequently,
as shown in Figure 30–2, every reflex alteration in sympathetic
activity has influences on fluid balance that become important
in the long term. Standing, which is associated with an increase
in sympathetic tone, ultimately results in an increase in fluid
volume. The ultimate benefit of this is that an increase in blood
volume generally reduces the magnitude of the reflex altera-
tions required to tolerate upright posture.
RESPONSES TO LONG-TERM BED REST
The cardiovascular system of an individual who is sub-
jected to long-term bed rest undergoes a variety of adaptive
changes. The most significant immediate change that occurs on
298 SECTION V Cardiovascular Physiology

Standing

↑ Venous pressure ↑ Arterial pressure

(lower extremities) (lower extremities)

↑ Capillary pressure
Central → Peripheral

Primary disturbances (uncompensated)

(lower extremities)
blood volume shift ↓ Blood volume

Capillary filtration
(lower extremities)
↓ Central venous pressure

Edema
↓ Stroke volume (lower extremities)

↓ Cardiac output
↓ Pulse
↓ Mean arterial pressure ↓ Firing rate of
pressure cardiopulmonary
baroreceptors

↓ Firing rate of
arterial baroreceptors
(increases set point)

Medullary cardiovascular centers

Compensatory responses

↓ Parasympathetic ↑ Sympathetic
activity activity

Heart ↑ Venous ↑ Arteriolar ↑ Fluid

FIGURE 30–2 Cardiovascular mechanisms ↑ ↑ Contractility
rate constriction constriction retention
involved when changing from a recumbent to
Heart Systemic organs Kidney
a standing position. (Modified with permission from
Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed.
New York: Lange Medical Books/McGraw-Hill, 2006.) Immediate Long-term

assuming a recumbent position is a shift of fluid from the lower
extremities to the upper portions of the body. The consequences
of this shift include distention of the head and neck veins, facial
edema, nasal stuffiness, and decreases in calf girth and leg vol-
ume. In addition, the increase in central blood volume stimu-
lates the cardiopulmonary mechanoreceptors, which influence
renal function by neural and hormonal pathways to reduce
sympathetic drive and promote fluid loss. The individual begins
to lose weight and, within just a few days, becomes hypo-
volemic. When the bedridden patient initially tries to stand up,
the normal responses to gravity as described in Figure 30–2 are
not as effective, primarily because of the substantial decrease in
circulating blood volume. Upon standing, blood shifts out of
the central venous pool into the peripheral veins, stroke vol-
ume decreases, and the individual often becomes dizzy and
may faint due to a dramatic decrease in blood pressure. This
phenomenon is referred to as orthostatic or postural hypoten-
sion. Because there are other cardiovascular changes that may
accompany bed rest, complete reversal of this orthostatic intol-
erance may take several days or even weeks. Efforts made to
diminish the cardiovascular changes for the bedridden patient
may include intermittent sitting up or tilting the bed to lower
the legs and trigger fluid retention mechanisms.
NORMAL CARDIOVASCULAR
ADAPTATIONS
RESPONSES TO
RESPIRATORY ACTIVITY
The physical processes associated with inhaling air into and
exhaling air out of the lungs have major effects on venous return
and cardiac output. The decrease in intrathoracic pressure with
inspiration transiently increases the pressure gradient between
the peripheral and central venous pools and contributes to
venous return from the systemic vascular beds to the right side
 CHAPTER 30 Cardiovascular Responses to Physiological Stress
of the heart. Because the one-way valves in peripheral veins pre-
vent backflow during expiration, the thoracic pressure changes
constitute a respiratory pump (also called the thoracoabdomi-
nal pump). Details of the effects of the respiratory pump on
venous return in exercise and the effects of positive pressure ven-
tilation on venous return and cardiac output are presented in
Chapters 34 and 72. A variety of complex signals from cardiopul-
monary receptors during the respiratory cycle contribute to a
respiratory-based cardiac arrhythmia that is mediated primarily
by changing activity of vagal efferents to the SA node.
There are other instances when the cardiovascular effect of
respiratory efforts has physiological consequences (i.e., yawn-
ing, coughing, laughing). One of the more important situations
occurs during the Valsalva maneuver, which is a forced expi-
ration against a closed glottis. This maneuver is normally per-
formed by individuals during defecation (“straining at stool”),
or when attempting to lift a heavy object. The sustained increase
in intrathoracic pressure leads to decreases in venous return
and blood pressure, which evokes a compensatory reflex
increase in heart rate and peripheral vasoconstriction. (During
this period, the red face and distended peripheral veins are
indicative of high peripheral venous pressures.) At the cessa-
tion of the maneuver, there is an abrupt decrease in pressure for
a few heart beats due to the reduction of intrathoracic pressure.
Venous blood then moves rapidly into the central venous pool;
stroke volume, cardiac output, and arterial pressure increase
rapidly; and a reflex bradycardia occurs. The combination of an
episode of high peripheral venous pressure followed by an epi-
sode of high arterial pressure and pulse pressure is particularly
dangerous for people who are candidates for cerebral vascular
accidents (strokes) because this combination may rupture a
weakened blood vessel.
CARDIOVASCULAR CHANGES
DURING PREGNANCY
Pregnancy causes alterations in vascular structure and blood
flow to many maternal organs in order to support growth of
the developing fetus. These organs include not only the
A B Ductus
arteriosus
Foramen
ovale
a
pv
pv
pa
vc la
ra
lv rv
rv lv
299
uterus and developing placenta, but also the kidneys and
the gastrointestinal organs. However, one of the most strik-
ing cardiovascular changes of pregnancy is the nearly
50% increase in circulating blood volume. The placenta,
being a low-resistance organ added in parallel with the other
systemic organs, reduces the overall systemic total peripheral
resistance by about 40%. Without the substantial increase in
circulating blood volume to support cardiac filling, the nec-
essary increase in cardiac output to balance the decrease in
total peripheral resistance would not be possible and preg-
nancy would result in a substantial decrease in mean arterial
pressure. At birth, the loss of the placenta contributes to an
abrupt increase of maternal total peripheral resistance back
toward normal levels.
FETAL CIRCULATION &
CHANGES AT BIRTH
During fetal development, the exchange of nutrients, gases,
and waste products between fetal and maternal blood occurs
in the placenta. This exchange occurs by diffusion between
separate fetal and maternal capillaries without any direct con-
nection between the fetal and maternal circulations. From a
hemodynamic standpoint, the placenta represents a tempo-
rary additional large systemic organ for both the fetus and the
mother. The fetal component of the placenta has a low vascu-
lar resistance and receives a substantial portion of the fetal car-
diac output.
Blood circulation in the developing fetus almost completely
bypasses the collapsed, fluid-filled fetal lungs. Very little blood
flows into the pulmonary artery because the vascular resis-
tance in the collapsed fetal lungs is very high. By the special
structural arrangements shown in Figure 30–3, the fetal right
and left hearts operate in parallel to pump blood through the
systemic organs and the placenta. As shown in Figure 30–3A,
fetal blood returning from the systemic organs and placenta
fills both the left and right hearts together because of an open-
ing in the intra-atrial septum called the foramen ovale. As
indicated in Figure 30–3B, most of the blood that is pumped
FIGURE 30–3 Fetal circulation (A) during cardiac
filling and (B) during cardiac ejection. pv, pulmonary
veins; la, left atrium; lv, left ventricle; rv, right ventricle;
ra, right atrium; vc, venae cavae; a, aorta; pa, pulmonary
artery. (Modified with permission from Mohrman DE, Heller
LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/
McGraw-Hill, 2006.)
300 SECTION V Cardiovascular Physiology
by the fetal right heart does not enter the constricted pulmo-
nary circulation but rather is diverted into the aorta through a
vascular connection between the pulmonary artery and the
aorta called the ductus arteriosus.
At birth, an abrupt decrease in pulmonary vascular resis-
tance occurs in the newborn with the onset of lung ventilation.
This is a partly a result of the introduction of oxygen into the
airways and the decrease in hypoxic pulmonary vasoconstric-
tion as discussed in Chapter 34. This permits more blood
to flow into the lungs from the pulmonary artery and tends to
lower pulmonary arterial pressure. Meanwhile, total systemic
vascular resistance of the newborn increases greatly because of
the interruption of flow through the placenta. This causes an
increase in aortic pressure. The combination of the reduced
pulmonary and elevated systemic arterial pressure retards or
even reverses the flow through the ductus arteriosus. Through
mechanisms that are incompletely understood but clearly
linked to an increase in blood oxygen tension, the ductus arte-
riosus gradually constricts and completely closes in a few hours
to a few days. The circulatory changes that occur at birth tend
to simultaneously increase the pressure afterload on the left
ventricle and decrease that on the right ventricle. This indi-
rectly causes left atrial pressure to increase above that in the
right atrium so that the pressure gradient for flow through the
foramen ovale is reversed. Reverse flow through the foramen
ovale is, however, prevented by a flaplike valve that covers the
opening in the left atrium. Normally, the foramen ovale even-
tually is closed permanently by the growth of fibrous tissue.
PEDIATRIC CARDIOVASCULAR
CHARACTERISTICS
Cardiovascular variables change significantly during the child-
hood. The normal neonate has, by adult standards, a high rest-
ing heart rate (average of 140 beats/min) and a low arterial
blood pressure (average of 60/35 mm Hg). These values rap-
idly change over the first year (to 120 beats/min and 100/65
mm Hg, respectively). By the time the child enters adoles-
cence, these values are near adult levels.
Pulmonary vascular resistance decreases precipitously at
birth as described above and then continues to decline during
the first year, at which time pulmonary vascular pressures
resemble adult levels. These resistance changes appear to be due
to a progressive remodeling of the microvascular arterioles from
thick-walled, small-diameter vessels to thin-walled, large-diam-
eter microvessels. Also as the lung grows, the number of alveoli
and therefore pulmonary vessels increases. (At birth there are
only about 20 million alveoli, compared to 300–450 million in
adults. Most of the growth occurs in the first 8 years).
It is noteworthy that distinct differences between right and
left ventricular mass and wall thickness develop only after
birth. Presumably these differences arise because of a hyper-
trophic response of the left ventricle to the increased afterload
it must assume at birth. Accordingly, the electrocardiogram of
children shows an early right ventricular dominance (electri-
cal axis orientation) that converts to the normal left ventricu-
lar dominance during childhood.
Heart murmurs are also quite common in childhood and
have been reported to be present in as many as 50% of healthy
children. Most of these murmurs fall in the category of “inno-
cent” murmurs resulting from normal cardiac tissue vibra-
tions, high flow through valves, and thin chest walls that make
noises from the vasculature easy to hear. Less than 1% of them
result from various congenital heart defects.
Growth and development of the vascular system parallels
growth and development of the body with most of the local
and reflex regulatory mechanisms becoming operational
shortly after birth.
CARDIOVASCULAR CHANGES
WITH NORMAL AGING
Changes in cardiovascular function occur over the normal
human lifetime. These changes are generally associated with a
slowing of some of the basic processes and a reduction in the
ability of the cardiovascular system as a whole to respond to
various stresses. Details of the aging process are discussed in
Chapter 73.
Age-dependent cardiac alterations include: (1) a decrease in
the resting and maximum cardiac index, (2) a decrease in the
maximum heart rate, (3) an increase in the contraction and
relaxation times of the heart muscle, (4) an increase in the myo-
cardial stiffness during diastole, (5) a decrease in number of
functioning myocytes, and (6) an accumulation of pigment in
the myocardial cells. Age-dependent vascular changes include:
(1) a decrease in capillary density in some tissues, (2) a decrease
in arterial and venous compliance, and (3) an increase in total
peripheral vascular resistance. These changes combine to pro-
duce the age-dependent increases in arterial pulse pressure
and mean arterial pressure that were discussed in Chapter 26
(see Figure 26–10). The increases in arterial pressure impose a
greater afterload on the heart, and this may be partially respon-
sible for the age-dependent decreases in cardiac index.
Arterial baroreceptor–induced responses to changes in
blood pressure are blunted with age. This is due in part to a
decrease in afferent activity from the arterial baroreceptors
because of the age-dependent increase in arterial rigidity. In
addition, the total amount of norepinephrine contained in
the sympathetic nerve endings of the myocardium decreases
with age, and the myocardial responsiveness to catecholamines
declines. Thus, the efferent component of the reflex is also
compromised. These changes may partially account for the
apparent age-dependent sluggishness in the responses to pos-
tural changes and recovery from exercise.
EFFECT OF GENDER
There are a few well-documented gender-dependent differ-
ences in the cardiovascular system. Compared with age-matched
men, premenopausal women have a lower left ventricular mass
 CHAPTER 30 Cardiovascular Responses to Physiological Stress
to body mass ratio, which may reflect a lower cardiac afterload
in women. This may result from their lower arterial blood pres-
sure, greater aortic compliance, and improved ability to induce
vasodilatory mechanisms (such as endothelial-dependent flow-
mediated vasodilation). These differences are thought to be
related to protective effects of estrogen and may account for the
lowered risk of premenopausal women for developing cardio-
vascular disease. After menopause, these gender differences
disappear. In fact, older women with ischemic heart disease
often have a worse prognosis than men.
There are also gender-dependent differences in cardiac elec-
trical properties. Women often have lower intrinsic heart rates
and longer QT intervals than do men. They are at greater risk
for developing long-QT syndrome and torsades de pointes.
They are also twice as likely as men to have atrioventricular
nodal reentry tachycardias.
CLINICAL CORRELATION
An elderly man was hunting with some friends when he
inadvertently shot himself in the foot. This resulted in a
significant loss of blood and, by the time he was brought
to the hospital, he was very weak and pale, his skin was
cold and clammy, and he was somewhat confused. His
heart rate was 105 beats/min, and blood pressure was
85/65 mm Hg. His breathing was rapid and shallow and
jugular venous pulses could not be observed when he was
recumbent. An intravenous catheter advanced from a
peripheral vein into his right atrium recorded central
venous pressure to be 0 mm Hg (normal 2–6 mm Hg). A
TABLE 30–1 Circulatory Shock
Type of Shock Causes
Cardiogenic -Myocardial infarction
-Severe arrhythmia
-Abrupt valve malfunction
Hypovolemic -Hemorrhage
-Severe burns
-Chronic vomiting or diarrhea
-Dehydration
Anaphylactic -Severe systemic allergic reaction associated
with release of histamine, prostaglandins,
leukotrienes, bradykinin
Septic -Circulating infective agents releasing
vasodilator substances such as endotoxin
(lipopolysaccharide) inducing
NO synthesis
Neurogenic -Reduced sympathetic and/or increased
parasympathetic activity (vasovagal
syncope)
301
blood sample was obtained and his hematocrit was 34
(normal 41–53%). The most immediate problem was
determined to be hemorrhagic hypovolemic shock and he
was given a liter of blood. Within an hour, his heart rate
was 90 beats/min and his blood pressure was 115/85 mm
Hg. He was still weak and pale but more alert. He had not
yet urinated and was very thirsty. Additional blood was
infused and his vital signs returned to normal.
Circulatory shock exists whenever there is a severe reduc-
tion in blood supply to the body tissues and the metabolic
needs of the tissues are not met. Even with all cardiovascular
compensatory mechanisms activated, arterial pressure is
usually (though not always) low in shock. The shock state is
precipitated by one of the following two conditions:
(1) severely depressed myocardial function or (2) grossly
inadequate cardiac filling due to low mean circulatory fill-
ing pressure. The former situation is called cardiogenic
shock and the latter situation can result from a variety of
non-cardiac causes. These shock states are described in
Table 30–1 along with the primary disturbance on the car-
diovascular system and the consequences on cardiac filling
pressure. The common primary disturbances in all forms of
shock lead to decreased mean arterial pressure and decreased
arterial baroreceptor discharge rate. In the case of hypo-
volemic, anaphylactic, and septic shock, diminished activ-
ity of the cardiopulmonary baroreceptors due to a decrease
in central venous pressure and/or volume acts on the med-
ullary cardiovascular centers to stimulate sympathetic out-
put. In the case of cardiogenic shock, central venous pressure
will increase, and in the case of neurogenic shock, central
venous pressure cannot be predicted because both cardiac
Effect on Central
Primary Disturbance Venous Pressure
-Decreased cardiac output -Increased CVP
-Right shift of cardiac
function curve
-Decreased circulating -Decreased CVP
blood volume
-Decreased total peripheral -Decreased CVP
resistance, reduced venous tone
-Decreased total peripheral -Decreased CVP
resistance, reduced venous tone
-Decreased cardiac output, -Variable effect on CVP because
total peripheral resistance, both cardiac output and venous
and venous tone return will decrease
302 SECTION V Cardiovascular Physiology
output and venous return are likely to be depressed. If arte-
rial pressure decreases below the autoregulatory range for
cerebral blood flow (below about 60 mm Hg), perfusion of
the brain begins to decrease, eliciting the cerebral ischemic
response that causes the most intense of all signals to acti-
vate sympathetic nerves.
Unless the primary disturbance precludes these com-
pensatory responses, the increase in sympathetic activity
(and decrease in parasympathetic activity) will lead to an
increase in cardiac output (by increasing heart rate and
cardiac contractility), an increase in total peripheral resis-
tance (by generalized arteriolar constriction), and an
increase in peripheral venous tone (which will shift blood
into the central venous pool). Many of the commonly rec-
ognized symptoms of shock (e.g., pallor, cold clammy
skin, rapid heart rate, muscle weakness, venous constric-
tion) are a result of greatly increased sympathetic nerve
activity. When the immediate compensatory processes
are inadequate, the individual may also show signs of
abnormally low arterial pressure, such as dizziness, con-
fusion, or loss of consciousness.
Additional compensatory processes during a shock
state may include (1) rapid, shallow breathing, which pro-
motes venous return to the heart by action of the respira-
tory pump (see Chapter 72), (2) release of various
powerful vasoconstrictor hormones such as epinephrine
(see Chapter 19), angiotensin II, and vasopressin
(see Chapter 45), which contribute to the increase in total
peripheral resistance, (3) a net shift of fluid from the
interstitial space into the vascular space due to the very
low capillary hydrostatic pressure downstream of the
vasoconstricted arterioles, and (4) an increase in extracel-
lular osmolarity (as a result of increased glycogenolysis in
the liver induced by epinephrine and norepinephrine)
that will induce a shift of fluid from the intracellular space
into the extracellular (including intravascular) space. The
latter two processes result in a sort of autotransfusion
that can move as much as a liter of fluid into the vascular
space in the first hour after the onset of the shock episode
(see Chapter 26). This fluid shift accounts for the reduc-
tion in hematocrit that is commonly observed in hemor-
rhagic shock.
In addition to the immediate compensatory responses
described above, fluid retention mechanisms are evoked
that promote renal retention of fluid and an increase in
circulating blood volume. These processes are described
in detail in Chapter 45 and contribute to the replenish-
ment of extracellular fluid volume within a few days of the
shock episode.
If the primary disturbances are not corrected soon, the
strong compensatory responses can reduce perfusion of
tissues (other than the heart and brain) despite nearly
normal arterial pressure. Intense sympathetic activation
can lead to renal, splanchnic, or hepatic ischemic damage.
If this ischemia is prolonged, self-reinforcing decompen-
satory mechanisms (positive feedback described in
Chapter 1) will progressively drive arterial pressure down
and unless corrective measures are taken quickly, death
will ultimately result.
CHAPTER SUMMARY
■ Cardiovascular responses to physiological stresses should be
evaluated in terms of the initial effects of the primary distur-
bance and the subsequent effects of the reflex compensatory
responses.
■ Gravity, and hence body position, has a significant effect on
the cardiovascular system, and various reflex compensatory
mechanisms are required to overcome venous pooling that
accompanies the upright position.
■ Long-term bed rest causes decreases in circulating blood
volume that contributes to orthostatic hypotension.
■ Cardiovascular characteristics are influenced by a variety of
conditions including respiratory activity, gender, pregnancy,
growth and development from the fetal period, through birth,
pediatric stages, adulthood, and old age.
STUDY QUESTIONS
1. All of the following tend to occur when a person lies down.
Which one is the primary disturbance that causes all the others to
happen?
A) Heart rate will decrease.
B) Stroke volume will decrease.
C) Sympathetic activity will decrease.
D) Parasympathetic activity will increase.
E) Central venous pressure will increase.
2. A 35-year-old man has had a severe bout of the flu with vomiting
and diarrhea for several days. All of the following conditions
would be expected to be present except
A) orthostatic hypotension.
B) increased cardiac preload.
C) increased cardiac ejection fraction.
D) increased hematocrit.
E) increased total peripheral vascular resistance.
3. Total systemic peripheral vascular resistance of a newborn
baby undergoes an abrupt and sustained increase at birth.
This is because
A) circulating blood volume increases.
B) the high-resistance lungs inflate.
C) the low-resistance placental circulation is removed.
D) sympathetic neural stimulation is increased.
E) cardiac output increases.
 CHAPTER 30 Cardiovascular Responses to Physiological Stress
4. Vertical immersion to the chest in tepid water produces a diuresis
in many individuals. What mechanisms might account for this
phenomenon?
A) an increase in sympathetic activity to the kidney
B) an increase in mean arterial pressure
C) a shift of blood from the central to the peripheral
venous pool
D) decreased firing of arterial baroreceptors
E) increased firing of the cardiopulmonary baroreceptors
303
5. All of the following help maintain circulation during states
of hypovolemic shock except
A) an increase in heart rate.
B) rapid respiratory effort to promote venous return of blood
to the heart.
C) vasoconstrictive contributions from increases in circulating
epinephrine.
D) autotransfusion of interstitial fluid into capillary beds.
E) transcapillary filtration of plasma into interstitial space.
This page intentionally left blank
 SECTION VI PULMONARY PHYSIOLOGY

31
C H A P T E R

Function and Structure

of the Respiratory System
Michael Levitzky

O B J E C T I V E S

■ Describe the exchange of oxygen and carbon dioxide with the atmosphere
and relate gas exchange to the metabolism of the tissues of the body.
■ List the functions of the lungs.
■ Describe functions and structures of the conducting airways,
the alveolar–capillary unit, and the chest wall.
■ Describe the central nervous system initiation of breathing and the
innervation of the respiratory muscles.

The main functions of the respiratory system are to obtain
oxygen from the external environment and supply it to the
cells, and to remove from the body the carbon dioxide pro-
duced by cellular metabolism.
The respiratory system is composed of the lungs, the
conducting airways, the parts of the central nervous system
concerned with the control of the muscles of respiration, and
the chest wall. The chest wall consists of the muscles of
respiration— the diaphragm, the intercostal muscles, and
the abdominal muscles—and the rib cage.
FUNCTIONS OF THE
RESPIRATORY SYSTEM
The functions of the respiratory system include gas exchange,
acid–base balance, phonation, pulmonary defense and metab-
olism, and the handling of bioactive materials.
GAS EXCHANGE
The exchange of carbon dioxide for oxygen takes place in the
lungs. As shown in Figure 31–1, fresh air, containing oxygen,
is inspired into the lungs through the conducting airways.
The forces needed to cause the air to flow are generated by the
respiratory muscles, acting on commands initiated by the
central nervous system. At the same time, venous blood
returning from the various body tissues is pumped into the
lungs by the right ventricle of the heart. This mixed venous
blood has a high carbon dioxide content and a low oxygen
content. In the pulmonary capillaries, carbon dioxide is
exchanged for oxygen. The blood leaving the lungs, which
now has a high oxygen content and a lower carbon dioxide
content, is distributed to the tissues of the body by the left side
of the heart. During expiration, gas with a high concentration
of carbon dioxide is expelled from the body.

305

Ch31_305-312.indd 305 11/26/10 11:50:59 AM

306 SECTION VI Pulmonary Physiology

EXTERNAL ENVIRONMENT
High O2, Low CO2

O2

Inspiration
Expiration
CONDUCTING AIRWAYS

CO2

ALVEOLI
O2

CO2
PULMONARY
PULMONARY CAPILLARIES PULMONARY
ARTERY VEINS
Low O2 High O2
High CO2 Low CO2

LEFT
RIGHT ATRIUM
VENTRICLE
LEFT
RIGHT VENTRICLE
ATRIUM

Low O2 High O2
High CO2 Low CO2
VEINS AORTA

SYSTEMIC
CAPILLARIES
O2

CO2

METABOLIZING TISSUES

FIGURE 31–1 Schematic representation of gas exchange between the tissues of the body and the environment. (Modified with
permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

OTHER FUNCTIONS OF THE Phonation

RESPIRATORY SYSTEM Phonation is the production of sounds by the movement of air
through the vocal cords. Speech, singing, and other sounds are
Acid–Base Balance produced by the actions of the central nervous system control-
In the body, increases in carbon dioxide lead to increases in lers on the muscles of respiration, causing air to flow through
hydrogen ion concentration (and vice versa) because of the the vocal cords and the mouth. The physiology of speech is
following reaction: discussed in Chapter 21.

CO2 + H2O H2CO3 H+ + HCO3–

The respiratory system can therefore participate in acid–
base balance by removing CO2 from the body. The central
nervous system has sensors for the CO2 and the hydrogen ion
levels in the arterial blood and in the cerebrospinal fluid that
send information to the controllers of breathing. Acid–base
balance is discussed in greater detail in Chapter 37; the control
of breathing is discussed in Chapter 38.
Pulmonary Defense Mechanisms
Each breath brings into the lungs a small sample of the local
atmospheric environment. This may include microorganisms
such as bacteria, dust, particles of silica or asbestos, toxic gases,
smoke (cigarette and other types), and other pollutants. In
addition, the temperature and humidity of the local atmo-
sphere can vary tremendously. As will be described below, as
 CHAPTER 31 Function and Structure of the Respiratory System
air passes through the airways, it is warmed to body temper-
ature and filtered to remove particulate matter. Most of the
particles in inspired air are removed before they reach the
alveoli. The mechanisms by which these impurities are
removed from the respiratory tract are described in the sec-
tion “Structure of the Respiratory System.”
Pulmonary Metabolism and
the Handling of Bioactive Materials
The cells of the lung must metabolize substrates to supply
energy and nutrients for their own maintenance. Some special-
ized pulmonary cells also produce substances necessary for
normal pulmonary function. These substances include pulmo-
nary surfactant, which is synthesized in type II alveolar epi-
thelial cells (described below) and released at the alveolar
surface. Surfactant plays an important role in reducing the
alveolar elastic recoil due to surface tension and in stabilizing
the alveoli, as discussed later in Chapter 32. Histamine, lyso-
somal enzymes, prostaglandins, leukotrienes, platelet-
activating factor, neutrophil and eosinophil chemotactic
factors, and serotonin can be released from mast cells in the
lungs in response to conditions such as pulmonary embolism
(see Chapter 34) and anaphylaxis (an acute life-threatening
systemic allergic reaction). These substances may cause bron-
choconstriction or immune or inflammatory responses, or they
may initiate cardiopulmonary reflexes. Many substances are
also produced by cells of the lung and released into the alveoli
and airways, including mucus and other tracheobronchial
secretions; surface enzymes, proteins, and other factors; and
immunologically active substances. These substances are pro-
duced by goblet cells, submucosal gland cells, Clara cells, and
macrophages. Substances produced by lung cells and released
into the blood under various circumstances include bradyki-
nin, histamine, serotonin, heparin, prostaglandins E2 and
F2α, and the endoperoxides (prostaglandins G2 and H2).
In addition, the pulmonary capillary endothelium contains
a great number of enzymes that can produce, metabolize, or
modify naturally occurring vasoactive substances. For exam-
307
ple, prostaglandins E1, E2, and F2α are nearly completely
removed in a single pass through the lungs. On the other
hand, prostaglandins A1, A2, and I2 (prostacyclin) are not
affected by the pulmonary circulation. Similarly, about 30% of
the norepinephrine in mixed venous blood is removed by the
lung, but epinephrine is unaffected. It appears that some sub-
stances released into specific vascular beds for local effects are
inactivated or removed as they pass through the lungs, pre-
venting them from entering the systemic circulation; other
substances, apparently intended for more general effects, are
not affected.
STRUCTURE OF THE
RESPIRATORY SYSTEM
THE AIRWAYS
Air enters the respiratory system through the nose or mouth.
Air entering through the nose is filtered, warmed to body tem-
perature, and humidified as it passes through the nose and
nasal turbinates. The upper airways (airways above the
trachea) are shown in Figure 31–2. The mucosa of the nose,
the nasal turbinates, the oropharynx, and the nasopharynx
have a rich blood supply and constitute a large surface area.
The nasal turbinates alone have a surface area said to be about
160 cm2. As inspired air passes through these areas and con-
tinues through the tracheobronchial tree, it is warmed to
body temperature and humidified. This protective function is
more effective if one is breathing through the nose than
through the mouth.
Because the olfactory receptors are located in the posterior
nasal cavity rather than in the trachea or alveoli, a person can
sniff to attempt to detect potentially hazardous gases or dan-
gerous material in the inspired air. This rapid, shallow inspira-
tion brings gases into contact with the olfactory sensors
without bringing them into the lung. Chapter 17 discusses the
physiology of olfaction (the sense of smell).

 



  


   


FIGURE 31–2 Schematic drawing of the



upper airways. (Reproduced with permission from Proctor
  
 
DF. Physiology of the upper airway. In: Fenn WO, Rahn H, eds.
 
Handbook of Physiology, sec 3: Respiration. Vol. 1. Washington,
 DC: American Physiological Society; 1964:309–345.)
308 SECTION VI Pulmonary Physiology
Number
Name of branches of tubes
in branch
Trachea 1
Bronchi 2
Conducting zone
4 tilage and completed dorsally by smooth muscle. The cartilage
8 as the bronchi enter the lungs, the cartilage rings disappear
Bronchioles 16
32
Terminal bronchioles
6 x 104
Respiratory bronchioles
Respiratory zone
5 x 105
Alveolar ducts
Alveolar sacs 8 x 106
FIGURE 31–3 Schematic representation of airway branching
in the human lung. (Reproduced with permission from Weibel ER.
Morphometry of the Human Lung. Berlin; Springer; 1963.)
Air then passes through the glottis and the larynx and enters
the tracheobronchial tree. After passing through the conduct-
ing airways, the inspired air enters the alveoli, where it comes
into contact with the mixed venous blood in the pulmonary
capillaries.
Starting with the trachea, the air may pass through as few as
10 or as many as 23 generations, or branchings, on its way to
the alveoli. The branchings of the tracheobronchial tree and its
nomenclature are shown in Figure 31–3. Alveolar gas exchange
units are denoted by the U-shaped sacs.
The first 16 generations of airways, the conducting zone,
contain no alveoli and thus are anatomically incapable of
gas exchange with the venous blood. They constitute the
anatomic dead space, which is discussed in Chapter 33.
Alveoli start to appear at the 17th to the 19th generations, in
the respiratory bronchioles, which constitute the transi-
tional zone. The 20th to 22nd generations are lined with
alveoli. These alveolar ducts and the alveolar sacs, which
terminate the tracheobronchial tree, are referred to as the
respiratory zone.
The portion of the lung supplied by a primary respiratory
bronchiole is called an acinus. All of the airways of an acinus
participate in gas exchange. The numerous branchings of
the airways result in a tremendous total cross-sectional area
of the distal portions of the tracheobronchial tree, even though
the diameters of the individual airways are quite small.
Structure of the Airways
The structure of the airways varies considerably, depending on
their location in the tracheobronchial tree. The trachea is a
fibromuscular tube supported ventrolaterally by C-shaped car-
of the large bronchi is semicircular, like that of the trachea, but
and are replaced by irregularly shaped cartilage plates. They
completely surround the bronchi and give the intrapulmonary
bronchi their cylindrical shape. These plates, which help sup-
port the larger airways, diminish progressively in the distal
airways and disappear in airways about 1 mm in diameter. Air-
ways with no cartilage are termed bronchioles. Because the
bronchioles and alveolar ducts contain no cartilage support,
they are subject to collapse when compressed, as will be dis-
cussed later in this chapter. This tendency is partly opposed by
the attachment of the alveolar septa, containing elastic tissue,
to their walls, as seen in Figure 31–4, a scanning electron
micrograph of the alveolar–capillary surface (also shown sche-
matically in Figure 32–18). As the cartilage plates become
irregularly distributed around distal airways, the muscular
layer completely surrounds these airways. The muscular layer
is intermingled with elastic fibers. As the bronchioles proceed
toward the alveoli, the muscle layer becomes thinner, although
smooth muscle can even be found in the walls of the alveolar
ducts. The outermost layer of the bronchiolar wall is sur-
rounded by dense connective tissue with many elastic fibers.
The entire respiratory tract, except for part of the pharynx, the
anterior third of the nose, and the respiratory units distal to the
terminal bronchioles, is lined with ciliated cells interspersed with
mucus-secreting goblet cells and other secretory cells. In the
bronchioles, the goblet cells become less frequent and are
replaced by another type of secretory cell, the Clara cell. The
ciliated epithelium, along with mucus secreted by glands along
the airways and the goblet cells and the secretory products of the
Clara cells, constitutes an important mechanism for the protec-
tion of the lung called the mucociliary escalator.
Filtration and Removal of Inspired
Particles by the Airways
Filtration of Inspired Air Air passing through the nose is
first filtered by passing through the nasal hairs, or vibrissae. This
removes most particles larger than 10–15 μm in diameter. Most of
the particles greater than 10 μm in diameter are removed on im-
pact in the large surface area of the nasal septum and turbinates
(Figure 31–2). The inspired air stream changes direction abruptly
at the nasopharynx so that many of these larger particles impact
the posterior wall of the pharynx. The tonsils and adenoids are
located near this impaction site, providing immunologic defense
against biologically active material filtered at this point. Air enter-
ing the trachea contains few particles larger than 10 μm, and most
 CHAPTER 31 Function and Structure of the Respiratory System
FIGURE 31–4 Scanning electron micrograph of human lung
parenchyma. A, alveolus; S, alveolar septa; D, alveolar duct; PK, pore
of Kohn; PA, small branch of the pulmonary artery. (Reproduced with
permission from Fishman AP, Elias JA: Fishman’s Pulmonary Diseases and Disorders,
3rd ed. New York: McGraw-Hill, Health Professions Division, 1998.)
of these will impact mainly at the carina or within the bronchi.
Sedimentation of most particles in the size range of 2–5 μm
occurs by gravity in the smaller airways, where airflow rates are
extremely low. Thus, most of the particles between 2 and 10 μm
in diameter are removed by impaction or sedimentation and
become trapped in the mucus that lines the upper airways,
trachea, bronchi, and bronchioles. Smaller particles and all
foreign gases reach the alveolar ducts and alveoli. Some smaller
particles (0.1 μm and smaller) are deposited as a result of Brown-
ian motion due to their bombardment by gas molecules. The
other particles, between 0.1 and 0.5 μm in diameter, mainly stay
suspended as aerosols, and about 80% of them are exhaled.
Removal of Filtered Material Filtered or aspirated mate-
rial trapped in the mucus that lines the respiratory tract can be
removed in several ways. Mechanical or chemical stimulation
of receptors in the nose, trachea, larynx, or elsewhere in the re-
spiratory tract may produce bronchoconstriction to prevent
deeper penetration of the irritant into the airways and may also
produce a cough or a sneeze. A sneeze results from stimulation
of receptors in the nose or nasopharynx; a cough results from
309
stimulation of receptors in the trachea. In either case, a deep in-
spiration is followed by a forced expiration against a closed glot-
tis. Pressure in the chest surrounding the lungs (intrapleural
pressure) may rise to more than 100 mm Hg during this phase
of the reflex. The glottis opens suddenly, and pressure in the air-
ways decreases rapidly, resulting in compression of the airways
and an explosive expiration, with linear airflow velocities said to
approach the speed of sound. Such high airflow rates through
the narrowed airways are likely to carry the irritant, along with
some mucus, out of the respiratory tract. In a sneeze, the expira-
tion is via the nose; in a cough, the expiration is via the mouth.
The cough or sneeze reflex is also useful in helping to move the
mucous lining of the airways toward the nose or mouth. The
term “cough” is not specific to this complete involuntary respi-
ratory reflex. Coughs can be initiated by many causes, including
postnasal drip from allergies or viral infections, asthma, gas-
troesophageal reflux, as an adverse effect of the very commonly
prescribed angiotensin-converting enzyme inhibitors, mucus
production from chronic bronchitis, infections, and other air-
way disorders. Voluntary coughs are not usually as pronounced
as the violent involuntary reflex described above.
Particles that are trapped in the mucus lining the airways
can be removed by the mucociliary escalator, which has an
estimated total surface area of 0.5 m2. The mucus is a complex
polymer of mucopolysaccharides. The mucous glands are
found mainly in the submucosa near the supporting cartilage
of the larger airways. In pathologic states, such as chronic
bronchitis, the number of goblet cells may increase and the
mucous glands may hypertrophy, resulting in greatly increased
mucous gland secretion and increased viscosity of mucus.
The cilia lining the airways beat in such a way that the mucus
covering them is always moved up the airway, away from the
alveoli and toward the pharynx. The mucous blanket appears
to be involved in the mechanical linkage between the cilia. The
cilia beat at frequencies between 600 and 900 beats/min, and
the mucus moves progressively faster as it travels from the
periphery. Several studies have shown that ciliary function is
inhibited or impaired by cigarette smoke.
The mucociliary escalator is an especially important mecha-
nism for the removal of inhaled particles that come to rest in the
airways. Material trapped in the mucus is continuously moved
upward toward the pharynx. This movement can be greatly
increased during a cough, as described previously. Mucus that
reaches the pharynx is usually swallowed, expectorated, or
removed by blowing one’s nose. Patients who cannot clear their
tracheobronchial secretions (e.g., an intubated patient or a
patient who cannot cough adequately) continue to produce
secretions. If the secretions are not removed from the patient by
suction or other means, airway obstruction may develop.
THE ALVEOLAR–CAPILLARY UNIT
The alveolar–capillary unit is the site of gas exchange in the
lung. The alveoli, traditionally estimated to number about 300
million in the adult (a more recent study calculated the mean
310 SECTION VI Pulmonary Physiology

the lung to injury. As type I alveolar epithelial cells are injured,

type II cells proliferate to reestablish a continuous epithelial
surface. Studies in animals have shown that these type II cells
can develop into type I cells after injury.
A cross-section of a pulmonary capillary is shown in the
transmission electron micrograph in Figure 31–6. An eryth-
rocyte is seen in cross-section in the lumen of the capillary.
Capillaries are formed by a single layer of squamous epithelial
cells that are aligned to form tubes. The nucleus of one of the
capillary endothelial cells can be seen in the micrograph.
The barrier to gas exchange between the alveoli and pulmonary
capillaries can also be seen in the figure. It consists of the alveolar
epithelium, the capillary endothelium, and the interstitial space
between them. Gases must also pass through the fluid lining the
alveolar surface (not visible in Figure 32–6) and the plasma in the
capillary. The barrier to diffusion is normally 0.2–0.5 μm thick.
Gas exchange by diffusion is discussed in Chapter 35.

FIGURE 31–5 Scanning electron micrograph of the surface and

cross-section of an alveolar septum. Capillaries (C) are seen sectioned
in the foreground, with erythrocytes (EC) within them. A, alveolus; D,
alveolar duct; PK, pore of Kohn; AR, alveolar entrance to duct; *,
connective tissue fibers. The encircled asterisk is at a junction of three
septa. (Reproduced with permission from Fishman AP, Elias JA: Fishman’s Pulmonary
Diseases and Disorders, 3rd ed. New York: McGraw-Hill, Health Professions Division, 1998.)

number of alveoli to be 480 million), are almost completely

enveloped in pulmonary capillaries. There may be as many as
280 billion pulmonary capillaries, or approximately 500–1,000
pulmonary capillaries per alveolus. The result of these stagger-
ing numbers of alveoli and pulmonary capillaries is a vast area
of contact between alveoli and pulmonary capillaries—
probably 50–100 m2 of surface area available for gas exchange
by diffusion. The alveoli are about 200–250 μm in diameter.
Figure 31–5 shows an even greater magnification of the site
of gas exchange than that shown in Figure 31–4.
The alveolar septum appears to be almost entirely composed
of pulmonary capillaries. Red blood cells (erythrocytes) can be
seen inside the capillaries at the point of section. Elastic and con-
nective tissue fibers, not visible in the figure, are found between
the capillaries in the alveolar septa. Also shown in these figures
are the pores of Kohn that are interalveolar communications.
The alveolar surface is mainly composed of a single thin
layer of squamous epithelial cells, the type I alveolar cells.
Interspersed among these are the larger cuboidal type II alveo-
lar cells that produce the fluid layer that lines the alveoli.
Although there are about twice as many type II cells as there
are type I cells in the human lung, type I cells cover 90–95% of
the alveolar surface, because the average type I cell has a much FIGURE 31–6 Transmission electron micrograph of a cross-
section of a pulmonary capillary. An erythrocyte (EC) is seen within the
larger surface area than the average type II cell does. A third
capillary. C, capillary; EN, capillary endothelial cell (note its large nucleus);
cell type, the free-ranging phagocytic alveolar macrophage, is EP, alveolar epithelial cell; IN, interstitial space; BM, basement membrane;
found in varying numbers in the extracellular lining of the FB, fibroblast processes; 2, 3, and 4, diffusion pathway through the
alveolar surface. These cells patrol the alveolar surface and alveolar–capillary barrier, the plasma, and the erythrocyte, respectively.
phagocytize inspired particles such as bacteria. The type II (Reproduced with permission from Weibel, E.R. : Morphometric estimation of pulmonary
alveolar epithelial cell also plays a major role in the response of diffusion capacity, I. Model and method. Respir Physiol 1970;11:54–75.)
 CHAPTER 31 Function and Structure of the Respiratory System
Removal of Material from
the Alveolar Surface
Inspired material that reaches the terminal airways and alveoli
may be removed in several ways, including ingestion by alveo-
lar macrophages, enzymatic destruction, entry into the lym-
phatics, and immunologic reactions. Inhaled particles engulfed
by alveolar macrophages may be destroyed by their lysosomes
(see Chapter 1). Most bacteria are digested in this manner.
Some material ingested by the macrophages, however, such as
silica, is not degradable by the macrophages and may even
be toxic to them. If the macrophages carrying such material
are not removed from the lung, the material will be redepos-
ited on the alveolar surface on the death of the macrophages.
The mean life span of alveolar macrophages is believed to be
1–5 weeks. The main exit route of macrophages carrying such
nondigestible material is migration to the mucociliary escala-
tor via the pores of Kohn and eventual removal through the
airways. Particle-containing macrophages may also migrate
from the alveolar surface into the septal interstitium, from
which they may enter the lymphatic system or the mucociliary
escalator. Macrophage function has been shown to be inhib-
ited by cigarette smoke. Alveolar macrophages are also impor-
tant in the lung’s immune and inflammatory responses. They
secrete many enzymes, arachidonic acid metabolites, immune
response components, growth factors, cytokines, and other
mediators that modulate the function of other cells, such as
lymphocytes.
Some particles reach the mucociliary escalator because the
alveolar fluid lining itself is slowly moving upward toward
the respiratory bronchioles. Others penetrate into the inter-
stitial space or enter the blood, where they are phagocytized
by interstitial macrophages or blood phagocytes, or enter the
lymphatics. Particles may be destroyed or detoxified by
surface enzymes and factors in the serum and in airway
secretions.
THE MUSCLES OF RESPIRATION
AND THE CHEST WALL
The muscles of respiration and the chest wall are essential com-
ponents of the respiratory system. The lungs are not capable of
inflating themselves—the force for this inflation must be
supplied by the muscles of respiration. The chest wall must be
intact and able to expand if air is to enter the alveoli normally.
The interactions among the muscles of respiration and the chest
wall and the lungs are discussed in detail later in Chapter 32.
The primary components of the chest wall include the rib
cage; the external and internal intercostal muscles and the dia-
phragm, which are the main muscles of respiration; and the
311
lining of the chest wall, the visceral and parietal pleura. Other
muscles of respiration include the abdominal muscles, includ-
ing the rectus abdominis; the parasternal intercartilaginous
muscles; and the sternocleidomastoid and scalenus muscles.
THE CENTRAL NERVOUS SYSTEM
AND THE NEURAL PATHWAYS
Another important component of the respiratory system is the
central nervous system. Unlike cardiac muscle, the muscles of
respiration do not contract spontaneously. Each breath is initi-
ated in the brain, and this message is carried to the respiratory
muscles via the spinal cord and the nerves innervating the
respiratory muscles.
Spontaneous automatic breathing is generated by groups of
neurons located in the medulla. This medullary respiratory
center is also the final integration point for influences from
higher brain centers, for information from chemoreceptors in
the blood and cerebrospinal fluid, and for afferent information
from neural receptors in the airways, joints, muscles, skin, and
elsewhere in the body. The control of breathing is discussed in
Chapter 38.
CHAPTER SUMMARY
■ The main function of the respiratory system is the exchange of
oxygen from the atmosphere for carbon dioxide produced by
the cells of the body.
■ Other functions of the respiratory system include participation
in the acid–base balance of the body, phonation, pulmonary
defense, and metabolism.
STUDY QUESTIONS
1. The functions of the respiratory system include
A) gas exchange.
B) acid–base balance.
C) phonation.
D) pulmonary defense and metabolism.
E) handling bioactive materials.
F) all of the above.
2. Particulate matter in the inspired air that enters the airways or
alveoli may be removed by
A) the mucociliary escalator.
B) alveolar macrophages.
C) surface enzymes.
D) the lymphatics.
E) all of the above.
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 32
C H A P T E R

Mechanics of the
Respiratory System
Michael Levitzky

O B J E C T I V E S

■ Describe the generation of a pressure gradient between the atmosphere

and the alveoli.
■ Describe the passive expansion and recoil of the alveoli.
■ Define the mechanical interaction of the lung and the chest wall.
■ Describe the pressure–volume characteristics of the lung and the chest wall,
and predict changes in the compliance of the lung and the chest wall in
different physiologic and pathologic conditions.
■ State the roles of pulmonary surfactant and alveolar interdependence
in the recoil and expansion of the lung.
■ Define the functional residual capacity (FRC), and predict changes in FRC in
different physiologic and pathologic conditions.
■ Define airway resistance and list the factors that contribute to or alter the
resistance to airflow.
■ Describe the dynamic compression of airways during a forced expiration.
■ List the factors that contribute to the work of breathing.
■ Predict alterations in the work of breathing in different physiologic and
pathologic states.

Air, like other fluids, moves from a region of higher pressure
to one of lower pressure. Therefore, for air to be moved into or
out of the lungs, a pressure difference between the atmosphere
and the alveoli must be established. If there is no pressure gra-
dient, no airflow will occur.
Under normal circumstances, inspiration is accomplished
by causing alveolar pressure to decrease below atmospheric
pressure. When the mechanics of breathing are being dis-
cussed, atmospheric pressure is conventionally referred to
as 0 cm H2O, so lowering alveolar pressure below atmo-
spheric pressure is known as negative-pressure breathing.
When a pressure gradient sufficient to overcome the resis-
tance to airflow offered by the conducting airways is estab-
lished between the atmosphere and the alveoli, air flows
into the lungs. It is also possible to cause air to flow into the
lungs by increasing the pressure at the nose or mouth above
alveolar pressure. This positive-pressure ventilation is gen-
erally used on patients unable to generate a pressure gradi-
ent between the atmosphere and the alveoli by normal
negative-pressure breathing. Air flows out of the lungs when
alveolar pressure is sufficiently greater than atmospheric
pressure to overcome the resistance to airflow offered by the
conducting airways.
GENERATION OF A PRESSURE
GRADIENT BETWEEN THE
ATMOSPHERE AND THE ALVEOLI
During normal negative-pressure breathing, alveolar pressure
is made lower than atmospheric pressure. This is accomplished
by causing the muscles of inspiration to contract, which
increases the volume of the alveoli, thus lowering the alveolar
pressure according to Boyle’s law: at constant temperature, the
product of the pressure and the volume of a gas is constant.

313

Ch32_313-330.indd 313 12/15/10 11:46:29 AM

314 SECTION VI Pulmonary Physiology

atmospheric pressure: 0 cm H2O atmospheric pressure: 0 cm H2O

no air flow: atmospheric air flows in : atmospheric
pressure = alveolar pressure pressure>alveolar pressure

outward recoil force generated by

of chest wall inspiratory muscles

alveolar pressure:
0 cm H2O alveolar pressure:
1 cm H2O

intrapleural pressure: inward recoil

of alveoli intrapleural pressure:
5 cm H2O
8 cm H2O

transmural pressure 
0 cm H2O(5 cm H2O)5 cm H2O
transmural pressure 
1 cm H2O (8 cm H2O)7 cm H2O

END EXPIRATION DURING INSPIRATION

FIGURE 32–1 Representation of the interaction of the lung and chest wall. Left: At end expiration, the muscles of respiration are
relaxed. The inward elastic recoil of the lung is balanced by the outward elastic recoil of the chest wall. Intrapleural pressure is –5 cm H2O; alveolar
pressure is 0. The transmural pressure gradient across the alveolus is therefore 0 – (–5) cm H2O, or 5 cm H2O. Since alveolar pressure is equal to
atmospheric pressure, no airflow occurs. Right: During inspiration, contraction of the muscles of inspiration causes intrapleural pressure to
become more negative. The transmural pressure gradient increases and the alveoli are distended, decreasing alveolar pressure below atmospheric
pressure, which causes air to flow into the alveoli. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

The alveoli are not capable of expanding themselves. They
expand passively in response to an increased distending pres-
sure across the alveolar wall. This increased transmural pres-
sure gradient, generated by the muscles of inspiration, further
opens the highly distensible alveoli and thus decreases the
alveolar pressure. The transmural pressure gradient is conven-
tionally calculated by subtracting the outside pressure (in this
case, the intrapleural pressure) from the inside pressure (in
this case, the alveolar pressure).
The pressure in the thin, liquid-filled space between the vis-
ceral and parietal pleura is normally slightly less than atmo-
spheric pressure, even when no inspiratory muscles are
contracting. This negative intrapleural pressure (sometimes
also referred to as negative intrathoracic pressure) of –3 to
–5 cm H2O is mainly caused by the mechanical interaction
between the lung and the chest wall. At the end of expiration,
when all the respiratory muscles are relaxed, the lung and the
chest wall are acting on each other in opposite directions. The
lung is tending to decrease its volume because of the inward
elastic recoil of the distended alveolar walls; the chest wall is
tending to increase its volume because of its outward elastic
recoil. Thus, the chest wall is acting to hold the alveoli open in
opposition to their elastic recoil. Similarly, the lung is acting
by its elastic recoil to hold the chest wall in. Because of this
interaction, the pressure is negative at the surface of the very
thin (about 10–30 μm in thickness at normal lung volumes),
fluid-filled pleural space, as seen on the left in Figure 32–1.
There is normally no free gas in the intrapleural space, and the
lung is held against the chest wall by the thin layer of serous
intrapleural liquid, estimated to have a total volume of about
15–25 mL in the average adult.
Initially, before any airflow occurs, the pressure inside the
alveoli is the same as atmospheric pressure—by convention
0 cm H2O. Alveolar pressure is greater than intrapleural pres-
sure because it represents the sum of the intrapleural pressure
plus the alveolar elastic recoil pressure:
Alveolar pressure =
(1)
Intrapleural pressure + Alveolar elastic recoil pressure
The muscles of inspiration act to increase the volume of the
thoracic cavity. As the inspiratory muscles contract, expand-
ing the thoracic volume and increasing the outward stress
on the lung, the intrapleural pressure becomes more negative.
Therefore, the transmural pressure gradient tending to distend
the alveolar wall (also called the transpulmonary pressure)
increases as shown in Figure 32–1, and the alveoli enlarge pas-
sively. Increasing alveolar volume lowers alveolar pressure and
establishes the pressure gradient for airflow into the lung. In
reality, only a small percentage of the total number of alveoli
are directly exposed to the intrapleural surface pressure, and at
first thought, it is difficult to see how alveoli located centrally
in the lung could be expanded by a more negative intrapleural
 CHAPTER 32 Mechanics of the Respiratory System 315

Intrapleural Negative pressure breathing

pressure
(A)

Interdependence of alveolar units

Positive pressure ventilation

(B)

FIGURE 32–2 Structural interdependence of alveolar units. The pressure gradient across the outermost alveoli is transmitted
mechanically through the lung via the alveolar septa. The insets show the author’s idea of what might happen in negative-pressure breathing
and positive-pressure ventilation. In negative-pressure breathing (inset A), the mechanical stress would likely be transmitted from the more
exterior alveoli (those closest to the chest wall) to more interior alveoli, so the exterior alveoli might be more distended. In positive-pressure
ventilation (inset B), the lungs must push against the diaphragm and rib cage to move them. The outermost alveoli might be more compressed
than those located more interiorly. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

pressure. However, careful analysis has shown that the pres-
sure at the pleural surface is transmitted through the alveolar
walls to more centrally located alveoli and small airways. This
structural interdependence of alveolar units is depicted in
Figure 32–2.
THE MUSCLES OF RESPIRATION
Inspiratory Muscles
The muscles of respiration are skeletal muscles and their activ-
ity is normally initiated by the nervous system.The muscles of
inspiration include the diaphragm, the external intercostal
muscles, and the accessory muscles of inspiration. The dia-
phragm is a large (about 250 cm2 in surface area), dome-
shaped muscle that separates the thorax from the abdominal
cavity. It is the primary muscle of inspiration. When a person
is in the supine position, the diaphragm is responsible for
about two thirds of the air that enters the lungs during normal
quiet breathing (which is called eupnea). When a person is
standing or seated in an upright posture, the diaphragm may
be responsible for only about one third to one half of the tidal
volume. It is innervated by the two phrenic nerves, which are
motor nerves that leave the spinal cord at the third to the fifth
cervical segments.
The muscle fibers of the diaphragm are inserted into the ster-
num and the six lower ribs and into the vertebral column by the
two crura. The other ends of these muscle fibers converge to
attach to the fibrous central tendon, which is also attached to
the pericardium on its upper surface (Figure 32–3). During
normal quiet breathing, contraction of the diaphragm causes its
dome to descend 1–2 cm into the abdominal cavity, with little
change in its shape. This elongates the thorax and increases its
volume. These small downward movements of the diaphragm
are possible because the abdominal viscera can push out against
the relatively compliant abdominal wall. During a deep inspira-
tion, the diaphragm can descend as much as 10 cm. With such
a deep inspiration, the limit of the abdominal wall to expand is
reached, abdominal pressure increases, and the indistensible
central tendon becomes fixed against the abdominal contents.
After this point, contraction of the diaphragm against the fixed
central tendon elevates the lower ribs as shown in the figure.
Contraction of the external intercostal, parasternal inter-
costal, and scalene muscles raises and enlarges the rib cage.
316 SECTION VI Pulmonary Physiology

Pleura

Rib cage
Mediastinum

Pericardium

Central tendon

Diaphragm

Crura

END EXPIRATION DEEP INSPIRATION

FIGURE 32–3 Illustration of the actions of diaphragmatic contraction in expanding the thoracic cavity. (Modified with permission from
Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

Figure 32–4 demonstrates how contraction of these muscles
increases the anteroposterior dimension of the chest as the
ribs rotate upward about their axes and also increases the trans-
verse dimension of the lower portion of the chest. These mus-
cles are innervated by nerves leaving the spinal cord at the 1st
to the 11th thoracic segments. During inspiration, the dia-
phragm and inspiratory rib cage muscles contract simultane-
ously. If the diaphragm contracted alone, the rib cage muscles
would be pulled inward (this is called retraction). If the
inspiratory muscles of the rib cage contracted alone, the dia-
phragm would be pulled upward into the thorax.
The accessory muscles of inspiration are not involved dur-
ing normal quiet breathing but may be called into play during
exercise, during the inspiratory phase of coughing or sneezing,
or in a pathologic state, such as asthma. Dyspnea, the feeling
that breathing is difficult, is probably often related to fatigue of
the inspiratory muscles. Other potential causes of dyspnea will
be discussed in Chapter 38.

INSPIRATION ACTIVE EXPIRATION

Accessory muscles

External intercostals

Internal intercostals

Diaphragm

Abdominal muscles

Posterior Anterior
FIGURE 32–4 Illustration of the actions of contraction of the intercostal muscles, abdominal muscles, and accessory muscles.
(Modified with permission of the publisher from by Weibel ER: The Pathway for Oxygen. Cambridge, MA: Harvard University Press, p. 304. Copyright © 1984 by the President and
Fellows of Harvard College.)
 CHAPTER 32 Mechanics of the Respiratory System 317

Expiratory Muscles
Expiration is passive during normal quiet breathing, and no
respiratory muscles contract. As the inspiratory muscles relax,
the increased elastic recoil of the distended alveoli is sufficient
to decrease the alveolar volume and raise alveolar pressure
above atmospheric pressure, establishing the pressure gradient
for airflow from the lung.
Although the diaphragm is usually considered to be com-
pletely relaxed during expiration, it is likely that some dia-
phragmatic muscle tone is maintained, especially when one is
in the horizontal position.
Active expiration occurs during exercise, speech, singing,
the expiratory phase of coughing or sneezing, and in patho-
logic states such as chronic bronchitis. The main muscles of
expiration are the muscles of the abdominal wall and the inter-
nal intercostal muscles. When the abdominal muscles con-
tract, they increase abdominal pressure and push the
abdominal contents against the relaxed diaphragm, forcing it
upward into the thoracic cavity. They also help depress the
lower ribs and pull down the anterior part of the lower chest.
Contraction of the internal intercostal muscles depresses the
rib cage downward in a manner opposite to the actions of the
external intercostals. Active expiration compresses the thorax
and causes positive intrapleural pressure. This has important
effects on the respiratory system, which will be discussed later
in this chapter, and on pulmonary blood flow, which will be
discussed in Chapter 34.
SUMMARY OF THE EVENTS
OCCURRING DURING THE
COURSE OF A BREATH
The events occurring during the course of an idealized nor-
mal quiet breath (summarized in Table 32–1) are shown in
Figure 32–5. For the purpose of clarity, inspiration and expira-
tion are considered to be of equal duration, although during
normal quiet breathing, the expiratory phase is longer than
the inspiratory phase.
Initially, alveolar pressure equals atmospheric pressure, so no
air flows into the lung. Intrapleural pressure is –5 cm H2O.
Contraction of the inspiratory muscles causes intrapleural pres-
sure to become more negative as the lungs are pulled open and
the alveoli are distended. As the alveoli are distended, the pres-
sure inside them decreases below atmospheric pressure and air
flows into the alveoli, as seen in the tidal volume panel. As the
air flows into the alveoli, alveolar pressure returns to 0 cm H2O
and airflow into the lung ceases. At the vertical line, the inspira-
tory effort ceases and the inspiratory muscles relax. Intrapleu-
ral pressure becomes less negative, and the elastic recoil of the

TABLE 32–1 Events involved in a normal tidal breath.

Inspiration

1. Brain initiates inspiratory effort

2. Nerves carry the inspiratory command to the inspiratory muscles

3. Diaphragm (and/or external intercostal muscles) contracts

4. Thoracic volume increases as the chest wall expandsa

5. Intrapleural pressure becomes more negative

6. Alveolar transmural pressure gradient increases

7. Alveoli expand (according to their individual compliance curves) in response to the increased transmural pressure gradient.
This increases alveolar elastic recoil

8. Alveolar pressure falls below atmospheric pressure as the alveolar volume increases, thus establishing a pressure gradient for airflow

9. Air flows into the alveoli until alveolar pressure equilibrates with atmospheric pressure

Expiration (passive)

1. Brain ceases inspiratory command

2. Inspiratory muscles relax

3. Thoracic volume decreases, causing intrapleural pressure to become less negative and decreasing the alveolar transmural pressure gradientb

4. Decreased alveolar transmural pressure gradient allows the increased alveolar elastic recoil to return the alveoli to their preinspiratory volumes

5. Decreased alveolar volume increases alveolar pressure above atmospheric pressure, thus establishing a pressure gradient for airflow

6. Air flows out of the alveoli until alveolar pressure equilibrates with atmospheric pressure
a
Note that numbers 4–8 occur simultaneously.
b
Note that numbers 3–5 occur simultaneously.
Reproduced with permission from Levitzky MG, Cairo JM, Hall SM: Introduction to Respiratory Care. Philadelphia: WB Saunders and Company, 1990.
318 SECTION VI Pulmonary Physiology

100
–5

Intrapleural
cm H2O pressure 75
Expiration

Total lung volume, %

–10
+1 Inspiration
50
Alveolar
cm H2O 0 pressure

–1 25

+0.5

L/sec 0 Air flow

0 10 20 30 40
Transpulmonary pressure cm H2O
–0.5
FIGURE 32–6 Pressure–volume curve for isolated lungs.
0.5 (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed.
Change in New York: McGraw-Hill Medical, 2007.)
L lung volume

0 lungs from an animal or a cadaver and then graph the changes

Onset of End of End of
inspiration inspiration expiration
FIGURE 32–5 Volume, pressure, and airflow changes during
a single idealized respiratory cycle. Described in text. (Reproduced
with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New
York: McGraw-Hill, 2009.)
alveolar walls (which is increased at the higher lung volume) is
allowed to compress the alveolar gas. This raises alveolar pres-
sure above atmospheric pressure so that air flows out of the
lung until an alveolar pressure of 0 cm H2O is restored. At this
point, airflow ceases until the next inspiratory effort.
PRESSURE–VOLUME
RELATIONSHIPS IN THE
RESPIRATORY SYSTEM
The relationship between changes in the pressure distending
the alveoli and changes in lung volume is important to under-
stand because it dictates how the lung inflates with each breath.
As mentioned before, the alveolar-distending pressure is often
referred to as the transpulmonary pressure.
COMPLIANCE OF THE LUNG
AND THE CHEST WALL
The pressure–volume characteristics of the lung can be
inspected in several ways. One of the simplest is to remove the
in volume that occur for each change in transpulmonary pres-
sure to which the lungs are subjected (Figure 32–6).
Figure 32–6 shows that as the transpulmonary pressure
increases, the lung volume increases. Of course, this relation-
ship is not a straight line: the lung is composed of living tissue,
and although the lung distends easily at low lung volumes, at
high lung volumes the distensible components of alveolar
walls have already been stretched, and large increases in trans-
pulmonary pressure yield only small increases in volume. The
lung also is difficult to distend at very low lung volumes
because some alveoli may be collapsed and extra energy is
necessary to reopen them.
The slope between two points on a pressure–volume curve is
known as the compliance. Compliance is defined as the change
in volume divided by the change in pressure. Lungs with high
compliance have a steep slope on their pressure–volume curves,
that is, a small change in distending pressure will cause a large
change in volume. It is important to remember that compliance
is the inverse of elasticity, or elastic recoil. Compliance denotes
the ease with which something can be stretched or distorted;
elasticity refers to the tendency for something to oppose stretch
or distortion, as well as to its ability to return to its original con-
figuration after the distorting force is removed.
There are several other interesting things to note about an
experiment like that illustrated in Figure 32–6. The curve
obtained is the same whether the lungs are inflated with posi-
tive pressure (by forcing air into the trachea) or with negative
pressure (by suspending the lung, except for the trachea, in a
closed chamber and pumping out the air around the lung). So
when the lung alone is considered, only the transpulmonary
pressure is important, not how the transpulmonary pressure is
generated. A second feature of the curve in Figure 32–6 is that
there is a difference between the pressure–volume curve for

inflation and the curve for deflation, as shown by the arrows.
Such a difference is called hysteresis. One possible explana-
tion for this hysteresis is the stretching on inspiration and the
compression on expiration of the surfactant that lines the air–
liquid interface in the alveoli (discussed later in this chapter).
Another is that some alveoli or small airways may open on
inspiration (“recruitment”) and close on expiration (“dere-
cruitment”) as noted above. Some researchers believe that lung
volume changes primarily by recruitment and derecruitment
Lung volume (ml)
of alveoli rather than by volume changes of individual alveoli.
Finally, it can be helpful to think of each alveolus as having its
own pressure–volume curve like that shown in the figure.
Clinical Evaluation of the Compliance
of the Lung and the Chest Wall
The compliance of the lung and the chest wall provides very
useful data for the clinical evaluation of a patient’s respiratory
system because many diseases or pathologic states affect the
compliance of the lung, the chest wall, or both. The lung and
the chest wall are physically in series with each other, and
therefore their compliances add as reciprocals:
1
____________
=
Total compliance (2)
1
_________________ 1
+ ____________________
Compliance of the lung Compliance of the chest wall
Compliances in parallel add directly. Therefore, both lungs
together are more compliant than either one alone.
The compliance curve for the lungs can be generated by
having the patient take a very deep breath and exhale in stages,
stopping periodically for pressure and volume determinations.
During these determinations, no airflow is occurring; alveolar
pressure therefore equals atmospheric pressure, 0 cm H2O.
Similar measurements can be made as the patient inhales in
stages from a low lung volume to a high lung volume. Such
curves are called static compliance curves because all mea-
surements are made when no airflow is occurring. The com-
pliance of the chest wall is normally obtained by determining
the compliance of the total system and the compliance of the
lungs alone and then calculating the compliance of the chest
wall according to the above formula. Dynamic compliance
assesses pressure–volume characteristics during the breath.
Representative static compliance curves for the lungs are
shown in Figure 32–7. Note that these curves correspond to
the expiratory curve in Figure 32–6. Many pathologic states
shift the curve to the right; that is, for any increase in transpul-
monary pressure, there is a smaller increase in lung volume. A
proliferation of connective tissue called fibrosis may occur in
sarcoidosis or after chemical or thermal injury to the lungs.
This will make the lungs less compliant, or “stiffer,” and
increase alveolar elastic recoil. Similarly, pulmonary vascular
engorgement or areas of collapsed alveoli (atelectasis) also
make the lung less compliant. Other conditions that interfere
with the lung’s ability to expand (such as the presence of air,
excess fluid, or blood in the intrapleural space) will decrease
the measured compliance of the lungs. Emphysema increases
CHAPTER 32 Mechanics of the Respiratory System 319
Δ Lung volume ΔV
Compliance = =
Δ (P alv – P ip) Δ P tp
Increased
compliance
Normal
compliance
Decreased
compliance
0 Transpulmonary pressure (P tp)
(P alv – P ip)
FIGURE 32–7 Representative static pulmonary compliance
curve for normal lungs; lungs with low compliance, for example,
lungs with fibrosis; and lungs with high compliance, for example,
lungs with emphysema. (Reproduced with permission from Widmaier EP, Raff
H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
the compliance of the lungs because it destroys the alveolar
septal tissue that normally opposes lung expansion.
The compliance of the chest wall is decreased in obese peo-
ple, for whom moving the diaphragm downward and the rib
cage up and out is much more difficult. Musculoskeletal disor-
ders that lead to decreased mobility of the rib cage, such as
kyphoscoliosis, also decrease the chest wall compliance.
Because they must generate greater transpulmonary pres-
sures to breathe in the same volume of air, people with
decreased compliance of the lungs must do more work
to inspire than those with normal pulmonary compliance.
Similarly, more muscular work must be done when chest wall
compliance is decreased.
ELASTIC RECOIL OF THE LUNG
So far, the elastic recoil of the lungs has been discussed as
though it were only due to the elastic properties of the pulmo-
nary parenchyma itself. However, there is another component
of the elastic recoil of the lung—the surface tension at the air–
liquid interface in the alveoli.
Surface tension forces occur at any gas–liquid interface and
are generated by the cohesive forces between the molecules of
the liquid. These cohesive forces balance each other within
the liquid phase but are unopposed at the surface of the liq-
uid. Surface tension causes water to bead and form droplets,
and a liquid to shrink to form the smallest possible surface
320 SECTION VI Pulmonary Physiology

Saline Air
200

150
Volume (mL)

T P T T  Pr
100

50
0 FIGURE 32–9 Relationship between the pressure inside a
4 8 12 16
Pressure (cm H2O)
FIGURE 32–8 Pressure–volume curves for excised cat lungs
inflated with air or saline. (Modified from Radford EP. Recent studies of
mechanical properties of mammalian lungs. In: Remington JW. Tissue Elasticity.
Washington: American Physiological Society; 1957.)
area. The role of the surface tension forces in the elastic recoil
of the lung can be demonstrated in an experiment shown in
Figure 32–8.
In this experiment, a pressure–volume curve for an excised
lung was first generated with air inflation, so an air–liquid
interface was present in the lung, and surface tension forces
contributed to alveolar elastic recoil. Then, all the gas was
removed from the lung, and it was inflated again, this time
with saline instead of with air. In this situation, surface tension
forces were absent because there was no air–liquid interface.
The elastic recoil was due only to the lung tissue itself. Note
that there is no hysteresis with saline inflation. Whatever
causes the hysteresis appears to be related to surface tension in
the lung. The curve at left (saline inflation) therefore repre-
sents the elastic recoil due to only the lung tissue itself; the
curve at right demonstrates the recoil due to both the lung tis-
sue and the surface tension forces. The difference between the
two curves is the recoil due to surface tension forces.
The demonstration of the large role of surface tension forces
in the recoil pressure of the lung led to consideration of how
surface tension affects the alveoli. One traditional way of
thinking about this has been to consider the alveolus to be a
sphere hanging from the airway, as in Figure 32–9. The rela-
tionship between the pressure inside the alveolus and the wall
tension of the alveolus would then be given by Laplace’s law
(units in brackets):
2 × tension [dyn/cm]
Pressure [dyn/cm ] = _______________
2
Radius [cm]
This can be rearranged as follows:
Pr
T = __
2
where T is the wall tension, P the pressure inside the alveolus,
and r the radius of the alveolus.
The surface tension of most liquids (such as water) is con-
stant and not dependent on the area of the air–liquid interface.
T
Resolved direction of tension
20
distensible sphere, such as an alveolus, and its wall tension.
(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New
York: McGraw-Hill Medical, 2007.)
If two alveoli of different sizes are connected by a common
airway (Figure 32–10) and the surface tension of the two alve-
oli is equal, then according to Laplace’s law, the pressure in the
small alveolus is greater than that in the larger alveolus and the
smaller alveolus will empty into the larger alveolus. If surface
tension is independent of surface area, the smaller the alveolus
on the right becomes, the higher the pressure in it.
Thus, if the lung were composed of interconnected alveoli of
different sizes (which it is) with a constant surface tension at
the air–liquid interface, it would be inherently unstable, with a
tendency for smaller alveoli to collapse into larger ones. This is
usually not the case, which is fortunate because collapsed alve-
oli require very great distending pressures to reopen, partly
because of the cohesive forces at the liquid–liquid interface of
collapsed alveoli. At least two factors cause the alveoli to be
more stable than this prediction based on constant surface
P1 r T
T P2
2r
T
P1 
(3) r
T
P2 
2r
(4) FIGURE 32–10 Schematic representation of two alveoli of
different sizes connected to a common airway. If the surface
tension is the same in both alveoli, then the smaller alveolus will have
a higher pressure and will empty into the larger alveolus. (Modified with
permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill
Medical, 2007.)

tension. The first factor is a substance called pulmonary sur-
factant, which is produced by specialized alveolar cells, and
the second is the structural interdependence of the alveoli.
Pulmonary Surfactant
Pulmonary surfactant decreases the elastic recoil due to surface
tension, thereby increasing the compliance of the lungs above
that predicted by an air–water interface and decreasing
the inspiratory work of breathing. Pulmonary surfactant has a
second major effect. It decreases the surface tension of smaller
alveoli. This helps equalize alveolar pressures throughout the
lung (so the end-expiratory pressure of all the alveoli is 0 cm
H2O and the situation depicted in Figure 32–10 does not occur)
and to stabilize alveoli. Pulmonary surfactant is a complex con-
sisting of about 85–90% lipids and 10–15% proteins. The lipid
portion is about 85% phospholipid, approximately 75% of
which is dipalmitoyl phosphatidylcholine. This complex is
produced by type II alveolar epithelial cells (described above).
Pulmonary surfactant appears to be continuously produced in
the lung, but it is also continuously cleared from the lung. Some
pulmonary surfactant is taken back into the type II cells
(reuptake), where it is recycled and secreted again, or it is
degraded and used to synthesize other phospholipids. Surfactant
is also cleared from the alveoli by alveolar macrophages, absorp-
tion into the lymphatics, or migration up to the small airways
and the mucociliary escalator (discussed in Chapter 31). Type
II alveolar epithelial cells may also help remove liquid from the
alveolar surface by actively pumping sodium and water from
the alveolar surface into the interstitium.
The clinical consequences of a lack of functional pulmonary
surfactant occur in several conditions. Surfactant is not pro-
duced by the fetal lung until about the fourth month of gesta-
tion, and it may not be fully functional until the seventh month
or later. Prematurely born infants who do not have functional
pulmonary surfactant experience great difficulty in inflating
their lungs, especially on their first breaths. Even if their alveoli
are inflated for them with positive-pressure ventilation, the ten-
dency toward spontaneous collapse is great because their alve-
oli are much less stable without pulmonary surfactant.
Therefore, the lack of functional pulmonary surfactant in a pre-
maturely born neonate may be a major factor in the infant
respiratory distress syndrome. Pulmonary surfactant may also
be important in maintaining the stability of small airways.
Alveolar hypoxia or hypoxemia (low oxygen in the arterial
blood), or both, may lead to a decrease in surfactant produc-
tion or an increase in surfactant destruction. This condition
may be a contributing factor in the acute respiratory distress
syndrome (also known as adult respiratory distress syndrome
or “shock lung syndrome”) that can occur in patients after
trauma or surgery. One approach to maintain patients with
acute or infant respiratory distress syndrome is to ventilate
their lungs with positive-pressure ventilators and to keep their
alveolar pressure above atmospheric pressure during expira-
tion (this is known as positive end-expiratory pressure
[PEEP]). This process opposes the increased elastic recoil of
CHAPTER 32 Mechanics of the Respiratory System 321
the alveoli and the tendency for spontaneous atelectasis to
occur because of a lack of pulmonary surfactant. Exogenous
pulmonary surfactant is now administered directly into the
airway of neonates with infant respiratory distress syndrome.
In summary, pulmonary surfactant helps decrease the work
of inspiration by lowering the surface tension of the alveoli,
thus reducing the elastic recoil of the lung and making the
lung more compliant. Surfactant also helps stabilize the alveoli
by lowering even further the surface tension of smaller alveoli,
equalizing the pressure inside alveoli of different sizes.
Alveolar Interdependence
A second factor tending to stabilize the alveoli is their mechan-
ical interdependence, which was discussed at the beginning of
this chapter. Alveoli do not hang from the airways like a
“bunch of grapes” (the translation of the Latin word “acinus”),
and they are not spheres. They are mechanically interdepen-
dent polygons with flat walls shared by adjacent alveoli. Alve-
oli are normally held open by the chest wall pulling on the
outer surface of the lung, as shown in Figure 32–2. If an alveo-
lus were to begin to collapse, it would increase the stresses on
the walls of the adjacent alveoli, which would tend to hold it
open. This process would oppose a tendency for isolated alve-
oli with a relative lack of pulmonary surfactant to collapse
spontaneously. Conversely, if a whole subdivision of the lung
(such as a lobule) has collapsed, as soon as the first alveolus is
reinflated, it helps to pull other alveoli open by its mechanical
interdependence with them. Thus, both pulmonary surfactant
and the mechanical interdependence of the alveoli help stabi-
lize the alveoli and oppose alveolar collapse (atelectasis).
MECHANICAL INTERACTION OF
THE LUNG AND CHEST WALL
The inward elastic recoil of the lung normally opposes the
outward elastic recoil of the chest wall, and vice versa. If the
integrity of the lung–chest wall system is disturbed by break-
ing the seal of the chest wall (e.g., by a penetrating knife
wound), the inward elastic recoil of the lung is no longer
opposed by the outward recoil of the chest wall, and their
interdependence ceases. Lung volume decreases, and alveoli
have a much greater tendency to collapse, especially if air
moves in through the wound (causing a pneumothorax) until
intrapleural pressure equalizes with atmospheric pressure and
abolishes the transpulmonary pressure gradient. At this point,
nothing is tending to hold the alveoli open and their elastic
recoil is causing them to collapse. Similarly, the chest wall
tends to expand because its outward recoil is no longer
opposed by the inward recoil of the lung.
When the lung–chest wall system is intact and the respiratory
muscles are relaxed, the volume of gas left in the lungs is deter-
mined by the balance of these two forces. The volume of gas
in the lungs at the end of a normal tidal expiration, when no
respiratory muscles are actively contracting, is known as the
322 SECTION VI Pulmonary Physiology
functional residual capacity (FRC). For any given situation, the
FRC will be that lung volume at which the outward recoil of the
chest wall is equal and opposite to the inward recoil of the lungs.
If the lung volume increases above the FRC, the increased
inward elastic recoil of the lung exceeds the decreased outward
elastic recoil of the chest wall. At high lung volumes (above
about 70% of the total lung capacity [TLC]), the chest wall
also has inward elastic recoil. Therefore, at high lung volumes,
the elastic recoil of both the lung and chest wall are inward. At
lung volumes below the FRC, the outward recoil of the chest
wall is greater than the reduced inward recoil of the lungs.
A change from the upright to the supine position decreases
FRC. The reason for this decrease of about 30% is the effect of
gravity on the mechanics of the chest wall, especially the dia-
phragm. When standing up or sitting, the contents of the
abdomen are being pulled away from the diaphragm by grav-
ity. When lying down, the abdominal contents are pushing
inward against the relaxed diaphragm. This decreases the
overall outward recoil of the chest wall and decreases the lung
volume at which the outward recoil of the chest wall is equal
and opposite to the inward recoil of the lungs.
AIRWAY RESISTANCE
Several factors besides the elastic recoil of the lungs and the
chest wall must be overcome to move air into or out of the
lungs. These factors are primarily the frictional resistance of
the lung and chest wall tissue, and the frictional resistance of
the airways to the flow of air. Pulmonary tissue resistance is
caused by the friction encountered as the lung tissues move
against each other as the lung expands. The airway resistance
plus the pulmonary tissue resistance is often referred to as the
pulmonary resistance. Pulmonary tissue resistance normally
contributes about 20% of the pulmonary resistance, with air-
way resistance responsible for the other 80%. Pulmonary tis-
sue resistance can be increased in such conditions as pulmonary
sarcoidosis and fibrosis. Because airway resistance is the major
component of the total resistance and because it can increase
tremendously both in healthy people and in those suffering
from various diseases, the remainder of this chapter will con-
centrate on airway resistance.
LAMINAR, TURBULENT, AND
TRANSITIONAL FLOW
As was discussed in Chapter 22, the relationship among
pressure, flow, and resistance is:
Pressure difference = Flow × Resistance (5)
Therefore, we have:
Pressure difference [cm H O]
Resistance = _____________________
2
(6)
Flow [L/s]
This means that resistance is a meaningful term only during
flow. When airflow is considered, the units of resistance are
usually cm H2O/[L/s].
The resistance to airflow is analogous to electrical resistance
in that resistances in series are added directly:
Rtot = R1 + R2 + … (7)
Resistances in parallel are added as reciprocals:
1 1 __
___ = __ + 1 +…
Rtot R1 R2
(8)
Airflow, like that of other fluids, can occur as either laminar or
turbulent flow, as was discussed in Chapter 26 (see Figure 26–6).
When a fluid such as air is in laminar flow through rigid, smooth
bore tubes, its behavior is governed by Poiseuille’s law, as was
discussed in Chapter 22.
Turbulent flow tends to occur if airflow is high, gas density
is high, the tube radius is large, or all three conditions exist.
True laminar flow probably occurs only in the smallest air-
ways, where the linear velocity of airflow is extremely low. Lin-
ear velocity (cm/s) is equal to the flow (cm3/s) divided by the
cross-sectional area. The sum of the cross-sectional areas of
the smallest airways is very large, so the linear velocity of air-
flow is very low. The airflow in the trachea and larger airways
is usually either turbulent or a mixture of laminar and turbu-
lent flow.
DISTRIBUTION OF
AIRWAY RESISTANCE
About 25–40% of the total resistance to airflow is located in
the upper airways: the nose, nasal turbinates, oropharynx,
nasopharynx, and larynx. Resistance is higher when one
breathes through the nose than when one breathes through
the mouth.
The vocal cords open slightly during normal inspirations
and close slightly during expirations. During deep inspira-
tions, they open widely. The muscles of the oropharynx also
contract during normal inspiration; this dilates and stabilizes
the upper airway. During deep forced inspirations, the devel-
opment of negative pressure could cause the upper airway to
be pulled inward and partly or completely obstruct airflow.
Reflex contraction of these pharyngeal dilator muscles nor-
mally keeps the airway open.
The component with the highest individual resistance of the
tracheobronchial tree is obviously the smallest airway, which
has the smallest radius. Nevertheless, because the smallest air-
ways are arranged in parallel, their resistances add as recipro-
cals, so that the total resistance to airflow offered by the
numerous small airways is extremely low during normal, quiet
breathing. Therefore, the greatest resistance to airflow usually
resides in the medium-sized bronchi.
CONTROL OF BRONCHIAL
SMOOTH MUSCLE
The smooth muscle of the airways from the trachea down to
the alveolar ducts is under the control of efferent fibers of the
 CHAPTER 32 Mechanics of the Respiratory System 323

TABLE 32–2 Active control of the airways.

100
Constrict
Parasympathetic stimulation

Airway resistance (% maximum)

Acetylcholine
Histamine 75
Leukotrienes
Thromboxane A2
Serotonin
α-Adrenergic agonists 50
Decreased Pco2 in small airways

Dilate
Sympathetic stimulation (β2 receptors) 25
Circulating β2 agonists
Nitric oxide
Increased Pco2 in small airways RV TLC
0
Decreased Po2 in small airways 0 2 4 6 8
Lung volume (L)

autonomic nervous system (see Chapter 19). Stimulation of FIGURE 32–11 Relationship between lung volume and
the cholinergic parasympathetic postganglionic nerves airway resistance. Total lung capacity (TLC) is at right; residual
causes constriction of bronchial smooth muscle as well as volume (RV) is at left. (Reproduced with permission from Kibble J, Halsey CR:
increased glandular mucus secretion. The preganglionic fibers The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

travel in the vagus nerve. Stimulation of the adrenergic sym-

pathetic nerves causes dilation of bronchial and bronchiolar
smooth muscle as well as inhibition of glandular secretion.
This dilation of the airway smooth muscle is mediated by beta2
(β2) receptors, which predominate in the airways. Selective
stimulation of the alpha (α) receptors with pharmacologic
agents causes bronchoconstriction. Adrenergic transmitters
carried in the blood may be as important as those released
from the sympathetic nerves in causing bronchodilation. The
bronchial smooth muscle is normally under greater parasym-
pathetic tone than sympathetic tone.
Inhalation of chemical irritants, smoke, or dust; stimulation
of the arterial chemoreceptors; and substances such as hista-
mine cause constriction of the airways. Decreased CO2 in the
branches of the conducting system causes a local constriction
of the smooth muscle of the nearby airways; increased CO2 or
decreased O2 causes a local dilation. This may help balance
ventilation and perfusion (see Chapter 35). Many other sub-
stances can have direct or indirect effects on airway smooth
muscle (Table 32–2). Leukotrienes usually cause bronchocon-
striction, as do some prostaglandins.
resistance, even with so many parallel pathways. To increase
lung volume, a person breathing normally takes a “deep
breath,” that is, makes a strong inspiratory effort. This effort
causes intrapleural pressure to become much more negative
than –7 or –10 cm H2O in a normal, quiet breath. The trans-
mural pressure gradient across the wall becomes much more
positive, and small airways are distended.
A second reason for the decreased airway resistance at
higher lung volumes is that the traction on the small airways
increases. As shown in the schematic drawing in Figure 32–12,
the small airways traveling through the lung form attachments
to the walls of alveoli. As the alveoli expand during the course
of a deep inspiration, the elastic recoil in their walls increases;
this elastic recoil is transmitted to the attachments at the air-
way, pulling it open.

LUNG VOLUME AND

AIRWAY RESISTANCE
AIRWAY Traction on airway by elastic
Airway resistance decreases with increasing lung volume, as recoil of alveolar septa
shown in Figure 32–11. There are two reasons for this rela-
tionship; both mainly involve the small airways that, as
described in this chapter, have little or no cartilaginous sup-
port. The small airways are therefore rather distensible and
also compressible. Thus, the transmural pressure gradient
across the wall of the small airways is an important determi- FIGURE 32–12 Representation of “traction” of the alveolar
nant of the radius of the airways: since resistance is inversely septa on a small distensible airway. Compare this figure with the
proportional to the radius to the fourth power, changes in the picture of the alveolar duct in Figure 31–4. (Modified with permission from
radii of small airways can cause dramatic changes in airway Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)
324 SECTION VI Pulmonary Physiology

DYNAMIC COMPRESSION OF AIRWAYS
Airway resistance is extremely high at low lung volumes, as
shown in Figure 32–11. To achieve low lung volumes, a person
must make a forced expiratory effort by contracting the mus-
cles of expiration, mainly the abdominal and internal intercos-
tal muscles. This effort generates a positive intrapleural
pressure, which can be as high as 120 cm H2O during a maxi-
mal forced expiratory effort. (Maximal inspiratory intrapleu-
ral pressures can be as low as –80 cm H2O.)
The effect of this high positive intrapleural pressure on the
transmural pressure gradient during a forced expiration can
be seen at right in Figure 32–13, a schematic drawing of a sin-
gle alveolus and airway.
The muscles of expiration are generating a positive intra-
pleural pressure of +25 cm H2O. Pressure in the alveolus is
higher than intrapleural pressure because of the alveolar elas-
tic recoil pressure of +10 cm H2O, which, together with intra-
pleural pressure, gives an alveolar pressure of +35 cm H2O.
The alveolar elastic recoil pressure decreases at lower lung vol-
umes because the alveolus is not as distended. In the figure, a
gradient has been established from the alveolar pressure of
+35 cm H2O to the atmospheric pressure of 0 cm H2O. If the
airways were rigid and incompressible, the large expiratory
pressure gradient would generate very high rates of airflow.
However, the airways are not uniformly rigid and the smallest
airways, which have no cartilaginous support and rely on the
traction of alveolar septa to help keep them open, may be com-
pressed or may even collapse. Whether or not they actually
collapse depends on the transmural pressure gradient across
the walls of the smallest airways.
The situation during a normal passive expiration at the same
lung volume (note the same alveolar elastic recoil pressure) is
shown in the left part of Figure 32–13. The transmural pres-
sure gradient across the smallest airways is +1 – (–8) cm H2O
= +9 cm H2O tending to hold the airway open. During the
forced expiration at right, the transmural pressure gradient is
30 – 25 cm H2O, or only 5 cm H2O holding the airway open.
The airway may then be slightly compressed, and its resistance
to airflow will be even greater than that during the passive
expiration. This increased resistance during a forced expira-
tion is called dynamic compression of airways.
Consider what occurs during a maximal forced expiration.
As the expiratory effort is increased to attain a lower lung
volume, intrapleural pressure is getting more and more posi-
tive, and more and more dynamic compression will occur.
Furthermore, as lung volume decreases, there will be less
alveolar elastic recoil pressure and the difference between

0 0

0.25 3

8 25 5 25
8
10
0.5
15
8 8 25 25 Contraction of
20 internal
intercostals and
25 accessory muscles
8 8 25 25 of expiration
30
1

10 10 10 10

2 35

10 10 10 10

8 8 25 25

Relaxed diaphragm pushed up by

abdominal muscle contraction

PASSIVE EXPIRATION FORCED EXPIRATION

FIGURE 32–13 Schematic diagram illustrating dynamic compression of airways and the equal pressure point hypothesis during
a forced expiration. Left: Passive (eupneic) expiration. Intrapleural pressure is –8 cm H2O, alveolar elastic recoil pressure is +10 cm H2O, and
alveolar pressure is +2 cm H2O. Right: Forced expiration at the same lung volume. Intrapleural pressure is +25 cm H2O, alveolar elastic recoil
pressure is +10 cm H2O, and alveolar pressure is +35 cm H2O. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill
Medical, 2007.)

alveolar pressure and intrapleural pressure will decrease. At
any instant during a forced expiration, there is a point along
the airways where the pressure inside the airway is just equal
to the pressure outside the airway. At that point (the “equal
pressure point”), the transmural pressure gradient is 0 (note
the arrows in Figure 32–13). Above that point, the transmu-
ral pressure gradient is negative: the pressure outside the air-
way is greater than the pressure inside it, and the airway will
collapse if cartilaginous support or alveolar septal traction is
insufficient to keep it open. As the forced expiratory effort
continues, the equal pressure point is likely to move down the
airway from larger to smaller airways. This movement hap-
pens because, as the muscular effort increases, intrapleural
pressure increases and because, as lung volume decreases,
alveolar elastic recoil pressure decreases. As the equal pres-
sure point moves down the airway, dynamic compression
increases and the airways begin to collapse. This airway clo-
sure can be demonstrated only at especially low lung volumes
in healthy subjects, but the closing volume may occur at
higher lung volumes in patients with high lung compliance as
in emphysema. The closing volume will be discussed in
Chapter 33.
During a passive expiration, the pressure gradient for air-
flow (ΔP in ΔP = V̇ R) is simply alveolar pressure minus atmo-
spheric pressure. But if dynamic compression occurs, the
effective pressure gradient is alveolar pressure minus intrapleu-
ral pressure (which equals the alveolar elastic recoil pressure)
because intrapleural pressure is greater than atmospheric pres-
sure and because intrapleural pressure can exert its effects on
the compressible portion of the airways.
Thus, during a forced expiration, when intrapleural pressure
becomes positive and dynamic compression occurs, the effective
driving pressure for airflow from the lung is the alveolar elastic
recoil pressure. Alveolar elastic recoil is also important in oppos-
ing dynamic compression of the airways because of its role in the
traction of the alveolar septa on small airways, as shown in
Figure 32–12. The effects of alveolar elastic recoil on airflow
during a forced expiration are illustrated in Figure 32–14.
ASSESSMENT OF AIRWAY RESISTANCE
The resistance to airflow cannot be measured directly but must
be calculated from the pressure gradient and airflow during a
breath:
ΔP
R = ___ (9)
V̇
The above formula is an approximation because it presumes
that all airflow is laminar, which is not true. But there is a sec-
ond problem: how can the pressure gradient be determined?
To know the pressure gradient, the alveolar pressure—which
also cannot be measured directly—must be known. Alveolar
pressure can be calculated using a body plethysmograph, an
expensive piece of equipment described in the next chapter,
but this procedure is not often done. Instead, airway resistance
is usually assessed indirectly. The assessment of airway resis-
CHAPTER 32 Mechanics of the Respiratory System 325
PA  Ppl ( Pel)
Intrapleural Dynamic
pressure compression
Alveolar Traction
elastic recoil
Alveolar Pel Pel
elastic PA
recoil Pel Pel
FIGURE 32–14 Representation of the effects of alveolar
elastic recoil on airflow during a forced expiration. When dynamic
compression occurs, alveolar elastic recoil helps to oppose it by
traction on the small airways. The alveolar elastic recoil pressure
becomes the effective driving pressure for airflow from the lung. PA,
alveolar pressure; Ppl, intrapleural pressure; Pel, the alveolar elastic
recoil pressure. (Modified with permission from Levitzky MG: Pulmonary
Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)
tance during expiration will be emphasized because that factor
is of interest in patients with lung disease.
Forced Vital Capacity
One way of assessing expiratory airway resistance is to look at
the results of a forced expiration into a spirometer, as shown in
Figure 32–15. This measurement is called a forced vital capac-
ity (FVC). The vital capacity (VC) is the volume of air a sub-
ject is able to expire after a maximal inspiration to the TLC.
An FVC means that a maximal expiratory effort was made
during this maneuver.
In an FVC test, a person makes a maximal inspiration to the
TLC. After a moment, he or she makes a maximal forced expi-
ratory effort, blowing as much air as possible out of the lungs.
At this point, only a residual volume (RV) of air is left in the
lungs. (The lung volumes will be described in detail in the next
chapter.) This procedure takes only a few seconds, as can be
seen on the time scale.
The part of the curve most sensitive to changes in expira-
tory airway resistance is the first second of expiration. The
volume of air expired in the first second of expiration (the
FEV1, or forced expiratory volume in 1 second), especially
when expressed as a ratio with the total amount of air expired
326 SECTION VI Pulmonary Physiology

7
6
5 Normal

Volume (L)
RV
4 FEV1 / FVC  80%

3 FEV1  3.6 L Obstruction

RV
FEV1 / FVC  50% FVC  4.5 L
2
FVC  3.0 L
1 FEV1  1.5 L

TLC 0 1 2 3 4 5 6
Time (s)

FIGURE 32–15 Forced vital capacity (FVC) maneuver using a rolling seal spirometer. FVCs from a normal subject and from a patient
with obstructive disease. FEV1, forced expiratory volume in the first second. Note that the total lung capacity (TLC) is at the bottom of the curves
and the residual volumes (RVs) are at the top; volume therefore refers to the volume exhaled into the spirometer in the bottom trace. The time
scale is from left to right. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

during the FVC, is a good index of expiratory airway resis-
tance. In normal subjects, the FEV1/FVC is greater than
0.80; that is, at least 80% of the FVC is expired in the first
second. A patient with an airway obstruction would be
expected to have an FEV1/FVC far below 0.80, as shown in
Figure 32–16, which shows FVC curves obtained from a
commonly used rolling seal spirometer. Note that the TLC is
at the bottom left, and the RVs are at the top right. The time
scale is left to right. Note the calculations of the FEV1 to
FVC ratios for a healthy person and for one with airway
obstruction.
Figure 32–15 clearly shows that elevated airway resistance
takes time to overcome.
Flow–Volume Curves
Flow–volume curves are also used to assess airway resis-
tance. A family of flow–volume curves such as that depicted in
Figure 32–16 is obtained by having a subject make repeated
expiratory maneuvers with different degrees of effort. Flow
rates are plotted against lung volume for expiratory efforts of
different intensities. There are two interesting points about
this family of curves. At high lung volumes, the airflow rate is
effort-dependent, which can be seen in the left-hand portion
of the curves. As the subject exhales with greater effort, flow
rate increases. At low lung volumes, however, the expiratory
efforts of different initial intensities all merge into the same
effort-independent curve, as seen in the right-hand portion
of the curve. This difference is because intrapleural pressures
high enough to cause dynamic compression are necessary to
attain very low lung volumes, no matter what the initial expi-
ratory effort. Also, at low lung volumes there is less alveolar
elastic recoil, so there is less traction on the same airways and
a smaller pressure gradient for airflow.
The maximal flow–volume curve is used as a diagnostic
tool, as shown in Figure 32–17, because it helps distinguish
between two major classes of pulmonary diseases—airway
obstructive diseases and restrictive diseases, such as fibrosis.
Obstructive diseases interfere with airflow; restrictive diseases
restrict the expansion of the lung.
Figure 32–17 shows that both obstruction and restriction can
cause a decrease in the maximal flow rate that the patient can
attain, the peak expiratory flow (PEF; shown in Figure 32–16),
but that this decrease occurs for different reasons. Restrictive
lung diseases, which usually entail increased alveolar elastic
recoil, may have decreased PEF because the TLC (and thus the
VC) is decreased. The effort-independent part of the curve is
similar to normal lungs. In fact, the FEV1/FVC is usually nor-
mal or even above normal since both the FEV1 and FVC are
decreased because the lung has a low volume and because alve-
olar elastic recoil pressure may be increased. On the other hand,
with obstructive diseases, the PEF and FEV1/FVC are both low.
Obstructive diseases—such as asthma, bronchitis, and
emphysema—are often associated with high lung volumes,
which is helpful because the high volumes increase the alveo-
lar elastic recoil pressure. The RV may be greatly increased if
airway closure occurs at relatively high lung volumes. A sec-
ond important feature of the flow–volume curve of a patient
with obstructive disease is the effort-independent portion of
the curve, which is depressed inward: flow rates are low for
any relative volume.
Flow–volume curves are very useful in assessing obstruc-
tions of the upper airways and the trachea. Flow–volume
loops can help distinguish between fixed obstructions (those
not affected by the inspiratory or expiratory effort) and vari-
able obstructions (changes in the transmural pressure gradi-
ent caused by the inspiratory or expiratory effort result in
changes in the cross-sectional area of the obstruction). If the
obstruction is variable, flow–volume loops can demonstrate
whether the obstruction is extrathoracic or intrathoracic
(Figure 32–18). A fixed obstruction affects both expiratory
and inspiratory airflow (Figure 32–18A). Both the expiratory
and inspiratory flow–volume curves are truncated, with
decreased peak expiratory and peak inspiratory flows. The
flow–volume loop is unable to distinguish between a fixed
extrathoracic and a fixed intrathoracic obstruction, which
 CHAPTER 32 Mechanics of the Respiratory System 327

10 Peak expiratory Maximal curve

flow

Effort independence

Effort dependence
Expiration

5
Airflow (L/s)

TLC RV
0
Inspiration

Maximal curve

10
Volume (L)
FIGURE 32–16 Flow–volume curves of varying intensities, demonstrating effort dependence at high lung volumes and effort
independence at low lung volumes. Note that there is no effort independence in inspiration. The peak expiratory flow (PEF) is labeled for the
maximal expiratory curve. TLC, total lung capacity; RV, residual volume. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York:
McGraw-Hill Medical, 2007.)

would usually be determined with a bronchoscope. Fixed
obstructions can be caused by foreign bodies or by scarring
that makes a region of the airway too stiff to be affected by the
transmural pressure gradient.
During a forced expiration, the cross-sectional area of a
variable extrathoracic obstruction increases as the pressure
inside the airway increases (Figure 32–18B). The expiratory
flow–volume curve is therefore nearly normal or not affected.
However, during a forced inspiration, the pressure inside the
upper airway decreases below atmospheric pressure, and
unless the stability of the upper airway is maintained by reflex
contraction of the pharyngeal muscles or by other structures,
the cross-sectional area of the upper airway will decrease.
Therefore, the inspiratory flow–volume curve is truncated
with variable extrathoracic obstructions. Variable extratho-
racic obstructions can be caused by tumors, fat deposits,
328 SECTION VI Pulmonary Physiology

15
Normal

12

Restrictive disease
Airflow (L/s) 9
Obstructive disease

0
9 8 7 6 5 4 3 2 1 0
Lung volume (L)
FIGURE 32–17 Maximal expiratory flow–volume curves representative of obstructive and restrictive diseases. (Modified with
permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

A. Expiration

Flow
TLC RV

Inspiration Expiration Inspiration

Fixed (intra- or extrathoracic)

B. expiration
Flow

TLC RV

Paw < Patm Paw > Patm

Inspiration Expiration Inspiration

Variable extrathoracic
FIGURE 32–18 Inspiratory and
C. Expiration
expiratory flow–volume curves representing
the patterns in: A) fixed intrathoracic or
extrathoracic obstruction; B) variable
TLC RV
extrathoracic obstruction; C) variable
Flow

intrathoracic obstruction. TLC, total lung

capacity; RV, residual volume; Paw, airway
pressure; Patm, atmospheric pressure; Ppl,
intrapleural pressure. (Modified with permission Paw > Ppl Paw < Ppl
from Burrows B, Knudson RJ, Quan SF, Kettel LJ:
Respiratory Disorders: A Pathophysiologic Approach, Inspiration Expiration Inspiration
2nd ed. Copyright © 1983 by Year Book Medical
Publishers, Chicago.) Variable intrathoracic

weakened or flabby pharyngeal muscles (as in obstructive
sleep apnea), paralyzed vocal cords, enlarged lymph nodes, or
inflammation.
During a forced expiration, positive intrapleural pressure
decreases the transmural pressure gradient across a variable
intrathoracic tracheal obstruction, decreasing its cross-
sectional area and decreasing the PEF (Figure 32–18C).
During a forced inspiration, as large negative intrapleural
pressures are generated, the transmural pressure gradient
across the variable intrathoracic obstruction increases and
its cross-sectional area increases. Thus, the inspiratory
flow–volume curve is nearly normal or not affected. Variable
intrathoracic obstructions of the trachea are most com-
monly caused by tumors.
CLINICAL CONSEQUENCES OF
INCREASED AIRWAY RESISTANCE AND
DECREASED ALVEOLAR COMPLIANCE
As discussed at the beginning of this chapter, the lung has mil-
lions of small airways and hundreds of millions of alveoli. If we
think of a pair of hypothetical alveoli supplied by the same
airway, we can consider the time courses of their changes in
volume in response to an abrupt increase in airway pressure
(a “step” increase). If the resistances and compliances of the
two units were equal, the two alveoli would fill with identical
time courses to identical volumes. If the resistances were equal,
but the compliance of one were half that of the other, then the
two alveoli would fill with nearly identical time courses but the
less compliant one would receive only half the volume received
by the other. If the compliances of the two units were equal but
one was supplied by an airway with twice the resistance to
airflow of the one supplying the other, the two units would
ultimately fill to the same volume. However, the one supplied
by the airway with elevated resistance will fill more slowly than
the other because of its elevated resistance. This difference
means that at high breathing frequencies, the one that fills
more quickly will receive a larger volume of air per breath; the
one that fills more slowly will receive less ventilation per
breath.
Now let us extrapolate this two-unit situation to a lung with
millions of airways supplying hundreds of millions of alveoli.
In a patient with small airways disease, many alveoli may be
supplied by airways with higher resistance to airflow than
normal. These alveoli are sometimes referred to as “slow alve-
oli” or alveoli with long “time constants.” As the patient
increases the breathing frequency, the slowest alveoli will not
have enough time to fill. As the frequency increases, more and
more slow alveoli will drop out.
This can also be a problem during positive-pressure ventila-
tion. There may be enough time for alveoli to fill because air is
forced into them by the ventilator. However, because expira-
tion is passive, there may not be enough time for the alveoli to
empty, resulting in overinflation, especially of more compliant
alveoli, causing lung injury.
CHAPTER 32 Mechanics of the Respiratory System 329
THE WORK OF BREATHING
The major points discussed in this chapter can be summa-
rized by considering the work of breathing. The work done
in breathing is proportional to the pressure change times the
volume change. The volume change is the volume of air
moved into and out of the lung—the tidal volume. The pres-
sure change is the change in transpulmonary pressure neces-
sary to overcome the elastic work of breathing and the
resistive work of breathing. The elastic work of breathing is
the work done to overcome the elastic recoil of the chest wall
and the pulmonary parenchyma and the work done to over-
come the surface tension of the alveoli. Restrictive diseases
are those diseases in which the elastic work of breathing is
increased. For example, the work of breathing is elevated in
obese patients (who have decreased outward chest wall elastic
recoil) and in patients with pulmonary fibrosis or a relative
lack of pulmonary surfactant (who have increased elastic
recoil of the alveoli). The resistive work of breathing is the
work done to overcome the tissue resistance and the airway
resistance. The tissue resistance may be elevated in conditions
such as sarcoidosis, asbestosis, or silicosis. Elevated airway
resistance is much more common and occurs in obstructive
diseases such as asthma, bronchitis, and emphysema; upper
airway obstruction; and accidental aspiration of foreign
objects. Normally, most of the resistive work is that done to
overcome airway resistance. The resistive work of breathing
can be very great during a forced expiration, when dynamic
compression occurs. This is especially true in patients who
already have elevated airway resistance during normal, quiet
breathing. For example, in patients with emphysema, a dis-
ease that attacks and obliterates alveolar walls, the work of
breathing can be tremendous because of the destruction of
the elastic tissue support of their small airways, which allows
dynamic compression to occur unopposed. Also, the
decreased elastic recoil of alveoli leads to a decreased pressure
gradient for expiration.
CLINICAL CORRELATION
A 26-year-old man comes to the emergency department
because of sudden dyspnea (a feeling that breathing is dif-
ficult, also called “shortness of breath”) and pain in the
upper part of the left side of his chest. He has no history of
any medical problems. He is 183-cm (6′2″) tall and weighs
about 63.5 kg (140 lb). Blood pressure is 125/80 mm Hg,
heart rate is 90/min, and respiratory rate is 22/min
(usually12–15/min in a healthy adult). There are no breath
sounds on the left side of his chest, which is hyperresonant
(louder and more hollow-sounding) to percussion (the
physician tapping on the chest with his or her fingers).
The patient has a pneumothorax. Air has entered the
pleural space on the left side of his chest and he is unable to
expand his left lung. Therefore, there are no breath sounds
330 SECTION VI Pulmonary Physiology
on the left side of his chest and it is hyperresonant to per-
cussion. In this case, the pneumothorax is a primary spon-
taneous pneumothorax because it occurred suddenly, and
is not attributable to an underlying pulmonary disease (sec-
ondary spontaneous pneumothorax) or trauma (traumatic
pneumothorax). The inability to ventilate his left lung,
combined with pain and anxiety, explains his high respira-
tory rate, as will be discussed in Chapters 33 and 38.
Primary spontaneous pneumothorax is most common in
tall, thin males between 10 and 30 years of age, although
the reason for this is not known. It is believed to occur
when overexpanded alveoli (“blebs”) rupture, perhaps as a
result of a cough or sneeze.
If the pneumothorax is mild and the patient is not in too
much distress, it may resolve without treatment other than
observation. More severe pneumothorax is treated by
inserting a catheter or chest tube through the skin and
intercostal muscles into the pleural space to allow removal
of the air by external suction.
A tension pneumothorax is a potentially life-threatening
disorder that most commonly occurs as a result of trauma
or lung injury. Air enters the pleural space on inspiration
but cannot leave on expiration, progressively increasing
intrapleural pressure above atmospheric. This can com-
press the structures on the affected side of the chest
(e.g., blood vessels, heart, etc.) and eventually the struc-
tures on the other side of the chest as well.
CHAPTER SUMMARY
■ A pressure gradient between the atmosphere and the alveoli
must be established to move air into or out of the alveoli.
■ During inspiration, alveoli expand passively in response to an
increased transmural pressure gradient; during normal quiet
expiration, the elastic recoil of the alveoli returns them to their
original volume.
■ The volume of gas in the lungs at the end of a normal tidal
expiration (the FRC), when no respiratory muscles are actively
contracting, is determined by the balance point of the inward
recoil of the lungs and the outward recoil of the chest wall.
■ At the FRC, intrapleural pressure is negative because the pleural
liquid is between the opposing forces of the inward recoil of the
lungs and the outward recoil of the chest wall.
■ Alveoli are more compliant (and have less elastic recoil) at low
volumes; alveoli are less compliant (and have more elastic
recoil) at high volumes.
■ Pulmonary surfactant increases alveolar compliance and helps
prevent atelectasis by reducing surface tension in the alveoli.
■ During forced expiration, when intrapleural pressure be-
comes positive, small airways are compressed (dynamic
compression) and may even collapse.
■ The two main components of the work of breathing are the
elastic recoil of the lungs and chest wall and the resistance
to airflow.
STUDY QUESTIONS
1. In a normal healthy adult at the functional residual capacity
A) alveolar pressure is greater than atmospheric pressure.
B) alveolar pressure is less than atmospheric pressure.
C) the inward recoil of the lungs is equal and opposite to
the outward recoil of the chest wall.
D) intrapleural pressure is positive.
E) the alveolar transmural pressure gradient is negative.
2. Which of the following would be expected to cause increased
static lung compliance (i.e., shift the pulmonary pressure–
volume curve upward and to the left)?
A) a relative lack of functional pulmonary surfactant
B) diffuse interstitial alveolar fibrosis
C) pulmonary vascular congestion
D) emphysema
E) diffuse alveolar collapse
3. The compliance of the lungs is
A) greater at low lung volumes than it is at high lung volumes.
B) in parallel with the compliance of the chest wall.
C) increased in a person after surgical removal of one lobe
of the lung.
D) increased in a person with pulmonary interstitial fibrosis.
E) less than the compliance of a single lobe of the lung.
4. During a forced expiration to the residual volume
A) intrapleural pressure becomes more negative.
B) alveolar elastic recoil is increasing.
C) the outward recoil of the chest wall is increasing.
D) intrapleural pressure is greater than alveolar pressure.
E) airflow remains dependent on expiratory effort.
5. Which of the following will likely decrease the work of breathing?
A) doubling the tidal volume at the same breathing frequency
B) breathing through the mouth instead of the nose
C) doubling the breathing frequency at the same tidal volume
D) breathing through a 1-cm diameter, 3-ft long tube
E) gaining 100 lb of body weight
6. The resistance to airflow in a normal healthy person would
be greatest
A) during a eupneic inspiration.
B) during a eupneic expiration.
C) during a forced inspiration.
D) during a forced expiration.
E) at the functional residual capacity.
 33
C H A P T E R

Alveolar Ventilation
Michael Levitzky

O B J E C T I V E S

■ Define alveolar ventilation.

■ Define the standard lung volumes.
■ Predict the effects of alterations in lung and chest wall mechanics, due to
normal or pathologic processes, on the lung volumes.
■ Define anatomic dead space and relate the anatomic dead space and the
tidal volume to alveolar ventilation.
■ Calculate alveolar ventilation.
■ Define and calculate physiologic and alveolar dead space.
■ Predict the effects of alterations of alveolar ventilation on alveolar carbon
dioxide and oxygen levels.
■ Describe and explain the regional differences in alveolar ventilation found in
the normal lung.
■ Define the closing volume.
■ Predict how changes in pulmonary mechanics affect the closing volume.

Alveolar ventilation is the exchange of gas between the
alveoli and the external environment. It is the process by
which oxygen is brought into the lungs from the atmo-
sphere and by which the carbon dioxide carried into the
lungs in the mixed venous blood is expelled from the body.
Although alveolar ventilation is usually defined as the vol-
ume of fresh air entering the alveoli per minute, a similar
volume of alveolar air leaving the body per minute is
implicit in this definition.
THE LUNG VOLUMES
The volume of gas in the lungs at any instant depends on the
mechanics of the lungs and chest wall and the activity of the
muscles of inspiration and expiration. The size of the lungs
depends the height and weight or body surface area, as well as
age and sex. Therefore, the lung volumes are usually compared
with “predicted” lung volumes matched to age, sex, and body
size, and are normally expressed as the body temperature and
ambient barometric pressure and saturated with water vapor
(BTPS).
THE STANDARD LUNG
VOLUMES AND CAPACITIES
There are four standard lung volumes and four standard
lung capacities, which consist of two or more of the standard
lung volumes (Figure 33–1).
The Tidal Volume
The tidal volume (VT) is the volume of air entering or leaving
the nose or mouth per breath. During normal, quiet breathing
(eupnea), the VT of a 70-kg adult is about 500 mL per breath,
but this volume can increase substantially, for example, during
exercise.

331

Ch33_331-340.indd 331 11/26/10 11:50:04 AM

332 SECTION VI Pulmonary Physiology

maximal inspiration

INSPIRATORY RESERVE
INSPIRATORY
VOLUME (IRV)
CAPACITY (IC)
2.5 L
3.0 L
VITAL
CAPACITY (VC)
TOTAL LUNG TIDAL VOLUME (VT) 4.5 L
CAPACITY (TLC) 0.5 L resting volume
6.0 L EXPIRATORY RESERVE
VOLUME (ERV)
FUNCTIONAL 1.5 L
RESIDUAL
FIGURE 33–1 The standard lung volumes and CAPACITY (FRC)
3.0 L maximal expiration
capacities. Typical values for a 70-kg adult are shown. RESIDUAL VOLUME (RV)
(Modified with permission from Levitzky MG: Pulmonary 1.5 L
Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.) no air in lungs

The Residual Volume between the inward elastic recoil of the lungs and the outward
elastic recoil of the chest wall, as discussed in Chapter 32.
The residual volume (RV) is the volume of gas remaining in
During exercise, the FRC may be lower than the relaxation
the lungs after a maximal forced expiration. It is determined
volume because of active contraction of the expiratory mus-
by the force generated by the muscles of expiration and the
cles. The FRC, as seen in Figure 33–1, consists of the RV plus
inward elastic recoil of the lungs as they oppose the outward
the ERV and is therefore about 3 L in a healthy 70-kg adult.
elastic recoil of the chest wall. Dynamic compression of the
airways during the forced expiratory effort may also be an
important determinant of the RV as airway collapse occurs The Inspiratory Capacity
and traps gas in the alveoli. The RV of a healthy 70-kg adult is
The inspiratory capacity (IC) is the volume of air that is
about 1.5 L, but it can be much greater in emphysema, a lung
inhaled into the lungs during a maximal inspiratory effort that
disease with increased compliance in which inward alveolar
begins at the end of a normal tidal expiration (the FRC). It is
elastic recoil is diminished and airway collapse and gas trap-
therefore equal to the VT plus the IRV, as shown in Figure 33–1.
ping occur. The RV is important to a healthy person because it
The IC of a healthy 70-kg adult is about 3 L.
prevents the lungs from collapsing at very low lung volumes.
Such collapsed alveoli would require great inspiratory efforts
to reinflate. The Total Lung Capacity
The total lung capacity (TLC) is the volume of air in the lungs
The Expiratory Reserve Volume after a maximal inspiratory effort. It is determined by the
strength of contraction of the inspiratory muscles and the
The expiratory reserve volume (ERV) is the volume of gas
inward elastic recoil of the lungs and the chest wall. The TLC
that is expelled from the lungs during a maximal forced expi-
is the sum of all four lung volumes: the RV, the VT, the IRV, and
ration that starts at the end of a normal tidal expiration. It is
the ERV. It is about 6 L in a healthy 70-kg adult.
therefore determined by the difference between the functional
residual capacity (FRC, see below) and the RV. The ERV is
about 1.5 L in a healthy 70-kg adult. The Vital Capacity
The vital capacity (VC), discussed in Chapter 32, is the vol-
The Inspiratory Reserve Volume ume of air expelled from the lungs during a maximal forced
The inspiratory reserve volume (IRV) is the volume of gas that expiration starting after a maximal forced inspiration. It is
is inspired into the lungs during a maximal forced inspiration therefore equal to the TLC minus the RV, or about 4.5 L in a
starting at the end of a normal tidal inspiration. It is determined healthy 70-kg adult. The VC is also equal to the sum of the VT
by the strength of contraction of the inspiratory muscles, the and the IRV and ERV. It is determined by the factors that
inward elastic recoil of the lung and the chest wall, and the start- determine the TLC and RV.
ing point, which is the FRC plus the VT . The IRV of a healthy
70-kg adult is about 2.5 L.
MEASUREMENT OF THE
LUNG VOLUMES
The Functional Residual Capacity
The FRC is the volume of gas remaining in the lungs at the end Measurement of the lung volumes is important clinically because
of a normal tidal expiration. It represents the balance point many pathologic states can alter specific lung volumes or their

relationships to one another. The lung volumes, however, can
also change for normal physiologic reasons. Changing from a
standing to a supine posture decreases the FRC because gravity
is no longer pulling the abdominal contents away from the dia-
phragm. This decreases the outward elastic recoil of the chest
wall, as noted in Chapter 32. Determination of the lung volumes
can be useful diagnostically in differentiating between two
major types of pulmonary disorders—the restrictive diseases
and the obstructive diseases. Restrictive diseases such as alveo-
lar fibrosis reduce the compliance of the lungs, increase elastic
recoil, and lead to compressed lung volumes (Figure 33–2). The
VT may even be decreased, with a corresponding increase in
breathing frequency, to minimize the work of breathing.
Obstructive diseases such as emphysema and chronic bron-
chitis cause increased resistance to airflow. Airways may become
completely obstructed because of mucous plugs and because of
the high intrapleural pressures generated to overcome the ele-
vated airway resistance during a forced expiration. This is espe-
cially a problem in emphysema, in which destruction of alveolar
septa leads to decreased elastic recoil of the alveoli and less
radial traction, which normally help hold small airways open.
For these reasons, the RV, the FRC, and the TLC may be greatly
increased in obstructive diseases, as seen in Figure 33–2. The
VC and ERV are usually decreased. The breathing frequency
may be decreased to reduce the work expended overcoming the
airway resistance, with a corresponding increase in the VT.
Spirometry
The spirometer is a simple device for measuring gas volumes.
As the person breathes in and out through a mouthpiece (a nose
clip prevents airflow via the nose) and a tube connected to the
spirometer, the volumes of gas entering and leaving the spirom-
IC
TLC
IRV
IC
VT VC
TLC
IC IRV
FRC
ERV VC
VT
FRC TLC
ERV
RV FRC
RV
normal restrictive
CHAPTER 33 Alveolar Ventilation 333
eter can be determined. The spirometer can therefore measure
only the lung volumes that the subject can exchange with it. As
is the case with many pulmonary function tests, the subject
must be conscious and cooperative and understand the instruc-
tions for performing the test. Figure 33–3 shows that the VT, IRV,
ERV, IC, and VC can all be measured with a spirometer (as can
the forced expiratory volume in 1 second [FEV1], forced vital
capacity [FVC], and the FEV1/FVC, as discussed in Chapter 32).
The RV, the FRC, and the TLC, however, cannot be determined
with a spirometer because the subject cannot exhale all the gas in
the lungs into the spirometer.
Measurement of Lung Volumes
Not Measurable with Spirometry
The lung volumes not measurable with spirometry can be
determined by the nitrogen-washout technique, the helium-
dilution technique, and body plethysmography. The FRC is
usually determined, and RV (which is equal to FRC minus
ERV) and the TLC (which is equal to VC plus RV) are then
calculated from volumes obtained by spirometry.
Nitrogen-washout technique
In the nitrogen-washout technique, the person breathes 100%
oxygen through a one-way valve to wash all of the nitrogen out
of the alveoli. The expired gas is collected and the volume of
nitrogen washed out of the person’s lungs is calculated. The
total volume of nitrogen in the person’s lungs at the beginning
of the test can thus be determined. Nitrogen constitutes about
80% of the person’s initial lung volume, so multiplying the ini-
tial nitrogen volume by 1.25 gives the person’s initial lung vol-
ume. If the test starts at the end of a normal tidal expiration,
the volume determined is the FRC.
IRV
VC
VT
ERV
FIGURE 33–2 Illustration of typical
alterations in the lung volumes and capacities
in restrictive and obstructive diseases. The
pattern shown for obstructive diseases is more
RV
characteristic for emphysema and asthma than
for chronic bronchitis. IC, inspiratory capacity;
TLC, total lung capacity; FRC, functional residual
capacity; IRV, inspiratory reserve volume; VT, tidal
volume; ERV, expiratory reserve volume; RV,
residual volume; VC, vital capacity. (Modified with
permission from Levitzky MG: Pulmonary Physiology, 7th
obstructive ed. New York: McGraw-Hill Medical, 2007.)
334 SECTION VI Pulmonary Physiology
Vital capacity
volume (L)
FIGURE 33–3 Determination of the
tidal volume, vital capacity, inspiratory
capacity, inspiratory reserve volume,
and expiratory reserve volume from a
spirometer trace. (Modified with permission
from Levitzky MG: Pulmonary Physiology, 7th ed.
New York: McGraw-Hill Medical, 2007.)
Helium-dilution technique
The helium-dilution technique makes use of the following
relationship: if the total amount of a substance dissolved in a
volume is known and its concentration can be measured, the
volume in which it is dissolved can be determined.
Helium is used for this test because it is not taken up by the
pulmonary capillary blood, so the total amount of helium used
in the test does not change during the test. The person breathes
in and out of a spirometer filled with a mixture of helium and
oxygen. When an equilibrium is reached, the concentration of
helium is the same in the lungs as it is in the spirometer, and
the test is stopped at the end of a normal tidal expiration, in
other words, at the FRC.
The calculated increase in the volume of distribution of
helium therefore represents the lung volume. Since it may take
several minutes for the helium concentration to equilibrate
between the lungs and the spirometer, CO2 is absorbed from
the system and oxygen is added to the spirometer at the rate
at which it is used by the person. Both the nitrogen-washout
and helium-dilution methods can be used on unconscious
patients.
Body plethysmography
A problem common to both the nitrogen-washout technique
and the helium-dilution technique is that neither can measure
trapped gas because nitrogen trapped in alveoli supplied by
closed airways cannot be washed out and because the helium
cannot enter alveoli supplied by closed airways. Furthermore,
if the lungs have many alveoli served by airways with high
resistance to airflow (the “slow alveoli” discussed at the end of
Chapter 32), it may take a long time for all the nitrogen to
wash out of the lungs or for the inspired and expired helium
concentrations to equilibrate. In such patients, measurements
of the lung volumes with a body plethysmograph are much
more accurate because they do include trapped gas.
SPIROMETER TRACE (SPIROGRAM)
Maximal inspiration
Inspiratory reserve volume
Inspiratory
capacity
Tidal
volume
Expiratory reserve volume
Maximal expiration
Time (s)
The body plethysmograph makes use of Boyle’s law: for a
closed container at a constant temperature, the pressure times
the volume of a gas mixture is constant. The body plethysmo-
graph is an airtight chamber large enough that the patient can sit
inside it and breathe through a mouthpiece and tubing. The
patient breathes in for an instant against a closed airway and the
pressures at the mouth and in the plethysmograph are moni-
tored. As the patient breathes in against the closed airway, the
chest expands and the pressure measured in the plethysmograph
increases because the volume of air in the plethysmograph
decreases by the amount the chest volume increased. The pres-
sure measured at the mouth decreases as the patient breathes in
against a closed airway. Boyle’s law is used to calculate the
changes in volumes of the body plethysmograph and the lungs
to determine the FRC.
ANATOMIC DEAD SPACE AND
ALVEOLAR VENTILATION
The volume of air entering and leaving the nose or mouth per
minute, the minute volume, is not equal to the volume of air
entering and leaving the alveoli per minute. Alveolar ventilation
is less than the minute volume because the last part of each inspi-
ration remains in the conducting airways and does not reach the
alveoli. Similarly, the last part of each expiration remains in the
conducting airways and is not expelled from the body.
The anatomic dead space is illustrated in Figure 33–4. When
a person breathes in a tidal volume of 500 mL, not all the air
reaches the alveoli: the final 150 mL of the inspired air remains
in the conducting airways. The volume of gas reaching the alve-
oli is equal to the volume inspired minus the volume of the ana-
tomic dead space, in this case 500 – 150 mL, or 350 mL. During
expiration, the first gas breathed out is inspired air that remained
in the anatomic dead space; the last 150 mL is alveolar gas that
 CHAPTER 33 Alveolar Ventilation 335

150 ml

Tidal volume = 500 ml

350 ml

Volume in Anatomic
conducting dead space = 150 ml Conducting
airways left over 150 ml 150 ml
airways
from preceding
breath
350 ml
FIGURE 33–4 Illustration of the anatomic dead
Alveolar gas
space. Of a 500-mL tidal volume, 150 mL remains in the
150 ml
conducting airways and does not participate in gas
exchange; only 350 mL enters the alveoli. (Reproduced with
permission from Widmaier EP, Raff H, Strang KT: Vander’s Human
Physiology, 11th ed. McGraw-Hill, 2008.)

remains in the anatomic dead space. Therefore, for any respira-
tory cycle, not all the tidal volume reaches the alveoli because
the last part of each inspiration and each expiration remains in
the dead space. The relationship for the VT breathed in and out
through the nose or mouth, the dead space volume (VD), and
the volume of gas entering and leaving the alveoli per breath
(VA) is:
VT = VD + VA
or
VA = VT – VD
The alveolar ventilation (per minute) can be determined by
multiplying both sides of the above equation by the breathing
frequency (f) in breaths per minute:
f (VA) = f (VT ) – f (VD )
Thus, for f = 12 breaths/min in the above example, we have:
4,200[mL/min] = 6,000[mL/min] – 1,800[mL/min] (4)
.
The alveolar ventilation (VA) in liters per minute is equal to
.
the minute volume (VE) minus
. the volume wasted ventilating
the dead space per minute (VD):
. . . the anatomic and the alveolar dead space. The anatomic dead
VA = VT – VD (5)
. The dot over the letter V indicates per minute. The symbol
VE is used because expired gas is usually collected. There is a
difference between the volume of gas inspired and the volume
of gas expired because as air is inspired, it is warmed to body
temperature and humidified and also because normally less
carbon dioxide is produced than oxygen is consumed.
MEASUREMENT OF ALVEOLAR
VENTILATION
Alveolar ventilation cannot be measured directly but must be
determined from the VT, the breathing frequency, and the dead
space ventilation, as noted in the previous section.
Estimation of Anatomic Dead Space
For a healthy subject, the anatomic dead space can be esti-
mated by referring to a table of standard values matched to
sex, age, height, and weight or body surface area. The anatomic
dead space is not measured clinically; a reasonable estimate of
anatomic dead space is 1 mL of dead space per pound (2.2 kg)
of ideal body weight.
(1)
Physiologic Dead Space:
(2) The Bohr Equation
The air in the anatomic dead space may not be the only
inspired air that does not participate in gas exchange. The
alveolar dead space is the volume of gas that enters unper-
fused alveoli per breath. Alveolar dead space is therefore alve-
(3) oli that are ventilated but not perfused with pulmonary
capillary blood. No gas exchange occurs in these alveoli for
physiologic, rather than anatomic, reasons. A healthy person
has little or no alveolar dead space, but a person with a low
cardiac output might have significant alveolar dead space, for
reasons explained in Chapter 34.
The Bohr equation permits the determination of the sum of
space plus the alveolar dead space is known as the physiologic
dead space:
Physiologic dead space =
(6)
Anatomic dead space + Alveolar dead space
The Bohr equation makes use of a simple concept: any
measurable volume of carbon dioxide found in the mixed
expired gas must come from alveoli that are both ventilated
and perfused because there are negligible amounts of carbon
dioxide in inspired air. Inspired air remaining in the anatomic
dead space or entering unperfused alveoli will leave the body
as it entered (except for having been warmed to body tem-
perature and humidified), contributing little or no carbon
dioxide to the mixed expired air, as shown in the following
Bohr equation:
336 SECTION VI Pulmonary Physiology

50
End-tidal

40

Pco2 (mm Hg)

30
FIGURE 33–5 Partial pressure of carbon dioxide at
the mouth during a breath. During inspiration, the Pco2
rapidly decreases to near zero (0.3 mm Hg). The first
expired gas comes from the anatomic dead space and 20
therefore also has a Pco2 near zero. After exhalation of a
mixture of gas from alveoli and anatomic dead space,
the gas expired is a mixture from all ventilated alveoli. 10
The slope of the alveolar plateau normally rises slightly
because the alveolar Pco2 increases a few mm Hg between
inspirations. The last alveolar gas expired before 0
inspiration is called end-tidal. (Modified with permission 0 1 2 3 4 5
from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Expiration starts Inspiration starts
Medical, 2007.) Time (s)

VDco Paco2 – PEco2

____2
= _________
VT Paco2
where VDco2 is the dead space for CO2 (the physiologic dead
space), VT the tidal volume, Paco2 the arterial partial pressure
of carbon dioxide, and PEco2 the mixed expired partial pres-
sure of carbon dioxide.
The arterial Pco2 must be determined from an arterial blood
sample; the Pco2 of the collected mixed expired gas can be
determined with a CO2 meter. After the physiologic dead space
is calculated using the Bohr equation, the estimated anatomic
dead space can be subtracted from it to calculate the alveolar
dead space.
The CO2 meter can also used to estimate the mean alveo-
lar Pco2 by analyzing the gas expelled at the end of a normal
tidal expiration, the “end-tidal CO2” (Figure 33–5). In a
person with significant alveolar dead space, however, the
estimated alveolar Pco2 obtained in this fashion may not
reflect the Pco2 of alveoli that are ventilated and perfused
because some of this mixed end-tidal gas comes from unper-
fused alveoli. This gas dilutes the CO2 coming from alveoli
that are both ventilated and perfused. There is, however, an
equilibrium between the Pco2 of perfused alveoli and their
end-capillary Pco2 (see Chapter 35 for detailed discussion),
so that in patients without significant venous-to-arterial
shunts, the arterial Pco2 represents the mean Pco2 of the per-
fused alveoli.
If the arterial Pco2 is greater than the mixed alveolar Pco2
determined by sampling the end-tidal CO2, then the physio-
logic dead space is probably greater than the anatomic dead
space, that is, a significant arterial–alveolar CO2 difference
means that there is significant alveolar dead space; a person
with no alveolar dead space has an arterial–end-tidal CO 2 dif-
ference of zero. As already noted, this difference is determined
from the Pco2 from an arterial blood gas sample and from the
end-tidal Pco2 . Young healthy people have no alveolar dead
(7) space, so their physiologic dead space is equal to their ana-
tomic dead space. Situations in which alveoli are ventilated but
not perfused include those in which portions of the pulmo-
nary vasculature have been occluded by blood clots or other
material in the venous blood (pulmonary emboli), those in
which there is low venous return leading to low right ventricu-
lar output (hemorrhage), and those in which alveolar pressure
is high (positive-pressure ventilation with positive end-
expiratory pressure). These will be discussed in greater detail
in Chapter 34.
The anatomic dead space can be altered by bronchocon-
striction, which decreases VD; bronchodilation, which
increases VD; or traction or compression of the airways, which
increases and decreases VD, respectively.
ALVEOLAR VENTILATION &
ALVEOLAR OXYGEN AND CARBON
DIOXIDE LEVELS
The levels of oxygen and carbon dioxide. in alveolar gas are
determined .by the alveolar ventilation (VA), the oxygen con-
sumption
. (VO2) of the body, and the carbon dioxide produc-
tion (VCO2 )of the body.
PARTIAL PRESSURES OF
RESPIRATORY GASES
According to Dalton’s law, in a gas mixture, the pressure
exerted by each individual gas is independent of the pres-
sures of other gases in the mixture. The partial pressure of a
particular gas is equal to its fractional concentration times
 CHAPTER 33 Alveolar Ventilation 337

the total pressure of all the gases in the mixture. Thus, for TABLE 33–1 Partial pressures in mm Hg of oxygen,
any gas in a mixture (gas1), its partial pressure is given as carbon dioxide, nitrogen, and water vapor in dry air,
follows: inspired air, alveolar air, and expired air at a barometric
Pgas = Total gas (%) × Ptot (8) pressure of 760 mm Hg.
1

Oxygen constitutes 20.93% of dry atmospheric air. At a PO2 PCO2 PN2 PH2O
standard barometric pressure of 760 mm Hg, we have:
Dry air 159 0.3 601 0
PO2 = 0.2093 × 760 mm Hg = 159 mm Hg (9)
Inspired air 149 0.3 564 47
Carbon dioxide constitutes only about 0.04% of dry atmo- Alveolar air 104 40 569 47
spheric air, so we have:
Expired air 120 27 566 47
PCO2 = 0.0004 × 760 mm Hg = 0.3 mm Hg (10)
As air is inspired through the upper airways, it is warmed
and humidified, as discussed in Chapter 31. The partial pres-
sure of water vapor is a relatively constant 47 mm Hg at body inspiration. Expired air is a mixture of about 350 mL of alve-
temperature, so the humidification of 1 L of dry gas in a closed olar air and 150 mL of air from the dead space. Therefore,
container at 760 mm Hg would increase its total pressure to the Po2 of mixed expired air is higher than alveolar Po2 and
760 + 47 mm Hg = 807 mm Hg. In the body, the gas will lower than the inspired Po2, or approximately 120 mm Hg.
expand, according to Boyle’s law, so that 1 L of gas at 760 mm Similarly, the Pco2 of mixed expired air is much higher than
Hg is diluted by the added water vapor. The Po2 of inspired air, the inspired Pco2 but lower than the alveolar Pco2 , or about 27
or PIo2 (saturated with water vapor at a standard barometric mm Hg. The expected partial pressures of oxygen, carbon
pressure), then is equal to the fractional concentration of dioxide, nitrogen, and water vapor in dry air, inspired air,
inspired oxygen (FIo2) times the barometric pressure minus the alveolar air, and expired air at an atmospheric pressure of
water vapor pressure: 760 mm Hg are shown in Table 33–1.

PIo2 = FIo2 (PB – PH2O) (11)

where PB is the barometric pressure and PH2O the water vapor ALVEOLAR VENTILATION
pressure. Then we have: AND CARBON DIOXIDE
0.2093(760 – 47) mm Hg = 149 mm Hg (12)
The concentration of carbon dioxide in the alveolar gas is, as
The Pco2 of inspired air (PIco2 ) is equal to FIco2 (PB – PH2O) or already discussed, dependent on the alveolar ventilation and
0.0004(760 – 47) mm Hg = 0.29 mm Hg (rounded up to 0.3 on the rate of carbon dioxide production by the body (and its
mm Hg). delivery to the lung in the mixed venous blood).. The volume
Alveolar gas is composed of 2.5–3.0 L of gas already in the of carbon dioxide expired. per unit of time (VEco2 ) is equal to
lungs at the FRC and approximately 350 mL per breath enter- the alveolar ventilation (VA ) times the alveolar fractional con-
ing and leaving the alveoli. About 300 mL of oxygen is con- centration of CO2 (FAco2 ). No carbon dioxide comes from the
tinuously diffusing from the alveoli into the pulmonary dead space:
capillary blood per minute at rest and is being replaced by . .
VEco2 = VA FAco2 (13)
alveolar ventilation. Similarly, about 250 mL of carbon dioxide
is diffusing from the mixed venous blood in the pulmonary Similarly, the fractional concentration of carbon dioxide in
capillaries into the alveoli per minute and is then removed by the alveoli is directly proportional
. to the carbon dioxide pro-
alveolar ventilation. (The Po2 and Pco2 of mixed venous blood duction by the body (Vco2) and inversely proportional to the
are about 40 and 45–46 mm Hg, respectively.) Therefore, the alveolar ventilation:
.
partial pressures of oxygen and carbon dioxide in the alveolar Vco
air are determined by the alveolar ventilation, pulmonary cap- FAco2 ∝ ___
. 2
(14)
VA
illary perfusion, oxygen consumption, and carbon dioxide
Since FAco2 (PB – PH2O) = PAco2 , we have:
production. Alveolar ventilation is normally adjusted by the .
V
respiratory control center in the brain to keep mean arterial ___
PAco2 ∝ co. 2 (15)
and alveolar Pco2 at about 40 mm Hg (see Chapter 38). Mean VA
alveolar Po2 is about 104 mm Hg (usually considered to be 100 In healthy people, alveolar Pco2 is in equilibrium with arterial
mm Hg for convenience). Pco2 (Paco2 ). Thus, if alveolar ventilation is doubled (and car-
The alveolar Po2 increases by 2–4 mm Hg with each nor- bon dioxide production is unchanged), then the alveolar and
mal tidal inspiration and decreases slowly until the next arterial Pco2 are reduced by one half. If alveolar ventilation is
inspiration. Similarly, the alveolar Pco2 decreases 2–4 mm Hg cut in half, then alveolar and arterial Pco2 will double. This can
with each inspiration and increases slowly until the next be seen in the upper part of Figure 33–6.
338 SECTION VI Pulmonary Physiology

150 REGIONAL DISTRIBUTION OF

ALVEOLAR VENTILATION
100 As previously discussed, a 70-kg person has about 2.5–3.0 L of
PACO2
(mm Hg) gas in the lungs at the FRC. Each breath brings about 350 mL
of fresh gas into the alveoli and removes about 350 mL of alve-
50 olar air from the lung. Studies performed on healthy subjects
standing or seated upright have shown that alveoli in the lower
regions of the lungs receive more ventilation per unit volume
0 than do those in the upper regions of the lung. The lower
2 4 6 8 10 regions of the lung are relatively better ventilated than the
Alveolar ventilation (L/min) upper regions of the lung.
If a similar study is done on a subject lying on his or her left
side, the regional differences in ventilation between the ana-
150 tomic upper, middle, and lower regions of the lung disappear,
although there is better relative ventilation of the left lung than
of the right lung. The regional differences in ventilation are
100 therefore mainly a result of the effects of gravity, with regions
of the lung lower with respect to gravity (the “dependent”
PAO2
regions) relatively better ventilated than those regions above
(mm Hg)
them (the “nondependent” regions).
50
The explanation for these regional differences in ventilation
is regional differences in intrapleural pressure. In Chapter 32,
the intrapleural surface pressure was discussed as if it were
0 uniform throughout the thorax, which is not the case. The
2 4 6 8 10
Alveolar ventilation (L/min) intrapleural surface pressure is less negative in the lower, grav-
ity-dependent regions of the thorax than it is in the upper,
FIGURE 33–6 Predicted alveolar gas tensions for different nondependent regions. There is a gradient of the intrapleural
levels of alveolar ventilation. (Modified with permission from Nunn JF: surface pressure such that for every centimeter of vertical dis-
Applied Respiratory Physiology, 4th ed. 1993. Reprinted by permission of Elsevier
placement down the lung (from nondependent to dependent
Science Limited.)
regions), the intrapleural surface pressure increases by about
+0.2 to +0.5 cm H2O. This gradient is caused by gravity and by
ALVEOLAR VENTILATION AND OXYGEN mechanical interactions between the lung and the chest wall.
The influence of this gradient of intrapleural surface pres-
As alveolar ventilation increases, the alveolar Po2 will also sure on regional alveolar ventilation can be explained by
increase. Doubling alveolar ventilation, however, cannot double predicting its effect on the transpulmonary pressure gradients
PAo2 in a person whose alveolar Po2 is already 104 mm Hg in upper and lower regions of the lung. In the left side of
because the highest PAo2 one could possibly achieve breathing Figure 33–7, alveolar pressure is assumed to be zero in both
air at sea level is the inspired Po2 of about 149 mm Hg. The alve- regions of the lung at the FRC, as discussed in Chapter 32.
olar Po2 can be calculated by using the alveolar air equation: Since the intrapleural pressure is more negative in upper
PAco regions of the lung than it is in lower regions of the lung, the
PAo2 = PIo2 – ____
R
+F2
(16) transpulmonary pressure (alveolar minus intrapleural) is
.
Vco2 greater in upper regions of the lung than it is in lower regions
where R is the respiratory exchange ratio ( ___
. ) and F a small
Vo2 of the lung. Because the alveoli in upper regions of the lung are
correction factor.
subjected to greater distending pressures than those in more
As already noted, PIo2 = FIo2(PB – PH2O). F is usually ignored.
dependent regions of the lung, they have greater volumes than
Therefore, we have:
the alveoli in more dependent regions.
PA
PAo2 = FIo2(PB – PH2O)– ____
co 2
(17) It is this difference in volume that leads to the difference in
R
ventilation between alveoli located in dependent and nonde-
As alveolar ventilation increases, the alveolar Pco2 decreases, pendent regions of the lung. This can be seen on the hypo-
bringing the alveolar Po2 closer to the inspired Po2, as can be thetical pressure–volume curve shown on the right side of
seen in the lower part of Figure 33–6. Note that the alveolar Po2 Figure 33–7. This curve is similar to the pressure–volume
obtained using the alveolar air equation is a calculated ideal- curve for a whole lung shown in Figure 32–6, except that this
ized average alveolar Po2. It represents what alveolar Po2 should curve is drawn with the pressure–volume characteristics of
be, not necessarily what it is. single alveoli in mind. The abscissa is the transpulmonary

pressure (alveolar pressure minus intrapleural pressure). The
ordinate is the volume of the alveolus expressed as a percent of
its maximum.
Because of the greater transpulmonary pressure, the alveo-
lus in the upper region of the lung has a greater volume than
the alveolus in a more gravity-dependent region of the lung. At
the FRC, the alveolus in the upper part of the lung is on a less
steep portion of the alveolar pressure–volume curve (i.e., it is
less compliant) in Figure 33–7 than is the more compliant
alveolus in the lower region of the lung. Therefore, any change
in the transpulmonary pressure during a normal respiratory
cycle will cause a greater change in volume in the alveolus in
the lower, gravity-dependent region of the lung than it will in
the alveolus in the nondependent region of the lung, as shown
by the arrows in the figure. Because the alveoli in the lower
parts of the lung have a greater change in volume per inspira-
tion and per expiration, they are better ventilated than those
alveoli in nondependent regions (during eupneic breathing
from the FRC).
A second effect of the intrapleural pressure gradient in a
person seated upright is on regional static lung volume, as is
evident from the above discussion. At the FRC, most of the
alveolar air is in upper regions of the lung because those alve-
oli have larger volumes. Most of the ERV is also in upper por-
tions of the lung. On the other hand, most of the IRV and IC
are in lower regions of the lung. Even at low lung volumes, the
upper alveoli are larger in volume than are the lower gravity-
dependent alveoli. They therefore constitute most of the RV.
Patients with emphysema have greatly decreased alveolar
elastic recoil, leading to high FRCs, extremely high RVs, and
airway closure in dependent parts of the lung even at high lung
Pleural pressure (cm H2O)
8.5
35 cm
1.5
10
Transpulmonary pressure (cm H2O)
FIGURE 33–7 Effect of the pleural surface pressure gradient on the distribution of inspired gas at the functional residual capacity
(FRC). (Modified with permission from Milic-Emili J: Pulmonary statics. In: Widdicombe JG, ed. MTP International Review of Sciences: Respiratory Physiology. London, England:
Butterworth; 1974:105–137.)
CHAPTER 33 Alveolar Ventilation 339
volumes, so they have relatively more ventilation of nonde-
pendent alveoli.
THE CLOSING VOLUME
During a forced expiration, the lung volume at which airway
closure begins to occur is known as the closing capacity; the
volume of air exhaled from the time the first airways close
until the subject reaches the RV and can exhale no more air is
called the closing volume. (The terms are often used inter-
changeably.) Because people with emphysema have dimin-
ished alveolar elastic recoil to provide traction on the airways
and help get air out of the alveoli during a forced expiration,
they have very high closing capacities. That is, their airways
begin to close at high lung volumes, trapping gas in the affected
alveoli. They learn to breathe at higher lung volumes to opti-
mize their elastic recoil. As discussed in Chapter 73, even
healthy people lose alveolar elastic recoil as they age, resulting
in higher closing capacities.
CLINICAL CORRELATION
A 38-year-old man with an obvious curvature of the spine
in the coronal and sagittal planes is seen by a pulmonolo-
gist because of dyspnea that has gotten worse during
the last few months. He is 163-cm (5′4″) tall and weighs
61.2 kg (135 lb). Blood pressure is 135/95 mm Hg, heart
rate is 80/min, and his respiratory rate is tachypnic at
FRC
100
80
60
Volume (%)
40
20
0
0 10 20 30 40
340 SECTION VI Pulmonary Physiology

25 breaths/min. His respiratory muscle strength appears

CHAPTER SUMMARY
to be normal. The pulmonologist orders pulmonary func- ■ Alveolar ventilation is less than the volume of air entering or
tion tests and an arterial blood gas (with reference ranges leaving the nose or mouth per minute (the minute volume)
because the last part of each inspiration remains in the
in parenthesis) with the following results:
conducting airways (the anatomic dead space).
TLC: 45% of predicted;
■ Alveoli that are ventilated but not perfused constitute alveolar
VC: 40% of predicted;
dead space.
RV: 75% of predicted;
■ The physiologic dead space is the sum of the anatomic dead
FRC: 50% of predicted;
space and the alveolar dead space.
FEV1: 40% of predicted;
FVC: 40% of predicted; ■ At constant carbon dioxide production, alveolar Pco2 is
approximately inversely proportional to alveolar ventilation;
FEV1/FVC: 80% of predicted;
alveolar Po2 is calculated using the alveolar air equation.
arterial Po2: 75 mm Hg (80–100 mm Hg);
■ At or near the FRC, alveoli in lower regions of the upright lung
arterial Pco2: 46 mm Hg (35–45 mm Hg);
are relatively better ventilated than those in upper regions of
arterial pH: 7.38 (7.35–7.45).
the lung.
The patient has kyphoscoliosis that is a lateral curva-
ture of the spine (scoliosis) as well as a sagittal curvature
(kyphosis). It can be congenital; secondary to many disor- STUDY QUESTIONS
ders, including muscular dystrophy, poliomyelitis, spina
1. Which of the following conditions are reasonable explanations
bifida, and cerebral palsy; or it may be idiopathic (of for a functional residual capacity that is significantly less than
unknown cause). Kyphoscoliosis results in decreased predicted?
compliance of the rib cage with much less outward recoil A) third trimester of pregnancy
of the chest wall at low thoracic volumes and much greater B) pulmonary fibrosis
inward recoil at higher volumes. Kyphoscoliosis is there- C) obesity
fore a restrictive disease. D) emphysema
It is difficult for the patient to breathe in and, as a E) all of the above
result, his inspiratory work of breathing is increased. It F) A, B, and C
explains his increased resting respiratory rate (normally 2–5. An unconscious patient’s ventilation is maintained with
12–15 breaths/min) because taking smaller tidal volumes positive-pressure ventilation with a tidal volume of 450 mL and
at an increased breathing frequency decreases his work a rate of 10 breaths/min. She weighs 100 lb. Her arterial Pco2 is
of breathing. The effects of the changes in the mechanics 42 mm Hg, her end-tidal Pco2 is 35 mm Hg, and her mixed expired
of his thorax can be seen in the lung volumes and capac- Pco2 is 28 mm Hg.
ities determined in this patient (see Figure 33–2). His 2. What is her minute volume?
FRC is low because, with less outward recoil of his chest A) 350 mL/min
wall, the balance point between the outward recoil of the B) 1,000 mL/min
chest wall and the inward recoil of his lungs occurs at a C) 3,500 mL/min
lower lung volume. His TLC is low because his ability to D) 4,500 mL/min
inhale maximally is severely impaired. His RV is also E) 5,500 mL/min
lower than predicted, but not as much as the TLC, 3. What is her alveolar ventilation?
because his ability to exhale is not as impaired. His VC, A) 350 mL/min
FVC, and FEV1 are all lower than predicted because his B) 1,000 mL/min
TLC is very low—he cannot exhale very much because C) 3,500 mL/min
D) 4,500 mL/min
he is unable to inhale very much. On the other hand, this
E) 5,500 mL/min
patient does not have airway obstruction. Although both
4. What is her physiologic dead space?
his FEV1 and FVC are low, the FEV1/FVC is within the
normal range. The blood gases demonstrate that the A) 50 mL
B) 100 mL
increased work of breathing has resulted in decreased
C) 150 mL
alveolar ventilation. His arterial Pco2 is high and his arte-
D) 200 mL
rial Po2 is low. E) 300 mL
Treatment of patients with kyphoscoliosis is aimed at
5. What is her alveolar dead space?
improving alveolar ventilation, for example, with nonin-
A) 50 mL
vasive mechanical ventilation at night. Orthopedic sur-
B) 100 mL
gery to help correct the problem may be effective in some C) 150 mL
patients. D) 200 mL
E) 300 mL
 34
C H A P T E R

Pulmonary Perfusion
Michael Levitzky

O B J E C T I V E S

■ Compare and contrast the bronchial circulation and the pulmonary

circulation.
■ Describe the anatomy of the pulmonary circulation, and explain its
physiologic consequences.
■ Compare and contrast the pulmonary circulation and the systemic
circulation.
■ Describe and explain the effects of lung volume on pulmonary vascular
resistance.
■ Describe and explain the effects of elevated intravascular pressures on
pulmonary vascular resistance.
■ List the neural and humoral factors that influence pulmonary vascular
resistance.
■ Describe the effect of gravity on pulmonary blood flow.
■ Describe the interrelationships of alveolar pressure, pulmonary arterial
pressure, and pulmonary venous pressure and their effects on the regional
distribution of pulmonary blood flow.
■ Predict the effects of alterations in alveolar pressure, pulmonary arterial
and venous pressures, and body position on the regional distribution of
pulmonary blood flow.
■ Describe hypoxic pulmonary vasoconstriction and discuss its role in localized
and widespread alveolar hypoxia.
■ Describe the causes and consequences of pulmonary edema.

The lung receives blood flow via both the bronchial circula-
tion and the pulmonary circulation. Bronchial blood flow
constitutes a very small portion of the output of the left
ventricle and supplies part of the tracheobronchial tree with
systemic arterial blood. Pulmonary blood flow constitutes
the entire output of the right ventricle and supplies the lung
with the mixed venous blood draining all the tissues of the
body. It is this blood that undergoes gas exchange with the
alveolar air in the pulmonary capillaries. Because the right and
left ventricles are arranged in series after birth, pulmonary
blood flow is approximately equal to 100% of the output of the
left ventricle (the cardiac output).
About 280 billion pulmonary capillaries supply the approxi-
mately 300–480 million alveoli, resulting in a potential surface
area for gas exchange estimated to be 50–100 m2. As was shown
in Figure 31—5, the alveoli are completely enveloped in pul-
monary capillaries.
THE BRONCHIAL CIRCULATION
The bronchial arteries supply arterial blood to the tracheo-
bronchial tree and to other structures of the lung down to the
level of the terminal bronchioles. They also provide blood flow

341

Ch34_341-352.indd 341 11/26/10 11:50:35 AM

342 SECTION VI Pulmonary Physiology
CONDUCTING AIRWAYS
PULMONARY 12
ARTERY
(Mean  15)
25/8
VENTRICLE
25/0
RIGHT
ATRIUM
2 120/0
VEINS
15
FIGURE 34–1 Pressures, expressed in mm Hg, in the systemic and pulmonary circulations. (Modified with permission from Levitzky MG:
Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)
to other thoracic structures. Lung structures distal to the ter-
minal bronchioles, including the respiratory bronchioles, alve-
olar ducts, alveolar sacs, and alveoli, receive oxygen directly by
diffusion from the alveolar air and nutrients from the mixed
venous blood in the pulmonary circulation. The bronchial cir-
culation may be important in the “air conditioning” of inspired
air (discussed in Chapter 31).
The blood flow in the bronchial circulation constitutes about
2% of the output of the left ventricle. Blood pressure in the bron-
chial arteries is the same as that in the other systemic arteries.
This is much higher than the blood pressure in the pulmonary
arteries (Figure 34–1). The venous drainage of the bronchial cir-
culation is atypical. Although some of the bronchial venous
blood enters the azygos and hemiazygos veins, a substantial
portion of bronchial venous blood enters the pulmonary veins.
The blood in the pulmonary veins has undergone gas exchange
with the alveolar air—that is, the pulmonary veins contain
“arterial” blood. Therefore, the bronchial venous blood entering
the pulmonary venous blood is part of the normal anatomic
right-to-left shunt, which will be discussed in Chapter 35.
THE PULMONARY CIRCULATION
The walls of the vessels of the pulmonary circulation are much
thinner than corresponding parts of the systemic circulation.
This is particularly true of the main pulmonary artery and its
ALVEOLI
PULMONARY
8
CAPILLARIES PULMONARY
VEINS
ATRIUM
5
LEFT
VENTRICLE
120/80
AORTA
(Mean  100)
SYSTEMIC
CAPILLARIES 30
TISSUES
branches. The pulmonary artery rapidly subdivides into ter-
minal branches that have thinner walls and greater internal
diameters than do corresponding branches of the systemic
arterial tree. There is much less vascular smooth muscle in the
walls of the vessels of the pulmonary arterial tree, and there
are no highly muscular vessels that correspond to the systemic
arterioles. The pulmonary arterial tree rapidly subdivides over
a short distance, ultimately branching into the approximately
280 billion pulmonary capillaries, where gas exchange occurs.
PULMONARY VASCULAR
RESISTANCE
The thin walls and small amount of smooth muscle found in
the pulmonary arteries have important physiologic conse-
quences. The pulmonary vessels offer much less resistance to
blood flow than do the systemic arterial vessels. They are also
much more distensible and compressible than systemic arterial
vessels. These factors lead to much lower intravascular pres-
sures than those found in the systemic arteries. The pulmo-
nary vessels are located in the thorax and are subject to alveolar
and intrapleural pressures that can change greatly, ranging
from as low as −80 cm H2O during a maximal inspiratory
effort to more than 100 cm H2O during a maximal forced
expiration. Therefore, factors other than the tone of the

pulmonary vascular smooth muscle may have profound effects
on pulmonary vascular resistance (PVR).
PVR cannot be measured directly but an approximation can
be calculated using the Poiseuille equation, as was discussed in
Chapter 22. For the pulmonary circulation, the PVR is equal to
the mean pulmonary artery pressure (Pa, the upstream pressure)
minus the mean left atrial pressure (the downstream pressure),
divided by pulmonary blood flow (the cardiac output). However,
the mean left atrial pressure may not be the effective downstream
pressure for the calculation of PVR under all lung conditions
(see the section on zones of the lung later in this chapter).
Because the right and left circulations are in series, the out-
puts of the right and left ventricles must be approximately equal
to each other. (If they are not, blood and fluid will build up in
the lungs or periphery.) If the two outputs are the same and the
measured pressure drops across the systemic circulation and
the pulmonary circulation are about 98 and 10 mm Hg, respec-
tively (see Figure 34–1), then the PVR must be about one tenth
that of the total peripheral resistance (TPR). TPR is some-
times called systemic vascular resistance (SVR).
DISTRIBUTION OF PULMONARY
VASCULAR RESISTANCE
The distribution of PVR can be estimated by the decrease in
pressure across each of the three major components of the pul-
monary vasculature: the pulmonary arteries, the pulmonary cap-
illaries, and the pulmonary veins. In Figure 34–1, the resistance
is fairly evenly distributed among the three components. At rest,
about one third of the resistance to blood flow is located in the
pulmonary arteries, about one third is located in the pulmonary
capillaries, and about one third is located in the pulmonary veins.
This is in contrast to the systemic circulation, in which about
70% of the resistance to blood flow is located in the systemic
arteries, mostly in the highly muscular systemic arterioles.
CONSEQUENCES OF DIFFERENCES IN
PRESSURE BETWEEN THE SYSTEMIC
AND PULMONARY CIRCULATIONS
The left ventricle must maintain a relatively high mean arterial
pressure because such high pressures are necessary to overcome
hydrostatic forces and pump blood to the brain. The apices of the
lungs are a much shorter distance above the right ventricle, so
such high pressures are unnecessary. The high arterial pressure
in the systemic circulation allows the redistribution of left ven-
tricular output and the control of blood flow to different tissues.
In the pulmonary circulation, redistribution of right ventricular
output is usually unnecessary because all alveolar–capillary units
that are participating in gas exchange are performing the same
function. The pressure is low and the small amount of smooth
muscle in the pulmonary vessels (which is in large part respon-
sible for the low pressure head) makes such local redistributions
unlikely. An exception to this will be described in the section
“Hypoxic Pulmonary Vasoconstriction.”
CHAPTER 34 Pulmonary Perfusion 343
Another consequence of the pressure differences between
the systemic and pulmonary circulations is that the workload
and metabolic demand of the left ventricle is much greater
than that of the right ventricle. The difference in wall thick-
ness of the left and right ventricles of the adult is a reminder of
the much greater workload of the left ventricle.
The relatively small amounts of vascular smooth muscle,
low intravascular pressures, and high distensibility of the pul-
monary circulation lead to a much greater importance of
extravascular effects (passive factors) on PVR. Gravity, body
position, lung volume, alveolar and intrapleural pressures,
intravascular pressures, and right ventricular output all can
have profound effects on PVR without any alteration in the
tone of the pulmonary vascular smooth muscle.
LUNG VOLUME AND PULMONARY
VASCULAR RESISTANCE
For distensible–compressible vessels, the transmural pressure
gradient is an important determinant of the vessel diameter
(see discussion of airway resistance in Chapter 32). As the
transmural pressure gradient (which is equal to pressure inside
minus pressure outside) increases, the vessel diameter increases
and resistance decreases; as the transmural pressure decreases,
the vessel diameter decreases and the resistance increases.
Negative transmural pressure gradients lead to compression or
even collapse of the vessel.
Two different groups of pulmonary vessels must be consid-
ered when the effects of lung volume changes on PVR are
analyzed—namely, the alveolar and extra-alveolar vessels
(Figure 34–2).
ALVEOLUS
“extraalveolar” “alveolar”
ALVEOLUS
During inspiration
FIGURE 34–2 Illustration of alveolar and extra-alveolar
pulmonary vessels during an inspiration. The alveolar vessels
(pulmonary capillaries) are exposed to the expanding alveoli and
elongated. The extra-alveolar vessels, here shown exposed to the
intrapleural pressure, expand as the intrapleural pressure becomes
more negative and as radial traction increases during the inspiration.
(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed.
New York: McGraw-Hill Medical, 2007.)
344 SECTION VI Pulmonary Physiology
As lung volume increases during a normal negative-pressure
inspiration, the alveoli increase in volume. While the alveoli
expand, the vessels between them, mainly pulmonary capillar-
ies, are elongated. As these vessels are stretched, their diame-
ters decrease, just as stretching a rubber tube causes its
diameter to narrow. Resistance to blood flow through the alve-
olar vessels increases as the alveoli expand because the alveolar
vessels are longer and because their radii are smaller. At high
lung volumes, then, the resistance to blood flow offered by the
alveolar vessels increases; at low lung volumes, the resistance
to blood flow offered by the alveolar vessels decreases.
One group of the extra-alveolar vessels, the larger arteries
and veins, is exposed to the intrapleural pressure. As lung vol-
ume is increased by making the intrapleural pressure more
negative, the transmural pressure gradient of the larger arteries
and veins increases and they distend. Another factor tending
to decrease the resistance to blood flow offered by the extra-
alveolar vessels at higher lung volumes is radial traction by the
connective tissue and alveolar septa holding the larger vessels
in place in the lung. (Look at the small branch of the pulmo-
nary artery at the bottom of Figure 31–4.) Thus, at high lung
volumes (attained by normal negative-pressure breathing), the
resistance to blood flow offered by the extra-alveolar vessels
decreases. During a forced expiration to low lung volumes,
however, intrapleural pressure becomes very positive. Extra-
alveolar vessels are compressed, and as the alveoli decrease in
size, they exert less radial traction on the extra-alveolar vessels.
The resistance to blood flow offered by the extra-alveolar ves-
sels therefore increases (see left side of Figure 34–3).
Because the alveolar and extra-alveolar vessels may be
thought of as two groups of resistances in series with each
Stretching of pulmonary
Pulmonary vascular resistance
capillaries
Compression of extra-
alveolar vessels
FRC = Lowest PVR
Lung volume
FIGURE 34–3 The effects of lung volume on pulmonary
vascular resistance (PVR). PVR is lowest near the functional residual
capacity (FRC) and increases at both high and low lung volumes
because of the combined effects on the alveolar and extra-alveolar
vessels. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture,
Medical Physiology. New York: McGraw-Hill, 2009.)
other, the resistances of the alveolar and extra-alveolar vessels
are additive at any lung volume. Thus, the effect of changes in
lung volume on the total PVR gives the U-shaped curve seen
in Figure 34–3. PVR is lowest near the functional residual
capacity and increases at both high and low lung volumes.
Also note that during mechanical positive-pressure ventila-
tion, alveolar pressure (PA) and intrapleural pressure are positive
during inspiration. In this case, both the alveolar and extra-
alveolar vessels are compressed as lung volume increases.
RECRUITMENT AND DISTENTION
During exercise, cardiac output can increase several-fold with-
out a correspondingly great increase in mean pulmonary
artery pressure. Although the mean pulmonary artery pres-
sure does increase, the increase is only a few millimeters of
mercury, even if cardiac output has doubled or tripled. Since
the pressure drop across the pulmonary circulation is propor-
tional to the cardiac output times the PVR (i.e., ΔP = Q̇ × R),
this must indicate a decrease in PVR.
Like the effects of lung volume on PVR, this decrease
appears to be passive—that is, it is not a result of changes in the
tone of pulmonary vascular smooth muscle caused by neural
mechanisms or humoral agents. In fact, a decrease in PVR in
response to increased blood flow or even an increase in perfu-
sion pressure can be demonstrated in a vascularly isolated per-
fused lung, as was used to obtain the data summarized in
Figure 34–4. (Note that the graph has blood pressure on the
x-axis; blood flow has a similar effect.) Increasing the left atrial
pressure also decreases PVR.
There are two different mechanisms that can explain
this decrease in PVR in response to elevated blood flow and
Pulmonary vascular resistance
Recruitment & distention
of pulmonary capillaries
Pulmonary blood flow
FIGURE 34–4 The effect of pulmonary blood flow (or blood
pressure) on pulmonary vascular resistance. Increased pulmonary
artery blood pressure or pulmonary blood flow decreases pulmonary
vascular resistance. (Reproduced with permission from Kibble J, Halsey CR: The
Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)
 CHAPTER 34 Pulmonary Perfusion 345

Recruitment Distention
FIGURE 34–5 Illustration of the mechanisms by which increased mean pulmonary artery pressure may decrease pulmonary
vascular resistance. The upper figure shows a group of pulmonary capillaries, some of which are perfused. At left, the previously unperfused
capillaries are recruited (opened) by the increased perfusion pressure. At right, the increased perfusion pressure has distended those vessels
already open. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

perfusion pressure: recruitment and distention (Figure 34–5).
As indicated in the diagram, at resting cardiac outputs, not all
the pulmonary capillaries are perfused. A substantial number
of capillaries are probably unperfused because of hydrostatic
effects that will be discussed later in this chapter. Others may
be unperfused because they have a relatively high critical
opening pressure. That is, these vessels, because of their high
vascular smooth muscle tone or other factors such as positive
alveolar pressure, require a higher perfusion pressure than
that solely necessary to overcome hydrostatic forces. Under
normal circumstances, it is not likely that the critical opening
pressures for pulmonary blood vessels are very great because
they have so little smooth muscle. Increasing blood flow
increases the mean pulmonary artery pressure, which opposes
hydrostatic forces and exceeds the critical opening pressure in
previously unopened vessels. This series of events opens new
parallel pathways for blood flow, which lowers the PVR. This
opening of new pathways is called recruitment. Note that
decreasing the cardiac output or pulmonary artery pressure
can result in a derecruitment of pulmonary capillaries.
As perfusion pressure increases, the transmural pressure
gradient of the pulmonary blood vessels increases, causing
distention of the vessels. This increases their radii and decreases
their resistance to blood flow.
Both recruitment and distention cause the decreased PVR
with elevated perfusion pressure or blood flow. Note that
recruitment increases the surface area for gas exchange and
may decrease alveolar dead space. Derecruitment caused by
low right ventricular output or high alveolar pressures
decreases the surface area for gas exchange and may increase
alveolar dead space.
CONTROL OF PULMONARY
VASCULAR SMOOTH MUSCLE
Pulmonary vascular smooth muscle is responsive to both neu-
ral and humoral influences. These produce active alterations
in PVR, as opposed to the passive factors discussed in the pre-
vious section. A final passive factor, gravity, will be discussed
later in this chapter. The main passive and active factors that
influence PVR are summarized in Tables 34–1 and 34–2.
The pulmonary vasculature is innervated by both sympa-
thetic and parasympathetic fibers of the autonomic nervous
system. The innervation of pulmonary vessels is relatively
sparse in comparison with that of systemic vessels, and the
autonomic nervous system has much less influence on the pul-
monary vessels. There is relatively more innervation of the
larger vessels and less of the smaller, more muscular vessels.
There appears to be no innervation of vessels smaller than
30 μm in diameter, with little innervation of intrapulmonary
veins and venules.
Sympathetic stimulation of the innervation of the pulmonary
vasculature may increase PVR or decrease the distensibility of
346 SECTION VI Pulmonary Physiology

TABLE 34–1 Passive influences on pulmonary vascular resistance.

Effect on Pulmonary
Cause Vascular Resistance Mechanism

Increased lung volume (above FRC) Increases Lengthening and compression of alveolar vessels

Decreased lung volume (below FRC) Increases Compression of and less traction on
extra-alveolar vessels

Increased pulmonary artery pressure, increased left Decreases Recruitment and distention
atrial pressure, increased pulmonary blood volume,
increased cardiac output

Gravity, body position Decreases in gravity-dependent Hydrostatic effects lead to recruitment and distention
regions of the lungs

Increased (more positive) interstitial pressure Increases Compression of vessels

Increased blood viscosity Increases Viscosity directly increases resistance

Positive-pressure ventilation

Increased alveolar pressure Increases Compression and derecruitment of alveolar vessels

Positive intrapleural pressure Increases Compression of extra-alveolar vessels; compression of

vena cava decreases pulmonary blood flow and leads
to derecruitment
FRC, functional residual capacity.

the larger vessels. Stimulation of the parasympathetic innerva-
tion of the pulmonary vessels generally causes vasodilation.
The catecholamines epinephrine and norepinephrine
both increase PVR when injected into the pulmonary circula-
tion. Histamine, found in the lung in mast cells, is also a
pulmonary vasoconstrictor. Certain prostaglandins and
related substances, such as PGF2α, PGE2, and thromboxane,
are also pulmonary vasoconstrictors, as is endothelin. Alveo-
lar hypoxia and hypercapnia also cause pulmonary vasocon-
striction, as will be discussed later in this chapter.
Acetylcholine, the β-adrenergic agonist isoproterenol, nitric
oxide (NO), and certain prostaglandins, such as PGE1 and
PGI2 (prostacyclin), are pulmonary vasodilators.

TABLE 34–2 Active influences on pulmonary

vascular resistance.
Increase
Stimulation of sympathetic
innervation (may have greater
effect by decreasing large-vessel
distensibility)
Norepinephrine, epinephrine
α-Adrenergic agonists
THE REGIONAL DISTRIBUTION OF
PULMONARY BLOOD FLOW: THE
Decrease ZONES OF THE LUNG
Stimulation of parasympathetic Gravity is another important passive factor affecting local PVR
innervation (if vascular tone is and the relative perfusion of different regions of the lung. The
already elevated)
interaction of the effects of gravity and extravascular pressures
may have a profound influence on the relative perfusion of dif-
Acetylcholine ferent areas of the lung.
β-Adrenergic agonists

PGF2α, PGE2 PGE1 THE REGIONAL DISTRIBUTION

Thromboxane Prostacyclin (PGI2) OF PULMONARY BLOOD FLOW
Endothelin Nitric oxide
If a radioactive substance such as the gas xenon (133Xe) is dis-
Angiotensin Bradykinin
solved in saline and infused into the venous blood, it can be
Histamine (primarily a used to determine regional pulmonary blood flow. The greater
pulmonary venoconstrictor) the radioactivity measured over a specific region, the greater the
Alveolar hypoxia blood flow. A pattern like that shown in Figure 34–6 is observed
Alveolar hypercapnia
in a healthy person seated upright or standing up. There is
greater blood flow per unit volume (per alveolus) to lower
Low pH of mixed venous blood regions of the lung than to upper regions of the lung. Note that
PG, prostaglandin. the test was made with the subject at the total lung capacity.

150
TLC
Blood flow/alveolus ( %)
100
50
bottom rib 2
0 greater than pulmonary artery pressure in the upper parts of
20 15 10 5 0
Lung distance (cm below rib 2)
FIGURE 34–6 Relative blood flow per alveolus (100% =
perfusion of each alveolus if all were perfused equally) versus
distance from the bottom of the lung in a human seated upright.
Measurement of regional blood flow was determined using an
intravenous injection of 133Xe. TLC, total lung capacity. (Modified with
permission from Hughes JM, Glazier JB, Maloney JE, West JB. Effect of lung volume
on the distribution of pulmonary blood flow in man. Respir Physiol. 1968;4(1):58–72.)
If the subject lies down, this pattern of regional perfusion is
altered so that perfusion to the anatomically upper and lower
portions of the lung is roughly evenly distributed, but blood
flow per unit volume is still greater in the more gravity-
dependent regions of the lung. For example, if the subject were
to lie down on the left side, the left lung would receive more
blood flow per unit volume than would the right lung. Exercise,
which increases the cardiac output, increases the blood flow per
unit volume to all regions of the lung, but the perfusion gradi-
ent persists so that there is still relatively greater blood flow per
unit volume in more gravity-dependent regions of the lung.
The reason for this gradient of regional perfusion of the
lung is gravity. The pressure at the bottom of a column of a
liquid is proportional to the height of the column times the
density of the liquid times gravity, so the intravascular pres-
sures in more gravity-dependent portions of the lung are
greater than those in upper regions. Because the pressures are
greater in the more gravity-dependent regions of the lung, the
resistance to blood flow is lower in lower regions of the lung
owing to more recruitment or distention of vessels in these
regions. It is therefore not only gravity, but also the character-
istics of the pulmonary circulation that cause the increased
blood flow to more gravity-dependent regions of the lung.
After all, the same hydrostatic effects occur to an even greater
extent in the systemic circulation, but the thick walls of the
systemic arteries are not affected.
There is also considerable heterogeneity in pulmonary
blood flow at any vertical distance up the lung, that is, there
may be significant variations in pulmonary blood flow within
a given horizontal plane of the lung. These variations are
caused by local factors and mechanical stresses.
CHAPTER 34 Pulmonary Perfusion 347
THE INTERACTION OF GRAVITY
AND EXTRAVASCULAR PRESSURE:
THE ZONES OF THE LUNG
When the pulmonary artery pressure is low, the uppermost
regions of the lung receive no blood flow. Perfusion of the lung
ceases at the point at which alveolar pressure (PA) is just equal
to pulmonary artery pressure (Pa). Above this point, there is
no perfusion because alveolar pressure exceeds pulmonary
artery pressure, and the transmural pressure across capillary
walls is negative. Below this point, perfusion per unit volume
increases steadily with increased distance down the lung.
Thus, under circumstances in which alveolar pressure is
the lung, no blood flow occurs in that region, and the region is
referred to as being in zone 1, as shown in Figure 34–7. (Note
that in this figure blood flow is on the x-axis and that distance
up the lung is on the y-axis.) Any zone 1, then, is alveoli that
are ventilated but not perfused. It is alveolar dead space. For-
tunately, during normal, quiet breathing in a person with a
normal cardiac output, pulmonary artery pressure, even in the
uppermost regions of the lung, is greater than alveolar pres-
sure, so there is no zone 1.
The lower portion of the lung in Figure 34–7 is said to be in
zone 3. In this region, the pulmonary artery pressure and the
pulmonary vein pressure (Pv) are both greater than alveolar
pressure. The driving pressure (ΔP) for blood flow through the
lung in this region is pulmonary artery pressure minus pulmo-
nary vein pressure. Note that this driving pressure stays con-
stant as one moves further down the lung in zone 3 because
the hydrostatic pressure effects are the same for both the arter-
ies and the veins.
Zone 1
PA>Pa>Pv
Zone 2
PA Pa>PA>Pv
Pa Pv
Distance
Zone 3
Pa>Pv>PA
Blood flow
FIGURE 34–7 The zones of the lung. The effects of gravity
and alveolar pressure on the perfusion of the lung. Described in text.
(Modified with permission from West, J.B., Dollery, C.T., Naimark, A.: Distribution of
blood flow in isolated lung: Relation to vascular and alveolar pressures. J Appl
Physiol 1964;19:713–724.)
348 SECTION VI Pulmonary Physiology
The middle portion of the lung in Figure 34–7 is in zone
2. In zone 2, pulmonary artery pressure is greater than alve-
olar pressure, so blood flow does occur. Nevertheless,
because alveolar pressure is greater than pulmonary vein
pressure, the effective driving pressure for blood flow is pul-
monary artery pressure minus alveolar pressure in zone 2.
(This is analogous to the situation described in Chapter 32:
during a forced expiration, the driving pressure for airflow
is equal to alveolar pressure minus intrapleural pressure.)
Notice that in zone 2 (at right in Figure 34–7), the increase
in blood flow per distance down the lung is greater than it is
in zone 3. This is because the upstream driving pressure, the
pulmonary artery pressure, increases according to the
hydrostatic pressure increase, but the effective downstream
pressure, alveolar pressure, is constant throughout the lung
at any instant.
To summarize: in zone 1, PA > Pa > Pv , and there is no blood
flow; in zone 2, Pa > PA > Pv, and the effective driving pressure
for blood flow is Pa – PA; in zone 3, Pa > Pv > PA, and the driving
pressure for blood flow is Pa – Pv.
It is important to realize that the boundaries between the
zones are dependent on physiologic conditions—they are not
fixed anatomic landmarks. Alveolar pressure changes during
the course of each breath. During eupneic breathing these
changes are only a few centimeters of water, but they may be
much greater during speech, exercise, and other conditions. A
patient on a positive-pressure ventilator with positive end-
expiratory pressure (PEEP) may have substantial amounts of
zone 1 because alveolar pressure is always high. After a hemor-
rhage or during general anesthesia, pulmonary blood flow and
pulmonary artery pressure are low and zone 1 conditions are
also likely. During exercise, cardiac output and pulmonary
artery pressure increase and any existing zone 1 will be
recruited to zone 2. The boundary between zones 2 and 3 will
move upward as well. Changes in lung volume also affect the
regional distribution of pulmonary blood flow and will there-
fore affect the boundaries between zones. Finally, changes in
body position alter the orientation of the zones with respect to
the anatomic locations in the lung, but the same relationships
exist with respect to gravity and alveolar pressure.
HYPOXIC PULMONARY
VASOCONSTRICTION
Alveolar hypoxia (low alveolar Po2) or atelectasis (collapsed
alveoli) causes an active vasoconstriction in the pulmonary circu-
lation. The site of vascular smooth muscle constriction appears to
be in the arterial (precapillary) vessels very close to the alveoli.
The mechanism of hypoxic pulmonary vasoconstriction is
not completely understood. The response occurs locally, that
is, only in the area of the alveolar hypoxia. Connections to the
central nervous system are not necessary. Hypoxia may act
directly on pulmonary vascular smooth muscle to produce
hypoxic pulmonary vasoconstriction. Hypoxia inhibits an
outward potassium current, which causes pulmonary vascular
smooth muscle cells to depolarize, allowing calcium to enter
the cells. This, in turn, causes them to contract.
The hypoxic pulmonary vasoconstriction response is
graded—constriction begins to occur at alveolar Po2’s of
approximately 100 mm Hg and increases until PAo2 decreases
to about 20–30 mm Hg.
If an area of the lung becomes hypoxic because of airway
obstruction or if localized atelectasis occurs, any mixed venous
blood flowing to that area will undergo little or no gas exchange
(Figure 34–8) and will mix with blood draining well-ventilated
areas of the lung as it enters the left atrium. This mixing will
lower the overall arterial Po2. The hypoxic pulmonary vasocon-
striction diverts mixed venous blood flow away from poorly
ventilated areas of the lung by locally increasing vascular resis-
tance, as shown in Figure 34–8C. Therefore, mixed venous blood
is sent to better-ventilated areas of the lung (Figure 34–8D). The
problem with hypoxic pulmonary vasoconstriction is that it is
not a very strong response because there is so little smooth mus-
cle in the pulmonary vasculature. Very high pulmonary artery
pressures can interfere with hypoxic pulmonary vasoconstric-
tion, as can other physiologic disturbances, such as alkalosis.
In hypoxia of the whole lung, such as might be encountered
at high altitude or in hypoventilation, hypoxic pulmonary
vasoconstriction occurs throughout the lung. Even this may be
useful in increasing gas exchange because greatly increasing
the pulmonary artery pressure recruits previously unperfused
pulmonary capillaries. This increases the surface area available
for gas diffusion and improves the matching of ventilation and
perfusion, as will be discussed in the next chapter. On the other
hand, such a whole-lung hypoxic pulmonary vasoconstriction
increases the workload on the right ventricle, and the high pul-
monary artery pressure may overwhelm hypoxic pulmonary
vasoconstriction in some parts of the lung, increase the capil-
lary hydrostatic pressure in those vessels, and lead to pulmo-
nary edema (see the next section of this chapter).
Alveolar hypercapnia (increased carbon dioxide) also
causes pulmonary vasoconstriction. Note that both hypoxic
and hypercapnic pulmonary vasoconstriction are opposite to
what occurs in the systemic circulation.
PULMONARY EDEMA
Pulmonary edema is the extravascular accumulation of fluid
in the lung. This pathologic condition may be caused by one or
more physiologic abnormalities, but the result is inevitably
impaired gas transfer. As the edema fluid builds up, first in the
interstitium and later in alveoli, diffusion of gases—particularly
oxygen—decreases.
The capillary endothelium is much more permeable to water
and solutes than is the alveolar epithelium. Edema fluid there-
fore accumulates in the interstitium before it accumulates in
the alveoli.
As discussed in Chapter 26, the Starling equation describes
the movement of liquid across the capillary endothelium:
Q̇f = Kf [(Pc – Pis) – σ(πpl – πis)] (1)
 CHAPTER 34 Pulmonary Perfusion 349

O2 ⴝ 150 mm Hg O2 ⴝ 150 mm Hg
CO2 ⴝ 0 mm Hg CO2 ⴝ 0 mm Hg

O2 ⴝ 100 mm Hg Decreased O2
CO2 ⴝ 40 mm Hg Increased CO2

O2 ⴝ 40 mm Hg O2 ⴝ 100 mm Hg O2 ⴝ 40 mm Hg Decreased O2
CO2 ⴝ 45 mm Hg CO2 ⴝ 40 mm Hg CO2 ⴝ 45 mm Hg Increased CO2

A C

O2 ⴝ 150 mm Hg
CO2 ⴝ 0 mm Hg

O2 ⴝ 100 mm Hg Decreased O2
CO2 ⴝ 40 mm Hg Increased CO2
Decreased O2
Increased CO2

O2 ⴝ 40 mm Hg Decreased O2
CO2 ⴝ 45 mm Hg Increased CO2

B D
FIGURE 34–8 Illustration of the physiologic function of hypoxic pulmonary vasoconstriction (HPV). A) Normal alveolar–capillary
unit. B) Perfusion of a hypoventilated alveolus results in blood with a decreased Po and an increased Pco entering the left atrium. C) HPV
2 2
increases the resistance to blood flow to the hypoventilated alveolus. D) This diverts blood flow away from the hypoventilated alveolus to
better-ventilated alveoli, thus helping to maintainV̇/Q̇ matching. HPV, hypoxic pulmonary vasoconstriction; V̇/Q̇ = ventilation–perfusion ratio.
(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

where Q̇f is the net flow of fluid, Kf the capillary filtration
coefficient (this describes the permeability characteristics of
the membrane to fluids), Pc the capillary hydrostatic pres-
sure, Pis the hydrostatic pressure of the interstitial fluid, σ the
reflection coefficient (this describes the ability of the mem-
brane to prevent extravasation of solute particles), πpl the col-
loid osmotic (oncotic) pressure of the plasma, and πis the
colloid osmotic pressure of the interstitial fluid.
The components of the Starling equation are very useful in
understanding the potential causes of pulmonary edema, even
though only the plasma colloid osmotic pressure (πpl) can be
measured clinically.
CONDITIONS THAT MAY LEAD
TO PULMONARY EDEMA
Infections, circulating or inhaled toxins, oxygen toxicity, and
other factors that destroy the integrity of the capillary endothe-
lium and increase its permeability lead to localized or general-
ized pulmonary edema.
The pulmonary capillary hydrostatic pressure is estimated
to be about 10 mm Hg under normal conditions. If the capil-
lary hydrostatic pressure increases dramatically, the filtration
of fluid across the capillary endothelium will increase greatly,
and enough fluid may leave the capillaries to exceed the lym-
phatic drainage. The pulmonary capillary hydrostatic pressure
often increases as a result of problems in the left side of the
circulation, such as infarction of the left ventricle, left ventricu-
lar failure, or mitral stenosis. As left atrial pressure and pulmo-
nary venous pressure increase because of accumulating blood,
the pulmonary capillary hydrostatic pressure also increases.
Other causes of increased pulmonary capillary hydrostatic
pressure include overzealous administration of intravenous
fluids and diseases that occlude the pulmonary veins.
The interstitial hydrostatic pressure of the lung is in the
range of –5 to –7 mm Hg when a healthy person is at FRC.
Conditions that would decrease (i.e., make it more negative)
the interstitial pressure would increase the tendency for pul-
monary edema to develop. These appear to be limited mainly
to potential actions of the health care worker, such as rapid
evacuation of chest fluids or treatment of a pneumothorax.
Situations that increase alveolar surface tension, for example,
when decreased amounts of pulmonary surfactant are present,
could also make the interstitial hydrostatic pressure more neg-
ative and increase the tendency for the formation of pulmo-
nary edema. Note that as fluid accumulates in the interstitium,
the interstitial hydrostatic pressure increases, which helps
limit further fluid extravasation.
Any situation that permits more solute to leave the capillar-
ies, such as a decreased reflection coefficient, will lead to more
fluid movement out of the vascular space.
350 SECTION VI Pulmonary Physiology
Decreases in the colloid osmotic pressure of the plasma,
which helps retain fluid in the capillaries, may lead to pulmo-
nary edema. Plasma colloid osmotic pressure, normally in the
range of 25–28 mm Hg, decreases with low plasma protein
concentration or overadministration of certain intravenous
solutions. On the other hand, increased colloid osmotic pres-
sure in the interstitium will pull fluid from the capillaries.
Any fluid that makes its way into the pulmonary intersti-
tium must be removed by the lymphatic drainage of the lung.
The volume of lymph flow from the human lung is capable of
increasing as much as 10-fold under pathologic conditions. It
is only when this large safety factor is overwhelmed that pul-
monary edema occurs. Conditions that block the lymphatic
drainage of the lung, such as tumors or scars, may predispose
patients to pulmonary edema.
Pulmonary edema can be associated with head injury, her-
oin overdose, and high altitude. The causes of the edema for-
mation in these conditions are not known, although
high-altitude pulmonary edema may be caused by high pul-
monary artery pressures secondary to the hypoxic pulmonary
vasoconstriction.
NONRESPIRATORY FUNCTIONS OF
THE PULMONARY CIRCULATION
The pulmonary circulation, strategically located between the
systemic veins and arteries, is well suited for several functions
not directly related to gas exchange. The entire cardiac output
passes over the very large surface area of the pulmonary capil-
lary bed, allowing the lungs to act as a site of blood filtration
and storage, as well as for the metabolism of vasoactive con-
stituents of the blood, as was discussed in Chapter 31.
A typical adult male has a pulmonary blood volume of about
500 mL, which allows the pulmonary circulation to act as a
reservoir for the left ventricle. If left ventricular output is tran-
siently greater than systemic venous return, left ventricular
output can be maintained for a few strokes by drawing on
blood stored in the pulmonary circulation.
Because virtually all mixed venous blood must pass through
the pulmonary capillaries, the pulmonary circulation acts as a
filter, protecting the systemic circulation from materials that
enter the blood. The particles filtered, which may enter the
circulation as a result of natural processes, trauma, or thera-
peutic measures, may include small fibrin or blood clots, fat
cells, bone marrow, detached cancer cells, gas bubbles, aggluti-
nated erythrocytes (especially in sickle cell disease), masses of
platelets or leukocytes, and debris from stored blood or intra-
venous solutions. If these particles were to enter the arterial
side of the systemic circulation, they might occlude vascular
beds with no other source of blood flow. This occlusion would
be particularly disastrous if it occurred in the blood supply to
the central nervous system or the heart.
The lung can perform this very valuable service because
there are many more pulmonary capillaries present in the lung
than are necessary for gas exchange at rest: previously
unopened capillaries will be recruited. Obviously, no gas
exchange can occur distal to a particle embedded in and
obstructing a capillary, so this mechanism is limited by the
ability of the lung to remove such filtered material. If particles
are experimentally suspended in venous blood and are then
trapped in the pulmonary circulation, the diffusing capacity
(see Chapter 35) usually decreases for 4–5 days and then
returns to normal. The mechanisms for removal of material
trapped in the pulmonary capillary bed include lytic enzymes
in the vascular endothelium, ingestion by macrophages, and
penetration to the lymphatic system. Patients on cardiopul-
monary bypass do not have the benefit of this pulmonary cap-
illary filtration, and blood administered to these patients must
be filtered for them.
The colloid osmotic pressure of the plasma proteins nor-
mally exceeds the pulmonary capillary hydrostatic pressure.
This tends to pull fluid from the alveoli into the pulmonary
capillaries and keep the alveolar surface free of liquids other
than pulmonary surfactant. Water taken into the lungs is rap-
idly absorbed into the blood. This protects the gas exchange
function of the lungs and opposes transudation of fluid from
the capillaries to the alveoli. As noted in Chapter 31, type II
alveolar epithelial cells may also actively pump sodium and
water from the alveolar surface into the interstitium.
Drugs or chemical substances that readily pass through the
alveolar–capillary barrier by diffusion or by other means rap-
idly enter the systemic circulation. The lungs are frequently
used as a route of administration of drugs and for anesthetic
gases, such as halothane and nitrous oxide. Aerosolized drugs
intended for the airways only, such as the bronchodilator iso-
proterenol and anti-inflammatory corticosteroids, may rap-
idly pass into the systemic circulation, where they may have
clinically significant effects. The effects of isoproterenol, for
example, could include cardiac stimulation and vasodilation.
CLINICAL CORRELATION
A 60-year-old man who had a left ventricular myocardial
infarction 3 months ago returns to the cardiologist
because of dyspnea on exertion but not at rest, a cough
productive of frothy fluid after exercise, and orthopnea
(easier breathing in the upright than recumbent posi-
tion). At rest, his heart rate is 105/min, blood pressure is
120/90 mm Hg, and his respiratory rate is increased at
20/min. His chest radiograph shows evidence of edema in
gravity-dependent lung regions.
The patient does not have dyspnea (the feeling of diffi-
cult breathing or “shortness of breath”) at rest and his
blood pressure is within the normal range. His heart rate
at rest is slightly above the normal range (50–100/min;
tachycardia) and his respiratory rate is high (normally
12–15/min; tachypnea). He does have orthopnea.

He had a left ventricular myocardial infarction 3 months
ago and the damaged heart muscle has been replaced with
scar tissue that cannot contract. Although his left ventri-
cle can generate a sufficient stroke volume at rest, it can-
not match the increased right ventricular output during
exercise, leading to increased left atrial pressure. Because
there are no valves between the left atrium and the pul-
monary veins and capillaries, pulmonary capillary hydro-
static pressure increases. Filtration of fluid from the
capillaries into the pulmonary interstitium increases suf-
ficiently to exceed the ability of the pulmonary lymphatic
drainage to remove it, resulting in interstitial edema and
then alveolar edema.
The dyspnea results from several factors. Pulmonary
vascular congestion (excess blood in the pulmonary
blood vessels) decreases the compliance of the lungs.
Interstitial and alveolar edema increases the alveolar–
capillary barrier for gas diffusion. This is particularly a
problem for oxygen diffusion, as will be discussed in the
next chapter. Stretch receptors in the pulmonary circula-
tion respond to pulmonary vascular congestion and the
arterial chemoreceptors respond to low arterial Po2, both
contributing to the sensation of dyspnea, as will be dis-
cussed in Chapter 38. He breathes more easily in the
upright position because the edema fluid collects in lower
regions of the lungs, allowing better gas exchange in upper
parts of the lungs.
CHAPTER SUMMARY
■ Compared with the systemic arteries, the pulmonary arteries
have much less vascular smooth muscle and therefore offer
much less resistance to blood flow. Pulmonary arteries are
more distensible, and because their intravascular pressures are
lower, more compressible than systemic arteries. The vascular
transmural pressure gradient is therefore an important
determinant of PVR.
■ Although pulmonary vascular smooth muscle can actively
contract or relax in response to neural and humoral influences,
passive factors play a more important role in determining PVR
than they do in determining SVR.
■ PVR is usually lowest at the functional residual capacity and
increases at higher and at lower lung volumes.
■ PVR usually decreases with increases in pulmonary blood flow,
pulmonary artery pressure, left atrial pressure, or pulmonary
capillary blood volume because of distention of already open
blood vessels, recruitment of previously unopened vessels, or
both.
CHAPTER 34 Pulmonary Perfusion 351
■ There is more blood flow in lower regions of the lung than
in upper regions. The effects of pulmonary artery pressure,
pulmonary vein pressure, and alveolar pressure on pulmonary
blood flow are described as the zones of the lung.
■ Alveolar hypoxia can cause constriction of precapillary
pulmonary vessels, diverting blood flow away from poorly
ventilated or unventilated alveoli.
STUDY QUESTIONS
1. Compared to the systemic circulation, the pulmonary circulation
has
A) greater arterial pressure.
B) less distensible vessels.
C) a more evenly distributed vascular resistance to blood flow
among its arteries, capillaries, and veins.
D) greater control of vascular resistance by the autonomic
nervous system.
E) greater total vascular resistance.
2. Which of the following would likely increase pulmonary vascular
resistance?
A) inhaling from the FRC to the TLC
B) exhaling from the FRC to the RV
C) breathing 10% O2–90% N2 for 10 minutes
D) decreasing the cardiac output from 5 to 2.5 L/min
E) all of the above
3. In zone 2 of the lung
A) alveolar pressure > pulmonary arterial pressure > pulmo-
nary venous pressure.
B) pulmonary arterial pressure > alveolar pressure > pulmo-
nary venous pressure.
C) pulmonary arterial pressure > pulmonary venous pressure >
alveolar pressure.
D) the effective pressure gradient for blood flow is pulmonary
arterial pressure minus pulmonary venous pressure.
E) there is no blood flow.
4. Compared to the pulmonary circulation, the bronchial
circulation has
A) more total blood flow.
B) higher mean arterial pressure.
C) more distensible arteries.
D) more even distribution of vascular resistance among
the arteries, capillaries, and veins.
E) lower arterial Po2.
5. Which of the following is least likely to cause pulmonary edema?
A) mitral stenosis
B) two liters of rapidly administered intravenous saline
solution
C) increased left atrial pressure
D) rapid administration of very negative intrapleural pressure
to alleviate a pneumothorax
E) positive pressure ventilation
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 35
C H A P T E R

Ventilation–Perfusion
Relationships and
Respiratory Gas Exchange
Michael Levitzky

O B J E C T I V E S

■ Predict the consequences of mismatched ventilation and perfusion.

■ Explain the regional differences in the matching of ventilation and perfusion
of the normal upright lung.
■ Predict the consequences of the regional differences in the ventilation and
perfusion of the normal upright lung.
■ Define diffusion, and distinguish it from bulk flow.
■ State Fick’s law for diffusion.
■ Distinguish between perfusion limitation and diffusion limitation of gas
transfer in the lung.
■ Describe the diffusion of oxygen from the alveoli into the blood, and carbon
dioxide from the blood to the alveoli.
■ Define the diffusing capacity and discuss its measurement.

Alveolar ventilation and pulmonary perfusion have been dis-
cussed in the previous chapters in this section. The respiratory
gases must diffuse through the alveolar–capillary barrier for
gas exchange to occur. For optimal diffusion, the alveolar ven-
tilation must be matched to the pulmonary perfusion.
0.8–1.2. However, ventilation and perfusion must be matched
on the alveolar–capillary level for optimal gas exchange
to occur and the V· /Q· for the whole lung is really of interest
only as an approximation of the situation in all the alveolar–
capillary units of the lung.

CONSEQUENCES OF HIGH AND LOW

VENTILATION–PERFUSION
RELATIONSHIPS
Alveolar ventilation brings oxygen into the lung and removes
carbon dioxide from it. Similarly, the mixed venous blood
brings carbon dioxide into the lung and takes up alveolar oxy-
gen. The alveolar Po2 and Pco2 are thus determined by the rela-
tionship between alveolar ventilation and perfusion.
Alterations in the ratio of ventilation to perfusion, called the
V·a /Q· c for alveolar ventilation/pulmonary capillary blood flow
(or just V· /Q· ), will result in changes in the alveolar Po2 and Pco2,
as well as in gas delivery to or removal from the lung.
Alveolar ventilation is normally about 4–6 L/min and pul-
monary blood flow (which is equal to cardiac output) has a
similar range, so the V· /Q· for the whole lung is in the range of
VENTILATION–PERFUSION RATIOS
Oxygen is delivered to the alveolus by alveolar ventilation, is
removed from the alveolus as it diffuses into the pulmonary
capillary blood, and is carried away by blood flow. Similarly,
carbon dioxide is delivered to the alveolus in the mixed venous
blood and diffuses into the alveolus in the pulmonary capillary.
It is removed from the alveolus by alveolar ventilation. As will
be discussed later in this chapter, at resting cardiac outputs, the
diffusion of both oxygen and carbon dioxide is normally lim-
ited by pulmonary perfusion. The alveolar partial pressures of
both oxygen and carbon dioxide are therefore determined by
the V· /Q· . If the V· /Q· in an alveolar–capillary unit increases, the
delivery of oxygen relative to its removal will increase, as will
the removal of carbon dioxide relative to its delivery. Alveolar

353

Ch35_353-362.indd 353 11/29/10 4:39:10 PM

354 SECTION VI Pulmonary Physiology

O2  150 mm Hg O2  150 mm Hg
CO2  0 mm Hg CO2  0 mm Hg
B. A. C.

O2  40 mm Hg O2  100 mm Hg O2  150 mm Hg
CO2  45 mm Hg CO2  40 mm Hg CO2  0 mm Hg

O2  40 mm Hg O2  40 mm Hg O2  40 mm Hg O2  100 mm Hg
CO2  45 mm Hg CO2  45 mm Hg CO2  45 mm Hg CO2  40 mm Hg

Mixed venous blood Inspired air

0 Decreasing VA/QC Normal Increasing VA/QC 
· · · ·
FIGURE 35–1 The effect of changes in the ventilation–perfusion ratio on the alveolar PO2 and PCO2. A) Normal VA / QC. B) VA / QC = 0.
· ·
C) VA / QC is infinite. Curved arrows denote direction of blood flow. (Modified with permission from West JB. Ventilation/Blood Flow and Gas Exchange. 5th ed.
Oxford: Blackwell; 1990.)

Po2 will therefore increase, and alveolar Pco2 will decrease. If the Units B and C represent the two extremes of a continuum of
V·/Q· in an alveolar–capillary unit decreases, the removal of oxy- ventilation–perfusion ratios. The V· /Q· ratio of a particular
gen relative to its delivery will increase and the delivery of car- alveolar–capillary unit can fall anywhere along this continuum,
bon dioxide relative to its removal will increase. Alveolar Po2 as shown at the bottom of Figure 35–1. The alveolar Po2 and Pco2
will therefore decrease, and alveolar Pco2 will increase. of such units will therefore fall between the two extremes
Figure 35–1 shows the consequences of alterations in the rela- shown in the figure: units with low V· /Q· ratios will have rela-
tionship of ventilation and perfusion on hypothetical alveolar– tively low Po2 and high Pco2; units with high V·/Q· ratios will have
capillary units. Unit A has a normal V·/Q· . Inspired air enters the relatively high Po2 and low Pco2. This is demonstrated graphi-
alveolus with a Po2 of about 150 mm Hg and a Pco2 of nearly 0 mm
Hg. Mixed venous blood enters the pulmonary capillary with a
Po2 of about 40 mm Hg and a Pco2 of about 45 mm Hg. This results
• •
in an alveolar Po2 of about 100 mm Hg and an alveolar Pco2 of 40 Shunt [V/Q = 0]
mm Hg. The partial pressure gradient for oxygen diffusion from Alveolar PO2 = Venous PO2 = 40
alveolus to pulmonary capillary is thus about 100 – 40, or 60 mm 50 • •
Decreasing V/Q
Hg; the partial pressure gradient for CO2 diffusion from pulmo- Normal values
nary capillary to alveolus is about 45 – 40, or 5 mm Hg. PO2 = 100
40 PCO2 = 40
The airway supplying unit B has become completely
occluded. Its V· /Q· is zero. As time goes on, the air trapped in
Alveolar PCO2 (mm Hg)

the alveolus equilibrates by diffusion with the gas dissolved in 30

the mixed venous blood entering the alveolar–capillary unit.
No gas exchange can occur, and any blood perfusing this alve- Increasing
• •
20 V/Q
olus will leave it exactly as it entered it. Unit B is therefore act-
ing as a right-to-left shunt.
The blood flow to unit C is blocked by a pulmonary embolus, 10 • •
and unit C is therefore completely unperfused. It has an infinite Deadspace [V/Q = ∞]
V·/Q· . Because no oxygen can diffuse from the alveolus into pul- Alveolar PO2 = inspired PO2 = 150
monary capillary blood and because no carbon dioxide can enter 0
0 10 20 30 40 50 60 70 80 90 100 110120 130 140 150
the alveolus from the blood, the Po2 of the alveolus is approxi-
Alveolar PO2 (mm Hg)
mately 150 mm Hg and its Pco2 is approximately zero; that is, the
gas composition of this unperfused alveolus is the same as that of FIGURE 35–2 The ventilation–perfusion ratio line on an
inspired air. Unit C is alveolar dead space. If unit C were unper- · ·
O2–CO2 diagram. Unit with a VA / QC of zero has the PO2 and PCO2 of
fused because its alveolar pressure exceeded its precapillary pres- · ·
mixed venous blood; a unit with an infinite VA / QC has the PO2 and PCO2
sure (rather than because of an embolus), then it would also of inspired air. (Reproduced with permission from Kibble J, Halsey CR: The Big
correspond to part of zone 1, as discussed in Chapter 34. Picture, Medical Physiology. New York: McGraw-Hill, 2009.)
 CHAPTER 35 Ventilation–Perfusion Relationships and Respiratory Gas Exchange
cally in an O2–CO2 diagram such as that seen in Figure 35–2.
The diagram shows the results of mathematical calculations of
alveolar Po2 and Pco2 for V· /Q· ratios between zero (for mixed
venous blood) and infinity (for inspired air). The resulting
curve is known as the ventilation–perfusion ratio line. This
simple O2–CO2 diagram can be modified to include correction
lines for other factors, such as the respiratory exchange ratios
of the alveoli and the blood or the dead space. The position of
the V· /Q· ratio line is altered if the partial pressures of the
inspired gas or mixed venous blood are altered.
TESTING FOR MISMATCHED
VENTILATION & PERFUSION
Several methods can demonstrate the presence or location of
areas of the lung with mismatched ventilation and perfusion.
These methods include calculations of the physiologic shunt,
and the physiologic dead space, differences between the alveo-
lar and arterial Po2 and Pco2, and lung scans after inhaled and
intravenously administered 133Xe or 99mTc.
Physiologic Shunts and
the Shunt Equation
A right-to-left shunt is the mixing of venous blood that has
not been oxygenated (or not fully oxygenated) into the arterial
blood. The physiologic shunt, which corresponds to the phys-
iologic dead space, consists of the anatomic shunts plus the
intrapulmonary shunts. The intrapulmonary shunts can be
absolute shunts, or they can be “shuntlike states,” that is, areas
of low ventilation–perfusion ratios in which alveoli are under-
ventilated and/or overperfused. Anatomic shunts consist of
systemic venous blood entering the left ventricle without hav-
ing entered the pulmonary vasculature. In a healthy adult,
about 2–5% of the cardiac output, including venous blood from
the bronchial veins, the thebesian veins, and the pleural veins,
enters the left side of the circulation directly without passing
through the pulmonary capillaries. Pathologic anatomic
shunts such as right-to-left intracardiac shunts can also occur.
Mixed venous blood perfusing pulmonary capillaries associ-
ated with totally unventilated or collapsed alveoli constitutes an
absolute shunt (like the anatomic shunts) because no gas
exchange occurs as the blood passes through the lung. Alveolar–
capillary units with low V·a / Q·c also act to lower the arterial oxy-
gen content because blood draining these units has a lower Po2
than blood from units with well-matched ventilation and perfu-
sion. Increasing the percentage of inspired oxygen (FIO2) does
not significantly increase the arterial Po2 of patients with absolute
intrapulmonary shunts or “shuntlike areas” because the pulmo-
nary capillary blood that flows to unventilated or very poorly
ventilated alveoli is not exposed to alveolar air.
The shunt equation conceptually divides all alveolar–
capillary units into two groups: those with well-matched
ventilation and perfusion and those with ventilation–
perfusion ratios of zero. Thus, the shunt equation combines
355
the areas of absolute shunt (including the anatomic shunts)
and the shuntlike areas into a single conceptual group. The
resulting ratio of shunt flow to the cardiac output, often
referred to as the venous admixture, is the part of the car-
diac output that would have to be perfusing absolutely
unventilated alveoli to cause the systemic arterial oxygen
content obtained from a patient. A much larger portion of
the cardiac output could be overperfusing poorly ventilated
alveoli and yields the same ratio:
Q· s _______
__ Ccʹ –Ca
= o2 o2 (1)
Q· t Ccʹo2 –C –V o2
where Q·t represents the total pulmonary blood flow per minute
(i.e., the cardiac output), Q· S represents the amount of blood flow
per minute entering the systemic arterial blood without receiv-
ing any oxygen (the “shunt flow”), Cao2 equals oxygen content
of arterial blood (see Chapter 36) in milliliters of oxygen per
100 mL of blood, and C–V o and Ccʹo equal the oxygen content of
2 2
the mixed venous blood and the end-capillary oxygen content
(the oxygen content in the blood at the end of the ventilated and
perfused pulmonary capillaries), respectively.
The shunt fraction is usually multiplied by 100% so that the
shunt flow is expressed as a percentage of the cardiac output.
The arterial and mixed venous oxygen contents can be
determined if blood samples are obtained from a systemic
artery and from the pulmonary artery (for mixed venous
blood), but the oxygen content of the blood at the end of the
pulmonary capillaries with well-matched ventilation and per-
fusion is, of course, impossible to measure directly. This must
be calculated from the alveolar air equation and the patient’s
hemoglobin concentration.
Physiologic Dead Space
The use of the Bohr equation to determine the physiologic
dead space was discussed in Chapter 33. If the anatomic dead
space is subtracted from the physiologic dead space, the result
(if there is a difference) is alveolar dead space, or areas of infi-
nite V· /Q·. Alveolar dead space also results in an arterial–
alveolar CO2 difference (or arterial–end-tidal CO2
difference), that is, the end-tidal Pco2 is normally equal to the
arterial Pco2. An arterial Pco2 greater than the end-tidal Pco2 usu-
ally indicates the presence of alveolar dead space.
ALVEOLAR–ARTERIAL
OXYGEN DIFFERENCE
The alveolar and arterial Po2 are often treated as though they are
equal. However, the arterial Po2 is usually a few mm Hg less than
the alveolar Do2. This normal alveolar–arterial oxygen differ-
ence, the (A –a)Do2, is caused by the normal anatomic shunt,
some degree of ventilation–perfusion mismatch (see later in
this chapter), and diffusion limitation in some parts of the lung.
Of these, V· /Q· mismatch is usually the most important, with a
small contribution from shunts and very little from diffusion
356 SECTION VI Pulmonary Physiology

TABLE 35–1 Causes of increased alveolar–arterial average alveolar Po2 that represents what alveolar Po2 should be,
oxygen difference. not necessarily what it is.

Increased right-to-left shunt

Anatomic
Intrapulmonary
Increased ventilation–perfusion mismatch
Impaired diffusion
Increased inspired partial pressure of oxygen
Decreased mixed venous partial pressure of oxygen
Shift of oxyhemoglobin dissociation curve
Adapted with permission from Marshall BE, Wyche MQ, Jr. Hypoxemia during and
after anesthesia. Anesthesiology. 1972;37(2):178–209.
limitation. Larger-than-normal differences between the alveolar
and arterial Po2 may indicate significant ventilation–perfusion
mismatch; however, increased alveolar–arterial oxygen differ-
ences (Table 35–1) can also be caused by anatomic or intrapul-
monary shunts, diffusion block, low mixed venous Po2, breathing
higher-than-normal oxygen concentrations, or shifts of the
oxyhemoglobin dissociation curve (also see Table 37–7).
The alveolar–arterial Po2 difference is normally about 5–15
mm Hg in a young healthy person breathing room air at sea
level. It increases with age because of the progressive decrease
in arterial Po2 that occurs with aging (Chapter 73). The normal
alveolar–arterial Po2 difference increases by about 20 mm Hg
between the ages of 20 and 70.
Note that the “alveolar” Po2 used in determining the alveo-
lar–arterial oxygen difference is the PAo calculated using the
2
alveolar air equation. As noted in Chapter 33, it is an idealized
REGIONAL DIFFERENCES IN
VENTILATION–PERFUSION
RATIOS AND THEIR
CONSEQUENCES
The regional variations in ventilation in the normal upright
lung were discussed in Chapter 33. They are summarized on
the left side of Figure 35–3. The right side of Figure 35–3 shows
that the more gravity-dependent regions of the lung also
receive more blood flow per unit volume than do the upper
regions of the lung, as discussed in Chapter 34.
REGIONAL DIFFERENCES IN THE
VENTILATION–PERFUSION RATIOS
IN THE UPRIGHT LUNG
Simplified graphs of the gradients of ventilation and perfusion
from the bottom to the top of normal upright lungs are shown
plotted on the same axes in Figure 35–4. The ventilation–
perfusion ratio was then calculated for several locations.
Figure 35–4 shows that even though the lower regions of the
lung receive both better ventilation and better perfusion than
do the upper portions of the lung, the gradient of perfusion
from the bottom of the lung to the top is greater than the gra-
dient of ventilation. Because of this, the ventilation–perfusion

Ventilation Perfusion
Intrapleural pressure Lower intravascular
more negative pressures
Greater transmural Less recruitment,
pressure gradient distention
Alveoli larger, less Higher resistance
compliant Less blood flow
Less ventilation

Intrapleural pressure Greater vascular

FIGURE 35–3 Summary of regional less negative
Smaller transmural
pressures
More recruitment,
differences in ventilation (left) and perfusion pressure gradient distention
(right) in the normal upright lung. (Modified with Alveoli smaller, more Lower resistance
permission from Levitzky MG: Pulmonary Physiology, 7th ed. compliant Greater blood flow
New York: McGraw-Hill Medical, 2007.) More ventilation
 CHAPTER 35 Ventilation–Perfusion Relationships and Respiratory Gas Exchange
3.0
• •
V/Q
Perfusion
2.0
V/Q ratio
Ventilation
• •
1.0
• •
Low V/Q
physiologic
at lung P(A–a)O2 gradient
bases
0
Base Distance up
the lung
(from base to apex)
FIGURE 35–4 Distribution of ventilation and perfusion and
ventilation–perfusion ratio down the upright lung. (Reproduced with
permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York:
McGraw-Hill, 2009.)
ratio is relatively low in more gravity-dependent regions of the
lung and higher in upper regions of the lung. The effects of the
regional differences in V· /Q· on the alveolar Po2 and Pco2 can
be predicted from Figure 35–2: the upper regions should have
a relatively high Po2 and a low Pco2; the lower regions should
have a relatively low Po2 and a high Pco2.
This means that the oxygen content of the blood draining the
upper regions is higher and the carbon dioxide content is lower
than that of the blood draining the lower regions. However,
these contents are based on milliliters of blood (see Chapter 36),
and there is much less blood flow to the uppermost sections
than there is to the bottom sections. Therefore, even though the
uppermost sections have the highest V·/Q· and Po2 and the lowest
Pco2, there is more gas exchange in the more basal sections.
DIFFUSION OF GASES
Diffusion of a gas occurs when there is a net movement of
molecules from an area in which that particular gas exerts a
high partial pressure to an area in which it exerts a lower par-
tial pressure. Movement of a gas by diffusion is therefore dif-
ferent from the movement of gases through the conducting
airways, which occurs by “bulk flow” (mass movement or
convection). In bulk flow, gas movement results from differ-
ences in total pressure, and molecules of different gases move
together along the total pressure gradient. In diffusion, each of
the different gases moves according to its own individual par-
tial pressure gradient. Gas transfer during diffusion occurs by
random molecular movement. It is therefore dependent on
temperature because molecular movement increases at higher
357
temperatures. Gases move in both directions during diffusion,
but the area of higher partial pressure, because of its greater
number of molecules per unit volume, has proportionately
more random “departures.” Thus, the net movement of gas is
dependent on the partial pressure difference between the two
areas. In a static situation, diffusion continues until no partial
Ventilation or perfusion
pressure differences exist for any gases in the two areas; in the
lungs, oxygen and carbon dioxide continuously enter and leave
the alveoli, so such an equilibrium does not take place.
FICK’S LAW FOR DIFFUSION
Oxygen is brought into the alveoli by bulk flow through the
conducting airways. When air flows through the conducting
airways during inspiration, the linear velocity of the bulk flow
decreases as the air approaches the alveoli. This is because the
Apex total cross-sectional area increases dramatically in the distal
portions of the tracheobronchial tree. By the time the air
reaches the alveoli, bulk flow probably ceases, and further gas
movement occurs by diffusion. Oxygen then moves through
the gas phase in the alveoli according to its own partial pres-
sure gradient. The distance from the alveolar duct to the
alveolar–capillary interface is usually less than 1 mm. Oxygen
then diffuses through the alveolar–capillary interface. It must
first, therefore, move from the gas phase to the liquid phase,
according to Henry’s law, which states that the amount of a
gas absorbed by a liquid with which it does not combine
chemically is directly proportional to the partial pressure of
the gas to which the liquid is exposed and the solubility of the
gas in the liquid. Oxygen must dissolve in and diffuse through
the thin layer of pulmonary surfactant, the alveolar epithe-
lium, the interstitium, and the capillary endothelium, as was
shown in Figure 31–6 (step 2, near the arrow). It must then
diffuse through the plasma (step 3), where some remains dis-
solved and the majority enters the erythrocyte and combines
with hemoglobin (step 4). The blood then carries the oxygen
out of the lung by bulk flow and distributes it to the other
tissues of the body, as was shown in Figure 31–1. At the tissues,
oxygen diffuses from the erythrocyte through the plasma, cap-
illary endothelium, interstitium, tissue cell membrane, and
cell interior and into the mitochondrial membrane. The pro-
cess is almost entirely reversed for carbon dioxide.
The factors that determine the rate of diffusion of gas
through the alveolar–capillary barrier are described by Fick’s
law for diffusion, shown as follows in a simplified form:
AD(P1 – P2)
V·gas = _________
T
(2)
where V· gas is the volume of gas diffusing through the tissue
barrier per time (mL/min), A the surface area of the barrier
available for diffusion, D the diffusion coefficient, or diffusiv-
ity, of the particular gas in the barrier, T the thickness of the
barrier or the diffusion distance, and P1 – P2 the partial pres-
sure difference of the gas across the barrier.
That is, the volume of gas per unit of time moving across the
alveolar–capillary barrier is directly proportional to the area of
358 SECTION VI Pulmonary Physiology
the barrier, the diffusivity, and the difference in concentration
between the two sides, but is inversely proportional to the bar-
rier thickness.
The surface area of the blood–gas barrier is believed to be at
least 70 m2 in a healthy average-sized adult at rest. That is,
about 70 m2 of the potential surface area is both ventilated and
perfused at rest. If more capillaries are recruited, as in exercise,
the surface area available for diffusion increases; if venous
return decreases, for example, because of hemorrhage, or if
alveolar pressure is increased by positive-pressure ventilation,
then capillaries may be derecruited and the surface area avail-
able for diffusion may decrease.
The thickness of the alveolar–capillary diffusion barrier is
only about 0.2–0.5 μm. This barrier thickness can increase in
interstitial fibrosis or interstitial edema, thus interfering with
diffusion. Diffusion probably increases at higher lung volumes
because as alveoli are stretched, the diffusion distance decreases
slightly (and also because small airways subject to closure may
be open at higher lung volumes).
The diffusivity, or diffusion constant, for a gas is directly
proportional to the solubility of the gas in the diffusion barrier
and is inversely proportional to the square root of the molecu-
lar weight (MW) of the gas:
Solubility
D α _______
____
√MW
Because oxygen is less dense than carbon dioxide, it should
diffuse 1.2 times as fast as carbon dioxide, but the solubility of
carbon dioxide in the liquid phase is about 24 times that of
oxygen, so carbon dioxide diffuses 20 times more rapidly
through the alveolar–capillary barrier than does oxygen. For
this reason, patients develop problems in oxygen diffusion
Alveolar
partial
pressure
FIGURE 35–5 Calculated changes in the
partial pressures of carbon monoxide, nitrous
oxide, and oxygen in the blood as it passes
through a functional pulmonary capillary. There
are no units on the ordinate because the scale is
different for each of the three gases, depending on
the alveolar partial pressure of each gas. The
abscissa is in seconds, indicating the time the blood
has spent in the capillary. At resting cardiac outputs,
blood spends an average of 0.75 of a second in a
pulmonary capillary. The alveolar partial pressure of
each gas is indicated by the dotted line. Note that
the partial pressures of nitrous oxide and oxygen
equilibrate rapidly with their alveolar partial
pressure. (Modified with permission from Comroe JH: The
Lung; Clinical Physiology and Pulmonary Function Tests, 2nd ed.
Chicago: Year Book Medical Publishers, 1962.)
through the alveolar–capillary barrier before carbon dioxide
retention due to diffusion impairment occurs.
The factors that limit the movement of a gas through the
alveolar–capillary barrier, as described by Fick’s law for diffu-
sion, can be arbitrarily divided into three components: the dif-
fusion coefficient, the surface area and thickness of the
alveolar–capillary membrane, and the partial pressure gradi-
ent across the barrier for each particular gas. The diffusion
coefficient, as discussed in the previous section, is dependent
on the physical properties of the gases and the alveolar–
capillary membrane. The surface area and thickness of the
membrane are physical properties of the barrier, but they can
be altered by changes in the pulmonary capillary blood vol-
ume, the cardiac output or the pulmonary artery pressure, or
changes in lung volume. The partial pressure gradient of a gas
(across the barrier) is the final major determinant of its rate of
diffusion. The partial pressure of a gas in the mixed venous
blood and in the pulmonary capillaries is just as important a
factor as its alveolar partial pressure in determining its rate of
diffusion.
Diffusion Limitation
An erythrocyte and its attendant plasma spend an average of
about 0.75–1.2 seconds inside the pulmonary capillaries at
(3)
resting cardiac outputs. Figure 35–5 shows the calculated
change with time in the partial pressures in the blood of three
gases: oxygen, carbon monoxide, and nitrous oxide. These are
shown in comparison to the alveolar partial pressures for each
gas, as indicated by the dotted line. This alveolar partial pres-
sure is different for each of the three gases, and it depends on
its concentration in the inspired gas mixture and on how rap-
N2O
Partial pressure in plasma
O2
CO
0
0 0.25 0.50 0.75
Time in capillary (s)
Enter capillary Leave capillary
 CHAPTER 35 Ventilation–Perfusion Relationships and Respiratory Gas Exchange
idly it is removed by the pulmonary capillary blood. The sche-
matic is drawn as though all three gases were administered
simultaneously, but this is not necessarily the case. Consider
each gas as though it were acting independently of the others.
The partial pressure of carbon monoxide in the pulmonary
capillary blood rises very slowly compared with that of the
other two gases in the figure if a low inspired concentration of
carbon monoxide is used for a very short time. However, if the
content of carbon monoxide (in milliliters of carbon monoxide
per milliliter of blood) were measured simultaneously, it would
be rising very rapidly. The reason for this rapid rise is that car-
bon monoxide combines chemically with the hemoglobin in
the erythrocytes. The affinity of carbon monoxide for hemo-
globin is about 210 times that of oxygen for hemoglobin. The
carbon monoxide that is chemically combined with hemoglo-
bin does not contribute to the partial pressure of carbon mon-
oxide in the blood because it is no longer physically dissolved in
it. Therefore, the partial pressure of carbon monoxide in the
pulmonary capillary blood does not come close to the partial
pressure of carbon monoxide in the alveoli during the time
that the blood is exposed to the alveolar carbon monoxide.
The partial pressure gradient across the alveolar–capillary bar-
rier for carbon monoxide is thus well maintained for the entire
time the blood spends in the pulmonary capillary. The diffu-
sion of carbon monoxide is therefore limited only by its diffu-
sivity in the barrier and by the surface area and thickness of
the barrier. Carbon monoxide transfer from the alveolus to the
pulmonary capillary blood is referred to as diffusion-limited
rather than perfusion-limited.
Perfusion Limitation
The partial pressure of nitrous oxide in the pulmonary capil-
lary blood equilibrates very rapidly with the partial pressure of
nitrous oxide in the alveolus because nitrous oxide moves
through the alveolar–capillary barrier very easily and because
it does not combine chemically with the hemoglobin in the
erythrocytes. After only about 0.1 of a second of exposure of
the pulmonary capillary blood to the alveolar nitrous oxide,
the partial pressure gradient across the alveolar–capillary bar-
rier has been abolished. From this point on, no further nitrous
oxide transfer occurs from the alveolus to the blood in the cap-
illary that has already equilibrated with the alveolar nitrous
oxide partial pressure; during the last 0.6–0.7 of a second, no
net diffusion occurs between the alveolus and the blood as it
travels through the pulmonary capillary. Blood just entering
the capillary at the arterial end will not be equilibrated with the
alveolar partial pressure of nitrous oxide, so nitrous oxide can
diffuse into the blood at the arterial end. The transfer of nitrous
oxide is therefore perfusion-limited. Nitrous oxide transfer
from a particular alveolus to one of its pulmonary capillaries
can be increased by increasing the cardiac output and thus
reducing the amount of time the blood stays in the pulmonary
capillary after equilibration with the alveolar partial pressure
of nitrous oxide has occurred. (Because increasing the cardiac
output may recruit previously unperfused capillaries, the total
359
diffusion of both carbon monoxide and nitrous oxide may
increase as the surface area for diffusion increases.)
Diffusion of Oxygen
As can be seen in Figure 35–5, the time course for oxygen trans-
fer falls between those for carbon monoxide and nitrous oxide.
The partial pressure of oxygen rises fairly rapidly (it starts at the
Po2 of the mixed venous blood, about 40 mm Hg, rather than at
zero), and equilibration with the alveolar Po2 of about 100 mm Hg
occurs within about 0.25 of a second, or about one third of the
time the blood is in the pulmonary capillary at typical resting
cardiac outputs. Oxygen moves easily through the alveolar–
capillary barrier and into the erythrocytes, where it combines
chemically with hemoglobin. The partial pressure of oxygen
rises more rapidly than the partial pressure of carbon monox-
ide. Nonetheless, the oxygen chemically bound to hemoglobin
(and therefore no longer physically dissolved) exerts no partial
pressure, so the partial pressure gradient across the alveolar–
capillary membrane is initially well maintained and oxygen
transfer occurs. The chemical combination of oxygen and
hemoglobin, however, occurs rapidly (within hundredths of a
second), and at the normal alveolar partial pressure of oxygen,
the hemoglobin becomes nearly saturated with oxygen very
quickly, as will be discussed in the next chapter. As this hap-
pens, the partial pressure of oxygen in the blood rises rapidly to
that in the alveolus, and from that point, no further oxygen
transfer from the alveolus to the equilibrated blood can occur.
Therefore, under the conditions of normal alveolar Po2 and rest-
ing cardiac output, oxygen transfer from alveolus to pulmonary
capillary is perfusion-limited.
During exercise, blood moves through the pulmonary capil-
lary much more rapidly than it does at resting cardiac outputs.
In fact, the blood may stay in the pulmonary capillary an average
of only about 0.25 of a second during strenuous exercise. Oxy-
gen transfer into the blood per time will be greatly increased
because there is little or no perfusion limitation of oxygen trans-
fer. (Indeed, that part of the blood that stays in the capillary less
than the average may be subjected to diffusion limitation of oxy-
gen transfer.) Of course, total oxygen transfer is also increased
during exercise because of recruitment of previously unperfused
capillaries, which increases the surface area for diffusion, and
because of better matching of ventilation and perfusion. A per-
son with an abnormal alveolar–capillary barrier due to a fibrotic
thickening or interstitial edema may approach diffusion limita-
tion of oxygen transfer at rest and may have a serious diffusion
limitation of oxygen transfer during strenuous exercise. A per-
son with an extremely abnormal alveolar–capillary barrier might
have diffusion limitation of oxygen transfer even at rest.
Diffusion of Carbon Dioxide
The equilibration of the partial pressure of carbon dioxide in
the pulmonary capillary blood with that of the alveolus in a
healthy person with a mixed venous partial pressure of car-
bon dioxide of 45 mm Hg and an alveolar partial pressure of
360 SECTION VI Pulmonary Physiology
carbon dioxide of 40 mm Hg is about 0.25 of a second, or
about the same as that for oxygen. This may seem surprising,
considering that the diffusivity of carbon dioxide is about
20 times that of oxygen, but the partial pressure gradient is
normally only about 5 mm Hg for carbon dioxide, whereas it
is about 60 mm Hg for oxygen. Carbon dioxide transfer is
therefore also normally perfusion-limited, although it may
be diffusion-limited in a person with an abnormal alveolar–
capillary barrier.
MEASUREMENT OF
DIFFUSING CAPACITY
It is often useful to determine the diffusion characteristics of a
patient’s lungs during their assessment in the pulmonary func-
tion laboratory. It may be particularly important to determine
whether an apparent impairment in diffusion is a result of per-
fusion limitation or diffusion limitation.
The diffusing capacity is the rate at which oxygen or carbon
monoxide is absorbed from the alveolar gas into the pulmo-
nary capillaries (in milliliters per minute) per unit of partial
pressure gradient (in millimeters of mercury). It is usually
measured with very low concentrations of carbon monoxide
because carbon monoxide transfer from alveolus to capillary is
diffusion-limited as was discussed previously in this chapter.
The mean partial pressure of oxygen or carbon monoxide is,
as already discussed, affected by their chemical reactions with
hemoglobin, as well as by their transfer through the alveolar–
capillary barrier. For this reason, the diffusing capacity of the
lung is influenced by both the diffusing capacity of the mem-
brane and the reaction with hemoglobin. The amount of
hemoglobin in the lung is dependent on the hemoglobin con-
centration in the blood and the amount of blood in the pulmo-
nary capillaries—the pulmonary capillary blood volume.
Diffusion through the alveolus is normally very rapid and usu-
ally can be disregarded, although it could be a major factor in
a person with pulmonary edema.
Several different methods are used clinically to measure the
carbon monoxide diffusing capacity (the DLCO) and involve
both single-breath and steady-state techniques, sometimes
during exercise.
The DLCO is decreased in diseases associated with interstitial
or alveolar fibrosis, such as sarcoidosis, scleroderma, and asbes-
tosis, or with conditions causing interstitial or alveolar pulmo-
nary edema, as indicated in Table 35–2. It is also decreased in
conditions causing a decrease in the surface area available for
diffusion, such as emphysema, tumors, a low cardiac output, or
a low pulmonary capillary blood volume, as well as in condi-
tions leading to ventilation–perfusion mismatch, which effec-
tively decreases the surface area available for diffusion.
The carbon monoxide diffusing capacity can be very useful
in assessing patients with chronic obstructive pulmonary dis-
ease (COPD). A low DLCO distinguishes patients whose disor-
der is primarily emphysema from those whose disorder is
primarily chronic bronchitis. The DLCO can also be helpful in
assessing patients with restrictive diseases.
TABLE 35–2 Conditions that decrease the
diffusing capacity.
Thickening of the barrier
Interstitial or alveolar edema
Interstitial or alveolar fibrosis
Sarcoidosis
Scleroderma
Decreased surface area
Emphysema
Tumors
Low cardiac output
Low pulmonary capillary blood volume
Decreased uptake by erythrocytes
Anemia
Low pulmonary capillary blood volume
Ventilation–perfusion mismatch
Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed.
New York: McGraw-Hill Medical, 2007.
CLINICAL CORRELATION
A 40-year-old man with a broken leg in a cast because of
a skiing injury and no history of respiratory problems
suddenly has difficulty breathing and complains of chest
pain. He is brought to the hospital. In the emergency
department, his breathing is observed to be rapid and
shallow. His heart rate is 120/min and his arterial blood
pressure is 80/60 mm Hg. His respiratory rate is 25/min.
A chest x-ray and an electrocardiogram (ECG) are per-
formed on the patient to help determine the cause of his
chest pain and dyspnea. The ECG shows no abnormalities
indicative of myocardial ischemia (insufficient blood
flow to the heart muscle) or myocardial infarction (injury
of the heart muscle) such as ST segment or T-wave abnor-
malities (see Chapter 23). The chest x-ray shows no
abnormalities indicative of pneumonia, atelectasis (col-
lapsed alveoli), or pneumothorax (air between the inside
of the chest wall and the outside of the lung). An arterial
blood sample is obtained from the patient while he was
breathing room air to determine his arterial blood gases
(arterial Po2, arterial Pco2, and arterial pH). His arterial Po2
was 70 mm Hg (normal >90); his arterial Pco2 was
30 mm Hg (normal range is 35–45); his pH was 7.50 (nor-
mal range is 7.35–7.45).
The patient has a pulmonary embolus, most likely as a
result of blood clotting in his immobilized leg. Flow of
venous blood in the broken leg is impaired by the cast
and the lack of muscle contraction to enhance venous
return from his leg to his heart. Stasis (low or absent
flow) of blood often leads to clotting (thrombosis). When
thrombosis occurs in nonsuperficial veins such as those
in the leg, it is called deep venous thrombosis (DVT).
The thrombus can break loose and be carried to the right
side of the heart and enter the pulmonary arterial tree,
 CHAPTER 35 Ventilation–Perfusion Relationships and Respiratory Gas Exchange
where it can block blood flow to part of the lung. This is
called a pulmonary embolus, in this case a thromboem-
bolus. Pulmonary emboli can be life-threatening if they
occlude a significant fraction of the pulmonary vascular
bed. The region of the lung with occluded blood flow cre-
ates alveolar dead space (ventilated but not perfused)
that contributes nothing to gas exchange. The patient’s
end-tidal Pco2 decreases because it contains air coming
from unperfused alveoli that contribute no carbon diox-
ide to the exhaled air. The arterial Pco2 is therefore greater
than the end-tidal (“alveolar”) Pco2. The diffusing capac-
ity of the patient is decreased because of decreased sur-
face area for gas exchange. Occlusion of pulmonary
vessels is likely to increase pulmonary vascular resistance,
increase pulmonary artery pressure, and increase right
ventricular work. Blood flow to the left side of the patient’s
heart decreases, which explains his low systemic blood
pressure. His tachycardia is likely a result of the response
of his baroreceptor reflex to his low blood pressure, and
the pain and anxiety he is experiencing. His tachypnea is
explained by the influence of receptors in his lungs (which
will be described in Chapter 38) and the pain and anxiety.
The tachypnea resulted in hyperventilation causing his
arterial Pco2 to decrease below the normal range and his
arterial pH to exceed the normal range (see discussion of
uncompensated respiratory alkalosis in Chapter 37). His
low arterial Po2 is a result of the occlusion of pulmonary
vessels forcing blood flow to poorly ventilated alveoli.
Treatment of patients with pulmonary emboli (some-
times called pulmonary embolism) depends on the sever-
ity of the disorder. Anticoagulants are used to prevent
further clotting, thrombolytic drugs are used to break clots
down, intravenous catheters with deployable filters can be
used to remove the emboli, and large life-threatening
emboli may be removed surgically (embolectomy).
CHAPTER SUMMARY
■ Ventilation and perfusion must be matched on the alveolar–
capillary level for optimal gas exchange.
■ Ventilation–perfusion ratios close to 1.0 result in alveolar Po2 of
approximately 100 mm Hg and Pco2 close to 40 mm Hg;
ventilation–perfusion ratios greater than 1.0 increase the Po2
and decrease the Pco2; ventilation–perfusion ratios less than 1.0
decrease the Po2 and increase the Pco2.
■ Alveolar dead space and intrapulmonary shunt represent the
two extremes of ventilation–perfusion ratios, infinite and zero,
respectively.
■ The ventilation–perfusion ratios in lower regions of the normal
upright lung are lower than 1.0, resulting in lower Po2 and
higher Pco2; the ventilation–perfusion ratios in upper parts of
the lung are greater than 1.0, resulting in higher Po2 and lower
361
Pco2; nonetheless, there is normally more gas exchange in lower
regions of the lung because they receive more blood flow.
■ The volume of gas per unit of time moving across the
alveolar–capillary barrier is directly proportional to the area
of the barrier, the diffusivity of the gas in the barrier, and the
difference in concentration of the gas between the two sides
of the barrier, but is inversely proportional to the barrier
thickness.
■ If the partial pressure of a gas in the plasma equilibrates
with the alveolar partial pressure of the gas within the
amount of time the blood is in the pulmonary capillary, its
transfer is perfusion-limited; if equilibration does not occur
within the time the blood is in the capillary, its transfer is
diffusion-limited.
STUDY QUESTIONS
1. An otherwise normal person is brought to the emergency
department after having accidentally aspirated a foreign body
into the right main-stem bronchus, partially occluding it.
Which of the following is/are likely to occur?
A) The right lung’s alveolar Po2 will be lower and its alveolar
Pco will be higher than those of the left lung.
2
B) The calculated shunt fraction will increase.
C) Blood flow to the right lung will decrease.
D) The arterial Po2 will decrease.
E) All of the above.
2. A healthy person lies down on her right side and breathes
normally. Her right lung, in comparison to her left lung, will
be expected to have a
A) lower alveolar Po2 and a higher alveolar Pco2.
B) lower blood flow per unit volume.
C) less ventilation per unit volume.
D) higher ventilation–perfusion ratio.
E) larger alveoli.
3. Which of the following conditions or circumstances is expected
to increase the diffusing capacity (DL) of the lungs?
A) changing from the supine to the upright position
B) exercise
C) emphysema
D) anemia
E) low cardiac output due to blood loss
F) diffuse interstitial fibrosis of the lungs
4. If the pulmonary capillary partial pressure of a gas equilibrates with
that in the alveolus before the blood leaves the capillary (assume
the gas is diffusing from the alveolus to the pulmonary capillary)
A) its transfer is said to be perfusion-limited.
B) its transfer is said to be diffusion-limited.
C) increasing the cardiac output will not increase the amount
of the gas diffusing across the alveolar–capillary barrier.
D) increasing the alveolar partial pressure of the gas will not
increase the amount of the gas diffusing across the
alveolar–capillary barrier.
E) recruiting additional pulmonary capillaries will not increase
the amount of the gas diffusing across the alveolar–capillary
barrier.
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 36
C H A P T E R

Transport of Oxygen and

Carbon Dioxide
Michael Levitzky

O B J E C T I V E S

■ State the relationship between the partial pressure of oxygen in the

blood and the amount of oxygen physically dissolved in the blood.
■ Describe the chemical combination of oxygen with hemoglobin and
the oxyhemoglobin dissociation curve.
■ Define hemoglobin saturation, oxygen-carrying capacity, and oxygen
content.
■ State the physiologic consequences of the shape of the oxyhemoglobin
dissociation curve.
■ List the physiologic factors that can influence the oxyhemoglobin
dissociation curve, and predict their effects on oxygen transport by
the blood.
■ State the relationship between the partial pressure of carbon dioxide in the
blood and the amount of carbon dioxide physically dissolved in the blood.
■ Describe the transport of carbon dioxide as carbamino compounds with
blood proteins.
■ Explain how most of the carbon dioxide in the blood is transported
as bicarbonate.
■ Describe the carbon dioxide dissociation curve for whole blood.

TRANSPORT OF OXYGEN normal arterial blood with a Po2 of approximately 100 mm Hg

BY THE BLOOD
Oxygen is transported both physically dissolved in blood and
chemically combined to the hemoglobin in the erythrocytes.
Much more oxygen is normally transported combined with
hemoglobin than is physically dissolved in the blood. Without
hemoglobin, the cardiovascular system could not supply suf-
ficient oxygen to meet tissue demands.
PHYSICALLY DISSOLVED
At a temperature of 37°C, 1 mL of plasma contains 0.00003mL
O2/(mm Hg Po2). Whole blood contains a similar amount of
dissolved oxygen per milliliter because oxygen dissolves in the
fluid of the erythrocytes in about the same amount. Therefore,
contains only about 0.003 mL O2/mL of blood, or 0.3 mL
O2/100 mL of blood. (Blood oxygen content is conventionally
expressed in milliliters of oxygen per 100 mL of blood, also
called volume percent.) The physically dissolved oxygen in
the blood therefore cannot meet the metabolic demand for
oxygen, even at rest.
CHEMICALLY COMBINED
WITH HEMOGLOBIN
The Structure of Hemoglobin
Hemoglobin is a complex molecule with a tetrameric struc-
ture consisting of four linked polypeptide chains (globin),
each of which is attached to a protoporphyrin (heme) group.
Each heme group has a ferrous (Fe2+) iron atom at its center

363

Ch36_363-374.indd 363 11/26/10 10:11:07 AM

364 SECTION VI Pulmonary Physiology
and can bind a molecule of oxygen (or carbon monoxide), so
the tetrameric hemoglobin molecule can combine chemically
with four oxygen molecules (or eight oxygen atoms). Varia-
tions in the amino acid sequences of the four globin subunits
may have important physiologic consequences. Normal adult
hemoglobin (HbA) consists of two alpha (α) chains, each of
which has 141 amino acids, and two beta (β) chains, each of
which has 146 amino acids. Fetal hemoglobin (HbF), which
consists of two α chains and two gamma (γ) chains, has a
higher affinity for oxygen than does HbA. Synthesis of β chains
normally begins about 6 weeks before birth, and HbA usually
replaces almost all the HbF by the time an infant is 4 months
old. Other, abnormal hemoglobin molecules may be produced
by genetic substitution of a single amino acid for the normal
one in an α or β chain or (rarely) by alterations in the structure
of heme groups. These alterations may produce changes in the
affinity of the hemoglobin for oxygen, change the physical
properties of hemoglobin, or alter the interaction of hemoglo-
bin and other substances that affect its combination with oxy-
gen, such as 2,3-bisphosphoglycerate (2,3-BPG) (discussed
later in this chapter). More than 120 abnormal variants of nor-
mal HbA have been demonstrated in patients. The best known
of these, hemoglobin S, is present in sickle cell disease. Hemo-
globin S tends to polymerize and crystallize in the cytosol of
the erythrocyte when it is not combined with oxygen. This
polymerization and crystallization decreases the solubility of
hemoglobin S within the erythrocyte and changes the shape of
the cell from the normal biconcave disk to a crescent or “sickle”
shape. A sickled cell is more fragile than a normal cell. In addi-
tion, the cells have a tendency to stick to one another, which
increases blood viscosity and also favors thrombosis or block-
age of blood vessels.
Chemical Reaction of
Oxygen and Hemoglobin
Hemoglobin rapidly combines reversibly with oxygen. It is the
reversibility of the reaction that allows oxygen to be released to
the tissues; if the reaction did not proceed easily in both direc-
tions, hemoglobin would be of little use in delivering oxygen
to satisfy metabolic needs. The reaction is very fast, with a
half-time of 0.01 of a second or less. Each gram of hemoglobin
is capable of combining with about 1.39 mL of oxygen under
optimal conditions, but under normal circumstances, some
hemoglobin exists in forms such as methemoglobin (in which
the iron atom is in the ferric state) or is combined with carbon
monoxide, in which case the hemoglobin cannot bind oxygen.
For this reason, the oxygen-carrying capacity of hemoglobin
is conventionally considered to be 1.34 mL O2/(g Hb), that is,
each gram of hemoglobin, when fully saturated with oxygen,
binds 1.34 mL of oxygen. Therefore, a person with 15 g Hb/
100 mL of blood has an oxygen-carrying capacity of 20.1 mL
O2/100 mL of blood:
15 g Hb
__________ 1.34 mL O 20.1 mL O2 (1)
× ________2 = __________
100 mL blood g Hb 100 mL blood
The reaction of hemoglobin and oxygen is conventionally
written as follows:
Hb + O2 HbO2 (2)
Deoxyhemoglobin Oxyhemoglobin
HEMOGLOBIN AND THE
PHYSIOLOGIC IMPLICATIONS
OF THE OXYHEMOGLOBIN
DISSOCIATION CURVE
The equilibrium point of the reversible reaction of hemoglobin
and oxygen is dependent on how much oxygen the hemoglobin
in blood is exposed to. This corresponds directly to the partial
pressure of oxygen (Po2) in the plasma under the conditions in
the body. Thus, the Po2 of the plasma determines the amount of
oxygen that binds to the hemoglobin in the erythrocytes.
THE OXYHEMOGLOBIN
DISSOCIATION CURVE
One way to express the proportion of oxygen that is bound to
hemoglobin is as percent saturation. This is equal to the con-
tent of oxygen in the blood (minus that part physically dis-
solved) divided by the oxygen-carrying capacity of the
hemoglobin in the blood times 100%:
O bound to Hb
% Hb saturation = _____________
2
× 100% (3)
O2 capacity of Hb
Note that the oxygen-carrying capacity of an individual
depends on the amount of hemoglobin in the blood. The blood
oxygen content also depends on the amount of hemoglobin
present (as well as on the Po2). Both content and capacity are
expressed as milliliters of oxygen per 100 mL of blood. On the
other hand, the percent hemoglobin saturation expresses only
a percentage and not an amount or volume of oxygen; “percent
saturation” is not interchangeable with “oxygen content.” For
example, two patients might have the same percent of hemo-
globin saturation, but if one has a lower blood hemoglobin
concentration because of anemia, he or she will have a lower
blood oxygen content.
The relationship between the Po2 of the plasma and the per-
cent of hemoglobin saturation can be expressed graphically as
the oxyhemoglobin dissociation curve. An oxyhemoglobin
dissociation curve for normal blood is shown in Figure 36–1.
The oxyhemoglobin dissociation curve is really a plot of
how the availability of one of the reactants, oxygen (expressed
as the Po2 of the plasma), affects the reversible chemical reac-
tion of oxygen and hemoglobin. The product, oxyhemoglobin,
is expressed as percent saturation—really a percentage of the
maximum for any given amount of hemoglobin.
As can be seen in Figure 36–1, the relationship between Po2
and HbO2 is not linear; it is a sigmoid (S-shaped) curve, steep
at the lower Po2 and nearly flat when the Po2 is above 70 mm Hg.
 CHAPTER 36 Transport of Oxygen and Carbon Dioxide 365

100

Hemoglobin saturation ( %)
80

60
50%

40

20

0
0 20 40 60 80 100 120 140 160
P50
Partial pressure of oxygen (mm Hg)

FIGURE 36–1 A typical “normal” adult oxyhemoglobin dissociation curve for blood at 37°C with a pH of 7.40 and a PCO2 of
40 mm Hg. The P50 is the partial pressure of oxygen at which hemoglobin is 50% saturated with oxygen. (Modified with permission from Levitzky MG:
Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

It is this S shape that is responsible for several very important Oxygen physically dissolved at a Po2 of 40 mm Hg is given
physiologic properties of the reaction of oxygen and hemoglo- as follows:
bin. The reason that the curve is S-shaped and not linear is 0.003 mL O2 0.12 mL O2
that it is actually a plot of four reactions rather than one, that ______________________ × 40 mm Hg = __________ (6)
100 mL blood Po2 (in mm Hg) 100 mL blood
is, each of the four subunits of hemoglobin can combine with
one molecule of oxygen. Total blood oxygen content at a Po2 of 40 mm Hg (37°C,
The reactions of the four subunits of hemoglobin with oxy- pH 7.4) is given as follows:
gen do not occur simultaneously. Instead they occur sequen- 15.08 mL O2 0.12 mL O2 15.2 mL O2
__________ + __________ = __________
tially in four steps, with an interaction between the subunits 100 mL blood 100 mL blood 100 mL blood (7)
occurring in such a way that during the successive combina- Bound to Hb Physically dissolved Total
tions of the subunits with oxygen, each combination facilitates
the next. Similarly, dissociation of oxygen from hemoglobin As the blood passes through the pulmonary capillaries, it
subunits facilitates further dissociations. The dissociation equilibrates with the alveolar Po2 of about 100 mm Hg. At a Po2
curve for a single monomer of hemoglobin is far different of 100 mm Hg, hemoglobin is about 97.4% saturated with oxy-
from that for the tetramer (see Figure 36–4C). gen, as seen in Figure 36–1. This corresponds to 19.58 mL
O2/100 mL of blood bound to hemoglobin plus 0.3 mL
O2/100 mL of blood physically dissolved, or a total oxygen con-
Loading Oxygen in the Lung tent of 19.88 mL O2/100 mL of blood.
Oxygen bound to hemoglobin at a Po2 of 100 mm Hg (37°C,
Mixed venous blood entering the pulmonary capillaries pH 7.4) is given as follows:
normally has a Po2 of about 40 mm Hg. At a Po2 of 40 mm Hg,
hemoglobin is about 75% saturated with oxygen, as seen in 20.1 mL O2
___________ 19.58 mL O
× 97.4% = __________
2

Figure 36–1. Assuming a blood hemoglobin concentration of 100 mL blood 100 mL blood (8)
Capacity % saturation Content
15 g Hb/100 mL of blood, this corresponds to 15.08 mL
O2/100 mL of blood bound to hemoglobin plus an additional Oxygen physically dissolved at a Po2 of 100 mm Hg is given
0.12 mL O2/100 mL of blood physically dissolved, or a total as follows:
oxygen content of approximately 15.2 mL O2/100 mL of 0.003 mL O2 0.3 mL O2
______________________ × 100 mm Hg = __________ (9)
blood. 100 mL blood Po2 (in mm Hg) 100 mL blood
Oxygen-carrying capacity is given as follows:
15 g Hg 1.34 mL O 20.1 mL O2 Total blood oxygen content at a Po2 of 100 mm Hg (37°C,
__________ × ________2 = __________ (4)
100 mL blood g Hb 100 mL blood pH 7.4) is given as follows:
Oxygen bound to hemoglobin at a Po2 of 40 mm Hg (37°C, 19.58 mL O2
__________ 0.3 mL O2
__________ 19.88 mL O2
__________
+ =
pH 7.4) is given as follows: 100 mL blood 100 mL blood 100 mL blood (10)
Bound to Hb Physically dissolved Total
20.1 mL O2
__________ 15.08 mL O2
× 75% = ___________ (5) Thus, in passing through the lungs, each 100 mL of blood
100 mL blood 100 mL blood
Capacity % saturation Content has loaded (19.88 – 15.20) mL O2, or 4.68 mL O2. Assuming a
366 SECTION VI Pulmonary Physiology
cardiac output of 5 L/min, this means that approximately
234 mL O2 is loaded into the blood per minute:
46.8 mL O2 ________
5 L blood ________
_______ 234 mL O
× = min 2 (11)
min liter blood
Note that the oxyhemoglobin dissociation curve is rela-
tively flat when Po2 is greater than approximately 70 mm Hg.
This is very important physiologically because it means that
there is only a small decrease in the oxygen content of blood
equilibrated with a Po2 of 70 mm Hg instead of 100 mm Hg. In
fact, the curve shows that at a Po2 of 70 mm Hg, hemoglobin
is still approximately 94.1% saturated with oxygen. This con-
stitutes an important safety factor because a patient with a
relatively low alveolar or arterial Po2 of 70 mm Hg (owing to
hypoventilation or intrapulmonary shunt, for example) is
still able to load adequate oxygen into the blood. A quick cal-
culation shows that at 70 mm Hg, the total blood oxygen con-
tent is approximately 19.12 mL O2/100 mL of blood compared
with the 19.88 mL O2/100 mL of blood at a Po2 of 100 mm Hg.
These calculations show that Po2 is often a more sensitive
diagnostic indicator of the status of a patient’s respiratory sys-
tem than the arterial oxygen content. Of course, the oxygen
content is more important physiologically to the patient.
Because hemoglobin is approximately 97.4% saturated at a
Po2 of 100 mm Hg, increasing the alveolar Po2 above 100 mm Hg
can add little additional oxygen to hemoglobin (only about
0.52 mL O2/100 mL of blood at a hemoglobin concentration of
15 g/100 mL of blood). Hemoglobin is fully saturated with
oxygen at a Po2 of about 250 mm Hg.
Unloading Oxygen at the Tissues
As blood passes from the arteries into the systemic capillaries, it
is exposed to lower Po2 and oxygen is released by the hemoglo-
bin. The Po2 in the capillaries varies from tissue to tissue, being
very low in some (e.g., myocardium) and relatively higher in
others (e.g., renal cortex). As can be seen in Figure 36–1, the
oxyhemoglobin dissociation curve is very steep in the range of
40–10 mm Hg. This means that a small decrease in Po2 can result
in a substantial further dissociation of oxygen and hemoglobin,
unloading more oxygen for use by the tissues. At a Po2 of 40 mm
Hg, hemoglobin is about 75% saturated with oxygen, with a
total blood oxygen content of 15.2 mL O2/100 mL of blood (at
15 g Hb/100 mL of blood). At a Po2 of 20 mm Hg, hemoglobin is
only 32% saturated with oxygen. The total blood oxygen content
is only 6.49 mL O2/100 mL of blood, a decrease of 8.71 mL
O2/100 mL of blood for only a 20-mm Hg decrease in Po2.
The unloading of oxygen at the tissues is also facilitated by
other physiologic factors that can alter the shape and position
of the oxyhemoglobin dissociation curve. These include
the pH, Pco2, temperature of the blood, and concentration of
2,3-BPG in the erythrocytes.
INFLUENCES ON THE OXYHEMOGLOBIN
DISSOCIATION CURVE
Figure 36–2 shows the influence of alterations in temperature,
pH, Pco2, and 2,3-BPG on the oxyhemoglobin dissociation
curve. High temperature, low pH, high Pco2, and elevated levels
of 2,3-BPG all shift the oxyhemoglobin dissociation curve to
the right; that is, for any particular Po2, there is less oxygen
chemically combined with hemoglobin at higher tempera-
tures, lower pH, higher Pco2, and elevated levels of 2,3-BPG.
The rightward shift represents a decreased affinity of hemo-
globin for oxygen.
The effects of blood pH and Pco2 on the oxyhemoglobin dis-
sociation curve are shown in Figure 36–2A and B. Low pH and
high Pco2 both shift the curve to the right. High pH and low
Pco2 both shift the curve to the left. These two effects often
occur together. The influence of pH (and Pco2) on the oxyhe-
moglobin dissociation curve is referred to as the Bohr effect.
The Bohr effect will be discussed in greater detail at the end of
this chapter.
Figure 36–2C shows the effects of blood temperature on the
oxyhemoglobin dissociation curve. High temperatures shift the
curve to the right; low temperatures shift the curve to the left.
At very low blood temperatures, hemoglobin has such a high
affinity for oxygen that it does not release the oxygen, even at
very low Po2. 2,3-BPG (also called 2,3-diphosphoglycerate, or
2,3-DPG) is produced by erythrocytes during their normal gly-
colysis and is present in fairly high concentrations within red
blood cells (about 15 mmol/(g Hb)). 2,3-BPG binds to the
hemoglobin in erythrocytes, which decreases the affinity of
hemoglobin for oxygen. Higher concentrations of 2,3-BPG
therefore shift the oxyhemoglobin dissociation curve to the
right, as shown in Figure 36–2D. It has been demonstrated that
more 2,3-BPG is produced during chronic hypoxic conditions,
thus shifting the dissociation curve to the right and allowing
more oxygen to be released from hemoglobin at a particular
Po2. Very low levels of 2,3-BPG shift the curve far to the left, as
shown in the figure. This means that blood deficient in 2,3-BPG
does not unload much oxygen. Blood stored in blood banks for
as little as 1 week has been shown to have very low levels of
2,3-BPG. Use of banked blood in patients may result in
decreased oxygen unloading to the tissues unless steps are
taken to restore the normal levels of 2,3-BPG.
As blood enters metabolically active tissues, it is exposed
to an environment different from that found in the arterial
tree. The Pco2 is higher, the pH is lower, and the temperature
is also higher than that of the arterial blood. The curve
shown in Figure 36–1 is for blood at 37°C, with a pH of 7.4
and a Pco2 of 40 mm Hg. Blood in metabolically active tissues
and therefore the venous blood draining them are no longer
subject to these conditions because they have been exposed
to a different environment. Because low pH, high Pco2,
increased 2,3-BPG, and higher temperature all shift the oxy-
hemoglobin dissociation curve to the right, they all can help
unload oxygen from hemoglobin at the tissues. On the other
hand, as the venous blood returns to the lung and CO2 leaves
the blood (which increases the pH), the affinity of hemoglo-
bin for oxygen increases as the curve shifts back to the left,
as shown in Figure 36–3. Note that the effects of pH, Pco2,
and temperature shown in Figure 36–2 have a more pro-
found effect on enhancing the unloading of oxygen at the
tissues than they do interfering with its loading at the lungs.
 CHAPTER 36 Transport of Oxygen and Carbon Dioxide 367

100 100
20°
37°
43°
0
80 7.6 80

0
Hemoglobin saturation ( %)

Hemoglobin saturation (%)

7.4

0
pH

7.2
pH


pH

60 60

40 40

20 20

0 0
0 20 40 60 80 100 0 20 40 60 80 100
A. PO (mm Hg) C.
2 PO2 (mm Hg)

100 100
Hemoglobin saturation ( %)

80

-BPG
80

G
BP
Hemoglobin saturation (%)

,3

PG
,3-
60
PCO  20 mm Hg
No 2

-B
al 2

2,3
2

rm

ed
PCO  40 mm Hg 60 No
Add
40 2

PCO2  80 mm Hg

20 40

0
0 20 40 60 80 100 120 140 160
20
B. PO (mm Hg)
2

0
0 20 40 60 80 100
D. PO (mm Hg)
2

FIGURE 36–2 The effects of pH (A), PCO2 (B), temperature (C), and 2,3-BPG (D) on the oxyhemoglobin dissociation curve. (Modified with
permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

A convenient way to discuss shifts in the oxyhemoglobin
dissociation curve is the P50, shown in Figures 36–1 and 36–3.
The P50 is the Po2 at which 50% of the hemoglobin present in
the blood is in the deoxyhemoglobin state and 50% is in the
oxyhemoglobin state. At a temperature of 37°C, a pH of 7.4,
and a Pco2 of 40 mm Hg, normal human blood has a P50 of 26
or 27 mm Hg. If the oxyhemoglobin dissociation curve is
shifted to the right, the P50 increases. If it is shifted to the left,
the P50 decreases.
Other Factors Affecting Oxygen Transport
Most forms of anemia (low blood hemoglobin concentra-
tion or low number of red blood cells) do not affect the oxy-
hemoglobin dissociation curve if the association of oxygen
and hemoglobin is expressed as percent saturation. For
example, anemia secondary to erythrocyte loss does not
affect the combination of oxygen and hemoglobin for the
remaining erythrocytes. It is the amount of hemoglobin that
decreases, not the percent saturation or even the arterial
Po2. The arterial content of oxygen, however, in milliliters of
oxygen per 100 mL of blood, is reduced, as shown in
Figure 36–4A, because the decreased amount of hemoglobin
per 100 mL of blood decreases the oxygen-carrying capacity
of the blood.
Carbon monoxide has a much greater affinity for hemoglo-
bin than does oxygen, as discussed in Chapter 35. It can there-
fore effectively block the combination of oxygen with
hemoglobin because oxygen cannot be bound to iron atoms
already combined with carbon monoxide. Carbon monoxide
has a second deleterious effect: it shifts the oxyhemoglobin
dissociation curve to the left. Thus, carbon monoxide can
368 SECTION VI Pulmonary Physiology
100
80
Hemoglobin saturation (%)
60 v-
50%
40
20
0 a heme group. It can therefore combine chemically with a sin-
0 20 40 60 80
P50 PO2 (mm Hg)
FIGURE 36–3 Oxyhemoglobin dissociation curves for arterial
and venous blood. The venous curve is shifted to the right because
the pH is lower and the PCO2 (and possibly the temperature) is higher.
The rightward shift results in a higher P50 for venous blood. a, arterial
point (P 2 = 100mm Hg); –v, mixed venous point (P 2 = 40mm Hg).
O O
(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York:
McGraw-Hill Medical, 2007.)
prevent the loading of oxygen into the blood in the lungs and
can also interfere with the unloading of oxygen at the tissues.
This can be seen in Figure 36–4A.
Carbon monoxide is particularly dangerous for several rea-
sons. A person breathing very low concentrations of carbon
monoxide can slowly reach life-threatening levels of carboxy-
hemoglobin (COHb) in the blood because carbon monoxide
has such a high affinity for hemoglobin. The effect is cumula-
tive. What is worse is that a person breathing carbon monox-
ide is not aware of doing so—the gas is colorless, odorless, and
tasteless and does not elicit any reflex coughing or sneezing,
increase in ventilation, or feeling of difficulty in breathing.
Smoking and living in urban areas cause small amounts of
COHb to be present in the blood of healthy adults. A non-
smoker who lives in a rural area may have only about 1%
COHb; a smoker who lives in an urban area may have 5–8%
COHb in the blood.
Hemoglobin within erythrocytes can rapidly scavenge nitric
oxide (NO). NO can react with oxyhemoglobin to form meth-
emoglobin and nitrate or react with deoxyhemoglobin to form
a hemoglobin–NO complex. In addition, hemoglobin may act
as a carrier for NO, in the form of S-nitrosothiol, on the cysteine
residues on the β-globin chain. This is called s-nitrosohemo-
globin (SNO-Hb). When hemoglobin binds oxygen, the for-
mation of this S-nitrosothiol is enhanced; when hemoglobin
releases oxygen, NO could be released. Thus, in regions where
the Po2 is low, NO—a potent vasodilator—could be released.
Methemoglobin is hemoglobin with iron in the ferric (Fe3+)
state. It can be caused by nitrite poisoning or by toxic reactions
a to oxidant drugs, or it can be found congenitally in patients
with hemoglobin M. Iron atoms in the Fe3+ state will not com-
bine with oxygen.
As already discussed in this chapter, variants of the normal
HbA may have different affinities for oxygen. HbF in red
blood cells has a dissociation curve to the left of that for
HbA, as shown in Figure 36–4B. Fetal Po2 is much lower than
in the adult; the curve is located properly for its operating
range. Furthermore, HbF’s greater affinity for oxygen relative
to the maternal hemoglobin promotes transport of oxygen
across the placenta by maintaining the diffusion gradient.
The shape of the HbF curve in blood appears to be a result of
the fact that 2,3-BPG has little effect on the affinity of HbF
for oxygen.
Myoglobin (Mb), a heme protein that occurs naturally in
muscle cells, consists of a single polypeptide chain attached to
100
gle molecule of oxygen and is similar structurally to a single
subunit of hemoglobin. As can be seen in Figure 36–4C, the
hyperbolic dissociation curve of Mb (which is similar to that
of a single hemoglobin subunit) is far to the left of that of nor-
mal HbA; that is, at lower Po2, much more oxygen remains
bound to Mb. Mb can therefore store oxygen in skeletal mus-
cle. As blood passes through the muscle, oxygen leaves hemo-
globin and binds to Mb. It can be released from the Mb when
conditions within muscle cause lower tissue Po2.
Cyanosis is not really an influence on the transport of oxy-
gen but rather is a sign of poor transport of oxygen. It occurs
when more than 5 g Hb/100 mL of arterial blood is in the
deoxy state. It is a bluish purple discoloration of the skin, nail
beds, and mucous membranes, and its presence is indicative of
an abnormally high concentration of deoxyhemoglobin in the
arterial blood. Its absence, however, does not exclude hypox-
emia because an anemic patient with hypoxemia may not have
sufficient hemoglobin to appear cyanotic.
TRANSPORT OF CARBON
DIOXIDE BY THE BLOOD
Carbon dioxide is carried in the blood in physical solution,
chemically combined to amino acids in blood proteins, and as
bicarbonate ions. About 200–250 mL of carbon dioxide is pro-
duced by the tissue metabolism each minute in a resting 70-kg
person and must be carried by the venous blood to the lung for
removal from the body. At a cardiac output of 5 L/min, each
100 mL of blood passing through the lungs must therefore
unload 4–5 mL of carbon dioxide.
PHYSICALLY DISSOLVED
Carbon dioxide is about 20 times more soluble in the plasma
(and inside the erythrocytes) compared to oxygen. As a result,
about 5–10% of the total carbon dioxide transported by the
blood is carried in physical solution.
 CHAPTER 36 Transport of Oxygen and Carbon Dioxide 369

20 100
Normal blood
O2 bound to hemoglobin, mL O2/100 mL

16 80

Mb

nit
bu
su
60

A
12

Hb
Saturation (%)

Hb
50% CO Hb

40
8
Anemia
(6 g Hb/100 mL blood)

20
4

0
0 0 20 40 60 80 100
0 20 40 60 80 100
A. C. PO (mm Hg)
PO2 (mm Hg) 2

100

80
Hemoglobin saturation (%)

HbF

60
A
Hb

40 FIGURE 36–4 Other physiologic factors influencing oxygen

transport and storage. A) The effects of carbon monoxide and
anemia on the carriage of oxygen by hemoglobin. Note that the
ordinate is expressed as the volume of oxygen bound to hemoglobin
20 in milliliters of oxygen per 100 mL of blood. B) A comparison of the
oxyhemoglobin dissociation curves for normal adult hemoglobin
(HbA) and fetal hemoglobin (HbF). C) Dissociation curves for normal
0 HbA, a single monomeric subunit of hemoglobin (Hb subunit), and
0 20 40 60 80 100 myoglobin (Mb). (Modified with permission from Levitzky MG: Pulmonary
B. PO2 (mm Hg) Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

About 0.0006mL CO2/(mm Hg Pco2) will dissolve in 1 mL CARBAMINO COMPOUNDS

of plasma at 37°C. One hundred milliliters of plasma or
whole blood at a Pco2 of 40 mm Hg, therefore, contains about Carbon dioxide can combine chemically with the terminal
2.4 mL CO2 in physical solution. Figure 36–5 shows that the amine groups in blood proteins, forming carbamino com-
total CO2 content of whole blood is about 48 mL CO2/100 pounds. The reaction occurs rapidly; no enzymes are necessary.
mL of blood at 40 mm Hg, so approximately 5% of the car- Note that a hydrogen ion is released when a carbamino com-
bon dioxide carried in the arterial blood is in physical solu- pound is formed:
tion. Similarly, multiplying 0.06mL CO2/100mL of blood/
(mm Hg Pco2) times a venous Pco2 of 45 mm Hg shows that H H
about 2.7 mL CO2 is physically dissolved in the mixed venous
blood. The total carbon dioxide content of venous blood is R N + CO2 R N + H+
about 52.5 mL CO2/100 mL of blood; a little more than 5% of
H COO–
the total carbon dioxide content of venous blood is in physi- Terminal Carbamino
cal solution. amine group compound
370 SECTION VI Pulmonary Physiology

70

Whole blood carbon dioxide content, mL CO2 /100 mL blood

HbO 2
0%
60 HbO 2
70%
v- bO 2
%H
50 97.5
a

40

30

20

FIGURE 36–5 Carbon dioxide dissociation curves 10

for whole blood (37°C) at different oxyhemoglobin
saturations. Note that the ordinate is whole blood CO2 content
in milliliters of CO2 per 100 mL of blood. a, arterial point; –v, 0
0 10 20 30 40 50 60 70 80
mixed venous point. (Modified with permission from Levitzky MG:
PCO (mm Hg)
Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.) 2

Because the protein found in greatest concentration in the dissociation of carbonic acid, thus allowing the reaction to
blood is the globin of hemoglobin, most of the carbon diox- continue. This will be discussed in detail in the last section of
ide transported in this manner is bound to amino acids of this chapter.
hemoglobin. Deoxyhemoglobin can bind more carbon diox-
ide as carbamino groups than can oxyhemoglobin. Therefore,
as the hemoglobin in the venous blood enters the lung THE CARBON DIOXIDE
and combines with oxygen, it releases carbon dioxide from
its terminal amine groups. About 5–10% of the total car- DISSOCIATION CURVE
bon dioxide content of blood is in the form of carbamino
The carbon dioxide dissociation curve for whole blood is
compounds.
shown in Figure 36–5. Within the normal physiologic range
of Pco2, the curve is nearly a straight line, with no steep or
BICARBONATE flat portions. The carbon dioxide dissociation curve for
whole blood is shifted to the right at greater levels of oxyhe-
The remaining 80–90% of the carbon dioxide transported by moglobin and shifted to the left at greater levels of deoxyhe-
the blood is carried as bicarbonate ions. This is made possible moglobin. This is known as the Haldane effect. The Haldane
by the following reaction: effect allows the blood to load more carbon dioxide at the
tissues, where there is more deoxyhemoglobin, and unload
CO2 + H2O Carbonic anhydrase H2CO3 H+ + HCO3– (12) more carbon dioxide in the lungs, where there is more oxy-
hemoglobin.
Carbon dioxide can combine with water to form carbonic The Bohr and Haldane effects are both explained by the fact
acid, which then dissociates into a hydrogen ion and a bicar- that deoxyhemoglobin is a weaker acid than oxyhemoglobin;
bonate ion. that is, deoxyhemoglobin more readily accepts the hydrogen
Very little carbonic acid is formed by the association of ion liberated by the dissociation of carbonic acid, thus permit-
water and carbon dioxide without the presence of the enzyme ting more carbon dioxide to be transported in the form of
carbonic anhydrase because the reaction occurs so slowly. bicarbonate ion. This is referred to as the isohydric shift. Con-
Carbonic anhydrase, which is present in high concentration versely, the association of hydrogen ions with the amino acids
in erythrocytes (but not in plasma), makes the reaction pro- of hemoglobin lowers the affinity of hemoglobin for oxygen,
ceed about 13,000 times faster. (Note that the product of the thus shifting the oxyhemoglobin dissociation curve to the
carbonic anhydrase reaction is actually not carbonic acid, but right at low pH or high Pco2. The following relationship can
a bicarbonate ion and a proton—see Chapter 47.) Hemoglo-
therefore be written:
bin also plays an integral role in the transport of carbon diox-
ide because it can accept the hydrogen ion liberated by the H+Hb + O2 H+ + HbO2 (13)
 CHAPTER 36 Transport of Oxygen and Carbon Dioxide 371

A. IN THE TISSUES

TISSUE PLASMA ERYTHROCYTE

Dissolved

CO2 CO2 CO2 Dissolved

H2O H2O  CO2

CAPILLARY WALL
Carbonic anhydrase CO2
H2CO3

HCO3 HCO3  H

Cl Cl
H  HbO2

O2 O2 O2  HHb HHb  CO2

Carbamino compounds

B. IN THE LUNG

ALVEOLUS PLASMA ERYTHROCYTE

Dissolved

CO2 CO2 CO2 Dissolved

H2O H2O  CO2

CAPILLARY WALL

Carbonic anhydrase CO2

H2CO3

HCO3 HCO3  H
Cl Cl
H  HbO2

O2 O2 O2  HHb HHb  CO2

Carbamino compounds

FIGURE 36–6 Schematic representation of uptake and release of carbon dioxide and oxygen at the tissues (A) and in the lung (B).
Note that small amounts of carbon dioxide can form carbamino compounds with blood proteins other than hemoglobin and may also be
hydrated in trivial amounts in the plasma to form carbonic acid and then bicarbonate (not shown in diagram). The circles represent the
bicarbonate–chloride exchange carrier protein. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

These effects can be seen in the schematic diagrams of oxy-
gen and carbon dioxide transport shown in Figure 36–6.
At the tissues, the Po2 is decreased and the Pco2 is increased.
Carbon dioxide dissolves in the plasma, and some diffuses
into the erythrocyte. Some of this carbon dioxide dissolves in
the cytosol, some forms carbamino compounds with hemo-
globin, and some is hydrated by carbonic anhydrase to form
carbonic acid. At low Po2, there are substantial amounts of
deoxyhemoglobin in the erythrocytes and the deoxyhemo-
globin is able to accept the hydrogen ions liberated by the dis-
sociation of carbonic acid and the formation of carbamino
compounds. The hydrogen ions released by the dissociation
of carbonic acid and the formation of carbamino compounds
bind to specific amino acid residues on the globin chains and
facilitate the release of oxygen from hemoglobin (the Bohr
effect). Bicarbonate ions diffuse out of the erythrocyte
372 SECTION VI Pulmonary Physiology
through the cell membrane much more readily than do
hydrogen ions. Because more bicarbonate ions than hydrogen
ions leave the erythrocyte, electrical neutrality is maintained
by the exchange of chloride ions for bicarbonate ions by the
bicarbonate–chloride carrier protein. This is the “chloride
shift.” Small amounts of water also move into the cell to main-
tain the osmotic equilibrium.
At the lung, the Po2 is increased and the Pco2 is decreased. As
oxygen combines with hemoglobin, the hydrogen ions that
were taken up when it was in the deoxyhemoglobin state are
released. They combine with bicarbonate ions, forming car-
bonic acid. This breaks down into carbon dioxide and water.
At the same time, carbon dioxide is also released from the car-
bamino compounds. Carbon dioxide then diffuses out of the
red blood cells and plasma and into the alveoli. A chloride
shift opposite in direction to that in the tissues also occurs to
maintain electrical neutrality.
CLINICAL CORRELATION
An 18-year-old man is brought by ambulance to the emer-
gency department about 35 minutes after being shot in the
leg. He is conscious, although disoriented and in pain, and
appears pale. Heart rate is 150/min and his arterial blood
pressure is 80/60 mm Hg. He is breathing spontaneously
with a high respiratory rate of 26/min. During the trip to
hospital, the wound was stabilized and he received 2 L of
normal saline (0.9% NaCl in water) solution intravenously.
In the emergency department, he continues to lose
blood while the physicians attempt to stop the hemor-
rhage. As his arterial blood pressure continues to
decrease to 60/45 mm Hg, he is given 2 additional liters
of saline. His hematocrit decreases to 21% (normal range
40–50%), corresponding to a hemoglobin concentration
of 7 g/100 mL of blood (normal range 13–18 g/100 mL
blood). His respiratory rate increases to 40/min.
Results of blood gas analysis (see Chapter 37) from an
arterial blood sample show an arterial Po2 of 95 mm Hg, an
arterial Pco2 of 28 mm Hg (normal range 35–45 mm Hg),
and an arterial pH of 7.30 (normal range 7.35–7.45) despite
the hypocapnia. He becomes agitated and loses conscious-
ness. He is intubated (a tube inserted into trachea) and
mechanically ventilated via the endotracheal tube.
The patient’s decreased blood volume led to decreased
venous return, decreased cardiac output, and decreased
systemic blood pressure. Decreased firing of the barore-
ceptors in the carotid sinuses and aortic arch decreased
parasympathetic stimulation of the heart and increased
sympathetic stimulation of the heart, arterioles, and the
veins. This resulted in increased heart rate and myocar-
dial contractility; increased arteriolar tone; and decreased
venous compliance to enhance venous return, cardiac
output, and blood pressure. However, all of these
responses were not sufficient to increase his blood pres-
sure or his cardiac output to normal levels, as he contin-
ued to lose blood. The decreased cardiac output and
increased vascular resistance to most vascular beds
resulted in decreased tissue perfusion (including his skin,
explaining his pale appearance). This ischemia resulted
in production of lactic acid causing hydrogen ion stimu-
lation of the arterial chemoreceptors (see Chapters 37
and 38), which explains his tachypnea (high respiratory
rate). He was hyperventilating in compensation as dem-
onstrated by the hypocapnia. As he continued to lose
blood, his blood pressure was no longer sufficient to pro-
vide adequate cerebral blood flow and he lost conscious-
ness and showed signs of circulatory shock.
Administration of normal saline temporarily increased
blood volume, but diluted his erythrocytes, decreasing his
hematocrit, hemoglobin concentration, oxygen-carrying
capacity, and arterial oxygen content, even if his alveolar
and arterial partial pressures of oxygen were normal.
Mixed venous Po2 would decrease as tissues extracted as
much oxygen as possible from the arterial blood. Renal
and endocrine responses to hemorrhage also would occur,
as will be discussed in Sections 7 and 9.
In the emergency department, his treatment would be
aimed at stopping blood loss and restoring cardiac output
and blood pressure with matched packed red blood cells
(red blood cells after most of the plasma and other cells
have been removed from whole blood) to restore his oxy-
gen carrying capacity.
CHAPTER SUMMARY
■ Blood normally carries a small amount of oxygen physically
dissolved in the plasma and a large amount chemically
combined to hemoglobin: only the physically dissolved oxygen
contributes to the partial pressure, but the partial pressure of
oxygen determines how much combines chemically with
hemoglobin.
■ The oxyhemoglobin dissociation curve describes the reversible
reaction of oxygen and hemoglobin to form oxyhemoglobin; it
is relatively flat at a Po2 above approximately 70 mm Hg and is
very steep at a Po2 in the range of 20–40 mm Hg.
■ Decreased pH, increased Pco2, increased temperature, and
increased 2,3-BPG concentration of the blood all shift the
oxyhemoglobin dissociation curve to the right.
■ Blood normally carries small amounts of carbon dioxide
physically dissolved in the plasma and chemically combined to
blood proteins as carbamino compounds and a large amount in
the form of bicarbonate ions.
■ Deoxyhemoglobin favors the formation of carbamino
compounds, and it promotes the transport of carbon dioxide
as bicarbonate ions by buffering hydrogen ions formed by
the dissociation of carbonic acid.
 CHAPTER 36 Transport of Oxygen and Carbon Dioxide 373

STUDY QUESTIONS 3. Which of the following should increase the P50 of the
oxyhemoglobin dissociation curve?
1. An otherwise healthy person has lost enough blood to decrease A) hypercapnia
the hemoglobin concentration from 15 to 12 g/100 mL blood. B) acidosis
Which of the following would be expected to decrease? C) increased blood levels of 2,3-BPG
A) arterial Po2 D) increased body temperature
B) blood oxygen-carrying capacity E) all of the above
C) arterial hemoglobin saturation 4. Most of the carbon dioxide in the blood is transported
D) arterial oxygen content
A) as bicarbonate.
E) B and D.
B) as carbamino compounds.
2. A woman’s hemoglobin concentration is 10 g of hemoglobin per C) physically dissolved in the plasma.
100 mL of blood. If her hemoglobin is 90% saturated with oxygen D) physically dissolved inside erythrocytes.
at an arterial Po2 of 80 mm Hg, what is her total arterial oxygen
content, including physically dissolved oxygen?
A) 10.72 mL O2/100 mL blood
B) 10.96 mL O2/100 mL blood
C) 12.06 mL O2/100 mL blood
D) 12.30 mL O2/100 mL blood
E) 13.40 mL O2/100 mL blood
This page intentionally left blank

Acid–Base Regulation
and Causes of Hypoxia
Michael Levitzky
O B J E C T I V E S
■ Define acids, bases, and buffers.
■ List the buffer systems available in the human body.
■ State the normal ranges of arterial pH, PCO2, and bicarbonate concentration,
and define alkalosis and acidosis.
■ List the potential causes of respiratory acidosis and alkalosis and metabolic
acidosis and alkalosis.
■ Discuss the respiratory mechanisms that help compensate for acidosis
and alkalosis.
■ Evaluate blood gas data to determine acid–base status.
■ Classify and explain the causes of tissue hypoxia.
The respiratory and renal systems maintain the balance of
acids and bases in the body. This chapter will introduce the
major concepts of the respiratory system’s contribution to
acid–base balance; Chapter 47 addresses the renal system con-
tribution to acid–base balance and includes a more detailed
discussion of the basic chemistry of acid–base physiology, buf-
fers, and the chemistry of the CO2–bicarbonate system.
INTRODUCTION TO
ACID–BASE CHEMISTRY
An acid can be simply defined as a substance that can donate
a hydrogen ion (a proton) to another substance and a base as
a substance that can accept a hydrogen ion from another sub-
stance. A strong acid is a substance that is completely or
almost completely dissociated into a hydrogen ion and its cor-
responding or conjugate base in dilute aqueous solution; a
weak acid is only slightly ionized in aqueous solution. In gen-
eral, a strong acid has a weak conjugate base and a weak acid
has a strong conjugate base. The strength of an acid or a base
should not be confused with its concentration.
A buffer is a mixture of substances in aqueous solution
(usually a combination of a weak acid and its conjugate base)
that can resist changes in hydrogen ion concentration when
Ch37_375-384.indd 375
37
C H A P T E R
strong acids or bases are added; that is, the changes in hydro-
gen ion concentration that occur when a strong acid or base is
added to a buffer system are much smaller than those that
would occur if the same amount of acid or base were added to
pure water or another nonbuffer solution.
The hydrogen ion activity of pure water is about 1.0 ×
10–7 mol/L. By convention, solutions with hydrogen ion activi-
ties above 10–7 mol/L are considered to be acid; those with
hydrogen ion activities below 10–7 are considered to be alka-
line. The range of hydrogen ion concentrations or activities in
the body is normally from about 10–1 for gastric acid to about
10–8 for the most alkaline pancreatic secretion. This wide range
of hydrogen ion activities necessitates the use of the more con-
venient pH scale. The pH of a solution is the negative loga-
rithm of its hydrogen ion activity. With the exception of the
highly concentrated gastric acid, in most instances in the body,
the hydrogen ion activity is about equal to the hydrogen ion
concentration.
The pH of arterial blood is normally close to 7.40, with a
normal range considered to be about 7.35–7.45. An arterial
pH (pHa) less than 7.35 is considered acidemia; a pHa greater
than 7.45 is considered alkalemia. The underlying condition
characterized by hydrogen ion retention or by loss of bicar-
bonate or other bases is referred to as acidosis; the underlying
condition characterized by hydrogen ion loss or retention of
375
11/29/10 4:40:09 PM
376 SECTION VI Pulmonary Physiology
TABLE 37–1 The pH scale.
pH Concentration (nmol/L)
6.90 126
7.00 100
7.10 79
7.20 63
7.30 50
7.40 40
7.50 32
7.60 25
7.70 20
7.80 16
Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed.
New York: McGraw-Hill Medical, 2007.
base is referred to as alkalosis. Under pathologic conditions,
the extremes of arterial blood pH have been noted to range as
high as 7.8 and as low as 6.9. These correspond to hydrogen
ion concentrations as seen in Table 37–1 (hydrogen ion con-
centrations are expressed as nanomoles [10–9 mol/L] for conve-
nience).
Note that the pH scale is “inverted” by the negative sign and
is also logarithmic as it is defined. An increase in pH repre-
sents a decrease in hydrogen ion concentration. In fact, an
increase of only 0.3 pH units indicates that the hydrogen ion
concentration was cut in half.
Hydrogen ions are the most reactive cations in body fluids,
and they interact with negatively charged regions of other
molecules, such as those of body proteins. Interactions of
hydrogen ions with negatively charged functional groups of
proteins can lead to marked changes in protein structural con-
formations with resulting alterations in the behavior of the
proteins. An example of this was already seen in Chapter 36,
where hemoglobin was noted to combine with less oxygen at a
lower pH (the Bohr effect). Alterations in the structural con-
formations and charges of protein enzymes affect their activi-
ties, with resulting alterations in the functions of body tissues.
Extreme changes in the hydrogen ion concentration of the
body can result in loss of organ system function and may be
fatal.
Under normal circumstances, cellular metabolism is the
main source of acids in the body. These acids are the waste
products of substances ingested as foodstuffs. The greatest
source of hydrogen ions is the carbon dioxide produced as one
of the end products of the oxidation of glucose and fatty acids
during aerobic metabolism. The hydration of carbon dioxide
results in the formation of carbonic acid, which then can dis-
sociate into a hydrogen ion and a bicarbonate ion, as discussed
in Chapter 36. This process is reversed in the pulmonary capil-
laries, and CO2 then diffuses through the alveolar–capillary
barrier into the alveoli, from which it is removed by alveolar
ventilation. Carbonic acid is therefore said to be a volatile acid
because it can be converted into a gas and then removed from
an open system such as the body. Very great amounts of car-
bon dioxide can be removed from the lungs by alveolar venti-
lation: under normal circumstances, about 15,000–25,000
mmol of carbon dioxide is removed via the lungs daily.
A much smaller quantity of fixed or nonvolatile acids is
also normally produced during the course of the metabolism
of foodstuffs. The fixed acids produced by the body include
sulfuric acid, which originates from the oxidation of sulfur-
containing amino acids such as cysteine; phosphoric acid from
the oxidation of phospholipids and phosphoproteins; hydro-
chloric acid, which is produced during the conversion of
ingested ammonium chloride to urea and by other reactions;
and lactic acid from the anaerobic metabolism of glucose.
Other fixed acids may be ingested accidentally or formed in
abnormally large quantities by disease processes, such as the
acetoacetic and butyric acid formed during diabetic ketoaci-
dosis (see Chapter 66). About 70 mEq of fixed acids is nor-
mally removed from the body each day (about 1 mEq/kg/body
weight per day); the range is 50–100 mEq. A vegetarian diet
may produce significantly less fixed acid and may even result
in no net production of fixed acids. The removal of fixed acids
is accomplished mainly by the kidneys, as will be discussed in
Chapter 47. Some may also be removed via the gastrointestinal
tract. Fixed acids normally represent only about 0.2% of the
total body acid production.
The body contains a variety of substances that can act as
buffers in the physiologic pH range. These include bicarbon-
ate, phosphate, and proteins in the blood, the interstitial fluid,
and inside cells (discussed in greater detail in Chapter 47). The
isohydric principle states that all the buffer pairs in a homo-
geneous solution are in equilibrium with the same hydrogen
ion concentration. For this reason, all the buffer pairs in the
plasma behave similarly, so that the detailed analysis of a single
buffer pair, like the bicarbonate buffer system, can reveal a
great deal about the chemistry of all the plasma buffers.
The main buffers of the blood are bicarbonate, phosphate,
and proteins. The bicarbonate buffer system consists of the
buffer pair of the weak acid, carbonic acid, and its conjugate
base, bicarbonate. The ability of the bicarbonate system to
function as a buffer of fixed acids in the body is largely due to
the ability of the lungs to remove carbon dioxide from the
body. In a closed system, bicarbonate would not be nearly as
effective.
At a temperature of 37°C, about 0.03 mmol of carbon diox-
ide per mm Hg of Pco2 will dissolve in a liter of plasma. (Note
that the solubility of CO2 was expressed as milliliters of CO2
per 100 mL of plasma in Chapter 36.) Therefore, the carbon
dioxide dissolved in the plasma, expressed as millimoles per
liter, is equal to 0.03 x Pco2 . At body temperature in the plasma,
the equilibrium of the reaction is such that there is roughly
1,000 times more carbon dioxide physically dissolved in the
plasma than there is in the form of carbonic acid. The dis-
solved carbon dioxide is in equilibrium with the carbonic acid,
though, so both the dissolved carbon dioxide and the carbonic
 CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia 377

acid are considered as the undissociated HA in the Hender-
son–Hasselbalch equation (see Chapter 47) for the bicarbon-
ate system:
pH = pK + log ___________
[CO + H CO ]
where [HCO3−]p stands for plasma bicarbonate concentration.
The concentration of carbonic acid is negligible, so we have:
pH = pK′ + log _______
0.03 P
where pK′ is the pK of the HCO3−–CO2 system in blood.
The pK′ of this system at physiologic pH values and at 37°C
is 6.1. Therefore, at a pHa of 7.40 and an arterial Pco2 of 40 mm
Hg, we have:
7.40 = 6.1 + log _________
Therefore, the arterial plasma bicarbonate concentration is
about 24 mmol/L (the normal range is 23–28 mmol/L) because
the logarithm of 20 is equal to 1.3.
Note that the term total CO2 refers to the dissolved carbon
dioxide (including carbonic acid) plus the carbon dioxide
present as bicarbonate.
A useful way to display the interrelationships among the
variables of pH, Pco2, and bicarbonate concentration of the
plasma, as expressed by the Henderson–Hasselbalch equation,
is the pH–bicarbonate diagram shown in Figure 37–1.
As can be seen from Figure 37–1, pH is on the abscissa of
the pH–bicarbonate diagram, and the plasma bicarbonate
concentration in millimoles per liter is on the ordinate. For
[H ] (nmol/L)
100 80 70 60 50
40
r
each value of pH and bicarbonate ion concentration, there is a
single corresponding Pco2 on the graph. Conversely, for any
particular pH and Pco2, only one bicarbonate ion concentra-
[HCO3–]p tion will satisfy the Henderson–Hasselbalch equation. If the
(1) Pco2 is held constant, for example, at 40 mm Hg, an isobar line
2 2 3
can be constructed, connecting the resulting points as the pH
is varied. The representative isobars shown in Figure 37–1 give
an indication of the potential alterations of acid–base status
[HCO3–]p
(2) when alveolar ventilation is increased or decreased. If every-
co2 thing else remains constant, hypoventilation leads to acidosis;
hyperventilation leads to alkalosis.
The bicarbonate buffer system is a poor buffer for carbonic
acid. The presence of hemoglobin makes blood a much better
buffer. The buffer value of plasma in the presence of hemoglobin
[HCO3–]p is four to five times that of plasma separated from erythrocytes.
(3) Therefore, the slope of the normal in vivo buffer line shown in
1.2 mmol/L
Figures 37–1 is mainly determined by the nonbicarbonate buf-
fers present in the body. The phosphate buffer system mainly
consists of the buffer pair of the dihydrogen phosphate (H2PO4−)
and the monohydrogen phosphate (HPO42−) anions.
Although several potential buffering groups are found on
proteins, only one large group has pK in the pH range
encountered in the blood. These are the imidazole groups in
the histidine residues of the peptide chains. The protein pres-
ent in the greatest quantity in the blood is hemoglobin. As
already noted, deoxyhemoglobin is a weaker acid than is
oxyhemoglobin. Thus, as oxygen leaves hemoglobin in the
tissue capillaries, the imidazole group removes hydrogen
ions from the erythrocyte interior, allowing more carbon
dioxide to be transported as bicarbonate. This process is
reversed in the lungs.
The bicarbonate buffer system is the major buffer found in
the interstitial fluid, including the lymph. The phosphate buffer
40 30 20 16 pair is also found in the interstitial fluid. The volume of the
A interstitial compartment is much larger than that of the plasma,

so the interstitial fluid may play an important role in buffering.

ba

35
iso

The extracellular portion of bone contains very large depos-

r
ba
Hg

iso

its of calcium and phosphate salts, mainly in the form of

mm

r
ba
Hg
[HCO3]p (mmol/L)

30 B
iso

hydroxyapatite. In an otherwise healthy adult, where bone

80

Hg
m


growth and resorption are in a steady state, bone salts can buf-
60

m
2
CO

m


fer hydrogen ions in chronic acidosis. Chronic buffering of

P

25 r
40

C ba
2
CO

iso


hydrogen ions by the bone salts may therefore lead to demin-

P

Hg
2
CO
P

20 m eralization of bone.
D 0m

2 The intracellular proteins and organic phosphates of most
E P CO
2 cells can function to buffer both fixed acids and carbonic acid.
15 Normal buffer line
Of course, buffering by the hemoglobin in erythrocytes is
intracellular.
10
7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8
pH

FIGURE 37–1 The pH–bicarbonate diagram with PCO isobars.

2
ACIDOSIS AND ALKALOSIS
Note the hydrogen ion concentration in nanomoles per liter at the
top of the figure corresponding to the pH values on the abscissa. Acid–base disorders can be divided into four major categories:
Points A to E correspond to different pH values and bicarbonate respiratory acidosis, respiratory alkalosis, metabolic acidosis,
concentrations all falling on the same PCO isobar. (Modified with and metabolic alkalosis. These primary acid–base disorders
2
permission of the University of Chicago Press from Davenport HW: The ABC of may occur singly (“simple”) or in combination (“mixed”) or
Acid–Base Chemistry, 6th ed. 1974.) may be altered by compensatory mechanisms.
378 SECTION VI Pulmonary Physiology

RESPIRATORY ACIDOSIS TABLE 37–2 Common causes of respiratory acidosis.

The arterial Pco2 is normally maintained at or near 40 mm Hg Depression of the respiratory control centers
Anesthetics
(normal range is 35–45 mm Hg) by the mechanisms that reg- Sedatives
ulate breathing. Sensors exposed to the arterial blood and to Opiates
the cerebrospinal fluid provide the central controllers of Brain injury or disease
breathing with the information necessary to regulate the arte- Severe hypercapnia, hypoxia
rial Pco2 at or near 40 mm Hg (see Chapter 38). Any short-term Neuromuscular disorders
alterations (i.e., those which occur without renal compensa- Spinal cord injury
tion) in alveolar ventilation that result in an increase in alveo- Phrenic nerve injury
Poliomyelitis, Guillain–Barré syndrome, etc.
lar and therefore also in arterial Pco2 tend to lower the pHa,
Botulism, tetanus
resulting in respiratory acidosis. This can be appreciated by Myasthenia gravis
examining the Pco2 = 60 and 80 mm Hg isobars in Figure 37–1. Administration of curarelike drugs
The pHa at any Paco2 depends on the bicarbonate and other Diseases affecting the respiratory muscles
buffers present in the blood. Pure changes in arterial Pco2 Chest wall restriction
caused by changes in ventilation travel along the normal in Kyphoscoliosis
vivo buffer line (Figures 37–1 and 37–2). Pure uncompen- Extreme obesity
sated respiratory acidosis would correspond with point C in Lung restriction
Figure 37–2 (at the intersection of an elevated Pco2 isobar and Pulmonary fibrosis
the normal buffer line). Sarcoidosis
In respiratory acidosis, the ratio of bicarbonate to CO2 Pneumothorax, pleural effusions, etc.
decreases. Yet, as can be seen at point C in Figure 37–2, in Pulmonary parenchymal diseases
uncompensated primary (simple) respiratory acidosis, the Pneumonia, etc.
absolute plasma bicarbonate concentration does increase Pulmonary edema
somewhat because of the buffering of some of the hydrogen Airway obstruction
ions liberated by the dissociation of carbonic acid by nonbi- Chronic obstructive pulmonary disease
carbonate buffers. Upper airway obstruction
Any impairment of alveolar ventilation can cause respira- Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed.
tory acidosis. As shown in Table 37–2, depression of the New York: McGraw-Hill Medical, 2007.
respiratory centers in the medulla (see Chapter 38) by anes-
thetic agents, narcotics, hypoxia, central nervous system dis-
ease or trauma, or even greatly increased PaCo2 itself results in processes, drugs or toxins, or dysfunctions or deformities of
hypoventilation and respiratory acidosis. Interference with the respiratory muscles or the chest wall can result in respi-
the neural transmission to the respiratory muscles by disease ratory acidosis. Restrictive, obstructive, and obliterative dis-
eases of the lungs can also result in respiratory acidosis.

40 RESPIRATORY ALKALOSIS
Metabolic alkalosis
and respiratory acidosis F
35
Uncompensated Alveolar ventilation in excess of that needed to keep pace with
metabolic alkalosis
D body’s carbon dioxide production results in alveolar and arte-
Metabolic alkalosis rial Pco2 below 35 mm Hg. Such hyperventilation leads to respi-
[HCO3]p (mmol/L)

30 Uncompensated
respiratory acidosis
E ratory alkalosis. Uncompensated primary respiratory alkalosis
Metabolic alkalosis
C
and respiratory alkalosis
results in movement to a lower Pco2 isobar along the normal buf-
25 Metabolic acidosis A fer line, as seen at point B in Figure 37–2. The decreased Paco2
and respiratory acidosis
I Normal buffer line shifts the equilibrium of the series of reactions describing car-
Metabolic
20 G acidosis
bon dioxide hydration and carbonic acid dissociation to the left.
Uncompensated B This results in a decreased arterial hydrogen ion concentration,
metabolic acidosis Uncompensated
respiratory alkalosis increased pH, and a decreased plasma bicarbonate concentra-
15
Metabolic acidosis H tion. The ratio of bicarbonate to carbon dioxide increases.
and respiratory alkalosis
The causes of respiratory alkalosis include anything leading
10
7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 to hyperventilation. As shown in Table 37–3, hyperventilation
pH syndrome, a psychological dysfunction of unknown cause,
FIGURE 37–2 Acid–base paths in vivo. (Modified with permission of results in chronic or recurrent episodes of hyperventilation and
the University of Chicago Press from Davenport HW: The ABC of Acid–Base Chemistry, respiratory alkalosis. Drugs, hormones (such as progesterone),
6th ed. 1974.) toxic substances, central nervous system diseases or disorders,
 CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia 379

TABLE 37–3 Common causes of respiratory alkalosis. TABLE 37–4 Common causes of metabolic acidosis.
Central nervous system Ingested drugs or toxic substances
Anxiety Methanol
Hyperventilation syndrome Ethanol
Inflammation (encephalitis, meningitis) Salicylates
Cerebrovascular disease Ethylene glycol
Tumors Ammonium chloride

Drugs or hormones Loss of bicarbonate ions

Salicylates Diarrhea
Progesterone Pancreatic fistulas
Renal dysfunction
Bacteremias, fever
Lactic acidosis
Pulmonary diseases Hypoxemia
Acute asthma Anemia, carbon monoxide
Pulmonary vascular diseases (pulmonary embolism) Shock (hypovolemic, cardiogenic, septic, etc.)
Severe exercise
Overventilation with mechanical ventilators Acute respiratory distress syndrome (ARDS)

Hypoxia; high altitude Ketoacidosis

Diabetes mellitus
Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed.
New York: McGraw-Hill Medical, 2007. Alcoholism
Starvation

Inability to excrete hydrogen ions

bacteremias, fever, overventilation by mechanical ventilators
Renal dysfunction
(or the clinician), or ascent to high altitude may all result in
respiratory alkalosis. Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed.
New York: McGraw-Hill Medical, 2007.

METABOLIC ACIDOSIS
Metabolic acidosis may be thought of as nonrespiratory
as a consequence of the ingestion, infusion, or excessive renal
acidosis. It can be caused by the ingestion, infusion, or
reabsorption of bases such as bicarbonate. Figure 37–2 shows
production of a fixed acid; decreased renal excretion of
that primary uncompensated metabolic alkalosis results in an
hydrogen ions; the movement of hydrogen ions from the
upward movement along the Pco2 = 40 mm Hg isobar to point
intracellular to the extracellular compartment; or the
D, that is, a net gain of buffer establishes a new blood–buffer
loss of bicarbonate or other bases from the extracellular com-
line higher than and parallel to the normal blood–buffer line.
partment. As can be seen in Figure 37–2, primary uncom-
Pco2 is unchanged, hydrogen ion concentration is decreased,
pensated metabolic acidosis results in a downward movement
and the ratio of bicarbonate concentration to carbon dioxide is
along the Pco2 = 40 mm Hg isobar to point G, that is, a net loss
increased.
of buffer establishes a new blood–buffer line lower than and
As shown in Table 37–5, loss of gastric juice by vomiting
parallel to the normal blood–buffer line. Pco2 is unchanged,
results in a loss of hydrogen ions and may cause metabolic
hydrogen ion concentration is increased, and the ratio of
alkalosis. Excessive ingestion of bicarbonate or other bases
bicarbonate concentration to CO2 is decreased.
(e.g., stomach antacids) or overinfusion of bicarbonate by
As shown in Table 37–4, ingestion of methyl alcohol or sali-
the clinician may cause metabolic alkalosis. In addition,
cylates can cause metabolic acidosis by increasing the fixed
acids in the blood. (Salicylate poisoning—for example, aspirin
overdose—causes both metabolic acidosis and later respira-
tory alkalosis.) Diarrhea can cause significant bicarbonate TABLE 37–5 Common causes of metabolic alkalosis.
losses, resulting in metabolic acidosis. Renal dysfunction can
lead to an inability to excrete hydrogen ions, as well as an Loss of hydrogen ions
inability to reabsorb bicarbonate ions, as will be discussed in Vomiting
Gastric fistulas
the next section. True “metabolic” acidosis may be caused by Diuretic therapy
an accumulation of lactic acid in severe hypoxemia or shock
and by diabetic ketoacidosis. Treatment with or overproduction of steroids (aldosterone or other
mineralocorticoids)
Ingestion or administration of excess bicarbonate or other bases
METABOLIC ALKALOSIS Intravenous bicarbonate
Ingestion of bicarbonate or other bases (e.g., antacids)
Metabolic, or nonrespiratory, alkalosis occurs when there is Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed.
an excessive loss of fixed acids from the body, or it may occur New York: McGraw-Hill Medical, 2007.
380 SECTION VI Pulmonary Physiology
diuretic therapy, treatment with steroids (or the overpro-
duction of endogenous steroids), and conditions leading to
severe potassium depletion may also cause metabolic
alkalosis.
COMPENSATORY MECHANISMS
Uncompensated primary acid–base disturbances, such as
those indicated by points B–D and G in Figure 37–2, seldom
occur because respiratory and renal compensatory mecha-
nisms are called into play to offset these disturbances. The two
main compensatory mechanisms are functions of the respira-
tory and renal systems.
RESPIRATORY COMPENSATORY
MECHANISMS
The respiratory system can compensate for metabolic acidosis
or alkalosis by altering alveolar ventilation. As discussed in
Chapter 33, if carbon dioxide production is constant, the alve-
olar Pco2 is inversely proportional to the alveolar ventilation. In
metabolic acidosis, the increased blood hydrogen ion concen-
tration stimulates chemoreceptors, which, in turn, increase
alveolar ventilation, thus decreasing arterial Pco2. This causes
an increase in pHa, returning it toward normal. (The mecha-
nisms by which ventilation is regulated are discussed in detail
in Chapter 38.) These events can be better understood by look-
ing at Figure 37–2. Point G represents uncompensated meta-
bolic acidosis. As the respiratory compensation for the
metabolic acidosis occurs, in the form of an increase in venti-
lation, the arterial Pco2 decreases. The point representing blood
pHa, Paco2, and bicarbonate concentration would then move a
short distance along the lower-than-normal buffer line (from
point G toward point H) until a new lower Paco2 is attained.
This returns the pHa toward normal; complete compensation
does not occur. The respiratory compensation for metabolic
acidosis occurs almost simultaneously with the development
of the acidosis. The blood pH, Pco2, and bicarbonate concen-
tration point does not really move first from the normal
(point A) to point G and then move a short distance along line
GH; instead, the compensation begins to occur as the acidosis
develops, so the point takes an intermediate pathway between
the two lines.
The respiratory compensation for metabolic alkalosis is to
decrease alveolar ventilation, thus increasing Paco2. This
decreases pHa toward normal, as can be seen in Figure 37–2.
Point D represents uncompensated metabolic alkalosis; respi-
ratory compensation would move the blood pHa, PaCo2, and
bicarbonate concentration point a short distance along the
new higher-than-normal blood–buffer line toward point F.
Again the compensation occurs as the alkalosis develops, with
the point moving along an intermediate course.
Under most circumstances, the cause of respiratory aci-
dosis or alkalosis is a dysfunction in the ventilatory control
mechanism or the breathing apparatus itself. Compensa-
tion for acidosis or alkalosis in these conditions must there-
fore come from outside the respiratory system. The
respiratory compensatory mechanism can operate very
rapidly (within minutes) to partially correct metabolic aci-
dosis or alkalosis.
RENAL COMPENSATORY MECHANISMS
The kidneys can compensate for respiratory acidosis and met-
abolic acidosis of nonrenal origin by excreting fixed acids and
by retaining filtered bicarbonate. They can also compensate
for respiratory alkalosis or metabolic alkalosis of nonrenal ori-
gin by decreasing hydrogen ion excretion and by decreasing
the retention of filtered bicarbonate. These mechanisms are
discussed in Chapter 47. Renal compensatory mechanisms for
acid–base disturbances operate much more slowly than respi-
ratory compensatory mechanisms. For example, the renal
compensatory responses to sustained respiratory acidosis or
alkalosis may take 3–6 days.
The kidneys help regulate acid–base balance by altering the
excretion of fixed acids and the retention of the filtered bicar-
bonate; the respiratory system helps regulate body acid–base
balance by adjusting alveolar ventilation to alter alveolar Pco2. For
these reasons, the Henderson–Hasselbalch equation is in effect:
Kidneys
pH = Constant + ______
Lungs
(4)
CLINICAL INTERPRETATION
OF ARTERIAL BLOOD GASES
Samples of arterial blood are usually analyzed clinically to
determine the “arterial blood gases”: the arterial Po2, Pco2, and
pH. The plasma bicarbonate can then be calculated from the
pH and Pco2 by using the Henderson–Hasselbalch equation.
This can be done directly, or by using a nomogram, or by
graphical analysis such as the pH–bicarbonate diagram
(the “Davenport plot,” after its popularizer), the pH– Pco2 dia-
gram (the “Siggaard-Andersen”), or the composite acid–base
diagram. Blood gas analyzers perform these calculations
automatically.
Table 37–6 summarizes the changes in pHa, Paco2, and
plasma bicarbonate concentration that occur in simple, mixed,
and partially compensated acid–base disturbances. It contains
the same information shown in Figure 37–2, depicted differ-
ently. A thorough understanding of the patterns shown in
Table 37–6 coupled with knowledge of a patient’s Pco2 and
other clinical findings can reveal a great deal about the under-
lying pathophysiologic processes in progress.
A simple approach to interpreting a blood gas set is to first
look at the pH to determine whether the predominant prob-
lem is acidosis or alkalosis. (Note that an acidemia could rep-
resent more than one cause of acidosis, an acidosis with some
compensation, or even an acidosis and a separate underlying
 CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia 381

TABLE 37–6 Acid–base disturbances. istered to a patient. The base excess or base deficit is the num-
ber of milliequivalents of acid or base needed to titrate 1 L of
pH PCO2 HCO3− blood to pH 7.4 at 37°C if the Paco2 were held constant at
Uncompensated respiratory ↓↓ ↑↑ ↑ 40 mm Hg. It is not, therefore, just the difference between the
acidosis plasma bicarbonate concentration of the sample in question
and the normal plasma bicarbonate concentration because
Uncompensated respiratory ↑↑ ↓↓ ↓
alkalosis respiratory adjustments also cause a change in bicarbonate
concentration: the arterial Pco2 must be considered, although
Uncompensated metabolic ↓↓ ↔ ↓↓ in most cases the vertical deviation of the bicarbonate level
acidosis
above or below the blood–buffer line on the Davenport dia-
Uncompensated metabolic ↑↑ ↔ ↑↑ gram at the pH of the sample is a reasonable estimate. Base
alkalosis excess can be determined by actually titrating a sample or by
using a nomogram, diagram, or calculator program. Most
Partially compensated ↓ ↑↑ ↑↑
respiratory acidosis blood gas analyzers calculate the base excess automatically.
The base excess is expressed in milliequivalents per liter above
Partially compensated ↑ ↓↓ ↓↓ or below the normal buffer-base range—it therefore has
respiratory alkalosis
a normal value of 0 ± 2 mEq/L. A base deficit is also called a
Partially compensated ↓ ↓↓ ↓↓ negative base excess.
metabolic acidosis The base deficit can be used to estimate how much sodium
Partially compensated ↑ ↑↑ ↑↑ bicarbonate (in mEq) should be given to a patient by multiply-
metabolic alkalosis ing the base deficit (in mEq/L) times the patient’s estimated
extracellular fluid (ECF) space (in liters), which is the distri-
Respiratory and metabolic ↓↓ ↑↑ ↓
acidosis
bution space for the bicarbonate. The ECF is usually estimated
to be 0.3 times the lean body mass in kilograms.
Respiratory and metabolic ↑↑ ↓↓ ↑
alkalosis
Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed.
ANION GAP
New York: McGraw-Hill Medical, 2007.
Calculation of the anion gap can be helpful in determining the
cause of a patient’s metabolic acidosis. It is determined by sub-
alkalosis. Similarly, an alkalemia could represent more than tracting the sum of a patient’s plasma chloride and bicarbonate
one cause of alkalosis, an alkalosis with some compensation, or concentrations (in mEq/L) from his or her plasma sodium
even an alkalosis and a separate underlying acidosis.) After concentration:
evaluating the pH, look at the arterial Pco2 to see if it explains
Anion gap =[Na+]–([C1–]+[HCO3–]) (5)
the pH. For example, if the pH is low and the Pco2 is increased,
then the primary problem is respiratory acidosis. If the pH is The anion gap is normally 12 ± 4 mEq/L.
low and the Pco2 is near 40 mm Hg, then the primary problem The sum of all of the plasma cations must equal the sum of
is metabolic acidosis with little or no compensation. If both the all of the plasma anions, so the anion gap exists only because
pH and the Pco2 are low, there is metabolic acidosis with respi- all of the plasma cations and anions are not measured when
ratory compensation. Then look at the bicarbonate concentra- standard blood chemistry is done. Sodium, chloride, and
tion to confirm your diagnosis. It should be slightly increased bicarbonate concentrations are almost always reported. The
in uncompensated respiratory acidosis, high in partially com- normal anion gap is a result of the presence of more unmea-
pensated respiratory acidosis, and low in metabolic acidosis. sured anions than unmeasured cations in normal blood:
If the pH is high and the Pco2 is low, then the primary prob-
lem is respiratory alkalosis. If the pH is high and the Pco2 is [Na+]+[Unmeasured cations]= (6)
near 40 mm Hg, then the problem is uncompensated meta- –
[ C1 ]+[HCO3–]+[Unmeasured anions]
bolic alkalosis. If both the pH and the Pco2 are high, then there
is partially compensated metabolic alkalosis. The bicarbonate [Na+]–([ C1–]+[HCO3–])=
(7)
should be slightly decreased in respiratory alkalosis, decreased [Unmeasured anions]–[Unmeasured cations]
in partially compensated respiratory alkalosis, and increased
The anion gap is therefore the difference between the unmea-
in metabolic alkalosis.
sured anions and the unmeasured cations.
The negative charges on the plasma proteins probably make
BASE EXCESS up most of the normal anion gap, because the total charges of
the other plasma cations (K+, Ca2+, Mg2+) are approximately
Calculation of the base excess or base deficit may be very equal to the total charges of the other anions (PO43−, SO42−,
useful in determining the therapeutic measures to be admin- organic anions).
382 SECTION VI Pulmonary Physiology

An increased anion gap usually indicates an increased num-
ber of unmeasured anions (those other than C1– and HCO3−)
or a decreased number of unmeasured cations (K+, Ca2+, or
Mg2+), or both. This is most likely to happen when the mea-
sured anions, [HCO3−] or [Cl–], are lost and replaced by unmea-
sured anions. For example, the buffering by HCO3− of H+ from
ingested or metabolically produced acids produces an increased
anion gap.
Thus, metabolic acidosis with an abnormally great anion
gap (i.e., greater than 16 mEq/L) would probably be caused by
lactic acidosis or ketoacidosis; ingestion of organic anions
such as salicylate, methanol, and ethylene glycol; or renal
retention of anions such as sulfate, phosphate, and urate.
THE CAUSES OF HYPOXIA
Thus far, only two of the three variables referred to as the arte-
rial blood gases, the arterial Pco2, and pH have been discussed.
Many abnormal conditions or diseases can cause a low arterial
Po2. They are discussed in the following section about the
causes of tissue hypoxia in the discussion of hypoxic hypoxia.
The causes of tissue hypoxia can be classified (in some cases
rather arbitrarily) into four or five major groups (Table 37–7).
The underlying physiology of most of these types of hypoxia
has already been discussed in this or previous chapters.
HYPOXIC HYPOXIA
Hypoxic hypoxia refers to conditions in which the arterial Po2
is abnormally low. Because the amount of oxygen that will
combine with hemoglobin is mainly determined by the Po2,
such conditions may lead to decreased oxygen delivery to the
tissues if reflexes or other responses cannot adequately increase
the cardiac output or hemoglobin concentration of the blood.
Low Alveolar PO2
Conditions causing low alveolar Po2 inevitably lead to low arte-
rial Po2 and oxygen contents because the alveolar Po2 deter-
mines the upper limit of arterial Po2. Hypoventilation leads to
both alveolar hypoxia and hypercapnia (high CO2), as dis-
cussed in Chapter 33. Hypoventilation can be caused by
depression or injury of the respiratory centers in the brain
(discussed in Chapter 38), interference with the nerves supply-
ing the respiratory muscles, as in spinal cord injury, neuro-
muscular junction diseases such as myasthenia gravis, and
altered mechanics of the lung or chest wall, as in noncompliant
lungs due to sarcoidosis, reduced chest wall mobility because
of kyphoscoliosis or obesity, and airway obstruction. Ascent to
high altitude causes alveolar hypoxia because of the reduced
total barometric pressure encountered above sea level. Reduced
FIo2 (fractional concentration of inspired oxygen) has a similar
effect. Alveolar carbon dioxide is decreased because of the
reflex increase in ventilation caused by hypoxic stimulation, as
will be discussed in Chapter 71. Hypoventilation and ascent to
high altitude lead to decreased venous Po2 and oxygen content
as oxygen is extracted from the already hypoxic arterial blood.
Administration of increased oxygen concentrations in the
inspired gas can alleviate the alveolar and arterial hypoxia in
hypoventilation and in ascent to high altitude, but it cannot
reverse the hypercapnia of hypoventilation. In fact, adminis-
tration of increased FIo2 to spontaneously breathing patients
hypoventilating because of a depressed central response to car-
bon dioxide (see Chapter 38) can further depress ventilation.
Diffusion Impairment
Alveolar–capillary diffusion is discussed in greater detail in
Chapter 35. Conditions such as interstitial fibrosis and inter-
stitial or alveolar edema can lead to low arterial Po2 and con-
tents with normal or elevated alveolar Po2. High FIo2 that
increases the alveolar Po2 to very high levels may increase the

TABLE 37–7 A classification of the causes of hypoxia.

Increased FIO2
Classification PAO2 PaO2 CaO2 P –V O2 C–V O2 Helpful?

Hypoxic hypoxia

Low alveolar PO Low Low Low Low Low Yes

2

Diffusion impairment N Low Low Low Low Yes

Right-to-left shunts N Low Low Low Low No

V̇/ Q̇ mismatch N Low Low Low Low Yes

Anemic hypoxia N N Low Low Low No

CO poisoning N N Low Low Low Possibly

Hypoperfusion hypoxia N N N Low Low No

Histotoxic hypoxia N N N High High No

N, normal.
Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.
 CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia
arterial Po2 by increasing the partial pressure gradient for oxy-
gen diffusion.
Shunts
True right-to-left shunts, such as anatomic shunts and abso-
lute intrapulmonary shunts, can cause decreased arterial Po2
with normal or even increased alveolar Po2. Patients with
intrapulmonary shunts have low arterial Po2, but may not have
significantly increased Pco2 if they are able to increase their alve-
olar ventilation or if they are mechanically ventilated. This is a
result of the different shapes of the oxyhemoglobin dissociation
curve (see Figure 36–1) and the carbon dioxide dissociation
curve (see Figure 36–5). The carbon dioxide dissociation curve
is almost linear in the normal range of arterial Pco2, and arterial
Pco2 is very tightly regulated by the respiratory control system
(see Chapter 38). Carbon dioxide retained in the shunted blood
stimulates increased alveolar ventilation, and because the car-
bon dioxide dissociation curve is nearly linear, increased venti-
lation will allow more carbon dioxide to diffuse from the
nonshunted blood into well-ventilated alveoli and be exhaled.
On the other hand, increasing alveolar ventilation will not get
any more oxygen into the shunted blood and, because of the
shape of the oxyhemoglobin dissociation curve, very little more
into the unshunted blood. This is because the hemoglobin of
well-ventilated and perfused alveoli is nearly saturated with
oxygen, and little more will dissolve in the plasma. Similarly,
arterial hypoxemia caused by true shunts is not relieved by high
FIo2 because the shunted blood does not come into contact with
the high levels of oxygen. The hemoglobin of the unshunted
blood is nearly completely saturated with oxygen at a normal
FIo2 of 0.21, and the small additional volume of oxygen dis-
solved in the blood at high FIo2 cannot make up for the low
hemoglobin saturation of the shunted blood.
VENTILATION–PERFUSION MISMATCH
Alveolar–capillary units with low ventilation–perfusion (V̇/Q̇)
ratios contribute to arterial hypoxia, as already discussed. Units
with high V̇/Q̇ do not by themselves lead to arterial hypoxia, of
course, but large lung areas that are underperfused are usually
associated either with overperfusion of other units or with low
cardiac outputs (see the section “Hypoperfusion Hypoxia”).
Hypoxic pulmonary vasoconstriction (discussed in Chapter
34) and local airway responses (discussed in Chapter 32) nor-
mally help minimize V̇ / Q̇ mismatch.
Note that diffusion impairment, shunts, and V̇ / Q̇ mismatch
increase the alveolar–arterial Po2 difference (see Table 35–1
and the first two columns in Table 37–7).
ANEMIC HYPOXIA
Anemic hypoxia is caused by a decrease in the amount of func-
tioning hemoglobin, which can be a result of decreased hemo-
globin or erythrocyte production, the production of abnormal
hemoglobin or red blood cells, pathologic destruction of eryth-
383
rocytes, or interference with the chemical combination of oxy-
gen and hemoglobin. Carbon monoxide poisoning, for example,
results from the greater affinity of hemoglobin for carbon mon-
oxide than for oxygen. Methemoglobinemia is a condition in
which the iron in hemoglobin has been altered from the Fe2+ to
the Fe3+ form, which does not combine with oxygen.
Anemic hypoxia results in a decreased oxygen content when
both alveolar and arterial Po2 are normal. Standard analysis of
arterial blood gases could therefore give normal values unless
blood oxygen content is measured independently. Venous Po2
and oxygen content are both decreased. Administration of
high FIo2 is not effective in greatly increasing the arterial oxy-
gen content (except possibly in carbon monoxide poisoning).
HYPOPERFUSION HYPOXIA
Hypoperfusion hypoxia (sometimes called stagnant hypoxia)
results from low blood flow. This can occur either locally, in a
particular vascular bed, or systemically, in the case of a low car-
diac output. The alveolar Po2 and the arterial Po2 and oxygen
content may be normal, but the reduced oxygen delivery to the
tissues may result in tissue hypoxia. Venous Po2 and oxygen con-
tent are low. Increasing the FIo2 is of little value in hypoperfusion
hypoxia (unless it directly increases the perfusion) because the
blood flowing to the tissues is already oxygenated normally.
HISTOTOXIC HYPOXIA
Histotoxic hypoxia refers to a poisoning of the cellular machin-
ery that uses oxygen to produce energy. Cyanide, for example,
binds to cytochrome oxidase in the respiratory chain and effec-
tively blocks oxidative phosphorylation. Alveolar Po2 and arte-
rial Po2 and oxygen content may be normal (or even increased,
because low doses of cyanide increase ventilation by stimulat-
ing the arterial chemoreceptors). Venous Po2 and oxygen con-
tent are increased because oxygen is not utilized in the tissues.
THE EFFECTS OF HYPOXIA
Hypoxia can result in reversible tissue injury or even tissue
death. The outcome of an hypoxic episode depends on whether
the tissue hypoxia is generalized or localized, how severe
the hypoxia is, the rate of development of the hypoxia (see
Chapter 71), and the duration of the hypoxia. Different cell
types have different susceptibilities to hypoxia; unfortunately,
brain cells and heart cells are the most susceptible.
CLINICAL CORRELATION
A 15-year-old adolescent entered the emergency depart-
ment with dyspnea (shortness of breath), a feeling of chest
tightness, coughing, wheezing, and anxiety. His nail beds
and lips were blue (cyanosis).
384 SECTION VI Pulmonary Physiology
He has had frequent episodes of dyspnea and wheezing
for several years, especially in the spring, and has been
diagnosed with asthma. Pulmonary function tests done at
the time of his diagnosis showed lower-than-predicted
forced expiratory volume in the first second (FEV1), forced
vital capacity (FVC), FEV1/FVC, and peak expiratory flow
(PEF). Inhaling a bronchodilator improved all of these.
An arterial blood gas was obtained to help determine the
severity of the episode. The arterial Po2 was 55 mm Hg, the
arterial Pco2 was 32 mm Hg, the arterial pH was 7.52, and the
bicarbonate was 25 mEq/L, indicating hypoxemia and uncom-
pensated respiratory alkalosis.
Asthma is an episodic obstructive disease and it is reason-
able to assume that it would cause CO2 retention and there-
fore respiratory acidosis during attacks. This is true in very
severe asthma attacks, but most asthma attacks result in
hypocapnia and respiratory alkalosis. As the asthma attack
occurs, bronchial smooth muscle spasm and mucus secretion
obstruct the ventilation to some alveoli. Although some
hypoxic pulmonary vasoconstriction may occur, it is not suf-
ficient to divert all of the mixed venous blood flow away from
these poorly ventilated alveoli. This results in a right-to-left
shunt or shuntlike state (Chapter 35), which would therefore
be expected to cause the arterial Po2 to decrease and the arte-
rial Pco2 to increase. However, the Pco2 decreases because the
patient increases alveolar ventilation if he or she is able to.
Irritant receptors in the airways are stimulated by the
mucus and by chemical mediators released during the
attack. Hypoxia caused by the shunt stimulates the arterial
chemoreceptors; the patient also has the feeling of dyspnea
(many asthma attacks have an emotional component). All
of these factors cause increased breathing and therefore
increased alveolar ventilation.
Increasing ventilation will get more CO2 out of the blood
perfusing ventilated alveoli (and therefore out of the body)
but it will not get much oxygen into alveoli supplied by
obstructed airways, nor will it get much more oxygen into
the blood of the unobstructed alveoli because of the shape
of the oxyhemoglobin dissociation curve. Remember that
the hemoglobin is already 97.4% saturated with oxygen and
not much more will dissolve in the plasma. Therefore, dur-
ing the attack the patient has hypoxemia, hypocapnia, and
respiratory alkalosis. It is only when the attack is so severe
that the patient cannot do the additional work of breathing
that hypercapnia and respiratory acidosis occur.
Acute treatment of asthma is aimed at dilating the airways
with a bronchodilator, such as a β2-adrenergic agonist, and
relieving the hypoxemia with oxygen. Mechanical ventila-
tion may be used in more severe cases. Chronic treatment
includes bronchodilators such as β2-adrenergic agonists;
anticholinergics, to block parasympathetically mediated
constriction and mucus production; antileukotriene drugs
and inhaled corticosteroids, to prevent inflammation; and
inhibition of mast cells to prevent them from releasing
cytokines.
CHAPTER SUMMARY
■ Hypoventilation causes respiratory acidosis; the compensation
for respiratory acidosis is renal retention of base and excretion
of hydrogen ions.
■ Hyperventilation causes respiratory alkalosis; the compensa-
tion for respiratory alkalosis is renal excretion of base and
retention of hydrogen ions.
■ Ingestion, infusion, overproduction, or decreased renal
excretion of hydrogen ions, or loss of bicarbonate ions, can
cause metabolic acidosis; the compensation for metabolic
acidosis is increased alveolar ventilation.
■ Ingestion, infusion, or excessive renal reabsorption of bases, or
loss of hydrogen ions, can cause metabolic alkalosis; the
compensation for metabolic alkalosis is decreased alveolar
ventilation.
■ Metabolic acidosis with an abnormally elevated anion gap
indicates an increased plasma concentration of anions other
than chloride and bicarbonate or a decreased plasma concen-
tration of potassium, calcium, or magnesium ions.
■ Tissue hypoxia can be a result of low alveolar Po2, diffusion
impairment, right-to-left shunts, or ventilation–perfusion
mismatch (hypoxic hypoxia), decreased functional hemoglo-
bin (anemic hypoxia), low blood flow (hypoperfusion hypoxia),
or an inability of the mitochondria to use oxygen (histotoxic
hypoxia).
STUDY QUESTIONS
1–4. Match each of the following sets of blood gas data to one
of the underlying problems listed below. Assume the body
temperature to be 37°C, and the hemoglobin concentration
to be 15 g Hb/100 mL blood. FIo2 is 0.21 (room air).
A) acute methanol ingestion
B) diarrhea
C) accidental hypoventilation of a patient on a mechanical
ventilator for 10 minutes
D) chronic obstructive pulmonary disease
1. pHa = 7.25, Paco2 = 50 mm Hg , [HCO3−] = 26 mEq/L, Pao2
= 70 mm Hg, anion gap = 11 mEq/L.
2. pHa = 7.34, Paco2 = 65 mm Hg, [HCO3−] = 40 mEq/L, Pao2
= 65 mm Hg, anion gap = 11 mEq/L.
3. pHa = 7.25, Paco2 = 30 mm Hg, [HCO3−] = 15 mEq/L, Pao2
= 95 mm Hg, anion gap = 10 mEq/L.
4. pHa = 7.25, Paco2 = 30 mm Hg, [HCO3−] = 15 mEq/L, Pao2
= 95 mm Hg, anion gap = 25mEq/L.
 38
C H A P T E R

Control of Breathing
Michael Levitzky

O B J E C T I V E S

■ Describe the general organization of the respiratory control system.

■ Localize the centers that generate the spontaneous rhythm of breathing.
■ Describe the groups of neurons that effect inspiration and expiration.
■ Describe the other centers in the brainstem that may influence the
spontaneous rhythm of breathing.
■ List the cardiopulmonary and other reflexes that influence the breathing
pattern.
■ State the ability of the brain cortex to override the normal pattern of
inspiration and expiration temporarily.
■ Describe the effects of alterations in body oxygen, carbon dioxide, and
hydrogen ion levels on the control of breathing.
■ Describe the sensors of the respiratory system for oxygen, carbon dioxide,
and hydrogen ion concentration.

ORGANIZATION OF THE ratory system during exercise or may even be temporarily

RESPIRATORY CONTROL SYSTEM
Breathing is spontaneously initiated in the central nervous
system. A cycle of inspiration and expiration is automatically
generated by neurons located in the brainstem. Usually, breath-
ing occurs without a conscious initiation of inspiration and
expiration.
This spontaneously generated cycle of inspiration and expi-
ration can be modified, altered, or even temporarily sup-
pressed by a number of mechanisms. As shown in Figure 38–1,
these include reflexes arising in the lungs, the airways, and the
cardiovascular system; information from receptors in contact
with the cerebrospinal fluid; and commands from higher cen-
ters of the brain such as the hypothalamus, the centers of
speech, or other areas in the cerebral cortex. The centers that
are responsible for the generation of the spontaneous rhythm
of inspiration and expiration are, therefore, able to alter their
activity to meet the increased metabolic demand on the respi-
superseded or suppressed during speech or breath holding.
The respiratory control centers in the brainstem affect the
automatic rhythmic control of breathing via a final common
pathway consisting of the spinal cord, the innervation of the
muscles of respiration such as the phrenic nerves, and the
muscles of respiration themselves. Alveolar ventilation is
therefore determined by the interval between successive
groups of discharges of the respiratory neurons and the inner-
vation of the muscles of respiration, which determines the
respiratory rate or breathing frequency; and by the frequency
of neural discharges transmitted by individual nerve fibers to
their motor units, the duration of these discharges, and the
number of motor units activated during each inspiration or
expiration, which determine the depth of respiration or the
tidal volume. Note that some pathways from the cerebral cor-
tex to the muscles of respiration, such as those involved in vol-
untary breathing, bypass the medullary respiratory center
described below and travel directly to the spinal α motor neu-
rons. These are represented by the dashed line in Figure 38–1.

385

Ch38_385-396.indd 385 11/26/10 10:11:26 AM

386 SECTION VI Pulmonary Physiology

Influences from
higher centers

Cycle of
inspiration
and
Reflexes from: expiration Reflexes from:
Lungs Arterial
Airways chemoreceptors
Cardiovascular Central
system chemoreceptors
Muscles and
joints
Skin
Muscles of
breathing

FIGURE 38–1 Schematic representation of the organization of the respiratory control system. A cycle of inspiration and expiration
is automatically established in the medullary respiratory center. Its output represents a final common pathway to the respiratory muscles,
except for some voluntary pathways that may go directly from higher centers to the respiratory muscles (dashed line). Reflex responses from
chemoreceptors and other sensors may modify the cycle of inspiration and expiration established by the medullary respiratory center.
(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

THE GENERATION OF
SPONTANEOUS RHYTHMICITY
The centers that initiate breathing are located in the reticular
formation of the medulla, beneath the floor of the fourth ven-
tricle. This area, known as the medullary respiratory center,
consists of inspiratory neurons, that fire during inspiration to
stimulate inspiratory muscles to contract, and expiratory neu-
rons, that fire during expiration to stimulate expiratory mus-
cles to contract. Because expiration is passive in normal quiet
breathing, the expiratory neurons may not discharge unless
expiration is active.
There are two dense bilateral aggregations of respiratory
neurons in the medullary respiratory center known as the dor-
sal respiratory groups (DRG) and the ventral respiratory
groups (VRG) (Figure 38–2). Inspiratory and expiratory neu-
rons are anatomically intermingled to a greater or lesser extent
within these areas. The dorsal respiratory groups are located
bilaterally in the nucleus of the tractus solitarius (NTS). They
consist mainly of inspiratory neurons that project primarily to
the contralateral spinal cord. They serve as the principal initia-
tors of the activity of the phrenic nerves and maintain the
activity of the diaphragm. Dorsal respiratory group neurons
send many collateral fibers to those in the ventral respiratory
group, but the ventral respiratory group sends only a few col-
lateral fibers to the dorsal respiratory group. The NTS receives
visceral afferent fibers of the 9th cranial nerve (the glossopha-
ryngeal) and the 10th cranial nerve (the vagus). These nerves
carry information about the arterial Po2, Pco2, and pH from the
carotid and aortic arterial chemoreceptors (Figure 38–3)
and information concerning the systemic arterial blood pres-
sure from the carotid and aortic baroreceptors (see Chapter 29).
In addition, the vagus carries information from stretch recep-
tors and other sensors in the lungs that may also exert pro-
found influences on the control of breathing. The effects of
information from these sensors on the control of breathing
will be discussed later in this chapter. The location of the DRG
within the NTS suggests that it may be the site of integration of
various inputs that can reflexly alter the spontaneous pattern
of inspiration and expiration.
The ventral respiratory groups are located bilaterally in the
retrofacial nucleus, the nucleus ambiguus, the nucleus
para-ambigualis, and the nucleus retroambigualis. They
consist of both inspiratory and expiratory neurons. The neu-
rons in the nucleus ambiguus are primarily vagal motor neu-
rons that innervate the ipsilateral laryngeal, pharyngeal, and
tongue muscles involved in breathing and in maintaining
the patency of the upper airway. They are both inspiratory
and expiratory neurons. Other neurons from the ventral
respiratory groups mainly project contralaterally to innervate
inspiratory muscles and the expiratory muscles. The retrofa-
cial nucleus, located most rostrally in the ventral respiratory
groups, mainly contains expiratory neurons in a group of
cells called the Bötzinger complex. Neurons in the area
called the pre-Bötzinger complex have been identified as the
 CHAPTER 38 Control of Breathing 387

Pons

Pneumotaxic center

Apneustic center

Medulla

Ventral respiratory group

(VRG)
Dorsal respiratory group
(DRG) Pre-Bötzinger complex
(rhythm-generating neurons)
Inspiratory neurons
Inspiratory Expiratory
neurons neurons

Inspiratory Expiratory
Spinal motor neurons
FIGURE 38–2 Brainstem respiratory
control centers responsible for respiratory
rhythm generation, activation of inspiratory Inspiratory Expiratory
and expiratory neuron and muscle Muscles
activation, and monitoring lung inflation via
pulmonary stretch receptors and alveolar
ventilation via changes in arterial blood gas
Lung stretch receptors Ventilation
partial pressures. Input from the central Lung
chemoreceptors was omitted for clarity.
(Reproduced with permission from Widmaier EP, Raff H,
Strang KT: Vander’s Human Physiology, 11th ed.
Arterial chemoreceptors Blood gas partial pressures
McGraw-Hill, 2008.)

pacemakers of the respiratory rhythm—the respiratory
rhythm generator.
An area in the in the pons (the part of the brainstem just
rostral to the medulla) called the apneustic center appears to
be an integration site for afferent information that can termi-
nate inspiration. The specific group of neurons that function
as the apneustic center has not been identified.
A group of respiratory neurons rostral to the apneustic cen-
ter known as the pontine respiratory groups (also called the
pneumotaxic center, as in Figure 38–2) functions to modu-
late the activity of the apneustic center. These cells, located in
the upper pons in the nucleus parabrachialis medialis and
the Kölliker-Fuse nucleus, probably function to “fine-tune”
the breathing pattern and smooth the transitions between
inspiration and expiration. The pontine respiratory groups
may also modulate the respiratory control system response to
stimuli such as lung inflation, hypercapnia, and hypoxia.
In the spinal cord axons projecting from the DRG, the VRG,
the cortex, and other supraspinal sites descend in the spinal
white matter to influence the diaphragm and the intercostal
and abdominal muscles of respiration, as already discussed.
There is integration of descending influences as well as the
presence of local spinal reflexes that can affect these motor
neurons. Descending axons with inspiratory activity excite
phrenic and external intercostal motor neurons and also
inhibit internal intercostal motor neurons by exciting spinal
inhibitory interneurons. They are actively inhibited during
expiratory phases of the respiratory cycle.
Ascending pathways in the spinal cord, carrying informa-
tion from pain, touch, and temperature receptors, as well as
from proprioceptors, can also influence breathing, as will be
discussed in the next section. Inspiratory and expiratory fibers
appear to be separated in the spinal cord.
The spontaneous rhythmicity generated in the medullary
respiratory center can be completely overridden (at least tem-
porarily) by influences from higher brain centers. In fact, the
greatest minute ventilations obtainable from healthy conscious
human subjects can be attained voluntarily, exceeding those
obtained with the stimuli of severe exercise, hypercapnia, or
hypoxia. This is the underlying concept of the maximum vol-
untary ventilation (MVV) test often used to assess respiratory
function. Conversely, the respiratory rhythm can be com-
pletely suppressed for several minutes by voluntary breath
holding, until the chemical drive to breath (high Pco2 and low
Po2 and pH) overrides the voluntary suppression of breathing
at the breakpoint. During speech, singing, or playing a wind
388 SECTION VI Pulmonary Physiology
Sensory nerves
Sensory nerves
Carotid bodies
Common carotid artery
Aortic bodies
Aorta
Heart
FIGURE 38–3 Location of the carotid and aortic bodies.
Note that the carotid bodies are close to the carotid sinuses, the
location of the major arterial baroreceptors. (Reproduced with
permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology,
11th ed. McGraw-Hill, 2008.)
instrument, the normal cycle of inspiration and expiration is
automatically modified by higher brain centers. In certain
emotional states, chronic hyperventilation severe enough to
cause respiratory alkalosis may occur.
RESPIRATORY REFLEXES
A large number of sensors located in the lungs, the cardiovas-
cular system, the muscles and tendons, and the skin and vis-
cera can elicit reflexes in the control of breathing. They are
summarized in Table 38–1, which lists the stimulus, receptor,
afferent pathway, and effects for each reflex.
PULMONARY STRETCH RECEPTORS
Three respiratory reflexes can be elicited by the activity of pul-
monary stretch receptors: the Hering–Breuer inflation reflex,
the Hering–Breuer deflation reflex, and the “paradoxical”
reflex.
Inflation of the lungs of anesthetized spontaneously breath-
ing animals decreases the frequency of the inspiratory effort
or causes a transient apnea (cessation of breathing). The
stimulus for this reflex is pulmonary inflation. The sensors
are stretch receptors located within the smooth muscle of
large and small airways. They are sometimes referred to as
slowly adapting pulmonary stretch receptors because their
activity is maintained with sustained stretches. The afferent
pathway consists of large myelinated fibers in the vagus,
which enter the brainstem and project to the DRGs, the
apneustic center, and the pontine respiratory groups. The
Hering–Breuer inflation reflex was originally believed to be
an important determinant of the rate and depth of ventila-
tion, but recent studies have cast doubt on this conclusion
because the threshold of the reflex is much higher than the
normal tidal volume during eupneic breathing. Tidal vol-
umes of 800–1,500 mL are generally required to elicit this
reflex in conscious eupneic adults. The Hering–Breuer infla-
tion reflex may help minimize the work of breathing by
inhibiting large tidal volumes as well as prevent overdisten-
tion of the alveoli. It may also be important in the control of
breathing in neonates. Neonates have Hering–Breuer infla-
tion reflex thresholds within their normal tidal volume
ranges, and the reflex may be an important influence on their
tidal volumes and respiratory rates.
Deflation of the lungs increases the ventilatory rate. This
could be a result of decreased stretch receptor activity or of
stimulation of other pulmonary receptors, or rapidly adapting
receptors such as the irritant receptors and J receptors, which
will be discussed later in this chapter. The afferent pathway is
the vagus, and the effect is increased minute ventilation
(hyperpnea). This reflex may be responsible for the increased
ventilation elicited when the lungs are deflated abnormally, as
in pneumothorax, or it may play a role in the periodic sponta-
neous deep breaths (sighs) that help prevent atelectasis. These
sighs occur occasionally and irregularly during the course of
normal, quiet, spontaneous breathing. They consist of a slow
deep inspiration (larger than a normal tidal volume) followed
by a slow deep expiration. This response appears to be very
important because patients maintained on mechanical ventila-
tors must be given large tidal volumes or periodic deep breaths
or they develop diffuse atelectasis, which may lead to arterial
hypoxemia.
The Hering–Breuer deflation reflex may be very important
in helping to actively maintain functional residual capacities
(FRCs) in infants. It is very unlikely that infants’ FRCs are
determined passively like those of adults because the inward
recoil of their lungs is considerably greater than the outward
recoil of their very compliant chest walls.
After partly blocking the vagus nerves with cold tempera-
tures, lung inflation causes a further inspiration instead of the
apnea expected when the vagus nerves are completely func-
tional. The receptors for this paradoxical reflex are located in
the lungs, but their precise location is not known. Afferent
information travels in the vagus; the effect is very deep inspi-
rations. This reflex may also be involved in the sigh response,
 CHAPTER 38 Control of Breathing 389

TABLE 38–1 Respiratory reflexes.

Stimulus Reflex Name Receptor Afferent Pathway Effects

Lung inflation Hering–Breuer Stretch receptors within Vagus Respiratory

inflation reflex smooth muscle of large Cessation of inspiratory effort, apnea,
and small airways or decreased breathing frequency;
bronchodilation
Cardiovascular
Increased heart rate, slight vasoconstriction

Lung deflation Hering–Breuer Possibly J receptors, Vagus Respiratory

deflation reflex irritant receptors in Hyperpnea
lungs, or stretch
receptors in airways
Lung inflation Paradoxical reflex Stretch receptors in Vagus Respiratory
lungs Inspiration

Negative pressure in Pharyngeal dilator Receptors in nose, Trigeminal, laryngeal, Respiratory

the upper airway reflex mouth, upper airways glossopharyngeal Contraction of pharyngeal dilator muscles

Mechanical or Cough Receptors in upper Vagus Respiratory

chemical irritation airways, Cough; bronchoconstriction
of airways tracheobronchial tree

Sneeze Receptors in nasal Trigeminal, olfactory Sneeze; bronchoconstriction

mucosa Cardiovascular
Increased blood pressure

Face immersiona Diving reflex Receptors in nasal Trigeminal Respiratory

mucosa and face Apnea
Cardiovascular
Decreased heart rate; vasoconstriction

Pulmonary J receptors in pulmonary Vagus Respiratory

embolism vessels Apnea or tachypnea

Pulmonary vascular J receptors in pulmonary Vagus Respiratory

congestion vessels Tachypnea, possibly sensation of dyspnea

Specific chemicals in Pulmonary J receptors in pulmonary Vagus Respiratory

the pulmonary chemoreflex vessels Apnea or tachypnea; bronchoconstriction
circulation

Low PaO , high Arterial Carotid bodies, aortic Glossopharyngeal, Respiratory

2
PaCO , low pHa chemoreceptor reflex bodies vagus Hyperpnea; bronchoconstriction, dilation
2
of upper airway
Cardiovascular
Decreased heart rate (direct effect),
vasoconstriction

Increased systemic Arterial baroreceptor Carotid sinus stretch Glossopharyngeal, Respiratory

arterial blood reflex receptors vagus Apnea, bronchodilation
pressure Cardiovascular
Decreased heart rate,
Aortic arch stretch vasodilation etc.
receptors
Stretch of muscles, Muscle spindles, tendon Various spinal Respiratory
tendons, movement organs, proprioreceptors pathways Provide respiratory controller with
of joints feedback about work of breathing,
stimulation of proprioreceptors in
joints causes hyperpnea

Somatic pain Pain receptors Various spinal Respiratory

pathways Hyperpnea
Cardiovascular
Increased heart rate, vasoconstriction, etc.
a
Discussed in Chapter 71.
Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.
390 SECTION VI Pulmonary Physiology
or it may be involved in generating the first breath of the
newborn baby; very great inspiratory efforts must be gener-
ated to inflate the fluid-filled lungs.
RECEPTORS IN THE AIRWAYS
AND THE LUNGS
Negative pressure in the upper airway causes reflex contrac-
tion of the pharyngeal dilator muscles. The receptors for the
pharyngeal dilator reflex appear to be located in the nose,
mouth, and upper airways; the afferent pathways appear to be
in the trigeminal, laryngeal, and glossopharyngeal nerves.
This reflex may be very important in maintaining the patency
of the upper airway during strong inspiratory efforts and dur-
ing sleep.
Mechanical or chemical irritation of the airways (and pos-
sibly the alveoli) can elicit a reflex cough or sneeze, or it can
cause hyperpnea, bronchoconstriction, and increased blood
pressure. The receptors are located in the nasal mucosa, upper
airways, tracheobronchial tree, and possibly the alveoli them-
selves. Those in the larger airways of the tracheobronchial
tree, which also respond to stretch, are sometimes referred to
as rapidly adapting pulmonary stretch receptors because
their activity decreases rapidly during a sustained stimulus.
The afferent pathways are the vagus nerves for all but the
receptors located in the nasal mucosa, which send information
centrally via the trigeminal and olfactory tracts. The cough
and the sneeze reflexes were discussed in Chapter 32.
PULMONARY VASCULAR
RECEPTORS (J RECEPTORS)
Pulmonary embolism causes rapid shallow breathing (tachy-
pnea) or apnea; pulmonary vascular congestion also causes
tachypnea. The receptors responsible for initiating these
responses are located in the walls of the pulmonary capillaries
or in the interstitium; therefore, they are called J (for juxtapul-
monary capillary) receptors. These receptors may also be
responsible for the dyspnea (a feeling of difficult or labored
breathing) encountered during the pulmonary vascular con-
gestion and edema secondary to left ventricular failure or even
the dyspnea that healthy people feel at the onset of exercise.
The afferent pathway of these reflexes is slow-conducting non-
myelinated vagal fibers. Other receptors that may contribute
to the sensation of dyspnea include the arterial chemorecep-
tors, stretch receptors in the heart and blood vessels, and
receptors in the respiratory muscles.
OTHER CARDIOVASCULAR RECEPTORS
The arterial chemoreceptors are located bilaterally in the
carotid bodies, which are situated near the bifurcations of the
common carotid arteries, and in the aortic bodies, which are
located in the arch of the aorta as shown in Figure 38–3. They
respond to low arterial Po2, high arterial Pco2, and low arterial
pH (as will be discussed later in this chapter), with the carotid
bodies generally capable of a greater response than the aortic
bodies. The afferent pathway from the carotid body is Hering’s
nerve, a branch of the glossopharyngeal nerve; the afferent
pathway from the aortic body is the vagus. The reflex effects of
stimulation of the arterial chemoreceptors are hyperpnea,
bronchoconstriction, dilation of the upper airway, and
increased blood pressure. The direct effect of arterial chemore-
ceptor stimulation is a decrease in heart rate; however, this is
usually masked by an increase in heart rate secondary to the
increase in lung inflation. The arterial baroreceptors exert a
very minor influence on the control of ventilation. Low blood
pressure may stimulate breathing.
OTHER RECEPTORS IN MUSCLE,
TENDONS, SKIN, AND VISCERA
Stimulation of receptors located in the muscles, the tendons,
and the joints can increase ventilation. Included are receptors
in the muscles of respiration (e.g., muscle spindles) and rib
cage as well as other skeletal muscles, joints, and tendons.
These receptors may play an important role in adjusting the
ventilatory effort to elevated workloads and may help mini-
mize the work of breathing. They may also participate in initi-
ating and maintaining the elevated ventilation that occurs
during exercise, as will be discussed in Chapter 72. Somatic
pain generally causes hyperpnea; visceral pain generally causes
apnea or decreased ventilation.
THE RESPONSE
TO CARBON DIOXIDE
The respiratory control system normally reacts very effectively
to alterations in the internal “chemical” environment of the
body. Changes in the Pco2, pH, and Po2 result in alterations in
alveolar ventilation designed to return these variables to their
normal values. Chemoreceptors alter their activity when their
own local chemical environment changes and can therefore
supply the central respiratory controller with the afferent
information necessary to make the appropriate adjustments in
alveolar ventilation to change the whole-body Pco2, pH, and
Po2. The respiratory control system therefore functions as a
negative-feedback system as discussed in Chapter 1.
The arterial and cerebrospinal fluid partial pressures of car-
bon dioxide are probably the most important inputs to the
ventilatory control system in establishing the breath-to-breath
levels of tidal volume and ventilatory frequency. (Of course,
changes in carbon dioxide lead to changes in hydrogen ion
concentration, so the effects of these two stimuli are comple-
mentary.) An increase in carbon dioxide is a very powerful
stimulus to ventilation: only voluntary hyperventilation and
the hyperpnea of exercise can surpass the minute ventilations
obtained with hypercapnia. However, the arterial Pco2 is so
 CHAPTER 38 Control of Breathing 391

20 drive. Metabolically produced carbon dioxide will then build

PaO  35 mm Hg
2
PaO  50 mm Hg
up and restore breathing.)
2
The ventilatory response of a normal conscious person to
physiologic levels of carbon dioxide is shown in Figure 38–4.
15 Alveolar (and arterial) Pco2 in the range of 38–50 mm Hg increase
Alveolar ventilation (L/min)

alveolar ventilation linearly. The slope of the line is quite steep

and varies from person to person. It decreases with age.
10 The figure also shows that hypoxia potentiates the ventila-
tory response to carbon dioxide. At lower arterial Po2 (e.g., 35
and 50 mm Hg), the response curve is shifted to the left and
the slope is steeper; that is, for any particular arterial Pco2, the
5 ventilatory response is greater at a lower arterial Po2. This may
PaO  100 mm Hg be caused by the effects of hypoxia at the chemoreceptor itself
2

or at higher integrating sites; changes in the central acid–base

0
30 35 40 45
PaCO2 (mm Hg)
FIGURE 38–4 Ventilatory carbon dioxide response curves at
three different levels of arterial PO . (Modified with permission from
2
Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)
precisely controlled that it changes little (<1 mm Hg) during
exercise severe enough to increase metabolic carbon dioxide
production 10-fold.
Acutely increasing the level of carbon dioxide in the inspired
air (the Fico2) increases minute ventilation. The effect is most
pronounced in Fico2 in the range of 0.05–0.10 (5–10% CO2 in
inspired gas), which produces alveolar Pco2 between about 40
and 70 mm Hg. Above 10–15% CO2 in inspired air, there is
little further increase in alveolar ventilation: very high arterial
Pco2 (>70–80 mm Hg) may directly produce respiratory depres-
sion. (Very low arterial Pco2 caused by hyperventilation may
temporarily cause apnea because of decreased ventilatory
status secondary to hypoxia may also contribute to the
50 enhanced response.
Other influences on the carbon dioxide response curve are
illustrated in Figure 38–5. Sleep shifts the curve slightly to
the right. The arterial Pco2 normally increases during slow-
wave sleep, increasing as much as 5–6 mm Hg during deep
sleep. Because of this rightward shift in the CO2 response
curve during non-REM sleep, it is possible that there is a
“wakefulness” component of respiratory drive. A depressed
response to carbon dioxide during sleep may be involved in
central sleep apnea, a condition characterized by abnormally
long periods (1–2 minutes) between breaths during sleep. This
lack of central respiratory drive is a potentially dangerous con-
dition in both infants and adults. (In obstructive sleep apnea,
the central respiratory controller does issue the command to
breathe, but the upper airway is obstructed because the pha-
ryngeal muscles do not contract properly, there is too much fat
around the pharynx, or the tongue blocks the airway.) Narcot-
ics and anesthetics may profoundly depress the ventilatory
response to carbon dioxide. Indeed, respiratory depression is

15 Metabolic acidosis Awake normal

Sleep
Alveolar ventilation (L/min)

10 Narcotics,
chronic obstruction

5
Deep anesthesia

0
25 35 45 55 65
PaCO (mm Hg)
2

FIGURE 38–5 The effects of sleep, narcotics, chronic obstructive pulmonary disease, deep anesthesia, and metabolic acidosis on
the ventilatory response to carbon dioxide. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)
392 SECTION VI Pulmonary Physiology
the most common cause of death in cases of overdose of opiate
alkaloids and their derivatives, barbiturates, and most anes-
thetics. Chronic obstructive pulmonary diseases (COPD)
depress the ventilatory response to hypercapnia, in part
because of depressed ventilatory drive secondary to central
acid–base changes, and because the work of breathing may be
so great that ventilation cannot be increased normally. Meta-
bolic acidosis displaces the carbon dioxide response curve to
the left, indicating that for any particular Paco2, ventilation is
increased during metabolic acidosis because of hydrogen ion
stimulation of the arterial chemoreceptors.
As already discussed, the respiratory control system consti-
tutes a negative-feedback system. This is exemplified by the
response to carbon dioxide. Increased metabolic production of
carbon dioxide increases the carbon dioxide brought to the lung.
If alveolar ventilation stayed constant, the alveolar Pco2 would
increase, as would arterial and cerebrospinal Pco2. This stimu-
lates alveolar ventilation by stimulating the arterial and central
chemoreceptors (described later in this chapter). Increased
alveolar ventilation decreases alveolar and arterial Pco2, as was
discussed in Chapter 33, returning the Pco2 to the original value.
The Pco2, pH, and Po2 are the principal controlled variables in
the respiratory control system. To act as a negative-feedback
system, the respiratory controller must receive information
concerning the levels of the controlled variables from sensors
in the system. The sensors are the arterial chemoreceptors
(peripheral chemoreceptors) and the central chemorecep-
tors located bilaterally near the ventrolateral surface of the
medulla in the brainstem and other sites. The arterial chemore-
ceptors are exposed to arterial blood; the central chemorecep-
tors are exposed to cerebrospinal fluid. The central
chemoreceptors are therefore on the brain side of the blood–
brain barrier. Both the peripheral and central chemoreceptors
respond to increases in the partial pressure of carbon dioxide,
although the response may be related to the local increase in
hydrogen ion concentration that occurs with increased Pco2;
that is, the sensors may be responding to the increased carbon
dioxide concentration, the subsequent increase in hydrogen
ion concentration, or both.
The arterial chemoreceptors increase their firing rate in
response to increased arterial Pco2, decreased arterial Po2, or
decreased arterial pH. The response of the receptors is both
rapid enough and sensitive enough that they can relay infor-
mation concerning breath-to-breath alterations in the compo-
sition of the arterial blood to the medullary respiratory center.
The response of the arterial chemoreceptors changes nearly
linearly with the arterial Pco2 over the range of 20–60 mm Hg.
The central chemoreceptors are exposed to the cerebrospi-
nal fluid and are not in direct contact with the arterial blood.
As shown in Figure 38–6, the cerebrospinal fluid is separated
from the arterial blood by the blood–brain barrier. Carbon
dioxide can easily diffuse through the blood–brain barrier, but
hydrogen ions and bicarbonate ions do not. Because of this,
alterations in the arterial Pco2 are rapidly transmitted to the
cerebrospinal fluid in about 60 seconds. Changes in arterial
pH that are not caused by changes in Pco2 take much longer to
influence the cerebrospinal fluid; in fact, the cerebrospinal
fluid may have changes in hydrogen ion concentration oppo-
site to those seen in the blood in certain circumstances, as will
be discussed later in this chapter.
The composition of the cerebrospinal fluid is considerably
different from that of the blood. The pH of the cerebrospinal
fluid is normally about 7.32, compared with the pH of 7.40 of
arterial blood. The Pco2 of the cerebrospinal fluid is about
50 mm Hg—about 10 mm Hg higher than the normal arterial
Pco2 of 40 mm Hg. The concentration of proteins in the cere-
brospinal fluid is only in the range of 0.02-0.05 g/100 mL,
whereas the concentration of proteins in the plasma normally
ranges from 6.6 to 8.6 g/100 mL. This does not even include
the hemoglobin in the erythrocytes. As a result, bicarbonate is
the main buffer in the cerebrospinal fluid. Arterial hypercap-
nia will therefore lead to greater changes in cerebrospinal fluid
hydrogen ion concentration than it does in the arterial blood.
The brain produces carbon dioxide as an end product of
metabolism. Brain carbon dioxide levels are higher than those
of the arterial blood, which explains the high Pco2 of the cere-
brospinal fluid.
The central chemoreceptors respond to local increases
in hydrogen ion concentration or Pco2, or both. They do not
respond to hypoxia.
About 80–90% of the normal total steady-state response to
increased inspired carbon dioxide concentrations comes
from the central chemoreceptors; the arterial chemoreceptors
contribute only 10–20% of the steady-state response. However,
the response comes from the arterial chemoreceptors when
rapid changes in arterial Pco2 occur, that is, the central chemore-
ceptors may be mainly responsible for establishing the resting
ventilatory level but the arterial chemoreceptors are more
important in short-term transient responses to carbon dioxide.
Both the arterial and central chemoreceptors likely respond to
hydrogen ion concentration, not Pco2. Of course, they are usu-
ally very closely related in the body, so it is difficult to distin-
guish their effects.
There may be other sensors for carbon dioxide in the body
that may influence the control of ventilation. Chemoreceptors
within the pulmonary circulation or airways have been pro-
posed but have not as yet been substantiated or localized.
THE RESPONSE TO
HYDROGEN IONS
Ventilation increases nearly linearly with changes in hydrogen
ion concentration over the range of 20–60 nEq/L (nmol/L), as
shown in Figure 38–7. A metabolic acidosis of nonbrain origin
results in hyperpnea coming entirely from the peripheral
chemoreceptors. Hydrogen ions cross the blood–brain barrier
too slowly to affect the central chemoreceptors initially. Aci-
dotic stimulation of the peripheral chemoreceptors increases
alveolar ventilation, and the arterial Pco2 decreases. Because
the cerebrospinal fluid Pco2 is in a sort of dynamic equilibrium
 CHAPTER 38 Control of Breathing 393

BRAIN TISSUE BRAIN TISSUE CSF

Venous blood

CO2 CO2 CO2

barrier

barrier
Central
Blood-brain

Metabolic H Chemoreceptor
H

Blood-brain
CO2
production

CO2 CO2 CO2 CO2

Dilates
HCO3 HCO3
Slow (h)
Smooth muscle

Smooth muscle

Dilates
CO2

Arterial CSF:
blood: pH  7.32
pH  7.40 PCO  50 mm Hg
2
PCO  40 mm Hg Little protein
2
Protein Buffers

FIGURE 38–6 Representation of the central chemoreceptor showing its relationship to carbon dioxide (CO2), hydrogen (H+), and
bicarbonate (HCO3−) ions in the arterial blood and cerebrospinal fluid (CSF). CO2 crosses the blood–brain barrier easily; H+ and HCO3− do not.
(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

with the arterial Pco2, carbon dioxide diffuses out of the cere-
brospinal fluid and the pH of the cerebrospinal fluid increases,
thus decreasing stimulation of the central chemoreceptor. If
15 the situation lasts a long time (hours to days), the bicarbonate
concentration of the cerebrospinal fluid decreases slowly,
12
returning the pH of the cerebrospinal fluid toward the normal
7.32. The mechanism by which this occurs is not completely
VE (L/min)

agreed on. It may represent the slow diffusion of bicarbonate

9 ions across the blood–brain barrier, active transport of bicar-
bonate ions out of the cerebrospinal fluid, or decreased forma-
6 tion of bicarbonate ions by carbonic anhydrase as the
cerebrospinal fluid is formed.
Similar mechanisms must alter the bicarbonate concentra-
40 41 42 43 44 45 46 tion in the cerebrospinal fluid in the chronic respiratory aci-
 dosis of chronic obstructive lung disease because the pH of
Plasma [H ], nEq/L
the cerebrospinal fluid is nearly normal. In this case, the cere-
FIGURE 38–7 The ventilatory response to increased plasma brospinal fluid concentration of bicarbonate increases nearly
hydrogen ion concentration. (Modified with permission from Levitzky MG: proportionately to its increased concentration of carbon
Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.) dioxide.
394 SECTION VI Pulmonary Physiology
70
60
Alveolar ventilation (L/min)
50
40
30
PaCO2 45 mm Hg
20
10
0 as carbon dioxide, explaining the low bicarbonate concen-
20 40 60 80
PaO (mm Hg)
2
FIGURE 38–8 The ventilatory responses to hypoxia at three
different levels of arterial PCO . (Modified with permission from Levitzky MG:
2
Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)
THE RESPONSE TO HYPOXIA
The ventilatory response to hypoxia arises solely from the periph-
eral chemoreceptors. The carotid bodies are much more impor-
tant in this response than are the aortic bodies. In the absence of
the peripheral chemoreceptors, the effect of increasing degrees of
hypoxia is a progressive direct depression of the central respira-
tory controller. Therefore, when the peripheral chemoreceptors
are intact, their excitatory influence on the central respiratory
controller must offset the direct depressant effect of hypoxia.
The response of the respiratory system to hypoxia is shown
in Figure 38–8. The figure shows that at a normal arterial Pco2
of about 38–40 mm Hg, there is very little increase in ventila-
tion until the arterial Po2 decreases below about 50–60 mm Hg.
The response to hypoxia is potentiated at higher arterial Pco2.
Experiments have shown that the respiratory response to
hypoxia is related to the change in Po2 rather than the change
in oxygen content. Hypoxia alone, by stimulating alveolar
ventilation, causes a decrease in arterial Pco2, which may lead
to respiratory alkalosis. This will be discussed in Chapter 71.
CLINICAL CORRELATION
A 14-year-old girl forgot her prescription drug on a week-
end sleepover party at her friend’s house. She arrives in the
emergency department lethargic, confused, and disori-
ented. She has vomited twice and says she is thirsty and her
stomach hurts. The symptoms developed gradually over-
night. Her heart rate is 110/min, her blood pressure is
95/75 mm Hg, and her respiratory rate is 22/min with
obvious large tidal volumes. Her blood glucose is very
high at 450 mg/dL, her arterial Po2 is slightly increased at
105 mm Hg, her arterial Pco2 is 20 mm Hg (normal range
35–45 mm Hg), and her arterial pH is 7.15 (normal range
7.35–7.45). Her bicarbonate concentration is 15 mEq/L
(normal range 22–26 mEq/L) and her anion gap is 22
mEq/L (normal range 8–16 mEq/L).
The patient has type 1 diabetes mellitus; she is in dia-
PaCO2 50 mm Hg betic ketoacidosis (see Chapter 66). The drug she did not
bring with her is insulin; as a result, her blood glucose
concentration is very high and she is producing ketone
bodies (see Chapter 66). Nausea, vomiting, abdominal
pain, and confusion are common symptoms and signs of
PaCO  38 mm Hg diabetes mellitus, as will be discussed in Sections 7 and 9.
2
Hydrogen ions from the ketone bodies, which are acids,
have been buffered by bicarbonate and have been exhaled
100 120 140
tration and the elevated anion gap (see Chapter 37). The
hydrogen ions are stimulating her arterial chemorecep-
tors causing her to hyperventilate, as shown by her low
arterial Pco2. Her central chemoreceptors are not contrib-
uting to the hyperventilation because the hydrogen ions
do not cross her blood–brain barrier and therefore cannot
stimulate them (Figure 38–6); it is likely that her central
chemoreceptors have decreased activity because as she
hyperventilates her cerebrospinal fluid Pco2 decreases and
her cerebrospinal fluid pH increases. Her acid–base disor-
der can be described as a primary metabolic acidosis,
with increased anion gap, with a secondary respiratory
alkalosis.
CHAPTER SUMMARY
■ A cycle of inspiration and expiration is automatically generated
by neurons in the medulla; this cycle can be modified or
temporarily suppressed by reflexes or influences from higher
brain centers.
■ The respiratory control system functions as a negative-feedback
system; arterial Po , Pco , and pH and cerebrospinal fluid Pco
2 2 2
and pH are the regulated variables.
■ The increases in alveolar ventilation in response to increases
in arterial Pco and hydrogen ion concentrations are nearly
2
linear within their normal ranges; the increase in alveolar
ventilation in response to decreases in arterial Po is small
2
near the normal range and very large when the Po falls below
50–60 mm Hg.
2
■ The arterial chemoreceptors rapidly respond to changes in
arterial Po , Pco , and pH; the central chemoreceptors are on the
2 2
brain side of the blood–brain barrier and respond to changes in
cerebrospinal fluid Pco and pH.
2
 CHAPTER 38 Control of Breathing 395

STUDY QUESTIONS 3. Stimulation of which of the following receptors should result in

decreased ventilation?
1. The ventral respiratory groups A) aortic chemoreceptors
A) are located in the nucleus of the tractus solitarius. B) carotid chemoreceptors
B) include the pacemaker for breathing. C) central chemoreceptors
C) consist solely of inspiratory neurons. D) Hering–Breuer inflation (stretch) receptors
D) consist solely of expiratory neurons. E) all of the above
E) all of the above. 4. Which of the following would be expected to increase the
2. Which of the following conditions would be expected to ventilatory response to carbon dioxide, shifting the CO2
stimulate the central chemoreceptors? response curve to the left?
A) mild anemia A) barbiturates
B) severe exercise B) hypoxia
C) hypoxia due to ascent to high altitude C) slow-wave sleep
D) acute airway obstruction D) deep anesthesia
E) all of the above E) all of the above
This page intentionally left blank
 SECTION VII RENAL PHYSIOLOGY

39
C H A P T E R

Renal Functions, Basic

Processes, and Anatomy
Douglas C. Eaton and John P. Pooler

O B J E C T I V E S

■ State the seven major functions of the kidneys.

■ Define the balance concept.
■ Define the gross structures and their interrelationships: renal pelvis,
calyces, renal pyramids, renal medulla (inner and outer zones), renal
cortex, and papilla.
■ Define the components of the nephron–collecting duct system and
their interrelationships: renal corpuscle, glomerulus, tubule, and collecting
duct system.
■ Draw the relationship between glomerulus, Bowman’s capsule, and the
proximal tubule.
■ Define juxtaglomerular apparatus and describe its three cell types; state the
function of the granular cells.
■ List the individual tubular segments in order; state the segments that
comprise the proximal tubule, Henle’s loop, and the collecting duct system;
define principal cells and intercalated cells.
■ Define the basic renal processes: glomerular filtration, tubular reabsorption,
and tubular secretion.
■ Define renal metabolism of a substance and give examples.

FUNCTIONS FUNCTION 1: REGULATION OF WATER

The kidneys perform a number of essential functions that go
far beyond their well-known role of eliminating waste. This
chapter describes these functions and presents an overview of
how the kidneys perform them. Ensuing chapters develop
more detail of the mechanisms involved.
AND ELECTROLYTE BALANCE
The balance concept states that our bodies are in balance for
any substance when the inputs and outputs of that substance are
matched (see Figure 1–4). The kidneys vary the output of water
and an array of electrolytes and other substances in close pace
with their input, thereby keeping the body content of those sub-
stances nearly constant, that is, in balance. As an example, our
input of water is enormously variable and is only sometimes

397

Ch39_397-408.indd 397 11/26/10 10:08:52 AM

398 SECTION VII Renal Physiology
driven in response to body needs. We drink water when thirsty,
but we also drink water because it is a component of beverages
that we consume for reasons other than hydration. In addition,
solid food often contains large amounts of water. The kidneys
respond by varying the output of water in the urine, thereby
maintaining balance for water (i.e., constant total body water
content). Similarly, electrolytes such as sodium, potassium, and
magnesium are components of foods and generally present far
in excess of body needs. As with water, the kidneys excrete elec-
trolytes at a highly variable rate that, in the aggregate, matches
input. One of the amazing feats of the kidneys is their ability to
regulate each of these minerals independently (i.e., we can be
on a high-sodium, low-potassium diet or low-sodium, high-
potassium diet, and the kidneys adjust excretion of each of these
substances appropriately). The reader should be aware that
being in balance does not by itself imply a normal state or good
health. A person may have an excess or deficit of a substance, yet
still be in balance so long as output matches input. This is often
the case in chronic disorders of renal function or metabolism.
FUNCTION 2: REGULATION OF
ACID–BASE BALANCE
Acids and bases enter the body fluids via ingestion and from
metabolic processes. The body has to excrete acids and bases
to maintain balance, and it also has to regulate the concentra-
tion of free hydrogen ions (pH) within a limited range. The
kidneys accomplish both tasks by a combination of elimina-
tion and synthesis. These interrelated tasks are among the
most complicated aspects of renal function and will be explored
thoroughly in Chapter 47.
FUNCTION 3: EXCRETION OF
METABOLIC WASTE AND BIOACTIVE
SUBSTANCES
Our bodies continuously form the end products of metabolic
processes that for the most part serve no function and are
harmful at high concentrations; thus, they must be excreted at
the same rate they are produced. These include urea (from
protein), uric acid (from nucleic acids), creatinine (from mus-
cle creatine), and the end products of hemoglobin breakdown
(which give urine much of its color). In addition, the kidneys
participate with the liver in removing drugs, hormones, and
foreign substances. Clinicians have to be mindful of how fast
drugs are excreted in order to prescribe a dose that achieves
the appropriate body levels.
FUNCTION 4: REGULATION OF
ARTERIAL BLOOD PRESSURE
Although most people appreciate that the kidneys excrete waste
substances such as urea (hence the name urine) and salts, few
realize the kidneys’ crucial role in controlling blood pressure
(BP). BP ultimately depends on blood volume, and the kidneys’
maintenance of sodium and water balance achieves regulation of
blood volume. Thus, through volume control, the kidneys par-
ticipate in BP control. They also participate in direct regulation
of BP via the generation of vasoactive substances that regulate
smooth muscle in the peripheral vasculature.
FUNCTION 5: REGULATION OF RED
BLOOD CELL PRODUCTION
Erythropoietin is a peptide hormone that is involved in the con-
trol of erythrocyte (red blood cell) production by the bone mar-
row. Its major source is the kidneys, although the liver also secretes
small amounts. The renal cells that secrete it are a particular group
of cells in the interstitium. The stimulus for its secretion is a
reduction in the partial pressure of oxygen in the kidneys, as
occurs, for example, in anemia, arterial hypoxia (see Chapter 71),
and inadequate renal blood flow. Erythropoietin stimulates the
bone marrow to increase its production of erythrocytes. Renal
disease may result in diminished erythropoietin secretion, and
the ensuing decrease in bone marrow activity is one important
causal factor of the anemia of chronic renal disease.
FUNCTION 6: REGULATION OF
VITAMIN D PRODUCTION
When we think of vitamin D, we often think of sunlight or
additives to milk. In vivo vitamin D synthesis involves a
series of biochemical transformations, the last of which
occurs in the kidneys. The active form of vitamin D
(1,25-dihydroxyvitamin D) is actually made in the kidneys,
and its rate of synthesis is regulated by hormones that control
calcium and phosphate balance that will be discussed in
detail in Chapter 64.
FUNCTION 7: GLUCONEOGENESIS
Our central nervous system is an obligate user of blood glucose
regardless of whether we have just eaten sugary doughnuts or
gone without food for a week. Whenever the intake of carbo-
hydrate is stopped for much more than half a day, our body
begins to synthesize new glucose (the process of gluconeogen-
esis) from noncarbohydrate sources (amino acids from protein
and glycerol from triglycerides). Most gluconeogenesis occurs
in the liver (see Chapters 66 and 69), but a substantial fraction
occurs in the kidneys, particularly during a prolonged fast.
OVERVIEW OF RENAL PROCESSES
Most of what the kidneys do to perform these various functions
is, at least conceptually, fairly straightforward. Of the consider-
able volume of plasma entering the kidneys each minute, they
 CHAPTER 39 Renal Functions, Basic Processes, and Anatomy
Diaphragm
Kidney
Ureter
Bladder
Urethra
FIGURE 39–1 Urinary system in a female, indicating the
location of the kidneys below the diaphragm and well above the
bladder, which is connected to the kidneys via the ureters.
(Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human
Physiology, 11th ed. McGraw-Hill, 2008.)
transfer (by filtration) about one fifth of it, minus the larger pro-
teins, into the renal tubules and then selectively reabsorb varying
fractions of the filtered substances back into the blood, leaving
the unreabsorbed portions to be excreted. In some cases addi-
tional amounts are added by secretion or synthesis. In essence,
the renal tubules operate like assembly lines; they accept the fluid
coming into them, perform some segment-specific modification
of the fluid, and send it on to the next segment.
ANATOMY OF THE KIDNEYS
AND URINARY SYSTEM
The kidneys lie just under the rib cage on each side of the ver-
tebral column, behind the peritoneal cavity and in front of the
major back muscles (Figure 39–1). Each of the two kidneys is
a bean-shaped structure about the size of a fist, with the
rounded, outer convex surface of each kidney facing the side
of the body, and the indented surface, called the hilum, facing
the spine. Each hilum is penetrated by blood vessels, nerves,
and a ureter, which carries urine out of the kidney to the blad-
der. Each ureter is formed from funnel-like structures called
major calyces, which, in turn, are formed from minor calyces
(Figure 39–2). The minor calyces fit over underlying cone-
shaped renal tissue called pyramids. The tip of each pyramid
is called a papilla and projects into a minor calyx. The calyces
act as collecting cups for the urine formed by the renal tissue
in the pyramids. The pyramids are arranged radially around
the hilum, with the papillae pointing toward the hilum and the
399
Cortex
Medulla
Papilla
Renal vein
Renal artery
Calyx
Pelvis
Ureter
Capsule
FIGURE 39–2 Major structural components of the kidney.
(Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical
Physiology. New York: McGraw-Hill, 2009.)
broad bases of the pyramids facing the outside, top, and bot-
tom of the kidney. The pyramids constitute the medulla of the
kidney. Overlying the medullary tissue is a cortex, and cover-
ing the cortical tissue on the very external surface of the kid-
ney is a thin connective tissue capsule.
The working tissue mass of both the cortex and medulla is
constructed almost entirely of tubules (nephrons and collect-
ing tubules) and blood vessels (mostly capillaries and capil-
larylike vessels). In the cortex, tubules and blood vessels are
intertwined randomly, something like a plateful of spaghetti.
In the medulla, they are arranged in parallel arrays like bun-
dles of sticks. In both cases, blood vessels and tubules are
always close to each other. Between the tubules and blood ves-
sels lies the interstitium, which comprises less than 10% of the
renal volume. The interstitium contains a small amount of
fluid and scattered interstitial cells (fibroblasts and others)
that synthesize an extracellular matrix of collagen, proteogly-
cans, and glycoproteins.
It is important to realize that the cortex and medulla have
very different properties both structurally and functionally. On
close examination, we see that (1) the cortex has a highly gran-
ular appearance, absent in the medulla, and (2) each medullary
pyramid is divisible into an outer zone (adjacent to the cortex)
and an inner zone, which includes the papilla. All these distinc-
tions reflect the different arrangement of the various tubules
and blood vessels in the different regions of the kidney.
THE NEPHRON
Each kidney contains approximately 1 million nephrons, one
of which is shown diagrammatically in Figure 39–3. Each
nephron begins with a spherical filtering component, called
the renal corpuscle, followed by a long tubule leading out of it
that continues until it merges with the tubules of other
nephrons to form collecting ducts, which are themselves long
400 SECTION VII Renal Physiology

Afferent TABLE 39–1 Terminology for the tubular segments.

arteriole
Macula Distal tubule
Bowman’s densa Combination Terms
capsule Sequence of Segments Used in Text
Proximal Proximal convoluted tubule Proximal tubule
tubule Proximal straight tubule
Cortical
Descending thin limb of Henle’s loop Henle’s loop
collecting
duct Ascending thin limb of Henle’s loop
Thick Thick ascending limb of Henle’s loop
ascending (contains macula densa near end)
limb Distal convoluted tubule
Thin
descending Connecting tubule Collecting duct
limb Cortical collecting duct system
Medullary
Thin Outer medullary collecting duct
collecting
ascending Inner medullary collecting duct (last portion
duct
limb is papillary duct)

Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
FIGURE 39–3 Components of the nephron. (Reproduced with 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.
permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York:
McGraw-Hill, 2009.)

tubes. Collecting ducts eventually merge with others in the
renal papilla to form a ureter that conveys urine to the bladder
(Figure 39–3).
THE RENAL CORPUSCLE
The renal corpuscle is a hollow sphere (Bowman’s capsule)
filled with a compact tuft of interconnected capillary loops,
the glomerulus (plural glomeruli) (Figure 39–4a). Blood
enters the capillaries inside Bowman’s capsule through an
afferent arteriole that penetrates the surface of the capsule at
one side, called the vascular pole. Blood then leaves the capil-
laries through a nearby efferent arteriole on the same side.
The space within Bowman’s capsule not occupied by the glom-
erulus is called the urinary space or Bowman’s space, and it is
into this space that fluid filters from the glomerular capillaries
before flowing into the first portion of the tubule, located
opposite the vascular pole.
The structure and properties of the filtration barrier that
separates plasma in the glomerular capillaries from fluid in
urinary space are crucial for renal function and will be
described thoroughly in the next chapter. For now, we note
simply that the functional significance of the filtration barrier
is that it permits the filtration of large volumes of fluid from
the capillaries into Bowman’s space, but restricts filtration of
large plasma proteins such as albumin.
Another cell type—the mesangial cell—is found in close
association with the capillary loops of the glomerulus.
Glomerular mesangial cells act as phagocytes and remove
trapped material from the basement membrane. They also
contain large numbers of myofilaments and can contract in
response to a variety of stimuli in a manner similar to vascu-
lar smooth muscle cells. The role of such contraction in
influencing filtration by the renal corpuscles is discussed in
Chapters 40 and 45.
THE TUBULE
Throughout its course, the tubule, which begins at and leads out
of Bowman’s capsule, is made up of a single layer of epithelial
cells resting on a basement membrane and connected by tight
junctions that physically link the cells together (like the plastic
form that holds a six pack of soft drinks together). Table 39–1
lists the names and sequence of the various tubular segments, as
illustrated in Figure 39–5. Physiologists and anatomists have
traditionally grouped two or more contiguous tubular segments
for purposes of reference, but the terminologies have varied
considerably. Table 39–1 also gives the combination terms used
in this text.
The proximal tubule, which drains Bowman’s capsule, con-
sists of a coiled segment—the proximal convoluted tubule—
followed by a straight segment—the proximal straight
tubule—which descends toward the medulla, perpendicular
to the cortical surface of the kidney.
The next segment is the descending thin limb of the loop
of Henle (or simply the descending thin limb). The descend-
ing thin limbs of different nephrons penetrate into the medulla
to varying depths, and then abruptly reverse at a hairpin turn
and begin an ascending portion of the loop of Henle parallel to
the descending portion. In long loops (depicted on the left
side of Figure 39–5) the epithelium of the first portion of the
ascending limb remains thin, although different functionally
from that of the descending limb. This segment is called the
ascending thin limb of Henle’s loop, or simply the ascending
thin limb (see Figure 39–5). Further up the ascending portion
the epithelium thickens, and this next segment is called the
thick ascending limb of Henle’s loop, or simply the thick
ascending limb. In short loops (depicted on the right side of
Figure 39–5) there is no ascending thin portion, and the thick
ascending portion begins right at the hairpin loop. The thick
ascending limb rises back into the cortex to the very same
Bowman’s capsule from which the tubule originated. Here it
passes directly between the afferent and efferent arterioles at
 CHAPTER 39 Renal Functions, Basic Processes, and Anatomy 401

Parietal layer
Bowman's capsule Visceral layer
Renal corpuscle (podocyte)
Glomerular capillary Proximal
(covered by visceral layer) tubule

Afferent arteriole Capillary

Juxtaglomerular
Juxtaglomerular cells a. Blood flows into the glomerulus through
apparatus Macula densa the afferent arterioles and leaves the
glomerulus through the efferent
arterioles. The proximal tubule exits
Distal
Bowman’s capsule.
tubule

Efferent
arteriole
(a)

Cell processes
Podocyte (visceral layer
of Bowman's capsule) Cell body

b. Podocytes of Bowman’s capsule

Filtration surround the capillaries. Filtration slits
slits between the podocytes allow fluid to
pass into Bowman’s capsule. The
glomerulus is composed of capillary
endothelium that is fenestrated.
Glomerular Surrounding the endothelial cells is
capillary (cut) a basement membrane.

(b) Fenestrae

Capsular space

Foot
processes

Filtration
slits c. Substances in the blood are filtered
through capillary fenestrae between
endothelial cells (single layer). The
filtrate then passes across the
basement membrane and through
slit pores between the foot processes
(also called pedicels) and enters the
capsular space. From here, the
Basement membrane filtrate is transported to the lumen
of the proximal convoluted tubule.

Fenestra
Capillary lumen

(c) Endothelium Movement

of filtrate
FIGURE 39–4 The renal corpuscle. a) Cutaway view of the renal corpuscle. b) Close-up of podocytes surrounding capillaries.
c) Transmission EM of the filtration barrier. (Reproduced with permission from Daniel Friend from William Bloom and Don Fawcett, Textbook of Histology, 10th ed.
W.B. Saunders Co. 1975.)
402 SECTION VII Renal Physiology

Peritubular
capillaries

Proximal Distal
convoluted convoluted Efferent arteriole
tubule tubule Afferent arteriole

Artery
Vein

C
o
r
t
Renal corpuscle e
x
Bowman’s
capsule
Glomerulus Cortical
collecting
Macula densa duct

Vein
Loop of Henie Artery

Descending
limb Corticomedullary M
junction e
Thick d
segment of u
ascending l
l
limb a
Medullary
Thin collecting duct
segment of Urine
ascending
limb
Vasa recta
Juxtamedullary nephron Cortical nephron
FIGURE 39–5 Basic structure of nephrons and vascular elements as described in the text. Note the difference between a
juxtamedullary nephron with its renal corpuscle located just above the corticomedullary border (left side of figure) and a cortical nephron with
its renal corpuscle higher in the cortex (right side of figure). Cortical nephrons have efferent arterioles that give rise to peritubular capillaries, and
they have short loops of Henle. In contrast, juxtamedullary nephrons have efferent arterioles that descend into the medulla to form vasa recta,
and they have long loops of Henle. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

the point where they enter and exit the renal corpuscle at its
vascular pole (see Figure 39–4a). The cells in the thick ascend-
ing limb closest to Bowman’s capsule (between the afferent
and efferent arterioles) are a group of specialized cells known
as the macula densa (see Figure 39–6). The macula densa
marks the end of the thick ascending limb and the beginning
of the distal convoluted tubule. This is followed by the con-
necting tubule, which leads to the cortical collecting tubule,
the first portion of which is called the initial collecting tubule.
From Bowman’s capsule to the proximal tubule, loop of
Henle, distal tubule, and initial collecting tubules, each of the
1 million nephrons in each kidney is completely separate from
the others. However, connecting tubules from several nephrons
merge to form cortical collecting tubules, and a number of ini-
 CHAPTER 39 Renal Functions, Basic Processes, and Anatomy 403

known more commonly as principal cells. Interspersed among

the segment-specific cells in each of these three segments are
individual cells of the second type, called intercalated cells.
The last portion of the medullary collecting duct contains nei-
ther principal cells nor intercalated cells but is composed
entirely of a distinct cell type called the inner medullary col-
lecting duct cells.

Podocytes
Sympathetic
nerve fiber
Mesangial cells
Juxtaglomerular
Efferent arteriole cells
Afferent arteriole
Smooth muscle
cells
Macula densa
Distal tubule
FIGURE 39–6 Components of the juxtaglomerular (JG)
apparatus. It is made up of (1) juxtaglomerular cells (granular cells),
which are specialized smooth muscle cells surrounding the afferent
arteriole, (2) extraglomerular mesangial cells, and (3) cells of the macula
densa, which are part of the tubule. The close proximity of these
components to each other permits chemical mediators released from
one cell to easily diffuse to other components. Note that sympathetic
nerve fibers innervate the granular cells. (Reproduced with permission from
Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
tial collecting tubules then join end to end or side to side to
form larger cortical collecting ducts. All the cortical collecting
ducts then run downward to enter the medulla and become
outer medullary collecting ducts, and then inner medullary
collecting ducts. The latter merge to form several hundred large
ducts, the last portions of which are called papillary collecting
ducts, each of which empties into a calyx of the renal pelvis.
Each renal calyx is continuous with the ureter, which empties
into the urinary bladder, where urine is temporarily stored and
from which it is intermittently eliminated. The urine is not
altered after it enters a calyx. From this point on, the remainder
of the urinary system serves only to maintain the composition
of the tubular fluid established by the kidney.
Up to the distal convoluted tubule, the epithelial cells form-
ing the wall of a nephron in any given segment are homoge-
neous and distinct for that segment. For example, the thick
ascending limb contains only thick ascending limb cells. How-
ever, beginning in the second half of the distal convoluted
tubule, two cell types are found intermingled in most of the
remaining segments. One type constitutes the majority of cells
in the particular segment, is considered specific for that seg-
ment, and is named accordingly: distal convoluted tubule cells,
connecting tubule cells, and collecting duct cells, the last
THE JUXTAGLOMERULAR APPARATUS
Reference was made earlier to the macula densa, a portion of the
late thick ascending limb at the point where this segment comes
between the afferent and efferent arterioles at the vascular pole of
the renal corpuscle from which the tubule arose. This entire area is
known as the juxtaglomerular apparatus (JG) (see Figure 39–6),
which, as will be described later, plays a very important signaling
function. (Do not confuse the term JG with juxtamedullary
nephron, meaning a nephron with a glomerulus located close to
the cortical–medullary border.) Each JG apparatus is made up of
the following three cell types: (1) granular cells (called juxtaglom-
erular cells in Figure 39–6), which are differentiated smooth mus-
cle cells in the walls of the afferent arterioles; (2) extraglomerular
mesangial cells; and (3) macula densa cells, which are specialized
thick ascending limb epithelial cells.
The granular cells are named because they contain secretory
vesicles that appear granular in light micrographs. These granules
contain the hormone renin (pronounced REE-nin). As we will
describe in Chapter 45, renin is a crucial substance for control of
renal function and systemic BP. The extraglomerular mesangial
cells are morphologically similar to and continuous with the
glomerular mesangial cells, but lie outside Bowman’s capsule. The
macula densa cells are detectors of the composition of the fluid
within the nephron at the very end of the thick ascending limb
and contribute to the control of glomerular filtration rate
(GFR—see below) and to the control of renin secretion.
BASIC RENAL PROCESSES
The working structures of the kidney are the nephrons and
collecting tubules into which the nephrons drain. Figure 39–7
illustrates the meaning of several keywords that we use to
describe how the kidneys function. It is essential that any stu-
dent of the kidney grasp their meaning.
Filtration is the process by which water and solutes in the
blood leave the vascular system through the filtration barrier
and enter Bowman’s space (a space that is topologically out-
side the body). Secretion is the process of moving substances
into the tubular lumen from the cytosol of epithelial cells
that form the walls of the nephron. Secreted substances may
originate by synthesis within the epithelial cells or, more
often, by crossing the epithelial layer from the surrounding
renal interstitium. Reabsorption is the process of moving
substances from the lumen across the epithelial layer into the
surrounding interstitium. In most cases, reabsorbed sub-
stances then move into surrounding blood vessels, so that
404 SECTION VII Renal Physiology
Artery
Afferent Glomerular Efferent
arteriole capillary arteriole
1. Glomerular
filtration
2. Tubular
1 secretion
3. Tubular
Bowman’s reabsorption
2
space
Peritubular
Tubule capillary
3 excrete large quantities of waste products and to regulate the
Vein
Urinary
excretion
FIGURE 39–7 Fundamental elements of renal function—
glomerular filtration, tubular secretion, and tubular
reabsorption—and the association between the tubule and
vasculature in the cortex. (Reproduced with permission from Widmaier EP,
Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
the term reabsorption implies a two-step process of removal
from the lumen followed by movement into the blood. Excre-
tion means exit of the substance from the body (i.e., the sub-
stance is present in the final urine produced by the kidneys).
Synthesis means that a substance is constructed from molec-
ular precursors, and catabolism means the substance is bro-
ken down into smaller component molecules. The renal
handling of any substance consists of some combination of
these processes.
GLOMERULAR FILTRATION
Urine formation begins with glomerular filtration, the bulk
flow of fluid from the glomerular capillaries into Bowman’s
capsule. The glomerular filtrate (i.e., the fluid within Bow-
man’s capsule) is very much like blood plasma, but contains
very little total protein because the large plasma proteins such
as albumin and the globulins are virtually excluded from mov-
ing through the filtration barrier. Smaller proteins, such as
many of the peptide hormones, are present in the filtrate, but
their mass in total is miniscule compared with the mass of
large plasma proteins in the blood. The filtrate contains most
inorganic ions and low-molecular-weight organic solutes in
virtually the same concentrations as in the plasma. Substances
that are present in the filtrate at the same concentration as
found in the plasma are said to be freely filtered. (Note that
freely filtered does not mean all filtered. It just means that the
amount filtered is in exact proportion to the fraction of plasma
volume that is filtered.) Many low-molecular-weight compo-
nents of blood are freely filtered. Among the most common
substances included in the freely filtered category are the ions
sodium, potassium, chloride, and bicarbonate; the uncharged
organics glucose and urea; amino acids; and peptides such as
insulin and antidiuretic hormone (ADH).
The volume of filtrate formed per unit time is known as the
glomerular filtration rate (GFR). In a healthy young adult
male, the GFR is an incredible 180 L per day (125 mL/min)!
Contrast this value with the net filtration of fluid across all the
other capillaries in the body: approximately 4 L per day. The
implications of this huge GFR are extremely important. When
we recall that the average total volume of plasma in humans is
approximately 3 L, it follows that the entire plasma volume is
filtered by the kidneys some 60 times a day. The opportunity
to filter such huge volumes of plasma enables the kidneys to
constituents of the internal environment very precisely. One of
the general consequences of healthy aging as well as many kid-
ney diseases is a reduction in the GFR.
TUBULAR REABSORPTION AND
TUBULAR SECRETION
The volume and composition of the final urine are quite dif-
ferent from those of the glomerular filtrate. Clearly, almost
all the filtered volume must be reabsorbed; otherwise, with a
filtration rate of 180 L per day, we would urinate ourselves
into dehydration very quickly. As the filtrate flows from Bow-
man’s capsule through the various portions of the tubule, its
composition is altered, mostly by removing material (tubular
reabsorption) but also by adding material (tubular secretion).
As described earlier, the tubule is, at all points, intimately
associated with the vasculature, a relationship that permits
rapid transfer of materials between the capillary plasma and
the lumen of the tubule via the interstitial space.
Most of the tubular transport consists of reabsorption rather
than tubular secretion. An idea of the magnitude and impor-
tance of tubular reabsorption can be gained from Table 39–2,
which summarizes data for a few plasma components that
undergo reabsorption. The values in Table 39–2 are typical for
a healthy person on an average diet. There are at least three
important generalizations to be drawn from this table:
1. Because of the huge GFR, the quantities filtered per day
are enormous, generally larger than the amounts of the
substances in the body. For example, the body contains
about 40 L of water, but the volume of water filtered each
day may be as large as 180 L.
2. Reabsorption of waste products, such as urea, is partial, so
that large fractions of their filtered amounts are excreted
in the urine.
3. Reabsorption of most “useful” plasma components (e.g.,
water, electrolytes, and glucose) is either complete
(e.g., glucose) or nearly so (e.g., water and most elec-
trolytes), so that little, if any, of the filtered amounts
are excreted in the urine.
For each plasma substance, a particular combination of fil-
tration, reabsorption, and secretion applies. The relative pro-
 CHAPTER 39 Renal Functions, Basic Processes, and Anatomy
TABLE 39–2 Average values for several substances handled by filtration and reabsorption.
Substance Amount Filtered Per Day
Water (L) 180
Sodium (g) 630
Glucose (g) 180
Urea (g) 56
Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.
portions of these processes then determine the amount excreted.
A critical point is that the rates of these processes are subject to
physiological control. By triggering changes in the rates of
filtration, reabsorption, or secretion when the body content of
a substance goes above or below normal, these mechanisms
regulate excretion to keep the body in balance. For example,
consider what happens when a person drinks a large quantity of
water: Within 1–2 hours, all the excess water has been excreted
in the urine, partly as the result of an increase in GFR but
mainly as the result of decreased tubular reabsorption of water.
The body is kept in balance for water by increasing excretion.
By keeping the body in balance, the kidneys serve to maintain
body water concentration within very narrow limits.
METABOLISM BY THE TUBULES
Although renal physiologists traditionally list glomerular
filtration, tubular reabsorption, and tubular secretion as the
three basic renal processes, we cannot overlook metabolism by
the tubular cells. The tubular cells extract organic nutrients
from the glomerular filtrate or peritubular capillaries and
metabolize them as dictated by the cells’ own nutrient require-
ments. In so doing, the renal cells are behaving no differently
from any other cells in the body. In addition, there are other
metabolic transformations performed by the kidney that are
directed toward altering the composition of the urine and
plasma. The most important of these are gluconeogenesis,
and the synthesis of ammonium from glutamine and the pro-
duction of bicarbonate, both described in Chapter 47.
REGULATION OF RENAL FUNCTION
By far the most complex feature of renal physiology is regula-
tion of renal processes, details of which will be presented in
later chapters. Neural signals, hormonal signals, and intrare-
nal chemical messengers combine to regulate the processes
described above in a manner to help the kidneys meet the
needs of the body. Neural signals originate in the sympathetic
celiac plexus (see Chapter 19). These sympathetic neural sig-
nals exert major control over renal blood flow, glomerular fil-
tration, and the release of vasoactive substances that affect
both the kidneys and the peripheral vasculature. Hormonal
signals originate in the adrenal gland, pituitary gland, and
405
Amount Excreted Reabsorbed (%)
1.8 99.0
3.2 99.5
0 100
28 50
heart. The adrenal cortex secretes the steroid hormones aldos-
terone and cortisol, and the adrenal medulla secretes the cat-
echolamines epinephrine and norepinephrine. All of these
hormones, but mainly aldosterone, are regulators of sodium
and potassium excretion by the kidneys. The posterior pitu-
itary gland secretes the hormone arginine vasopressin (AVP,
also called antidiuretic hormone [ADH]). ADH is a major
regulator of water excretion, and, via its influence on the renal
vasculature and possibly collecting duct principal cells, prob-
ably sodium excretion as well. The heart secretes hormones—
natriuretic peptides—that increase sodium excretion by the
kidneys. The least understood aspect of regulation lies in the
realm of intrarenal chemical messengers (i.e., messengers that
originate in one part of the kidney and act in another part). It
is clear that an array of substances (e.g., nitric oxide, puriner-
gic agonists, superoxide, eicosanoids) influence basic renal
processes, but, for the most part, the specific roles of these
substances are not well understood.
OVERVIEW OF REGIONAL FUNCTION
We conclude this chapter with a broad overview of the tasks
performed by the individual nephron segments. Later, we
examine renal function substance by substance and see how
tasks performed in the various regions combine to produce an
overall result that is useful for the body.
The glomerulus is the site of filtration—about 180 L per day
of volume and proportional amounts of solutes that are freely
filtered, which is the case for most solutes (large plasma pro-
teins are an exception). The glomerulus is where the greatest
mass of excreted substances enters the nephron. The proximal
tubule (convoluted and straight portions) reabsorbs about
two thirds of the filtered water, sodium, and chloride. The
proximal convoluted tubule reabsorbs all of the useful organic
molecules that the body conserves (e.g., glucose, amino acids).
It reabsorbs significant fractions, but by no means all, of many
important ions, such as potassium, phosphate, calcium, and
bicarbonate. It is the site of secretion of a number of organic
substances that are either metabolic waste products (e.g., uric
acid, creatinine) or drugs (e.g., penicillin) that clinicians must
administer appropriately to make up for renal excretion.
The loop of Henle contains different segments that perform
different functions, but the key functions occur in the thick
ascending limb. As a whole, the loop of Henle reabsorbs about
406 SECTION VII Renal Physiology
20% of the filtered sodium and chloride and 10% of the fil-
tered water. A crucial consequence of these different propor-
tions is that, by reabsorbing relatively more salt than water, the
luminal fluid becomes diluted relative to normal plasma and
the surrounding interstitium. During periods when the kid-
neys excrete dilute final urine, the role of the loop of Henle in
diluting the luminal fluid is crucial.
The end of the loop of Henle contains cells of the macula
densa, which sense the sodium and chloride content of the
lumen and generate signals that influence other aspects of
renal function, specifically the renin–angiotensin system
(discussed in Chapter 45). The distal tubule and connecting
tubule together reabsorb some additional salt and water, per-
haps 5% of each. The cortical collecting tubule is where sev-
eral (6–10) connecting tubules join to form a single tubule.
Cells of the cortical collecting tubule are strongly responsive to
and are regulated by the hormones aldosterone and ADH.
Aldosterone enhances sodium reabsorption and potassium
secretion by this segment, and ADH enhances water reabsorp-
tion. The degree to which these processes are stimulated or
not stimulated plays a major role in regulating the amount of
solutes and water present in the final urine. With large amounts
of ADH present, most of the water remaining in the lumen is
reabsorbed, leading to concentrated, low-volume urine. With
little ADH present, most of the water passes on to the final
urine, producing dilute, high-volume urine.
The medullary collecting tubule continues the functions
of the cortical collecting tubule in salt and water reabsorp-
tion. In addition, it plays a major role in regulating urea reab-
sorption and in acid–base balance (secretion of protons or
bicarbonate).
CLINICAL CORRELATION
A 57-year-old woman with type 2 diabetes mellitus has
managed her condition quite well via dietary control and
has been in good health otherwise. Lately, however, she
has been feeling increasingly fatigued and so schedules a
checkup with her primary care physician (PCP). No
remarkable physical signs are noted, except that her BP is
increased at 137/92 mm Hg. Analysis of her blood shows
a slightly increased fasting blood glucose of 117 mg/dL
and a low normal hematocrit of 36%. Her PCP reminds
her to be extra careful about diet in terms of salt and sugar,
and suggests supplemental iron to maintain her hemoglo-
bin. She schedules another checkup in 6 months.
The fatigue worsens over the next 6 months, and she suf-
fers a bone fracture after a seemingly minor fall. At the
6-month checkup her fasting blood glucose is 121 mg/dL,
and hematocrit is decreased to 29%. BP is 135/95 mm Hg.
Her PCP orders additional blood tests and a bone density
scan out of concern for possible loss of bone mineral
(osteoporosis). New blood test results reveal elevated levels
of several waste substances, indicative of a decreased GFR.
The evidence strongly points to chronic renal failure, and
she is referred to a nephrologist for evaluation and treatment.
Chronic renal failure that has reached the point of significant
renal dysfunction is called end-stage renal disease (ESRD). It
is the consequence of major loss of functional tissue mass
(nephrons and interstitial tissue). One of the common causes
of ESRD is diabetes mellitus. Chronic hyperglycemia causes
the formation of glycosylated proteins that deposit in the
glomerular filtration apparatus. This interferes with filtration
function and leads to pathology of glomerular cells. Hyper-
tension can be both a cause and an effect of ESRD. The two
normal kidneys have a considerable reserve capacity. Patients
can do perfectly well with just one kidney, and ESRD may
progress to a considerable degree before symptoms appear.
When enough nephrons are lost, function declines, although
some functions are preserved better than others; thus, symp-
toms do not develop uniformly. Another problem in ESRD is
decreased production of erythropoietin, resulting in decreased
red blood cell production and a low hematocrit. The anemia
and possible accumulations of toxic substances due to the low
GFR may account for the fatigue. A more complex problem
in ESRD involves phosphorus, calcium, and bone. As renal
function is lost, the ability to excrete phosphate declines and
plasma phosphate rises, in turn leading to excessive loss of
calcium. The body does not replace the loss, in part because
of decreased renal production of 1,25-dihydroxyvitamin D.
Treatment for ESRD includes the possibility of dialysis to
make up for lost excretory function, renal transplant, and var-
ious dietary controls, including adding phosphate binders to
the diet to prevent accumulation of phosphate in the blood.
CHAPTER SUMMARY
■ The role of the kidneys in the body includes many functions
that go well beyond simple excretion of waste.
■ A major function of the kidneys is to regulate the excretion of
substances at a rate that, on average, exactly balances their
input into the body, and thereby maintains appropriate body
content of many substances.
■ Another major function of the kidneys is to regulate blood
volume and vascular resistance, thereby assisting with the
maintenance of BP.
■ The structure of the kidneys reflects the arrangement of tubules
and closely associated blood vessels.
■ Each functional renal unit is composed of a filtering compo-
nent (glomerulus) and a transporting tubular component (the
nephron and collecting duct).
■ The tubules are made up of multiple segments with distinct
functions.
■ Basic renal mechanisms consist of filtering a large volume,
reabsorbing most of it, and adding substances by secretion,
and, in some cases, synthesis.
 CHAPTER 39 Renal Functions, Basic Processes, and Anatomy
STUDY QUESTIONS
1. Renal corpuscles are located
A) along the corticomedullary border.
B) throughout the cortex.
C) throughout the cortex and outer medulla.
D) throughout the whole kidney.
2. Relative to the number of glomeruli, how many loops of Henle
and collecting ducts are present?
A) same number of loops of Henle; same number of
collecting ducts
B) fewer loops of Henle; fewer collecting ducts
C) same number of loops of Henle; fewer collecting ducts
D) same number of loops of Henle; more collecting ducts
3. In which of the following lists are all the named substances
synthesized in the kidneys and released into the blood?
A) insulin, renin, and glucose
B) red blood cells, active vitamin D, and albumin
C) renin, 1,25-dihydroxyvitamin D, and erythropoietin
D) glucose, urea, and erythropoietin
4. The macula densa is a group of cells located in the wall of
A) Bowman’s capsule.
B) the afferent arteriole.
C) the end of the thick ascending limb.
D) the glomerular capillaries.
407
5. The volume of the ultrafiltrate of plasma entering the tubules by
glomerular filtration in 1 day is typically
A) about three times the renal volume.
B) about the same as the volume filtered by all the capillaries in
the rest of the body.
C) about equal to the circulating plasma volume.
D) greater than the total body fluid volume.
6. A substance known to be freely filtered has a certain
concentration in the afferent arteriole. What can we predict
about its concentration in the efferent arteriole?
A) almost zero
B) close to the value in the afferent arteriole
C) about 20% lower than the value in the afferent arteriole
D) we cannot predict without knowing what happens in
the tubules
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 40
C H A P T E R

Renal Blood Flow and

Glomerular Filtration
Douglas C. Eaton and John P. Pooler

O B J E C T I V E S

■ Define renal blood flow, renal plasma flow, glomerular filtration rate, and
filtration fraction, and give normal values.
■ State the formula relating flow, pressure, and resistance in an organ.
■ Identify the successive vessels through which blood flows after leaving
the renal artery.
■ Describe the relative resistances of the afferent arterioles and efferent
arterioles.
■ Describe the effects of changes in afferent and efferent arteriolar resistances
on renal blood flow.
■ Describe the three layers of the glomerular filtration barrier, and define
podocyte, foot process, and slit diaphragm.
■ Describe how molecular size and electrical charge determine filterability
of plasma solutes; state how protein binding of a low-molecular-weight
substance influences its filterability.
■ State the formula for the determinants of glomerular filtration rate, and state,
in qualitative terms, why the net filtration pressure is positive.
■ State the reason glomerular filtration rate is so large relative to filtration
across other capillaries in the body.
■ Describe how arterial pressure, afferent arteriolar resistance, and efferent
arteriolar resistance influence glomerular capillary pressure.
■ Describe how changes in renal plasma flow influence average glomerular
capillary oncotic pressure.
■ Define autoregulation of renal blood flow and glomerular filtration rate.

RENAL BLOOD FLOW
Renal blood flow (RBF) is huge relative to the mass of the
kidneys—about 1 L/min, or 20% of the resting cardiac output.
Considering that the volume of each kidney is less than 150
cm3, this means that each kidney is perfused with over three
times its total volume every minute. All of this blood is deliv-
ered to the cortex. A small fraction of the cortical blood flow is
then directed to the medulla. Blood enters each kidney at the
hilum via a renal artery. After several divisions into smaller
arteries, blood reaches arcuate arteries that course across the
tops of the pyramids between the medulla and cortex. From
these, cortical radial arteries project upward toward the kid-
ney surface and give off a series of afferent arterioles, each of
which leads to a glomerulus within Bowman’s capsule (see
Figure 39–5). These arteries and glomeruli are found only in
the cortex, never in the medulla. In most organs, capillaries
recombine to form the beginnings of the venous system, but
the glomerular capillaries instead recombine to form another
set of arterioles, the efferent arterioles. The efferent arterioles
soon subdivide into a second set of capillaries. These are the
peritubular capillaries, which are profusely distributed
throughout the cortex. The peritubular capillaries then rejoin
to form the veins by which blood ultimately leaves the kidney.

409

Ch40_409-416.indd 409 11/26/10 10:10:19 AM

410 SECTION VII Renal Physiology

Blood flow to the medulla is far less than cortical blood flow,
perhaps 0.1 L/min, and derives from the efferent arterioles of
glomeruli situated just above the corticomedullary border (jux-
tamedullary glomeruli). These efferent arterioles do not branch Interlobular

CORTEX
into peritubular capillaries, but rather descend downward into artery

the outer medulla, where they divide many times to form bun-
Arcuate
dles of parallel vessels called vasa recta (Latin recta for “straight” Efferent artery
and vasa for “vessels”). These bundles of vasa recta penetrate arteriole

deep into the medulla (see Figure 40–1). Vasa recta on the out-
side of the vascular bundles “peel off ” and give rise to inter-
bundle plexi of capillaries that surround Henle’s loops and the

Outer
stripe
collecting ducts in the outer medulla. Only the center-most vasa Interbundle
plexus

OUTER MEDULLA
Vascular
recta supply capillaries in the inner medulla; thus, little blood bundle
flows into the papilla. The capillaries from the inner medulla
re-form into ascending vasa recta that run in close association
with the descending vasa recta within the vascular bundles. The

stripe
Inner
structural and functional properties of the vasa recta are rather
complex, and will be elucidated further in Chapter 44.
The significance of the quantitative differences between cor-
tical and medullary blood flow is the following: the high blood
flow in the cortical peritubular capillaries maintains the inter-
stitial environment of the cortical renal tubules very close in
composition to that of blood plasma throughout the body. In
contrast, the low blood flow in the medulla permits an intersti-

DVR

AVR
tial environment that is quite different from blood plasma. As
INNER MEDULLA

described in Chapter 44, the interstitial environment in the

medulla plays a crucial role in regulating water excretion.
H2O

FLOW, RESISTANCE, AND BLOOD
PRESSURE IN THE KIDNEYS
Blood flow in the kidneys obeys the basic hemodynamic prin-
ciples described in Chapter 22. The basic equation for blood
flow through any organ is as follows:
ΔP
Q = ___
R
(1)
where Q is organ blood flow, ΔP the mean pressure in the artery
supplying the organ minus mean pressure in the vein draining
that organ, and R the total vascular resistance in that organ. The
high RBF is accounted for by low total renal vascular resistance.
The resistance is low because there are so many pathways in
parallel, that is, so many glomeruli and their associated vessels.
The resistances of the afferent and efferent arterioles are
about equal in most circumstances and account for most of the
total renal vascular resistance. Resistances in arteries preced-
ing afferent arterioles (i.e., cortical radial arteries) and in the
capillaries play some role also, but we concentrate on the arte-
rioles because arteriolar resistances are variable and are the
sites of regulation. A change in the afferent arteriole or efferent
arteriole resistance produces the same effect on RBF because
these vessels are in series. When the two resistances both
change in the same direction (the most common state of
affairs), their effects on RBF are additive. When they change in
different directions—one resistance increasing and the other
decreasing—the changes offset each other.
NaCl
Urea
FIGURE 40–1 The renal microcirculation. Arcuate arteries run
just above the corticomedullary border, parallel to the surface, and
give rise to cortical radial (interlobular) arteries radiating toward the
surface. Afferent arterioles originate from the cortical radial arteries at
an angle that varies with cortical location. Blood is supplied to the
peritubular capillaries of the cortex from the efferent flow out of
superficial glomeruli. It is supplied to the medulla from the efferent
flow out of juxtamedullary glomeruli. Efferent arterioles of
juxtamedullary glomeruli give rise to bundles of descending vasa recta
in the outer stripe of the outer medulla. In the inner stripe of the outer
medulla, descending vasa recta and ascending vasa recta returning
from the inner medulla run side by side in the vascular bundles,
allowing exchange of solutes and water as described in Chapter 44.
Descending vasa recta from the bundle periphery supply the
interbundle capillary plexus of the inner stripe, whereas those in the
center supply blood to the capillaries of the inner medulla. Contractile
pericytes in the walls of the descending vasa recta regulate flow. DVR,
descending vasa recta; AVR, ascending vasa recta. (Modified with
permission from Pallone TL, Zhang Z, Rhinehart K: Physiology of the renal medullary
microcirculation. Am J Physiol Renal Physiol 2003;284(2):F253–F266.)
Vascular pressures (i.e., hydrostatic or hydraulic pressures)
are much higher in the glomerular capillaries than in the
 CHAPTER 40 Renal Blood Flow and Glomerular Filtration 411

Sites of largest
vascular resistance
100
Pressure (mm Hg)

75

50

25

0
FIGURE 40–2 Blood pressure decreases as blood flows
le

lary
le

l vein
ry

l vein
capil lar
lary

r terio
r terio
l ar te

eru

capil

through the renal vascular network. The largest drops occur in the
rena

Rena
Glom

ent a
ent a
Rena

sites of largest resistance—the afferent and efferent arterioles. The

bular

Intra

location of the glomerular capillaries, between the sites of high

Effer
Affer

resistance, results in their having a much higher pressure than the

u
Perit

peritubular capillaries. (Reproduced with permission from Kibble J, Halsey CR:

The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

peritubular capillaries. As blood flows through any vascular capillaries and rest on the basement membrane. The podocytes
resistance, the pressure progressively decreases. Pressure at the have an unusual octopuslike structure. Small “fingers,” called
beginning of a given afferent arteriole is close to mean systemic pedicels (or foot processes), extend from each arm of the podo-
arterial pressure (about 100 mm Hg) and decreases to about 60 cyte and are embedded in the basement membrane (see Fig-
mm Hg at the point where it feeds a glomerulus. Because there ure 39–4c). Pedicels from a given podocyte interdigitate with the
are so many glomerular capillaries in parallel, pressure decreases pedicels from adjacent podocytes. Spaces between adjacent
very little during flow through those capillaries; thus, glomeru- pedicels constitute the path through which the filtrate, once it
lar capillary pressure remains close to 60 mm Hg. Then pres- has passed through the endothelial cells and basement mem-
sure decreases again during flow through an efferent arteriole, brane, travels to enter Bowman’s space. The foot processes are
to about 20 mm Hg at the point where it feeds a peritubular coated by a thick layer of extracellular material, which partially
capillary (see Figure 40–2). The high glomerular pressure of occludes the slits. Extremely thin processes called slit dia-
about 60 mm Hg is necessary to drive glomerular filtration, phragms bridge the slits between the pedicels. Slit diaphragms
whereas the low peritubular capillary pressure of 20 mm Hg is are widened versions of the tight junctions and adhering junc-
equally necessary to permit the reabsorption of fluid. tions that link all contiguous epithelial cells together and are like
miniature ladders. The pedicels form the sides of the ladder, and
the slit diaphragms are the rungs.
GLOMERULAR FILTRATION Both the slit diaphragms and basement membrane are com-
posed of an array of proteins, and while the basement mem-
FORMATION OF GLOMERULAR brane may contribute to selectivity of the filtration barrier,
FILTRATE integrity of the slit diaphragms is essential to prevent excessive
leak of plasma protein (mainly albumin). Some protein-wasting
The glomerular filtrate contains most inorganic ions and low- diseases are associated with abnormal slit diaphragm structure.
molecular-weight organic solutes in virtually the same concen- Selectivity of the barrier to filtered solute is based on both
trations as in the plasma. It also contains small plasma peptides molecular size and electrical charge. Let us look first at size.
and a very limited amount of albumin (see Chapter 43). Filtered The filtration barrier of the renal corpuscle provides no hin-
fluid must pass through a three-layered glomerular filtration drance to the movement of molecules with molecular weights
barrier. The first layer, the endothelial cells of the capillaries, is less than 7,000 d (i.e., solutes this small are all freely filtered).
perforated by many large fenestrae (“windows”), like a slice of This includes all small ions, glucose, urea, amino acids, and
Swiss cheese, which occupy about 10% of the endothelial surface many hormones. The filtration barrier almost totally excludes
area. They are freely permeable to everything in the blood except plasma albumin (molecular weight of approximately 66,000 d).
cells and platelets. The middle layer, the capillary basement (We are, for simplicity, using molecular weight as our reference
membrane, is a gel-like acellular meshwork of glycoproteins and for size; in reality, it is molecular radius and shape that is criti-
proteoglycans, with a structure like a kitchen sponge. The third cal.) The hindrance to plasma albumin is not 100%, however, so
layer consists of epithelial cells (podocytes) that surround the the glomerular filtrate does contain extremely small quantities
412 SECTION VII Renal Physiology
of albumin, on the order of 10 mg/L or less. This is only about
0.02% of the concentration of albumin in plasma and is the rea-
son for the use of the phrase “nearly protein-free” earlier. Some
small substances are partly or mostly bound to large plasma
proteins and are thus not free to be filtered, even though the
unbound fractions can easily move through the filtration bar-
rier. This includes hydrophobic hormones of the steroid and
thyroid classes and about 40% of the calcium in the blood.
For molecules with a molecular weight ranging from 7,000
to 70,000 d, the amount filtered becomes progressively smaller
as the molecule becomes larger (Figure 40–3). Thus, many
normally occurring small- and medium-sized plasma pep-
tides and proteins are actually filtered to a significant degree.
Moreover, when certain small proteins not normally present
in the plasma appear because of disease (e.g., hemoglobin
A.
1.0
Filtrate/plasma concentration ratio
Inulin
(~ 5,000)
0.5
Hemoglobin (68,000)
Albumin (~ 69,000)
0 equal, a higher GFR means greater excretion of salt and water.
0 35
Molecular weight (thousands)
B.
Positively charged = more filtered
Neutral
Filtration
Molecular size
Negatively charged = less filtered
FIGURE 40–3 A) As molecular weight (and therefore size)
increases, filterability declines, so that proteins with a molecular
weight above 70,000 d are hardly filtered at all. B) For any given
molecular size, negatively charged molecules are restricted far more
than neutral molecules, while positively charged molecules are
restricted less. (Reproduced with permission from Kibble J, Halsey CR: The Big
Picture, Medical Physiology. New York: McGraw-Hill, 2009.)
released from damaged erythrocytes or myoglobin released
from damaged muscles), considerable filtration of these may
occur as well.
Electrical charge is the second variable determining filter-
ability of macromolecules. For any given size, negatively
charged macromolecules are filtered to a lesser extent, and
positively charged macromolecules to a greater extent, than
neutral molecules. This is because the surfaces of all the com-
ponents of the filtration barrier (the cell coats of the endothe-
lium, the basement membrane, and the cell coats of the
podocytes) contain fixed polyanions, which repel negatively
charged macromolecules during filtration. Because almost all
plasma proteins bear net negative charges, this electrical
repulsion plays a very important restrictive role, enhancing
that of purely size hindrance. In other words, if either albumin
or the filtration barrier were not charged, even albumin would
be filtered to a considerable degree (see Figure 40–3). Certain
diseases that cause glomerular capillaries to become “leaky”
to protein do so by eliminating negative charges in the
membranes.
It must be emphasized that the negative charges in the filtra-
tion membranes act as a hindrance only to macromolecules,
not to mineral anions or low-molecular-weight organic anions.
Thus, chloride and bicarbonate ions, despite their negative
charge, are freely filtered.
DIRECT DETERMINANTS OF GFR
Variation in glomerular filtration rate (GFR) is a crucial
determinant of renal function because, everything else being
70 Regulation of the GFR is straightforward in terms of physical
principles but very complex functionally because there are
many regulated variables. The rate of filtration in all capillaries,
including the glomeruli, is determined by the hydraulic perme-
ability of the capillaries, their surface area, and the net filtra-
tion pressure (NFP) acting across them, given as follows:
Rate of filtration = (2)
Hydraulic permeability × Surface area × NFP
Because it is difficult to estimate the area of a capillary bed,
a parameter called the filtration coefficient (Kf) is used to
denote the product of the hydraulic permeability and the
area.
The NFP is the algebraic sum of the hydrostatic pressures
and the osmotic pressures resulting from protein—the oncotic,
or colloid osmotic pressures—on the two sides of the capil-
lary wall. There are four pressures to consider: two hydrostatic
pressures and two oncotic pressures. These are the Starling
forces that were described earlier in Chapter 26. Applying this
same principle to the glomerular capillaries, we have:
NPF = (PGC – PBC) – (πGC – πBC) (3)
where PGC is glomerular capillary hydraulic pressure, πBC the
oncotic pressure of fluid in Bowman’s capsule, PBC the
hydraulic pressure in Bowman’s capsule, and πGC the oncotic

Bowman’s
space
PBS
PGC
Glomerular
capillary
πGC
Forces
Favoring filtration*:
Glomerular capillary blood pressure (PGC)
Opposing filtration:
Fluid pressure in Bowman’s space (PBS)
Osmotic force due to protein in plasma (π GC)
Net glomerular filtration pressure = PGC – PBS – πGC
FIGURE 40–4 Forces involved in glomerular filtration as
described in the text. (Reproduced with permission from Widmaier EP, Raff H,
Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
pressure in glomerular capillary plasma, shown schemati-
cally in Figure 40–4, along with typical average values.
Because there is normally little total protein in Bowman’s
capsule, πBC may be taken as zero and not considered in our
analysis. Accordingly, the overall equation for GFR becomes:
GFR = Kf (PGC – PBC – πGC)
Figure 40–5 shows that the hydraulic pressure changes only
slightly along the glomeruli. This is because there are so many
glomeruli in parallel, and collectively they provide only a small
resistance to flow, but the oncotic pressure in the glomerular
capillaries does change substantially along the length of the
glomeruli. Water moves out of the vascular space and leaves
protein behind, thereby increasing protein concentration and,
hence, the oncotic pressure of the unfiltered plasma remaining
in the glomerular capillaries. Mainly because of this large
increase in oncotic pressure, the NFP decreases from the
beginning of the glomerular capillaries to the end. The NFP
when averaged over the whole length of the glomerulus is
about 16 mm Hg. This average NFP is higher than that found
in most nonrenal capillary beds. Taken together with a very
high value for Kf, it accounts for the enormous filtration of 180
L of fluid per day (compared with 3 L per day or so in all other
capillary beds combined).
The GFR is not fixed but shows marked fluctuations in differ-
ing physiological states and in disease. To grasp this situation, it
is essential to see how a change in any one factor affects GFR
under the assumption that all other factors are held constant.
CHAPTER 40 Renal Blood Flow and Glomerular Filtration 413
PGC
60
NFP
50
40
Pressure (mm Hg)
30
πGC
20
mmHg
10
PBC
60
0 50% 100%
Capillary length
15
FIGURE 40–5 Forces affecting glomerular filtration along
29 the length of the glomerular capillaries. Note that the oncotic
pressure within the capillaries (πGC) rises due to loss of water and that
16 the net filtration pressure (shaded region) decreases as a result. (Modified
with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed.
New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)
Table 40–1 presents a summary of these factors. It provides,
in essence, a checklist to review when trying to understand
how diseases or vasoactive chemical messengers and drugs
change GFR. It should be noted that the major cause of
decreased GFR in renal disease is not a change in these param-
eters within individual nephrons, but rather simply a decrease
(4) in the number of functioning nephrons, which reduces Kf.
Kf
Changes in Kf are caused most often by glomerular disease,
but also by normal physiological control. The details are still
not completely clear, but chemical messengers released within
the kidneys cause contraction of glomerular mesangial cells.
Such contraction may restrict flow through some of the capil-
lary loops, effectively reducing the area available for filtration,
Kf, and, hence GFR.
PGC
Hydrostatic pressure in the glomerular capillaries (PGC) is
influenced by many factors. We can help depict the situation by
using the analogy of a leaking garden hose. If pressure in the
pipes feeding the hose changes, the pressure in the hose and,
hence, the rate of leak will be altered. Resistances in the hose
also affect the leak. If we kink the hose upstream from the leak,
pressure at the region of leak decreases and less water leaks out.
However, if we kink the hose beyond the leak, this increases
pressure at the region of leak and increases the leak rate.
414 SECTION VII Renal Physiology

TABLE 40–1 Summary of direct GFR determinants PBC

and factors that influence them. Changes in this variable are usually of very minor importance.
However, obstruction anywhere along the tubule or in the exter-
Direct Determinants Major Factors that Tend
of GFR: to Increase the Magnitude
nal portions of the urinary system (e.g., the ureter) increases the
GFR = Kf (PGC − PBC − πGC) of the Direct Determinant tubular pressure everywhere proximal to the occlusion, all the
way back to Bowman’s capsule. The result is to decrease GFR.
Kf 1. ↑ Glomerular surface area
(because of relaxation of
glomerular mesangial cells) πGC
Result: ↑ GFR
Oncotic pressure in the plasma at the very beginning of the glom-
PGC 1. ↑ Renal arterial pressure erular capillaries is, of course, simply the oncotic pressure of sys-
temic arterial plasma. Accordingly, a decrease in arterial plasma
2. ↓ Afferent arteriolar resistance
(afferent dilation)
protein concentration, as occurs, for example, in liver disease,
decreases arterial oncotic pressure and tends to increase GFR,
3. ↑ Efferent arteriolar resistance whereas increased arterial oncotic pressure tends to reduce GFR.
(efferent constriction) However, recall that πGC is the same as arterial oncotic pres-
Result: ↑ GFR sure only at the very beginning of the glomerular capillaries;
PBC 1. ↑ Intratubular pressure because πGC then progressively increases along the glomerular capillar-
of obstruction of tubule or ies as protein-free fluid filters out of the capillary, concentrat-
extrarenal urinary system ing the protein left behind. This means that NFP and, hence,
Result: ↓ GFR filtration progressively decrease along the capillary length.
πGC 1. ↑ Systemic plasma oncotic
Accordingly, anything that causes a steeper increase in πGC
pressure (sets πGC at beginning tends to lower average NFP and hence GFR.
of glomerular capillaries) Such a steep increase in oncotic pressure occurs when RBF is
very low. Since blood is composed of cells and plasma, low RBF
2. ↓ Renal plasma flow (causes
increased rise of πGC along means that renal plasma flow (RPF) is also low. When RPF is
glomerular capillaries) low, any given rate of filtration removes a larger fraction of the
Result: ↓ GFR plasma, leaving a smaller volume of plasma behind in the glom-
GFR, glomerular filtration rate; Kf, filtration coefficient; PGC, glomerular capillary
eruli to contain all the plasma protein. This causes the πGC to
hydraulic pressure; PBC, Bowman’s capsule hydraulic pressure; πGC, glomerular reach a final value at the end of the glomerular capillaries that is
capillary oncotic pressure. A reversal of all arrows in the table will cause higher than normal. This increases the average πGC along the
a decrease in the magnitudes of Kf, PGC, PBC, and πGC.
Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
capillaries and lowers average NFP and, hence, GFR. Conversely,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.) a high RPF, all other factors remaining constant, causes πGC to
increase less steeply and reach a final value at the end of the cap-
illaries that is less than normal, which will increase the GFR.
These concepts can be expressed as a filtration fraction: the
These same principles apply to PGC and GFR. First, a change in
ratio GFR/RPF, which is normally about 20%. The increase in
renal arterial pressure causes a change in PGC in the same direc-
πGC along the glomerular capillaries is directly proportional to
tion. If resistances remain constant, PGC rises and falls as renal
the filtration fraction (i.e., the greater the percentage of vol-
artery pressure rises and falls. This is a crucial point because a
ume filtered from the plasma, the greater the increase in πGC).
major influence on renal function is arterial blood pressure.
Therefore, if you know that filtration fraction has changed,
Second, changes in the resistance of the afferent and efferent
you can be certain that there has also been a proportional
arterioles have opposite effects on PGC. An increase in afferent
change in πGC and that this has played a role in altering GFR.
arteriolar resistance, which is upstream from the glomerulus,
is like kinking the hose above the leak (it decreases PGC),
whereas an increase in efferent arteriolar resistance is down- FILTERED LOAD
stream from the glomerulus and is like kinking the hose
beyond the leak (it increases PGC). Of course, dilation of the A term we use in other chapters is filtered load. It is the amount
afferent arteriole raises PGC, and hence GFR, while dilation of of substance that is filtered per unit time. For freely filtered sub-
the efferent arteriole lower PGC and GFR. It should also be clear stances, the filtered load is just the product of GFR and plasma
that when the afferent and efferent arteriolar resistances both concentration. Consider sodium. Its normal plasma concentra-
change in the same direction (i.e., they both increase or tion is 140 mEq/L, or 0.14 mEq/mL. A normal GFR in healthy
decrease), they exert opposing effects on PGC. young adult males is 125 mL/min, so the filtered load of sodium
The real significance for this is that the kidney can regu- is 0.14 mEq/mL × 125 mL/min = 17.5 mEq/min. We can do the
late PGC and, hence, GFR independently of RBF. The effects of same calculation for any other substance, being careful in each
changes in arteriolar resistances are summarized in case to be aware of the unit of measure in which concentration
Figure 40–6. is expressed. The filtered load is what is presented to the rest of
 CHAPTER 40 Renal Blood Flow and Glomerular Filtration 415

Decreased GFR Increased GFR

Constrict AA Constrict EA

Blood Blood
flow flow
PGC PGC

GFR GFR

(a) (b)

Dilate Dilate
Blood Blood
EA AA
flow flow
PGC PGC

GFR GFR

(c) (d)

FIGURE 40–6 Effect of changes in resistance on GFR. a–d) Constricting the afferent arteriole (AA) or dilating the efferent arteriole (EA)
leads to a decreased GFR, while dilating the AA or constricting the EA leads to increased GFR. (Reproduced with permission from Widmaier EP, Raff H, Strang
KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

the nephron to handle. The filtered load varies with plasma con- RBF varies only modestly when mean arterial pressure changes.
centration and GFR. An increase in GFR, at constant plasma This is partly a result of the myogenic response, which is the
concentration, increases the filtered load, as does an increase in contraction or relaxation of arteriolar smooth muscle in
plasma concentration at constant GFR. response to changes in vascular pressures. Autoregulation is

AUTOREGULATION 1.5 150

Glomerular filtration rate (mL/min)

“Autoregulatory range”
It is extremely important for the kidneys to keep the GFR at a
Renal blood flow (L/min)

level appropriate for the body because the excretion of salt and
water is strongly influenced by the GFR. GFR is strongly influ-
enced by renal arterial pressure. The effect is so strong that
urinary excretion would tend to vary widely with ordinary
daily excursions of arterial pressure. Also, vascular pressure in
the thin-walled glomerular capillaries is higher than in capil-
laries elsewhere in the body, and hypertensive damage ensues
if this pressure is too high.
0 0
To protect the glomerular capillaries from hypertensive 0 80 180
damage and to preserve a healthy GFR at different arterial Renal perfusion pressure (mm Hg)
pressure values, changes in GFR and RBF are minimized by
several mechanisms that we collectively call autoregulation. FIGURE 40–7 Autoregulation of renal blood flow (RBF) and
An increase in renal artery pressure is counteracted by an glomerular filtration rate (GFR). Over the span of renal perfusion
increase in vascular resistance that almost offsets the increase pressure (pressure in renal artery minus pressure in renal vein) from
in pressure. The word “almost” is crucial here. Higher driving 80 to about 170 mm Hg, RBF and GFR rise only modestly as renal
pressures do indeed lead to higher blood flow and GFR, but perfusion pressure increases. Outside of this range, however, the
not proportionally. Consider Figure 40–7. Within the usual changes are much greater. (Reproduced with permission from Kibble J, Halsey
range of mean arterial pressure (renal perfusion pressure), CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)
416 SECTION VII Renal Physiology
also partly the result of rather complicated intrarenal signals
that affect vascular resistance and mesangial cell contraction
(see Chapter 45). The myogenic response is very fast-acting
and protects the glomeruli from short-term fluctuations in
blood pressure. In addition to keeping changes in RBF fairly
small, autoregulatory processes also keep changes in GFR
fairly small. Again, GFR does increase slightly with an increase
in arterial pressure.
CLINICAL CORRELATION
A 10-year-old boy developed a severe sore throat and a
mild fever. The family pediatrician took a throat swab and
concluded the boy had strep throat and so prescribed a
10-day course of antibiotics. The boy recovered and
resumed his normal activities. One week later the boy told
his mother that his urine was “brownish.” She checked the
bowl after his next urination, and it was indeed a rusty
brown color. As the toilet flushed, she noticed that the
water frothed up. Very concerned now, she brought her
son back to the pediatrician, who performed a urine dip-
stick test. This revealed increased protein in the urine
(accounting for the frothiness). In addition, his blood
pressure was somewhat elevated, and the pediatrician
noted some puffiness in the face. Further tests confirmed
that this was a case of poststreptococcal glomerulo-
nephritis (inflammation of the glomeruli).
In glomerulonephritis, mesangial and endothelial cells
proliferate within Bowman’s capsule, with deposition of
antigen–antibody complexes between the various cells in
the glomeruli. It manifests in several forms; in this case, it
was the result of an immune response to the streptococci.
These events disrupt the barrier function of the podocytes,
allowing the passage of larger than normal amounts of
albumin into the filtrate, which is then excreted in the urine.
The rust-brownish color of the urine is due to the presence
of intact red blood cells (hematuria) and hemoglobin
released from hemolyzed red blood cells. A paradoxical fea-
ture of some forms of glomerulonephritis is decreased
excretion of sodium, despite the apparent increased leaki-
ness of the filtration barrier. The accumulation of sodium
and accompanying water can lead to edema (explaining the
puffiness in the boy’s face) and elevated blood pressure.
When occurring in older adults, glomerulonephritis may
be accompanied by a greatly reduced RBF and GFR, but
this is less likely in children. Some evidence suggests that
increased reabsorption of sodium in the distal nephron is
responsible for the sodium retention in cases where GFR is
not reduced, demonstrating that the pathology is not lim-
ited to Bowman’s capsule. In the case of poststreptococcal
glomerulonephritis, no specific treatment is usually neces-
sary, and over time normal renal function returns.
CHAPTER SUMMARY
■ The kidneys have a very large blood flow relative to their mass
because it is regulated for functional reasons rather than
metabolic demand.
■ The cortex has a much higher blood flow and a different
arrangement of blood vessels than the medulla.
■ Glomerular filtration proceeds through a three-layered barrier
that restricts filtration of large macromolecules.
■ Both molecular charge and size affect the filterability of plasma
solutes.
■ The GFR is determined by the same Starling forces that govern
filtration in blood vessels elsewhere.
■ Control of the resistances of the afferent and efferent arterioles
permits independent control of glomerular filtration rate
and RBF.
■ Autoregulation of RBF limits the variation in RBF in the face of
large changes in arterial pressure.
STUDY QUESTIONS
1. Blood enters the renal medulla immediately after passing
through which vessels?
A) arcuate arteries
B) peritubular capillaries
C) afferent arterioles
D) efferent arterioles
2. Which cell type is the main determinant of the filterability of
plasma solutes?
A) mesangial cells
B) podocytes
C) endothelial cells
D) vascular smooth muscle
3. Which of the following is not subject to physiological control on a
moment-to-moment basis?
A) hydrostatic pressure in glomerular capillaries
B) selectivity of the filtration barrier
C) filtration coefficient
D) resistance of efferent arterioles
4. If autoregulation is effective, we expect to see which one of the
following held almost constant?
A) pressure in the renal artery.
B) total renal vascular resistance.
C) the filtered load of water and small ions.
D) the contractile state of smooth muscle in the
afferent arteriole.
5. In the face of a 20% decrease in arterial pressure, GFR decreases
by only 2%. What could account for this finding?
A) The resistances of the afferent and efferent arterioles both
decrease equally.
B) Glomerular mesangial cells contract.
C) Efferent arteriolar resistance increases.
D) Afferent arteriolar resistance increases.
 41
C H A P T E R

Clearance
Douglas C. Eaton and John P. Pooler

O B J E C T I V E S

■ Define the terms clearance and metabolic clearance rate, and differentiate
between general clearance and specific renal clearance.
■ List the information required to calculate clearance.
■ State the criteria that must be met for a substance so that its clearance can
be used as a measure of glomerular filtration rate; state which substances are
used to measure glomerular filtration rate and effective renal plasma flow.
■ Given data, calculate the clearance of any excreted substance.
■ Predict whether a substance undergoes net reabsorption or net secretion
by comparing its clearance with that of inulin or by comparing its rate of
filtration with its rate of excretion.
■ Given data, calculate net rate of reabsorption or secretion for any substance.
■ Given data, calculate fractional excretion of any substance.
■ Describe how to estimate glomerular filtration rate from creatinine clearance
and describe the limitations of this estimate.
■ Describe how to use plasma concentrations of urea and creatinine as
indicators of changes in glomerular filtration rate.

Ingested substances and metabolic waste products are con-

stantly being removed from the body (cleared) by a number of
means, including disposal in the urine and feces, biochemical
transformation in the liver, and, for volatile substances, exhala-
tion. The rate of removal can be expressed in several ways, for
example, the plasma half-life. Another way to express removal
rate is clearance, which is the volume of plasma per unit time
from which all of a specific substance is removed. Clearance in a
biomedical context has both a general meaning and a specific
renal meaning. The general meaning is simply that a substance
is removed from the blood by any of the mechanisms men-
tioned above (see Figure 1–4). Its quantitative measure is called
the metabolic clearance rate. Renal clearance, on the other
hand, means that the substance is removed from the blood and
excreted in the urine. Evaluation of renal clearance is com-
monly used clinically as an overall assessment of renal health.
Repeated assessments over a period of time can indicate
whether renal function is stable or deteriorating.
CLEARANCE UNITS
The units of renal clearance are often confusing to the first-
time reader, so let us be sure of the meaning. First, the units are
volume per time (not amount of a substance per time). The eas-
iest way to think of this is to ask what volume of plasma sup-
plies the amount excreted in a given time. For example, if each
liter of plasma contains 1 mg of substance X, and 0.5 mg of X is
excreted in 1 hour, then half a liter of plasma supplies the
amount excreted, that is, the clearance is 0.5 L/h. The reader
should appreciate that removing all of a substance from a small
volume of plasma is equivalent to removing some of it from a
larger volume, which is actually the way the kidneys do it. For
example, if all of substance X is removed from 0.5 L, this is
equivalent to removing half of it from 1 L, or one quarter of it
from 2 L, etc. The clearance is still 0.5 L/min in all these cases.
The general meaning and specific renal meaning of clear-
ance can be illustrated by comparing how the body handles

417

Ch41_417-422.indd 417 11/26/10 10:09:24 AM

418 SECTION VII Renal Physiology
two substances with similar-sounding names but very differ-
ent properties: inulin and insulin. Insulin is the familiar pan-
creatic hormone involved in regulating blood glucose. It is a
protein with a molecular weight of 5.8 kd and is small enough
to be freely filtered by the glomerulus. Once in Bowman’s
space, it moves along with every other filtered substance into
the proximal convoluted tubule, where it is largely taken up by
endocytosis and degraded into its constituent amino acids.
Very little insulin escapes this uptake, and very little of the fil-
tered insulin makes it all the way to the urine. Thus, the kidney
takes part in clearing insulin from the blood, but because so
little appears in the urine, the specific renal clearance is very
low (<1 mL/min). However, the body has additional mecha-
nisms for clearing insulin, and its metabolic clearance rate is
quite high (half-life less than 10 minutes). Let us contrast this
with inulin. Inulin is a polysaccharide starch of about 5-kd
molecular weight that is not usually found in the body. Like
insulin, it is freely filtered by the glomerulus, but it is not reab-
sorbed or secreted by the nephron. All the inulin that is filtered
flows through the nephron and appears in the urine. Thus,
inulin’s renal clearance is relatively large. Inulin in the blood is
not taken up by other tissues, and the kidneys are the only
excretion route. As we will see, this makes inulin a very special
substance with respect to assessing renal function.
QUANTIFICATION OF CLEARANCE
Consider again a substance X that is excreted in the urine.
How do we actually calculate its clearance in the proper units?
The amount of X removed from a given volume of plasma
equals the amount excreted in the urine. The amount cleared
from the plasma in a given time is the product of the volume
of plasma cleared per unit time (Cx) and the plasma concen-
tration (Px), that is, amount cleared/time = Cx × Px. That same
Plasma before clearance
Plasma during clearance
FIGURE 41–1 Derivation of the basic clearance formula.
Over time, substance X (dots) is removed from the plasma (large
boxes) and put into the urine (small boxes) and excreted. The
amount of X removed from the plasma during that time (Cx × Px)
must equal the amount excreted (V × Ux) in that same time, as
shown in equations (1) and (2). By rearrangement (equation (3)),
we solve for the clearance of X.
amount now appearing in the urine during this time is the
product of the urine flow rate (V) and the urine concentration
of X (Ux), that is, amount in urine/time = V × Ux. This equal-
ity is shown in equations (1) and (2) in Figure 41–1. Finally, by
rearrangement, we solve for clearance (Cx) as shown in equa-
tion (3). Thus, we have equated the amount removed from the
plasma with that appearing in the urine, and by rearrangement
we end up with clearance in its proper units—volume per time.
While we are addressing the quantification of clearance, note
that the product of urine flow rate and urine concentration of
X (numerator on the right-hand side of equation (3)) is excre-
tion rate. Therefore, we can also state that the clearance of sub-
stance X is the excretion rate divided by the plasma concentration.
The process of clearance and derivation of the clearance for-
mula is depicted in Figure 41–1.
Let us now examine the clearance of several substances
important for the quantification of renal function, starting
with inulin. Inulin, as described previously, is a polysaccharide
that is freely filtered and neither reabsorbed nor secreted.
Thus, once filtered, it must flow through the nephron into the
urine (Figure 41–2). The volume of plasma cleared of inulin is
the volume filtered, that is, inulin clearance equals the glom-
erular filtration rate (GFR). Inulin clearance is indeed the
hallmark experimental method of measuring the GFR.
Can something have a clearance greater than the GFR?
Indeed, yes. One such substance is para-aminohippurate
(PAH). This is a small (molecular weight of 194 d) water-
soluble organic anion not normally found in the body, but that
is used experimentally. It is freely filtered and also avidly
secreted by the proximal tubule epithelium (via the transcel-
lular route). The secretion rate is saturable. That is, there is a
maximum rate of PAH secretion into the tubule. Such a tubu-
lar maximum, (Tm) is common in transport systems (see
Chapter 42). However, at low plasma concentrations, almost
all of the PAH entering the kidney is removed from the plasma
Amount in plasma = Cx × Px
Urine before clearance
Urine during clearance
Amount in urine = V × Px
Urine after clearance
Plasma after clearance
Amount in plasma = Amount in urine (1)
Cx × Px = V × Ux (2)
Cx = V × Ux (3)
Px

Concentration
of inulin in
plasma = 4 mg/L
Glomerular
capillary
Rate of fluid
Bowman’s filtration (GFR) = 7.5 L/h
space Concentration of
inulin in filtrate = 4 mg/L
Total inulin filtered = 30 mg/h
No reabsorption of inulin
No secretion of inulin
Total inulin excreted = 30 mg/h
FIGURE 41–2 Renal handling of inulin. All filtered inulin
is excreted. Since the volume of plasma cleared of inulin is the
volume filtered, the inulin clearance equals the GFR. (Modified with
permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology,
11th ed. McGraw-Hill, 2008.)
and excreted in the urine. About 20% of the excreted PAH
appears by filtration and the rest by secretion. Its clearance,
therefore, is nearly as great as the renal plasma flow. In fact, the
PAH clearance can be used experimentally as a measure of
renal plasma flow, usually called the effective renal plasma
flow to indicate that its value is slightly less than the true renal
plasma flow.
What can the clearance of any freely filtered substance tell
us? If we know the GFR (as assessed from inulin clearance)
and the clearance of the substance, then any difference between
clearance and GFR represents net secretion or reabsorption
(or, in a few rare cases, renal synthesis). If the clearance of a
substance exactly equals the GFR, then there has been no net
reabsorption or secretion. If the clearance is greater than the
GFR, there must have been net secretion. Finally, if the clear-
ance is less than the GFR, there must have been net reabsorp-
tion. The word net in this description is important. As we will
see in later chapters, a number of substances are reabsorbed in
certain regions of the nephron and secreted in other regions.
The net result of these processes is the sum of everything that
happens along the nephron. Of course, if a substance is not
freely filtered, low clearance may simply indicate that little of
the substance entered the tubule.
A PRACTICAL METHOD OF
MEASURING GFR: CREATININE
CLEARANCE
The gold standard for measuring GFR is the inulin clearance,
and this method is used in research studies. The method is
cumbersome, however, because either inulin must be infused
at a rate sufficient to keep its plasma concentration constant
CHAPTER 41 Clearance 419
during the period of urine formation and collection or there
must be multiple samplings and a complex regression analysis.
For routine assessment of GFR in patients, there is a much
easier method: creatinine clearance. Creatinine is an end
product of creatine metabolism and is exported into our blood
continuously by skeletal muscle. The rate is proportional to
skeletal muscle mass, and to the extent that muscle mass is
constant in a given individual, the creatinine production is
constant. Creatinine is freely filtered and not reabsorbed. A
small amount, however, is secreted by the proximal tubule.
Therefore, the creatinine appearing in the urine represents a
filtered component (mostly) and a much smaller secreted
component. Because of the secretion, creatinine clearance is
slightly higher than the GFR, normally by about 10–20%. For
routine assessment of GFR, this degree of error is acceptable.
How does one measure creatinine clearance? Usually, a
patient’s urine is collected for 24 hours, and a blood sample is
taken sometime during the collection period. Blood and urine
are assayed for creatinine concentration, and we apply the
clearance formula (Figure 41–1, equation (3)) to yield creati-
nine clearance.
For a patient with a very low GFR, the secreted component
is a relatively larger fraction of the total amount excreted;
therefore, the creatinine clearance more severely overestimates
GFR in patients with a very low GFR than in those with higher
GFR values. Nevertheless, because of low cost and conve-
nience, creatinine clearance continues to be the most common
method for routine assessment of patient GFR and the integ-
rity of renal filtration.
PLASMA CREATININE AND
UREA CONCENTRATIONS AS
INDICATORS OF CHANGES IN GFR
Although creatinine clearance is a valuable clinical determi-
nant of GFR, in routine practice, it is far more common to
measure plasma creatinine alone and to use this as an indica-
tor of GFR. If we ignore the small amount secreted, there
should be an excellent inverse correlation between plasma
creatinine concentration and GFR (Figure 41–3).
A healthy person’s plasma creatinine concentration is about
1 mg/dL. It remains stable because each day the amount of
creatinine excreted is equal to the amount of creatinine pro-
duced. Suppose one day, the GFR suddenly decreases by 50%
because of an obstruction in the renal artery. On that day, the
person filters only 50% as much creatinine as normal. There-
fore, creatinine excretion is also reduced by 50%. (We are
ignoring the small contribution of secreted creatinine.) Assum-
ing no change in creatinine production, the person transiently
goes into positive creatinine balance, and the plasma creati-
nine increases. However, despite the persistent 50% GFR
reduction, the plasma creatinine does not continue to rise
indefinitely; rather, it stabilizes at 2 mg/dL (i.e., after it has
doubled). At this point, the person once again is able to excrete
420 SECTION VII Renal Physiology
8
PCr, mg/100 mL
5 Because urea is also handled by filtration, the same type of
4 centration could also serve as an indicator of GFR. However, it
3
2 widely, depending on protein intake and changes in tissue
1 monal regulation.
45 90 135 180 225
GFR, L/day
FIGURE 41–3 Steady-state relation between plasma
creatinine and GFR for a person with a normal creatinine
production. When GFR is low, plasma creatinine rises to high levels,
making plasma creatinine a convenient indicator of GFR. (Modified with
permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY:
Lange Medical Books/McGraw- Hill, Medical Pub. Division, 2009.)
creatinine at the normal rate and so goes back in balance with
a stable plasma level. The 50% GFR reduction has been just
offset by the doubling of plasma creatinine concentration,
restoring the filtered load of creatinine to normal. To under-
stand this point, assume an original daily filtration volume of
180 L (1,800 dL).
The original normal state is given by:
Filtered creatinine = 1 mg/dL × 1,800 dL per day
= 1,800 mg per day
The new steady state is given by:
Filtered creatinine = 2 mg/dL × 900 dL per day
= 1,800 mg per day
In the new steady state, creatinine excretion is normal, even
though the plasma concentration has doubled (the person is in
balance). In other words, creatinine excretion is below normal
only transiently until plasma creatinine has increased as much
proportionally as the GFR has decreased.
What if the GFR then decreased to 300 dL per day? Again,
creatinine retention would occur until a new steady state had
been established (i.e., until the person was again filtering 1,800
mg per day). What would the new plasma creatinine be?
1,800 mg per day = Pcr × 300 dL per day
Pcr = 6 mg/dL
The increase in plasma creatinine results directly from the
decrease in GFR. Therefore, a single plasma creatinine mea-
surement is a reasonable indicator of GFR. It is not completely
accurate, however, for several reasons: (1) as before, some cre-
atinine is secreted; (2) an original creatinine measurement
when GFR was normal may not be available; (3) creatinine
production may not remain completely unchanged. However,
an increasing plasma creatinine is a red flag that there may be
a renal problem.
analysis suggests that the measurement of plasma urea con-
is a much less accurate indicator than plasma creatinine
because the range of normal plasma urea concentration varies
catabolism, and because urea excretion is under partial hor-
360
CLINICAL CORRELATION
A 72-year-old, rather thin and frail female is experiencing
bouts of atrial fibrillation. Her serum electrolytes are all
within normal limits, her creatinine is 1.1 mg/dL (high
normal), and there is no indication of a major renal disor-
der. Her body weight is 47 kg. Her primary care physician
(PCP) prescribes digoxin for its antiarrhythmic effective-
ness, but is concerned about overdosing and producing
digitalis toxicity. The choice of an appropriate dosing regi-
men (amount and schedule) is a difficult one, particularly
for drugs such as digoxin with significant side effects. The
goal is to find a “therapeutic window” in which the body
levels of the drug are high enough to be effective, but low
enough not to invoke side effects. For drugs whose major
excretion route is the kidneys, which include digoxin, it is
often necessary to make adjustments based on the patient’s
(4)
GFR. This is particularly appropriate in patients whose
renal function is impaired due to disease or natural decline
with age. In common medical settings it is not feasible to
measure GFR via inulin clearance, or even to measure crea-
(5)
tinine clearance using 24-hour urine collection in nonhos-
pitalized patients. The question is: how does one obtain an
estimate of GFR?
A common method is to estimate creatinine clearance
using a formula, known as the Cockcroft–Gault formula
(shown below), that includes plasma creatinine, age, body
weight, and gender. The use of this formula, or any of the sev-
eral others that have been derived over the years, is subject to
error. However, it is still useful as a guide for drug dosing pur-
poses, where a precise clearance value is not really needed:
creatinine clearance [mL/min] =
(6)
(140–age) × body weight [Kg] × 0.85 [if female]
_________________________________ (8)
(7) 72 × serum creatinine [mg/dL]
This works out to be 34.3 mL/min in our patient. (For
comparison, the estimated creatinine clearance using the

Cockcroft–Gault formula for a 21-year-old, 70-kg male
with a serum creatinine of 1.0 mg/dL is 116 ml/min.) Her
GFR, estimated by creatinine clearance, is low relative to
that of young adults, but is sufficient to permit adequate
excretory function. However, because the clearance of
digoxin will be somewhat slow, her prescription is likely to
be for lower doses, or for greater intervals between doses,
than it would be in a much younger patient.
CHAPTER SUMMARY
■ Clearance has both a general meaning, describing loss of
material from the body, and a specific renal meaning involving
the kidney’s ability to remove substances from the blood.
■ Clearance is always expressed in units of volume per time.
■ Renal clearance of any substance is quantified by a general
clearance formula relating urine flow to urine and plasma
concentrations.
■ Inulin clearance can be used to measure GFR because inulin
is freely filtered and neither secreted nor reabsorbed.
■ PAH clearance can be used as an estimate of renal plasma flow.
■ Creatinine clearance is used as practical estimate of GFR.
■ Plasma creatinine concentration is used clinically as an
indicator of the GFR.
STUDY QUESTIONS
1. We can calculate the renal clearance of any substance if we know
which pair of values?
A) urine flow rate and urine concentration
B) plasma concentration and urine concentration
C) GFR and urinary excretion rate
D) plasma concentration and urinary excretion rate
CHAPTER 41 Clearance 421
2. A drug X has a short plasma half-life and must be administered
frequently to maintain therapeutic levels. The urinary
concentration of X is much higher than the plasma
concentration. A substantial amount of X also appears in the
feces. What can we say about the renal clearance of X compared
with the metabolic clearance rate of X?
A) The metabolic clearance rate is higher than the renal
clearance.
B) The renal clearance is higher than the metabolic clearance
rate.
C) The two clearances are the same.
D) There is insufficient information to answer the question.
3. Inulin clearance is measured twice: the first time at a low inulin
infusion rate, and the second time at a higher infusion rate that
results in a higher plasma inulin concentration during the test.
Assuming the kidneys behave the same in both cases, which
measurement will yield a higher inulin clearance?
A) the first
B) the second
C) both measurements are the same
D) there is insufficient information to answer the question
4. Which of the following indicates correct relative renal
clearances?
A) Glucose clearance is greater than urea clearance.
B) PAH clearance is greater than inulin clearance.
C) Urea clearance is greater than PAH clearance.
D) Creatinine clearance is greater than PAH clearance.
5. An acute poisoning episode destroys 80% of a patient’s nephrons.
If the plasma urea concentration prior to the episode was
5 mmol/L, and assuming dietary protein remains the same, what
is the expected value of plasma urea now?
A) 5 mmol/L
B) 6.25 mmol/L
C) 25 mmol/L
D) continuously rising
This page intentionally left blank
 42
C H A P T E R

Tubular Transport
Mechanisms
Douglas C. Eaton and John P. Pooler

O B J E C T I V E S

■ Identify the major morphological components of an epithelial tissue,

including lumen, interstitium, apical and basolateral membranes, and
tight junctions.
■ State how transport mechanisms combine to achieve active transcellular
reabsorption in epithelial tissues.
■ Define iso-osmotic transport.
■ Define paracellular transport and differentiate between transcellular
and paracellular transport.
■ Describe qualitatively the forces that determine movement of reabsorbed
fluid from the interstitium into peritubular capillaries.
■ Explain why volume reabsorption in the proximal tubule depends on
activity of the Na,K-ATPase.
■ Compare the Starling forces governing glomerular filtration with those
governing peritubular capillary absorption.
■ Compare and contrast the concepts of Tm and gradient-limited transport.
■ Contrast “tight” and “leaky” epithelia.

PROXIMAL TUBULE Most of the solute reabsorbed in the proximal tubule

REABSORPTION
Virtually all of the 180 L of water and several pounds of salt and
other solutes filtered each day into Bowman’s space are reab-
sorbed, along with large amounts of many other substances.
Quantitatively most of this reabsorption occurs in the proxi-
mal tubule, a process that is very nearly iso-osmotic, meaning
that water and solutes are reabsorbed in equal proportions.
Recall that filtration in the glomerulus is also iso-osmotic.
Almost all solutes (except large plasma proteins) are filtered
from plasma into Bowman’s space in the same proportion as
water; thus, their concentrations in the glomerular filtrate are
the same as in the plasma. By the end of the proximal tubule,
about two thirds of the water and two thirds of the solutes have
been reabsorbed. In the later portions of the nephron, reab-
sorption is generally not iso-osmotic, which is crucial for our
ability to independently regulate solute and water balance.
consists of sodium and the anions (mostly chloride and bicar-
bonate) that must accompany sodium to maintain electroneu-
trality. These solutes are removed from the tubular lumen
and move into the interstitium by a combination of processes
that we describe below. The large amount of solute trans-
ferred from lumen to interstitium sets up an osmotic gradient
that favors the parallel movement of water. The proximal
tubule epithelium is very permeable to water, which fol-
lows the solute across in equal proportions. Thus, both the
fluid removed from the lumen and that remaining behind are
essentially iso-osmotic with the original filtrate. We say
“essentially” because there must be some difference in osmo-
lality to induce water movement, but for an epithelial barrier
such as the proximal tubule that is very permeable to water, a
difference of less than 1 mOsm/kg is sufficient to drive reab-
sorption of water. An osmolality difference of 1 mOsm/kg is
equal in driving force to 19 mm Hg of hydrostatic pressure.
Once in the interstitium, the solutes and water move from

423

Ch42_423-428.indd 423 11/26/10 10:08:31 AM

424 SECTION VII Renal Physiology

LUMEN INTERSTITIUM

apical Peritubular
membrane Interstital capillary
Channel or space
transporter

Trancellular
reabsorption
FIGURE 42–1 Transcellular and paracellular
reabsorption. Transcellular reabsorption is a two-step Basolateral
membrane
process with separate influx and efflux steps utilizing
transporters or channels. Paracellular reabsorption is always Paracellular
a passive process through the tight junctions. (Modified reabsorption
with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. tight junction Basement
Division, 2009.) membrane

interstitium into the peritubular capillaries and are returned
to the systemic circulation.
Reabsorption across the tubular epithelium can be either
through the cells (the transcellular route) or around the
cells (the paracellular route), that is, through the matrix of
the tight junctions that link each epithelial cell to its neigh-
bor. The transcellular route is a two-step process: into the
cells across the apical membrane facing the tubular lumen
and out of the cells across the basolateral membrane facing
the interstitium. These structures and pathways are depicted
in Figure 42–1.
Substances cross the membranes of epithelial cells by an
array of mechanisms. These mechanisms are no different from
those used elsewhere in the body to transport substances across
cell membranes as described in Chapter 3. We can view these
mechanisms as a physiological toolbox. Renal cells use which-
ever set of tools is most suitable for the task. These mechanisms
include simple diffusion through the bilayer, movement
through channels, and movement through transporters of
various types. This variety is depicted in Figure 42–2. Except
for simple diffusion, all of these processes are regulated by sig-
naling pathways. It is through regulation of transporters and

Diffusion
Substance A 1
Me
mb

Uniporter
ran

Substance B 2
e

Symporter
Substance C
Substance D 3

Antiporter
Substance E 4
Substance F

Substance G 5 Ion channel

6
Primary active
Substance H
transport
FIGURE 42–2 Mechanisms of transmembrane
solute transport. With the exception of simple diffusion
through the lipid bilayer, all transport involves channels
and transporters that are regulated by signaling ADP + Pi
pathways. (Modified with permission from Eaton DC, Pooler JP:
Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical ATP
Books/McGraw-Hill, Medical Pub. Division, 2009.)
 CHAPTER 42 Tubular Transport Mechanisms 425

Lumen Interstitium brane and sites of inactivity or degradation, with lifetimes in

1. Insert or retrieve
from storage sites
2. Transcribe and
synthesize,
or degrade
3. Attach ligand
L the movement of sodium through the cells from lumen to inter-
FIGURE 42–3 Common mechanisms for regulating channel
and transporter activity. 1) Transport proteins are shuttled back and
forth between the surface membrane, where they function normally,
and sites of sequestration at the base of microvilli or in intracellular
vesicles. 2) Transport protein is synthesized and inserted in the
membrane or removed and degraded. 3) Transport proteins are
activated or inhibited by attaching ligands, either covalently (e.g.,
phosphorylation) or reversibly (e.g., ATP).
channels that the kidneys control the excretion of various sub-
stances. Figure 42–3 depicts some of the ways flux is regulated.
This includes trafficking of channels and transporters between
the surface membrane and inactive sites within the cell, genetic
expression of new protein, degradation of existing protein, and
the attachment of ligands that either directly alter protein func-
tion or target the protein for trafficking. Transporter and chan-
nel proteins are not permanent fixtures in the membrane;
rather, they are constantly being shuttled between the mem-
the membrane generally being only a few hours.
While some substances cross the epithelial barrier by the par-
acellular route, it is transcellular transport that controls the
overall process, that is, transcellular processes set up the condi-
tions favoring paracellular transport. All of this requires polar-
ization of the epithelial cells, meaning that the transport proteins
present in the apical membrane are different from those in the
basolateral membrane. In the proximal tubule, the key process
achieved by this polarized distribution of transport proteins is
stitium. The transport of virtually every other substance depends
on the movement of sodium. Figure 42–4 shows the morphol-
ogy of a generalized proximal tubule epithelium in which salt
and water transport can be viewed as a multistep process.
Step 1 is the active extrusion of sodium from epithelial cell
to interstitium across the basolateral membrane. Step 2 is the
passive entrance of sodium from the tubular lumen across the
apical membrane into the cell to replace the sodium removed
in step 1. Step 3 is the parallel movement of anions that must
accompany the sodium to preserve electroneutrality. Step 4 is
the osmotic flow of water from tubular lumen to interstitium.
Finally, step 5 is the bulk flow of water and solute from inter-
stitium into the peritubular capillary. Let us examine these
steps more closely.
The active extrusion of sodium in step 1 is via the Na,K-
ATPase, which is the major energy consumer in the cell. The
action of the Na,K-ATPase has several consequences, the key
one being that it keeps the concentration of sodium within the
cell low enough to favor the passive entrance of sodium from
lumen to cell in all the processes of step 2.
The entrance of sodium into the cell in step 2 is via multiple
pathways. Quantitatively most of sodium enters via the

1. Sodium is actively extruded into the interstitium

2. Sodium enters passively from the tubular lumen
3. Anions follow the sodium
4. Water follows the solute
5. Water and solutes move by bulk flow into the peritubular capillary

Lumen Interstitium

ATP Na+ Peritubular

2 Na+ 1 +
capillary
K

3 Anions

4 Water

Water, anions

FIGURE 42–4 Epithelial salt and water reabsorption. See text for explanation of each individual step.
426 SECTION VII Renal Physiology
sodium–proton antiporter (NHE3 isoform). As we will see
later, regulation of this transporter is a key player in regulating
sodium excretion.
Step 3, the movement of anions, is the most complex, as it
involves two ions (chloride and bicarbonate) and a variety of
transcellular and paracellular processes. We will examine the
details in Chapters 44 and 47, but for now we emphasize that
the movement of sodium, which is a cation, must be matched
quantitatively by the equal movement of anions.
Step 4 is the osmotic movement of water. The tubular cells
possess a complement of aquaporins (water channels) in both
the apical and basolateral membranes, and the tight junctions
are also permeable to water. Therefore, as steps 1–3 lower the
local luminal osmotic concentration by even a few milliosmoles
per liter, water flows osmotically from lumen to interstitium.
The movement of water into the interstitium in step
4 promotes step 5. This is the bulk flow of fluid from intersti-
tium to peritubular capillary driven by Starling forces (hydro-
static and oncotic pressure gradients). The capillary hydraulic
pressure opposes the uptake of interstitial fluids, but its value
of 15–20 mm Hg is much lower than the 60 mm Hg in the
glomerular capillaries, where there is net filtration. Meanwhile,
the plasma oncotic pressure has increased to more than
30 mm Hg because loss of water by filtration in the glomerular
capillaries concentrates the large plasma proteins. There is also
a small but significant interstitial pressure (Table 42–1). The
sum of these Starling forces is a net absorptive pressure, and it
drives fluid movement into the peritubular capillaries. The
reader can appreciate the fact that if cortical Starling forces are
abnormal (e.g., low plasma oncotic pressure as when liver dis-
ease prevents normal production of serum albumin), absorp-
tion of fluid from the cortical interstitium can be slowed,
causing a backup of fluid that inhibits fluid movement from
TABLE 42–1 Estimated forces involved in movement
of fluid from interstitium into peritubular capillaries.a
Forces mm Hg
1 Favoring uptake
(a) Interstitial hydraulic pressure, PInt 3 amounts of the filtered load are not reabsorbed. In general,
(b) Oncotic pressure in peritubular 33
capillaries, πPC
2 Opposing uptake
(a) Hydraulic pressure in peritubular 20
capillaries, PPC
(b) Interstitial oncotic pressure, πInt 6 sider first gradient-limited systems. When the tight junctions
3 Net pressure for uptake (1 – 2) 10
a
The values for peritubular capillary hydraulic and oncotic pressures are for the early
portions of the capillary. The oncotic pressure, of course, decreases as protein-free
fluid enters it (i.e., as absorption occurs) but would not go below 25 mm Hg (the
value of arterial plasma) even if all fluid originally filtered at the glomerulus were
absorbed.
Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.
tubular lumen to interstitium. Ultimately, this can lead to
increased excretion of water and electrolytes from the body.
The events just described have consequences for any filtered
solute that is not specifically removed from the lumen in step
2 or 3. As water follows sodium and its anions across the epi-
thelium, the luminal volume decreases, thereby concentrating
the remaining solutes. If two thirds of the water is removed,
any solute not previously removed will increase in concentra-
tion by a factor of 3. As its luminal concentration rises, this
generates a concentration gradient across the tight junctions
between the lumen and the interstitium. (The interstitial con-
centration of transported substances is essentially clamped to
the plasma value because of the high peritubular blood flow
and high permeability of the fenestrated capillaries.) If the
tight junctions are permeable to the substance in question
(“leaky”), the substance diffuses from the lumen to the inter-
stitium, and then into the peritubular capillaries along with
sodium and water. This is precisely what happens to many sol-
utes (e.g., urea, potassium, chloride, calcium, and magnesium)
in the proximal tubule. The exact fractions that are reabsorbed
depend on the permeability of the tight junctions, but are gen-
erally in the range of one half to two thirds. (One substance
that does not move by the paracellular route is glucose, which
is impermeable in the tight junctions. We will describe the fate
of filtered glucose in Chapter 43.)
In summary, active sodium transport by the Na,K-ATPase is
the crucial process, necessary not only for the reabsorption of
sodium, but also for creating the conditions that drive the
reabsorption of water and every other solute.
LIMITS ON RATE OF TRANSPORT:
Tm AND GRADIENT-LIMITED
SYSTEMS
Although the transport capacity of the renal cortex is huge, it
is not infinite. There are upper limits to the rate at which
sodium or any other solute can be reabsorbed or secreted. In
many situations, these limits are reached, with the conse-
quence that, in the case of reabsorption, larger than normal
transport mechanisms can be classified by the properties of
these upper limits as either (1) gradient-limited systems or
(2) tubular maximum–limited (Tm) systems. These proper-
ties are significant both for normal function and, as explained
in subsequent chapters, in pathological situations. The classifi-
cation is based on the leakiness of the tight junctions. Con-
are very leaky to a given substance, for example, sodium, it is
impossible for the removal of the substance from the lumen to
reduce its luminal concentration very much below that in the
cortical interstitium, because as the luminal concentration
decreases, the gradient between these two media is increased,
causing the substance to leak back as fast as it is removed.
Thus, for sodium and all other substances whose reabsorption
 CHAPTER 42 Tubular Transport Mechanisms 427

is characterized by a gradient-limited system, the luminal con-

comprehensive analysis. The results reveal several abnor-
centration remains close to the interstitial concentration.
malities. His urine contains more than trace amounts of glu-
However, the existence of a limit does not stop reabsorption in
cose and amino acids, high amounts of phosphate and
normal circumstances because water is being reabsorbed
potassium, and a low pH (5.5). His blood analysis indicates
simultaneously, so that the luminal concentration does not
low bicarbonate (17 mEq/L), low potassium (3.1 mEq/L),
decrease very much, permitting large amounts of the sub-
and low phosphate (1.7 mg/dL).
stance to be removed. In contrast, if unusual osmotic condi-
The diagnosis is heavy metal–induced damage to the
tions retard water reabsorption, then removal of the substance
proximal tubule cells, producing a constellation of renal
occurs without a corresponding amount of water. Conse-
defects called Fanconi syndrome. The key pathology in
quently, its concentration does decrease and the limiting gra-
Fanconi syndrome is mitochondrial damage that reduces
dient is indeed reached, resulting in unusually high amounts
Na,K-ATPase activity in the proximal tubule. This decreases
of the substance remaining in the large volume of unreab-
reabsorption of sodium and of many substances that are
sorbed water.
directly or indirectly tied to the reabsorption of sodium.
Now consider Tm-limited systems in which the tight junctions
Chief among these are bicarbonate, phosphate, potassium,
are impermeable to the solutes in question. There is no back leak
and, of course, water. Glucose and amino acids in the urine
and no limit on the size of the difference in concentration
provide diagnostic clues, but the losses are not serious. The
between lumen and interstitium. The limit on transport rate
patient’s low bicarbonate is consistent with renal tubular
instead is placed on the capacity of the transporters to remove
acidosis, which is a primary component of Fanconi syn-
the substance (the inherent kinetic properties of the transport
drome. His respiratory system attempts to compensate for
proteins and their density in the membrane). As the filtered
plasma acidity by increasing the rate of ventilation.
load rises, increasing amounts of the filtered substance are reab-
(His breathing discomfort could also be related to the result
sorbed, up to the point of saturating the transporters. Any fur-
of his smoking as well as heavy metal toxicity.) His low
ther increase in filtered load above the saturation point does not
plasma potassium is the result of excessive potassium secre-
increase the rate at which the substance is transported out of the
tion in the distal nephron stimulated by the large amount
lumen; thus, more and more is left behind. In most cases, the
of non-reabsorbed tubular sodium, and accounts for his
amount that escapes reabsorption is excreted.
feeling of muscle weakness. His high excretion of phos-
For many substances governed by a Tm system, their filtered
phate and acidosis lead to complicated effects in bone,
loads are usually well below their Tm, and the tubule has no trou-
including loss of bone mineral that may lead to spontane-
ble reabsorbing virtually all that is filtered. This is the case for
ous fractures. Treatment in this case consists of supple-
glucose and many other organic substances, which, under nor-
mental electrolytes, vitamin D to promote bone health, and
mal circumstances, are completely reabsorbed by the end of the
any measures that will result in a reduction or elimination
proximal tubule. But solutes handled by gradient-limited sys-
of the cadmium exposure.
tems are never reabsorbed completely, because a finite interstitial
concentration ensures there will be a finite tubular concentra-
tion, and therefore a substantial amount passed on to the next
nephron segment. This holds true for sodium. The consequences CHAPTER SUMMARY
of these differences will be discussed in Chapters 43 and 45.
■ Reabsorption in the proximal tubule is iso-osmotic.
■ Flux from lumen to interstitium can be transcellular, using
separate transport steps in the apical and basolateral mem-
CLINICAL CORRELATION branes; or paracellular, around the cells through tight junctions.
■ The kidneys regulate excretion by regulating channels and
A 42-year-old man has worked at a metal recycling plant for transporters in epithelial cell membranes.
the past 5 years, where he has been exposed to toxic heavy ■ The reabsorption of water and almost all solutes is linked,
metals, including cadmium. He has a history of smoking, directly or indirectly, to the activity of Na,K-ATPases in the
but for the most part has been in good health. Over the past basolateral membranes.
year, however, he has noticed gradually increasing cough ■ High water permeability in the proximal tubule epithelium
and lung irritation, and some feeling of difficulty breathing. ensures that water reabsorption is tightly coupled to solute
He also reports vague muscle weakness and pain in his legs. reabsorption.
In addition, he has experienced increased thirst and urinary ■ Volume reabsorption is a multistep process involving transport
frequency, and has developed a craving for salty foods such across epithelial membranes from lumen to interstitium, and
as pickles and potato chips. His physical exam is unremark- bulk flow from interstitium to peritubular capillaries driven by
able except for a somewhat high respiratory rate (tachyp- Starling forces.
nea) of 21 breaths/min. A urine dipstick test reveals a mild ■ All reabsorptive processes have a limit on how fast they can
proteinuria (increased protein in the urine), and samples of occur, either because the transporters saturate (Tm systems) or
because the substance leaks back into the lumen (gradient-
his blood and urine are sent to the clinical laboratory for a
limited systems).
428 SECTION VII Renal Physiology

STUDY QUESTIONS 4. In the proximal tubule, water can move through

A) apical membranes of proximal tubule cells.
1. A healthy patient has a normal plasma osmolality (close B) basolateral membranes of proximal tubule cells.
to 300 mOsm/kg). If 100 mmol of solutes is reabsorbed C) tight junctions.
iso-osmotically from the proximal tubule, approximately D) all of the above.
how much water is reabsorbed with the solute? (Remember: 1
5. A drug X is secreted into the proximal tubule by a Tm-limited
mmol of solute ≅ 1 mOsm and 1 g H2O ≅ 1 mL.)
system. This implies that
A) 100 mL
A) X cannot easily diffuse by the paracellular route.
B) 300 mL
B) all the X that enters the renal vasculature will be secreted.
C) 333 mL
C) the rate of X secretion is independent of the plasma
D) 1,000 mL
concentration.
2. Quantitatively, most sodium gains entrance to proximal tubule D) X is not filtered at the glomerulus.
cells by
A) paracellular diffusion.
B) transcellular diffusion.
C) the Na,K-ATPase.
D) antiport with hydrogen ions.
3. The tight junctions linking proximal tubule cells permit passive
diffusion of
A) glucose.
B) sodium.
C) all filtered solutes.
D) no filtered solutes.
 43
C H A P T E R

Renal Handling of
Organic Substances
Douglas C. Eaton and John P. Pooler

O B J E C T I V E S

■ State the physiological utility of either excreting or reabsorbing organic

solutes.
■ State the general characteristics of the proximal tubular systems for active
reabsorption or secretion of organic nutrients.
■ Describe the renal handling of glucose, and state the conditions under which
glucosuria is likely to occur.
■ Describe the renal handling of proteins and small peptides.
■ Describe the secretion of para-aminohippurate.
■ Outline the handling of urate.
■ Describe the secretion of organic cations.
■ Describe how tubular pH affects the excretion and reabsorption of weak
acids and bases.
■ Describe the renal handling of urea, including the medullary recycling of urea
from the collecting duct to the loop of Henle.

OVERVIEW this chapter and again in the following chapter in the discus-
sion of renal handling of water.
As pointed out in Chapter 39, a major function of the kidneys
is the excretion of organic waste products, and foreign chemi-
cals and their metabolites. Furthermore, the kidneys filter PROXIMAL REABSORPTION OF
large amounts of organic substances that they do not excrete; ORGANIC NUTRIENTS: GLUCOSE
therefore, reabsorptive processes must exist to prevent inap-
propriate loss of useful organic nutrients. Because the blood AND AMINO ACIDS
contains many small, filterable molecular species, the kidney
Most of the major cellular nutrients in the plasma that the kid-
has to handle all of them. An analysis of the renal handling of
neys must not lose in the urine are freely filterable and must be
every one of these organic substances would be prohibitive, so
almost completely reabsorbed. These include glucose, amino
we will discuss a few key solutes and establish generalities
acids, acetate, Krebs cycle intermediates, some water-soluble
about the others. In essence, the kidneys perform a kind of tri-
vitamins, lactate, acetoacetate, β-hydroxybutyrate, and many
age. They (1) reabsorb organic metabolites that should not be
others. The proximal tubule is the major site for reabsorption
lost, (2) eliminate waste products and unwanted foreign
of the large quantities of these organic nutrients filtered each
organic substances by not reabsorbing them or actually secret-
day by the renal corpuscles. We can make the following
ing them, and (3) partially reabsorb others.
generalities:
One organic substance, urea, is unique in this regard. It is a
waste product that must be excreted to prevent accumulation. 1. They are actively transported (i.e., are reabsorbed up
However, it also plays a key role in renal regulation of water [against] their respective electrochemical gradients) by
balance. The renal handling of urea is briefly discussed later in transport proteins that are specific for one or only a few

429

Ch43_429-436.indd 429 11/26/10 11:21:33 AM

430 SECTION VII Renal Physiology
solute species. There is not a separate transporter for ev-
ery solute in the body. Two or more closely related sub-
stances may use the same transporter. For example, amino
acid transporters are distinct from those for glucose, but
there are not 20 separate amino acid transporters. Rather
there is one for arginine, lysine, and ornithine; another for
glutamate and aspartate; and so on. In most cases, reab-
sorption is very close to complete.
2. The “uphill” step is across the apical membrane, usually
via a symporter with sodium.
3. Most are characterized as Tm systems (have an upper limit
to the rate at which they can transport). These limits are
usually well above the amounts normally filtered. Accord-
ingly, the kidneys have no trouble returning all that is fil-
tered back to the plasma. However, because none is ex-
creted, the kidneys do not help regulate their levels in the
body; the kidneys are merely reclaiming them from the
tubular fluid. It is also true, however, that under abnormal
conditions, the plasma concentration of these substances
may increase so much that the filtered load exceeds the
reabsorptive Tm. In this case, large quantities are excreted
in the urine. Examples are glucose, acetoacetate, and
β-hydroxybutyrate in patients with severe uncontrolled
diabetes mellitus.
4. The transporters can be inhibited by a variety of drugs,
and several monogenetic diseases are associated with loss
of function in one or more of these proximal reabsorptive
systems. In some cases, the deficit may be highly specific
(e.g., involving only one amino acid), whereas in others,
multiple systems may be involved (e.g., glucose and many
amino acids). These defects also occur when the deficit is
due to an ingested toxin (e.g., heavy metal toxicity) rather
than a genetic abnormality.
GLUCOSE
Under most circumstances, it would be deleterious to lose glu-
cose in the urine, particularly in conditions of prolonged fast-
ing. Thus, the kidneys normally reabsorb all of the glucose
that is filtered. A typical plasma glucose level is about 90 mg/dL
(5 mmol/L). It increases transiently to well over 100 mg/dL
during meals and decreases somewhat during fasting. Usually
all the filtered glucose is reabsorbed in the proximal tubule.
This involves taking up glucose from the tubular lumen along
with sodium via a sodium-dependent glucose symporter
(SGLUT) across the apical membrane of proximal convoluted
tubule epithelial cells, followed by its exit across the basolat-
eral membrane into the interstitium via a glucose transporter
(GLUT), a uniporter. Unlike the case for sodium and many
other solutes, the tight junctions are not significantly perme-
able to glucose. Therefore, as glucose is removed from the
lumen and the luminal concentration decreases, there is no
backleak, resulting in virtually complete reabsorption.
Because glucose reabsorption is a Tm system, abnormally
high filtered loads overwhelm the reabsorptive capacity (exceed
900
800
Filtered
Glucose filtered load, reabsorption
load
700
or excretion (mg/min)
600
Transport
Excretion
500
maximum
400
300
Normal Reabsorption
200
100
Threshold
0
100 200 300 400 500 600 700 800
Plasma glucose concentration
(mg/100 ml)
FIGURE 43–1 Glucose handling by the kidney. The filtered
load, amount reabsorbed, and amount excreted are plotted as a
function of plasma glucose concentration. At a given GFR, the filtered
load is always exactly proportional to the plasma concentration. At
normal levels of plasma glucose the filtered load is well below the Tm,
and therefore all the filtered glucose is reabsorbed and none is
excreted. However, as plasma glucose rises into the hyperglycemic
range, the Tm is reached, and any glucose filtered in excess of the Tm is
excreted. (Reproduced with permission from Widmaier EP, Raff H, Strang KT:
Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
the Tm; Figure 43–1). This occurs when plasma glucose
increases above roughly 300 mg/dL, a situation often found in
untreated diabetes mellitus. In very severe cases, blood glucose
can exceed 1,000 mg/dL, or over 55 mmol/L, leading to signifi-
cant loss of glucose. Assume that the glucose Tm is 375 mg/min
(a typical value). With a glomerular filtration rate (GFR) of
125 mL/min (1.25 dL/min) and a normal plasma glucose of
90 mg/dL, the filtered load is 1.25 dL/min × 90 mg/dL =
112.5 mg/min, much less than the Tm of 375 mg/min. Thus, the
kidneys easily reabsorb the entire filtered load. When plasma
glucose reaches 300 mg/dL, the filtered load is now 1.25 dL/
min × 300 mg/dL = 375 mg/min. At this point, the proximal
convoluted tubule has reached the upper limit of what it can
reabsorb, and a little glucose begins to spill into the urine. Fur-
ther increases in plasma glucose above 300 mg/dL lead to pro-
gressively greater renal losses. This leads to an unwanted
diuresis (high urine volume) that we will discuss later, but one
can appreciate that any glucose not reabsorbed is an osmole in
the tubule that has consequences for water reabsorption.
PROTEINS AND PEPTIDES
Although we sometimes say the glomerular filtrate is protein
free, it is not truly free of all protein; it just has a total protein
content much lower than plasma. First, peptides and smaller
proteins (e.g., angiotensin, insulin), although present at low

concentrations in the blood, are filtered in considerable quan-
tities. Second, while the movement of large plasma proteins
across the glomerular filtration barrier is extremely limited, a
small amount does make it through into Bowman’s space. For
albumin, the plasma protein of highest concentration in the
blood, the concentration in the filtrate is normally about
1 mg/dL, or roughly 0.02% of the plasma albumin concentra-
tion (5 g/dL). Because of the huge volume of fluid filtered per
day, the total filtered amount of protein is not negligible. Nor-
mally all of these proteins and peptides are reabsorbed com-
pletely, although not in the conventional way. They are
enzymatically degraded into their constituent amino acids,
which are then returned to the blood.
For the larger proteins, the initial step in recovery is endocy-
tosis at the apical membrane. This energy-requiring process is
triggered by the binding of filtered protein molecules to spe-
cific receptors on the apical membrane. The rate of endocyto-
sis is increased in proportion to the concentration of protein
in the glomerular filtrate until a maximal rate of vesicle forma-
tion, and thus the Tm for protein uptake, is reached. The
pinched-off intracellular vesicles resulting from endocytosis
merge with lysosomes, whose enzymes degrade the protein to
low-molecular-weight fragments, mainly individual amino
acids. These end products then exit the cells across the baso-
lateral membrane into the interstitial fluid, from which they
gain entry to the peritubular capillaries.
To understand the potential problem associated with a fail-
ure to take up filtered protein, remember that for a healthy
young adult:
Total filtered protein
= GFR × concentration of protein in filtrate (1)
= 180 L per day × 10 mg/L = 1.8g per day
If this protein was not removed from the lumen, the entire
1.8 g would be lost in the urine. In fact, most of the filtered
protein is endocytosed and degraded so that the excretion of
protein in the urine is normally only 100 mg per day. The
endocytic mechanism by which protein is taken up is easily
saturated, so a large increase in filtered protein resulting from
increased glomerular permeability causes the excretion of
large quantities of protein.
Discussions of the renal handling of protein logically tend to
focus on albumin because it is by far the most abundant plasma
protein. There are, of course, many other plasma proteins.
Although present in lower levels than albumin, they are smaller
and thus more easily filtered. For example, growth hormone
(molecular weight, 22,000 d) is approximately 60% filterable,
and insulin is 100% filterable. The total mass of these filtered
hormones is insignificant; however, because even tiny levels in
the plasma have important signaling functions in the body,
renal filtration becomes an important influence on concentra-
tions in the blood. Relatively large fractions of these smaller
plasma proteins are filtered and then degraded in tubular cells.
The kidneys are major sites of catabolism of many plasma pro-
teins, including polypeptide hormones. Decreased rates of
CHAPTER 43 Renal Handling of Organic Substances 431
degradation occurring in renal disease may result in elevated
plasma hormone concentrations.
Very small peptides, such as angiotensin II, are catabolized
into amino acids or dipeptides and tripeptides within the
proximal tubular lumen by peptidases located on the apical
surface of the plasma membrane. These products are then
reabsorbed by the same transporters that normally reabsorb
filtered amino acids.
Finally, in certain types of renal damage, proteins released
from damaged tubular cells rather than filtered at the renal
corpuscles may appear in the urine and provide important
diagnostic information.
PROXIMAL SECRETION
OF ORGANIC ANIONS
So far we have described reabsorption of useful organic sub-
stances the body does not normally excrete. There are of course
many organic anions that it does excrete, both endogenously
produced and foreign (see Table 43–1 for a partial listing).
Many of these organic anions are filterable at the renal cor-
puscles, with proximal secretion adding to the amount filtered.
Others, however, are extensively bound to plasma proteins and
undergo glomerular filtration only to a limited extent; accord-
ingly, proximal tubular secretion constitutes the only signifi-
cant mechanism for their excretion.
The active secretory pathway for organic anions in the prox-
imal tubule in some sense is the reverse of reabsorption of
organic solutes: there are active transporters for the anions at
the basolateral membrane of tubular epithelial cells that are
the rate-limiting step in overall transport. Transport out of the
cell across the apical membrane into the lumen uses a variety
of uniporters or more specific sodium-dependent antiporters.
Because the basolateral membrane of proximal convoluted
tubule epithelial cells contains all of these different transport-
TABLE 43–1 Some organic anions actively secreted
by the proximal tubule.
Endogenous Substances Drugs
Bile salts Acetazolamide
Fatty acids Chlorothiazide
Hippurates Ethacrynate
Hydroxybenzoates Furosemide
Oxalate Penicillin
Prostaglandins Probenecid
Urate Saccharin
Salicylates
Sulfonamides
Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.
432 SECTION VII Renal Physiology

ers, the proximal tubule has the capacity to secrete all the Although urate reabsorption is greater than secretion, the
organic anions listed in Table 43–1 and many more. Like glu- secretory process is controlled to maintain relative constancy
cose, organic anions are not significantly permeable through of plasma urate. In other words, if plasma urate begins to
tight junctions or lipid membranes, so that their transport is increase because of increased urate production, the active
also characterized by a Tm. If the blood concentration of an proximal secretion of urate is stimulated, thereby increasing
organic anion is too high, it will not be efficiently removed urate excretion.
from the blood by the kidneys. The relatively nondiscriminat- Given these mechanisms of renal urate handling, the reader
ing nature of this collection of transporters accounts for their should be able to deduce the three ways by which altered renal
ability to eliminate so many drugs and other foreign environ- function can lead to decreased urate excretion and hence
mental chemicals from the body. In this regard, the liver’s increased plasma urate, as in gout: (1) decreased filtration of
metabolic transformations are very important. In the liver, urate secondary to decreased GFR, (2) excessive reabsorption
many foreign (and endogenous) substances are conjugated of urate, and (3) diminished secretion of urate.
with either glucuronate or sulfate. The addition of these groups
renders the parent molecule far more water soluble. These two
types of conjugates are actively transported by the organic PROXIMAL SECRETION
anion secretory pathway.
The most intensively studied organic anion secreted by this OF ORGANIC CATIONS
pathway is para-aminohippurate (PAH), the substance used
The proximal tubules possess several closely related transport
for the measurement of effective renal plasma flow (see
systems for organic cations that are analogous to those for
Chapter 41). PAH secretion involves a pair of antiporters, one
organic anions. Because of the large number of different trans-
at each membrane. At the basolateral membrane, PAH is taken
porters, a substantial amount of foreign and endogenous
up in exchange for the anion (base) form of a dicarboxylic
organic cations is transported (Table 43–2). The cations com-
acid. PAH is extruded into the lumen across the apical mem-
pete with one another for transport, and the transporters man-
brane via another antiporter.
ifest Tm limitation. Organic cations enter across the basolateral
As the plasma concentration of an anion secreted by this
membrane via one of the several uniporters, members of the
system increases, so does the rate of secretion (until the Tm for
OCT (organic cation transporter) family, and exit into
that substance is reached). This provides a mechanism for
the lumen via an antiporter, which exchanges a proton for the
regulating the endogenous organic anions handled by the sys-
organic cation.
tem and for speeding the excretion of foreign organic anions.
The proximal secretion of organic cations, as for organic
PAH is typical, in yet another way, of many of the organic
anions, is particularly critical for the excretion of those cations
anions secreted proximally. It undergoes no significant trans-
extensively bound to plasma proteins and not filterable at the
port anywhere else along the nephron. In contrast, some of the
renal corpuscle. However, again similar to organic anions,
other organic anions secreted by the proximal tubule can also
many of the organic cations secreted by the proximal tubules
undergo other forms of transport in both the proximal tubule
and more distal segments. The most important of these is pas-
sive tubular reabsorption or secretion, which is described later.

TABLE 43–2 Some organic cations actively secreted

URATE by the proximal tubule.

Endogenous Substances Drugs

Urate (the base form of uric acid) provides a fascinating
example of the renal handling of organic anions that is partic- Acetylcholine Atropine
ularly important for clinical medicine and is illustrative of Choline Isoproterenol
renal pathology. An increase in the plasma concentration of
urate can cause gout; therefore, its removal from the blood is Creatinine Cimetidine
important. However, it is as though the kidney cannot make Dopamine Meperidine
up its mind what to do with urate. Urate is not protein bound Epinephrine Morphine
and so is freely filterable. Almost all the filtered urate is reab-
sorbed early in the proximal tubule; however, further on in the Guanidine Procaine
proximal tubule, urate undergoes active tubular secretion. Histamine Quinine
Then, in the straight portion, some of the urate is once again Serotonin Tetraethyl ammonium
reabsorbed. The total rate of tubular reabsorption is normally
much greater than the rate of tubular secretion, so the mass of Norepinephrine
urate excreted per unit time is only a small fraction of the mass Thiamine
filtered. Most of this transport involves antiporters that Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
exchange urate for another organic anion. 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.
 CHAPTER 43 Renal Handling of Organic Substances 433

are not protein bound and, therefore, also undergo glomerular
filtration and tubular secretion; creatinine is a good example.
Finally, and again analogous to organic anions, some organic
cations not only are actively secreted by the proximal tubules,
but may also undergo other forms of tubular handling, mainly
passive reabsorption or secretion.
pH DEPENDENCE OF PASSIVE
REABSORPTION OR SECRETION
Many substances handled by the kidney are weak acids or
bases. At a given pH, some are in the neutral form and some
are in the ionized form. The state of ionization affects both
the aqueous solubility and membrane permeability of the
substance. In most cases, the neutral forms of organic acids
and bases are more permeable in lipid membranes than the
ionized forms. The neutral forms, being permeable, can
equilibrate with the interstitial levels, while the ionized forms,
once in the lumen, are effectively trapped there. Many weak
acids are predominantly neutral at low pH (acid form) and
are dissociated into an anion and a proton at higher pH. The
lower the pH, the greater the amount in the neutral acid form.
Imagine the case in which the tubular fluid becomes acidified
relative to the plasma, which it does on a typical Western diet.
For a weak acid in the tubular fluid, relatively more will be
converted to the neutral form and, therefore, become more
permeable. This favors diffusion out of the lumen (reabsorp-
tion). Therefore, highly acidic urine (low pH) tends to
increase passive reabsorption of weak acids (and promote
less excretion). For many weak bases, the pH dependence is
just the opposite. At low pH they are protonated cations
(trapped in the lumen). As the urine becomes acidified, more
is converted to the impermeable charged form and is trapped
in the lumen. Less is reabsorbed passively, and more is
excreted.
Having said this, what difference does it make? Because so
many medically useful drugs are weak organic acids and bases,
all these factors have important clinical implications. For
example, if one wishes to enhance the excretion of a drug that
is a weak acid, one attempts to alkalinize the urine (because
this traps the ionic form in the lumen). In contrast, acidifica-
tion of the urine is desirable if one wishes to prevent excretion
of the drug. Of course, exactly the opposite applies to weak
organic bases. At any luminal fluid pH, increasing the urine
flow increases the excretion of both weak acids and bases
(Figure 43–2). Finally, excretion can be reduced by adminis-
tering another drug that interferes with any active proximal
secretory pathway for the drug.
UREA
Urea is a very special substance for the kidney. It is an end
product of protein metabolism, waste to be excreted, and also
a useful tool for the regulation of water excretion.
Excess dietary protein not needed for tissue synthesis is
either oxidized or converted to fat and stored for later oxida-
tion. During fasting the body breaks down the fat and protein

TUBULAR RENAL TUBULAR PERITUBULAR

LUMEN CELLS PLASMA
(Filtered)
HA A

H H

HA HA A

(Filtered)
BH B FIGURE 43–2 pH dependence of passive reabsorption
or secretion. Acidification of the urine favors reabsorption,
H H andtherefore retention, of weak acids because the neutral,
protonated forms can passively diffuse out of the tubule (top
dashed line). At the same time, acidification favors secretion
B BH (and therefore loss) of weak bases because the protonated
BH (Impermeable)
forms are charged and trapped in the lumen, and the neutral,
 nonprotonated forms can passively diffuse into the tubule
B (bottom dashed line). The processes that acidify the urine are
described in Chapter 47. (Reproduced with permission from Eaton DC,
Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical
Books/McGraw-Hill, Medical Pub. Division, 2009.)
434 SECTION VII Renal Physiology

for fuel, in essence consuming itself. When oxidized for fuel, 110%
protein is first split into its constituent amino acids. These are 5.5
then separated into a nitrogen moiety (ammonium) and a car-
bohydrate moiety. The carbohydrate goes on to further meta-
bolic processing, but the ammonium cannot be further
oxidized and is a waste product. The problem is that ammo-
nium is rather toxic to most tissues (except the medullary
interstitium), and the liver immediately converts most ammo-
nium to urea and a smaller, but crucial amount to glutamine.
(We will take up the fate of this glutamine in Chapter 47.)
100%
Whether a person is well fed or fasting, urea production pro- 1
ceeds continuously. In fact, it constitutes about half of the nor-
mal solute content of urine; thus, it is a crucial player in
osmotic considerations.
The normal level of urea in the blood is quite variable 50%
(3–9 mmol/L), reflecting variations in both protein intake 1.2
and renal handling of urea. (For ease in converting to osmo-
lality, we express urea concentration in units of mmol/L
rather than the clinical unit of blood urea nitrogen [BUN].)
Over days to weeks, renal urea excretion must match hepatic
production; otherwise, plasma levels would increase into
the pathological range, producing a condition called
uremia. On a shorter-term basis (hours to days), urea
excretion rate may not exactly match production rate
because urea excretion is also regulated for purposes other
than keeping a stable plasma level. As discussed in the next
chapter, urea is a key solute involved in regulating excretion
of water.
The gist of the renal handling of urea is the following: it is 50%
25
freely filtered. About half is reabsorbed in the proximal
tubule. Then an amount equal to that reabsorbed is secreted FIGURE 43–3 Urea handling by the kidney. The arrows
back into the loop of Henle. Finally, about half is reabsorbed indicate that urea is reabsorbed in the proximal tubule, secreted in
a second time in the medullary collecting duct. The net the thin portions of the loop of Henle, and reabsorbed again in the
result is that about half the filtered load is excreted medullary collecting ducts. The top halves of boxes indicate the
(Figure 43–3). percentage of the filtered load remaining in the tubule at a given
As a molecule, urea is small (molecular weight, 60 d), water location, and the bottom halves indicate tubular concentration
soluble, and freely filtered. Because of its highly polar nature, relative to plasma. Note that while the amount remaining in the
it does not permeate lipid bilayers, but a set of uniporters collecting duct (and thus excreted) is half the amount filtered,
the concentration is much higher than that in plasma because
(UT family) transports urea in various places in the kidney
most of the water has been reabsorbed. These numbers are highly
and in other sites within the body (particularly red blood
variable, depending on several factors, particularly the hydration
cells). Because urea is freely filtered, the filtrate contains urea status. (Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal
at a concentration identical to that in plasma. Let us assume Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical
a normal plasma level (5 mmol/L). Roughly half the filtered Pub. Division, 2009.)
load is reabsorbed in the proximal tubule. This occurs pri-
marily by the paracellular route. As water is reabsorbed, the
urea concentration increases, driving diffusion through the all the way down to the papilla. For simplicity we consider all
leaky tight junctions. By the time the tubular fluid enters the nephrons together.
loop of Henle, about half the filtered urea has been reab- The interstitium of the medulla has a considerably higher
sorbed, and the urea concentration has increased somewhat urea concentration than does plasma. The concentration
above its level in the filtrate because proportionally more increases from the outer to the inner medulla (part of the so-
water than urea was reabsorbed. At this point, the process called medullary osmotic gradient that we describe in the next
becomes fairly complicated. First, conditions in the medulla chapter). Since the medullary interstitial urea concentration is
depend highly on the individual’s state of hydration. Second, greater than that in the tubular fluid entering the loop of
there is a difference between superficial nephrons, with short Henle, there is a concentration gradient favoring secretion into
loops of Henle that only penetrate the outer medulla, and the lumen. The tight junctions in the loop of Henle are no lon-
juxtamedullary nephrons, with long loops of Henle that reach ger permeable (as they were in the cortex), but the epithelial
 CHAPTER 43 Renal Handling of Organic Substances 435

membranes of the thin regions of the Henle loops express urea

through a strainer. Sure enough, she indeed passed a stone
uniporters, members of the UT family. This permits secretion
and brought it to her primary care physician for labora-
of urea into the tubule. In fact, the urea secreted from the
tory analysis. She had never had a stone before. She is
medullary interstitium into the thin regions of the loop of
moderately obese and mildly hypertensive. Previous labo-
Henle replaces the urea previously reabsorbed in the proximal
ratory analysis showed that she has increased plasma
tubule. Thus, when tubular fluid enters the thick ascending
triglycerides. She may be becoming diabetic, and to avoid
limb, the amount of urea in the lumen is at least as large as the
carbohydrate she eats a large amount of seafood and
filtered load (the loop of Henle has essentially reversed what
chicken, but not many vegetables. The stone proved to be
was accomplished in the proximal tubule). However, because
a uric acid stone, which accounts for only about 7% of all
about 80% of the filtered water has now been reabsorbed, the
kidney stones. What might predispose her to develop uric
luminal urea concentration is now several times greater than
acid stones?
that in the plasma. Beginning with the thick ascending limb
Uric acid has a pK of 5.75. In plasma and in all but very
and continuing all the way to the medullary collecting ducts
acidic urine, the vast majority of uric acid exists as the urate
(through the distal tubule and cortical collecting ducts), the
anion, which is the form recognized by renal transporters.
apical membrane urea permeability (and the tight junction
The neutral acid has a lower solubility than the anionic
permeability) is essentially zero. Therefore, an amount of urea
urate. Therefore, increased urinary content of urate, and
roughly equal to the filtered load remains within the tubular
particularly low urinary pH, which converts much of the
lumen and flows from the cortical into the medullary collect-
urate to uric acid, leads to much more urinary uric acid and
ing ducts.
increased likelihood of forming stones. Her diet of fish and
During the transit through the cortical collecting ducts,
chicken has a high content of purines, the precursors of
variable amounts of water are reabsorbed, further concentrat-
uric acid. Therefore, because of the high metabolic produc-
ing the urea. Just how much depends on factors discussed in
tion and low urinary pH, her urine contains high amounts
the next chapter, but the luminal urea concentration can easily
of the rather insoluble uric acid. To complicate the matter,
reach 50 times that of plasma. We indicated earlier that the
her profile fits that of a person with metabolic syndrome, a
urea concentration in the medullary interstitium is greater
cluster of conditions that includes truncal obesity, hyper-
than that in plasma, but the luminal concentration in the
tension, hyperlipidemia, and insulin resistance that will be
medullary collecting ducts is even higher, so in the inner
discussed in Chapter 69. For reasons that are still being
medulla the gradient now favors reabsorption, and urea is
unraveled, patients with metabolic syndrome often have
reabsorbed a second time. It is this reabsorbed urea that leads
decreased urinary ammonium. Because ammonium is a
to the high medullary interstitial concentration that drives
major buffer on which hydrogen ions are excreted (see
urea secretion into the thin regions of the loop of Henle. In
Chapter 47), low ammonium production in the face of nor-
fact, some of the urea recycles, that is, it is reabsorbed from
mal acid loads leads to decreased urinary pH. The urinary
medullary collecting ducts and secreted into thin limbs of the
pH was indeed very low. The stone formation is based pri-
loop of Henle, from where it travels within the tubule to the
marily on her low urinary pH, which, at all pH values less
collecting ducts again to repeat the process. The overall result
than 5.75, converts most of the urate to the less soluble uric
of these events is that half the original amount of filtered urea
acid. The patient was counseled to include more vegetables
passes into the final urine, an amount that, over the long term,
in her diet and consume more water. These measures
must match hepatic production of urea if the body is to remain
should increase her urinary pH and lower the urate con-
in balance for urea. The concentration of urea in the final
centration, and therefore decrease the concentration of uric
urine can be more than 50× that in plasma, depending on how
acid.
much water is reabsorbed. These processes are summarized in
Figure 43–3.

CHAPTER SUMMARY
CLINICAL CORRELATION
A 41-year-old mother of five children presented at a hos-
pital ER with severe right flank pain. The pain was present
all the time, and was accentuated in waves. A urine speci-
men was pink, with a pH of 5.1. The ER personnel sus-
pected that she had a kidney stone located in the right
ureter. Accordingly they gave her large amounts of fluid
and nonsteroidal anti-inflammatories (NSAIDS) to help
ease the pain. After several hours the pain eased, and she
was sent home with instructions to pass all her urine
■ Important organic metabolites are almost completely reab-
sorbed (saved), whereas waste products are for the most part
excreted.
■ Most organic solutes are transported transcellularly by a large
number of different saturable multiporters (Tm systems).
■ Normal filtered loads of glucose are completely reabsorbed,
but in conditions of pathological hyperglycemia the trans-
port saturates, leading to the appearance of glucose in the
urine.
■ Urea is reabsorbed proximally and recycled between the
collecting ducts and loop of Henle in the medulla, resulting
in a net excretion of about half the filtered load.
436 SECTION VII Renal Physiology

STUDY QUESTIONS 4. A high urinary pH favors

A) low excretion of drugs that are weak acids.
1. When plasma glucose reaches such high levels that substantial B) active reabsorption of drugs that are weak bases.
amounts of glucose appear in the urine (glucosuria) C) low excretion of drugs that are weak bases.
A) glucose is leaking back into the tubule through tight D) high passive permeability of drugs that are weak acids.
junctions. 5. The tubular concentration of urea
B) there is not enough luminal sodium to move in symport
A) exceeds the plasma concentration at the hairpin turn of the
with glucose.
loop of Henle.
C) all the glucose transporters are working at their maximum rate.
B) decreases to below the plasma concentration by the end of
D) the glucose transporters are being inhibited by the high
the loop of Henle.
levels of glucose.
C) decreases to below the plasma concentration by the end of
2. Useful small organic metabolites that should not be excreted are the proximal tubule.
A) generally not filtered. D) reaches its highest value in the cortical collecting duct.
B) reabsorbed paracellularly. 6. Urea is secreted into the tubules
C) taken up by endocytosis and degraded.
A) in proximal tubules.
D) reabsorbed transcellularly.
B) in Henle’s loop.
3. Organic anion secretion C) in medullary collecting ducts.
A) involves a step of active influx across the basolateral D) at any of the above sites depending on hydration status.
membrane.
B) is passive and paracellular.
C) is via simple diffusion through the tubular membranes.
D) utilizes the same membrane transporters as organic cation
secretion.
 44
C H A P T E R

Basic Renal Processes

for Sodium, Chloride,
and Water
Douglas C. Eaton and John P. Pooler

O B J E C T I V E S

■ List approximate percentages of sodium reabsorbed in major

tubular segments.
■ List approximate percentages of water reabsorbed in major tubular
segments.
■ Describe proximal tubule sodium reabsorption, including the functions of the
apical membrane sodium entry mechanisms and the basolateral Na,K-ATPase.
■ Explain why chloride reabsorption is coupled with sodium reabsorption, and
list the major pathways of proximal tubule chloride reabsorption.
■ State the maximum and minimum values of urine osmolality.
■ Define osmotic diuresis and water diuresis.
■ Explain why there is always an obligatory water loss.
■ Describe the handling of sodium by the descending and ascending limbs,
distal tubule, and collecting duct system.
■ Describe the role of sodium–potassium–2 chloride symporters in the thick
ascending limb.
■ Describe the handling of water by descending and ascending limbs, distal
tubule, and collecting duct system.
■ Describe the process of “separating salt from water,” and discuss why this is
required to excrete either concentrated or dilute urine.
■ Describe how antidiuretic hormone affects water reabsorption.
■ Describe the characteristics of the medullary osmotic gradient.
■ Explain the role of the thick ascending limb, urea recycling, and medullary
blood flow in generating the medullary osmotic gradient.
■ State why the medullary osmotic gradient is partially “washed out” during
a water diuresis.

OVERVIEW
BODY FLUID COMPARTMENTS
Body water (about 60% of body weight) is distributed into
various aqueous spaces in proportion to their osmotic content.
The collective volume of all the cells in the body is called the
intracellular fluid (ICF). It contains roughly two thirds of the
body osmotic content, and therefore two thirds of the water.
The remaining one third of the osmotic content and water is
called the extracellular fluid (ECF). It is mostly accounted for
by interstitial fluid and blood plasma. Because of the ease with
which water crosses cell membranes (see Chapter 3), the ECF
and ICF are in osmotic equilibrium. Changes in body water
affect the volume of one or both compartments, depending on
how much solute, and what kind, accompanies the water. In
contrast, additions or losses of sodium from the body are
almost exclusively to or from the ECF only because the actions

437

Ch44_437-448.indd 437 11/26/10 10:29:16 AM

438 SECTION VII Renal Physiology

Plasma
Interstitial
Normal
ECF ICF

Plasma
Add Interstitial
water
ECF ICF

Plasma
Add Interstitial
isotonic
saline ECF ICF

FIGURE 44–1 Distribution of total body water into

Plasma
the intracellular (ICF) and extracellular (ECF) Interstitial
compartments. As explained in the text, addition of water, Add salt
salt, or both alters the volumes of the compartments.
Expanded volumes are indicated by the dashed lines. ECF ICF

of cellular Na,K-ATPases keep intracellular sodium nearly

TABLE 44–1 Normal routes of sodium intake and loss.
constant. The effects of adding sodium and water are depicted
in Figure 44–1. The addition of water alone expands both the Route Amount (g per Day)
ICF and ECF (indicated by the dashed lines). Adding isotonic
Intake
sodium chloride expands only the ECF because the added
osmoles remain in the ECF. Adding sodium chloride without Food 10.5
water does not change the total volume, but causes a shift of Output
water from the ICF to the ECF in order to restore equality of
Sweat 0.25
osmolality between the two compartments.
The transport of water by the renal tubules is straightfor- Feces 0.25
ward—“water follows the osmoles”—so much of the descrip- Urine 10.00
tion of water transport really amounts to describing solute
Total output 10.50
transport, recognizing that in some regions of the kidney, low
Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
water permeability limits the amount of water that follows the 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.
osmoles. Transport of chloride is more complicated, but
because of the constraints of electroneutrality, it is tied to the
transport of sodium. Sodium transport is clearly the crux of
and chloride are reabsorbed. Table 44–2 summarizes the
the matter because the transport of chloride, water, and many
approximate quantitative contribution of each tubular seg-
other substances is linked to the transport of sodium.
ment to sodium reabsorption. In an individual with an average
The excretory rates of sodium, chloride, and water vary over
salt intake, the proximal tubule reabsorbs 65% of the filtered
an extremely wide range depending on diet. For example, some
sodium, the thin and thick ascending limbs of Henle’s loop
persons may ingest 20–25 g of sodium chloride per day, whereas
25%, and the distal convoluted tubule and collecting duct
a person on a low-salt diet may ingest only 0.05 g. The healthy
system most of the remaining 10%, so that the final urine con-
kidney can readily alter its excretion of salt over this range.
tains less than 1% of the total filtered sodium. As will be
Similarly, urinary water excretion can be varied physiologically
discussed in Chapter 45, reabsorption at several of these tubu-
from approximately 0.4 to 25 L per day, depending on whether
lar sites is under physiological control by neural, hormonal,
one is lost in the desert or maximizing one’s water intake.
and paracrine signals, so that the exact amount of sodium
excreted is regulated. Because so much sodium is filtered, even
SODIUM REABSORPTION a small percentage change in reabsorption results in a rela-
tively large change in excretion.
Table 44–1 is a balance sheet for sodium chloride. The major In all nephron segments, the essential event is the primary
route of salt excretion from the body under normal circum- active transport of sodium from cell to interstitial fluid by the
stances is via the kidneys. The large amount excreted should Na,K-ATPase pumps in the basolateral membrane. These
not obscure the fact that nearly all the filtered loads of sodium pumps keep the intracellular sodium concentration lower than
 CHAPTER 44 Basic Renal Processes for Sodium, Chloride, and Water
TABLE 44–2 Comparison of sodium and water
reabsorption along the tubule.
Tubular Segment Filtered Load Reabsorbed (%)
Sodium Water
Proximal tubule 65 65
Descending thin limb of — 10
Henle’s loop
Ascending thin limb and 25 —
thick ascending limb of
Henle’s loop
Distal convoluted tubule 5 —
Collecting duct system 4–5 5 (during water
loading)
>24 (during
dehydration)
Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.
that in the surrounding media. Because the inside of the cell is
negatively charged with respect to the lumen, luminal sodium
ions enter the cell passively, down their electrochemical gradi-
ent. The entry paths are far more numerous than the exit paths.
We will examine these entry paths more closely as we go
through the tubule segment by segment.
CHLORIDE REABSORPTION
Because chloride reabsorption is dependent on sodium reab-
sorption, the tubular locations that reabsorb chloride and the
percentages of filtered chloride reabsorbed by these segments
are similar to those for sodium (see Table 44–1). When exam-
ining chloride reabsorption, it is helpful to keep in mind the
absolute constraint of electroneutrality: any finite volume of
fluid reabsorbed must contain equal amounts of anion and
cation equivalents. Let us do a “guesstimate” calculation. One
liter of normal filtrate contains 140 mEq of sodium, and thus
must contain about 140 mEq of anions, mainly chloride (110
mEq) and bicarbonate (24 mEq). (We say “about” because
there are other cations [e.g., potassium and calcium] and
anions [e.g., sulfate and phosphate] that must factor into the
calculation to achieve an exact balance, but their contributions
are much smaller than sodium, chloride, and bicarbonate.) If
65% of the filtered sodium is reabsorbed in the proximal
tubule, then 0.65 × 140 = 91 mEq of sodium in each liter of
filtrate is reabsorbed. Therefore, 91 mEq of some combination
of chloride and bicarbonate must also be reabsorbed to accom-
pany this sodium. As will be described in Chapter 47, about
90% of the filtered bicarbonate is reabsorbed in the proximal
tubule (0.9 × 24 ≈ 22). This leaves 91 – 22 = 69 mEq of chloride
that must be reabsorbed in the proximal tubule. This is more
than 60% of the 110 mEq of filtered chloride and almost as
much as the fractional reabsorption of sodium and water.
Later segments reabsorb almost all of the remaining 40%.
439
TABLE 44–3 Normal routes of water gain and loss
in adults.
Route Amount (mL per Day)
Intake
Beverage 1,200
Food 1,000
Metabolically produced 350
Total 2,550
Output
Insensible loss (skin and lungs) 900
Sweat 50
In feces 100
Urine 1,500
Total 2,550
Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.
WATER REABSORPTION
A balance sheet for total body water is given in Table 44–3.
These are average values, which are subject to considerable
variation. The two sources of body water are metabolically
produced water, resulting largely from the oxidation of carbo-
hydrates, and ingested water, obtained mostly from liquids,
but also from so-called solid food (e.g., a rare steak is approxi-
mately 70% water). There are several sites from which water is
always lost to the external environment: skin, lungs, gastroin-
testinal tract, and kidneys. Menstrual flow and, in lactating
women, breast milk constitute two other potential sources of
water loss in women.
The loss of water by evaporation from the cells of the skin
and the lining of respiratory passageways is a continuous pro-
cess, often referred to as insensible loss because people are
unaware of its occurrence. Additional water evaporates from
the skin during production of sweat. Fecal water loss is nor-
mally quite small but can be severe in diarrhea. Gastrointesti-
nal loss can also be large during severe bouts of vomiting.
Under conditions of normal hydration, the kidneys are, of
course, the main route of water loss.
With a large water load, the renal response is to produce a
large volume of very dilute urine (osmolality much lower than
that in blood plasma). In contrast, during a state of dehydration,
the urine volume is low and very concentrated (i.e., the urine
osmolality is much greater than that in blood plasma). That the
urine osmolality is so variable brings us to a crucial aspect of
renal function. Terrestrial animals must be able to indepen-
dently control excretion of salt and water, because their inges-
tion and loss is not always linked (see Tables 44–1 and 44–3). To
excrete water in excess of salt and vice versa (i.e., produce a
range of urine osmolalities), the kidneys must be able to sepa-
rate the reabsorption of solute from the reabsorption of water,
440 SECTION VII Renal Physiology
that is, to “separate salt from water.” How do they do this?
Regardless of hydration state, the proximal tubule reabsorbs
water and solute in equal proportions (isosmotic reabsorption),
but the loop of Henle reabsorbs proportionally more solute than
water. This is a key step in the separation process—reabsorption
of solute, leaving water in the tubule. By the time tubular fluid
leaves the loop of Henle and enters the distal tubule, the loss of
solute has typically decreased the osmolality to about 110
mOsm/kg H2O. If an individual is overhydrated and, therefore,
requires maximum water excretion, most of this dilute fluid
simply passes through the collecting duct system to appear in
the urine, with only limited further water reabsorption. In con-
trast, when an individual is dehydrated, the vast majority of this
dilute water is reabsorbed in the collecting ducts, leaving a low
volume of concentrated final urine.
The ability of the kidneys to produce low-volume hyperos-
motic urine is a major determinant of one’s ability to survive
without water, which for most people is at least several days,
and longer if conditions are right. The human kidney can pro-
duce a maximal urinary concentration of 1,400 mOsm/kg in
extreme dehydration. This is almost five times the osmolality
of plasma. The sum of the urea, sulfate, phosphate, other waste
products, and a small number of nonwaste ions excreted each
day normally averages approximately 600 mOsm per day.
These solutes continue to be excreted even in severe dehydra-
tion; therefore, the minimal volume of water in which this
mass of solute can be dissolved is roughly 600 mOsm/1,400
mOsm/L = 0.43 L per day.
This volume of urine is known as the obligatory water loss.
It is not a strictly fixed volume but changes with different phys-
iological states. For example, increased tissue catabolism, as
during fasting or trauma, releases excess solute and so increases
obligatory water loss. The obligatory water loss contributes to
dehydration when a person is deprived of water intake. The
obligatory solute loss also explains why a thirsty sailor cannot
drink seawater for hydration. To excrete all the salt in the sea-
water plus the obligatory solute would require more urinary
water than was contained in the seawater consumed.
INDIVIDUAL TUBULAR SEGMENTS
The important principles regarding individual tubular seg-
ments are how the reabsorption of sodium, chloride, and water
is related to one another and how the amount of reabsorption
varies quantitatively from one segment to another.
PROXIMAL TUBULE
As shown in Figure 44–2, several apical membrane entry pathways
are involved in the active transcellular reabsorption of sodium in
the proximal tubule. In the early portion, a large fraction of the
filtered sodium enters the cell across the apical membrane via anti-
port with protons. As will be described in Chapter 47, these pro-
tons, which are released when carbon dioxide combines with
LUMEN INTERSTITIUM
Na+
ATP
HCO3 H+ H+ Na+
Hbase K+
CO2 + H2O
base– base– HCO3
Cl– Na+
H2O H2O
Glucose, Cl–
Na+
phosphate,
amino acids,
organics etc
H2O, Cl– H2O, Cl–
FIGURE 44–2 Major pathways for reabsorption of sodium,
chloride, and water in the proximal tubule. The entire proximal
tubule is the major site for reabsorption of salt and water. Sodium entry
is coupled to the secretion or uptake of a variety of substances, the
major one being hydrogen ions, which are secreted in exchange for
sodium via the NHE3 antiporter. These hydrogen ions, once in the
lumen, combine with filtered bicarbonate and secreted organic base
(see text and Chapter 47 for further explanation). Additional sodium
enters in symport with glucose, amino acids, and phosphate. Sodium is
transported to the interstitium mostly via the basolateral Na,K-ATPase,
but also in symport with bicarbonate. (The coupling between sodium
and bicarbonate is described fully in Chapter 47.) Chloride that enters
in antiport with organic base leaves mostly via channels. In addition, a
substantial amount of chloride is reabsorbed paracellularly. Water
moves both paracellularly and intracellularly via aquaporins. (Modified
with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York,
NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)
water, cause the secondary active reabsorption of filtered bicar-
bonate. Therefore, in the early proximal tubule, bicarbonate is a
major anion reabsorbed with sodium and the luminal bicarbonate
concentration decreases markedly (Figure 44–3). Organic nutri-
ents and phosphate are also absorbed with sodium, and their lumi-
nal concentrations also decrease rapidly.
A major percentage of chloride reabsorption in the proxi-
mal tubule occurs via paracellular diffusion. The concentra-
tion of chloride in Bowman’s capsule is, of course, essentially
the same as it is in plasma (about 110 mEq/L). Along the early
proximal tubule, the reabsorption of water causes the chloride
concentration in the tubular lumen to increase somewhat
above that in the peritubular capillaries (see Figure 44–3).
Then, as the fluid flows through the middle and late proximal
tubules, this concentration gradient, maintained by continued
water reabsorption, provides the driving force for paracellular
chloride reabsorption by diffusion.
There is also an important component of active chloride
transport from lumen to cell in the later proximal tubule. As
illustrated in Figure 44–2, it uses parallel Na–H and Cl–base
antiporters. Chloride is actively transported into the cell in
exchange for the downhill antiport (secretion) of small organic
 CHAPTER 44 Basic Renal Processes for Sodium, Chloride, and Water
1.2 Cl−
Na+
1.0
osmolarity
0.8
TF/P
Pi
0.6
0.4
− fall. In contrast, the concentration of chloride increases somewhat because
0.2 HCO3
Amino acids,
glucose, lactate
2 4 6 plasma. (Modified with permission from Rector FC. Sodium, bicarbonate, and chloride
Distance from Bowman's space (mm)
base anions. These include formate and oxalate, which are
continuously generated in the cell by dissociation of their
respective uncharged acids into a proton and the base. Simul-
taneously, the protons released within the cell by the dissocia-
tion of those acids are actively transported into the lumen by
the Na–H antiporters. In the lumen, the protons and organic
bases recombine to form the neutral acids, which then diffuse
across the apical membrane back into the cell, where the
entire process is repeated. Notice that both the protons and
the organic bases endlessly recycle, moving into the cells while
paired as a neutral molecule and then move out via separate
transporters after the proton dissociates. The overall achieve-
ment of the parallel Na–H and Cl–base antiporters is the
same as though the Cl and Na were simply cotransported into
the cell together. Importantly, the recycling of protons and
bases means that most of the protons are not acidifying the
lumen but are simply combining with base and moving back
into the cells. It should also be recognized that everything
ultimately depends on the basolateral membrane Na,K-
ATPases to establish the gradient for sodium that powers the
apical Na–H antiporter.
Regarding water reabsorption, the proximal tubule, as men-
tioned, has a very high permeability to water, allowing very
small differences in osmolality (less than 1 mOsm/L) to drive
the reabsorption of very large quantities of water, normally
about 65% of the filtered water. This osmolality difference is
created by the reabsorption of sodium and the various solutes
linked directly or indirectly with sodium (Table 44–4).
If the tight coupling between proximal sodium and water
reabsorption is disrupted, we have a phenomenon known as
osmotic diuresis. The term diuresis simply means increased
urine flow, and osmotic diuresis denotes the situation in which
the increased urine flow is due to an abnormally high amount
of any substance in the glomerular filtrate that is reabsorbed
441
FIGURE 44–3 Changes in tubular fluid composition along the
proximal convoluted tubule, expressed as the ratio of concentration in
the tubule relative to the plasma value. Values above 1.0 indicate that
relatively less of the substance than water has been reabsorbed, and
therefore its concentration increases. Values below 1.0 indicate that
relatively more of the substance than water has been reabsorbed. Inorganic
phosphate, bicarbonate, glucose, and lactate are preferentially reabsorbed
with sodium early in the proximal tubule, and their concentrations rapidly
chloride reabsorption lags behind sodium and, hence, water reabsorption
in the early proximal tubule. The concentration of sodium and the total
concentration of all solutes (osmolarity) remains nearly the same as in
absorption by the proximal tubule. Am J Physiol. 1983;244(5):F461–F471.)
incompletely or not at all by the proximal tubule (e.g., infused
mannitol, a monosaccharide that is not transported). As water
is reabsorbed in the proximal tubule, the concentration of any
unusual unreabsorbed solute rises, and its osmotic presence
retards the further reabsorption of water (here and downstream
as well). The failure of water to follow the sodium being
removed from the lumen means that the sodium concentration
in the proximal tubular lumen decreases slightly below that in
the interstitial fluid. This concentration difference, even though
small, drives a passive diffusion of sodium across the epithe-
lium (mostly the tight junctions) back into the lumen, that is,
sodium transport reaches the gradient limit we described in
Chapter 42. The result is that more than the usual amount of
TABLE 44–4 Summary of mechanisms by which
reabsorption of sodium drives reabsorption of other
substances in the proximal tubule.
Reabsorption of sodium
1. Creates transtubular osmolality difference, which favors
reabsorption of water by osmosis; in turn, water reabsorption
concentrates many luminal solutes (e.g., chloride and urea), thereby
favoring their reabsorption by diffusion
2. Achieves reabsorption of many organic nutrients, phosphate, and
sulfate by cotransport across the luminal membrane
3. Achieves secretion of hydrogen ion by countertransport across the
luminal membrane; these hydrogen ions are required for
reabsorption of bicarbonate (as described in Chapter 47)
4. Achieves reabsorption of chloride by indirect cotransport across the
luminal membrane (the parallel Na/H and Cl/base
countertransporters)
Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.
442 SECTION VII Renal Physiology
FIGURE 44–4 Major transport pathways for sodium and
chloride in thick ascending limb. The major transporter in the thick
ascending limb is the Na–K–2Cl symporter (NKCC), which is the target
for inhibition by loop diuretics such as furosemide and bumetanide.
In addition to NKCC, the cells contain potassium channels that recycle
potassium from the cell interior to the lumen and to the interstitium
(see Chapter 46). Besides transcellular routes, some sodium also
moves paracellularly in response to the lumen positive potential. The
apical membranes and tight junctions have a very low water
permeability, and water is not reabsorbed in this segment. Because
the cells reabsorb salt, but not water, the thick ascending limb is the
point in the nephron at which salt is separated from water. This
ultimately allows water excretion and salt excretion to be controlled
independently. (Modified with permission from Eaton DC, Pooler JP: Vander’s
Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical
Pub. Division, 2009.)
sodium is not reabsorbed as well as the unusual solute, and
both are passed on to the loop of Henle. Thus, osmotic diuret-
ics inhibit the reabsorption of both water and sodium (as well
as other ions). Osmotic diuresis can occur in persons with
uncontrolled diabetes mellitus; the filtered load of glucose
exceeds the tubular maximum (Tm) for this substance, and the
unreabsorbed glucose then acts as an osmotic diuretic.
HENLE’S LOOP
Henle’s loop reabsorbs both salt and water, but, taken as a
whole, more salt (about 25% of the filtered loads) than water
(10% of the filtered water). See Table 44–2. This is a key differ-
ence from the proximal tubule, which reabsorbs water and
sodium in essentially equal proportions.
Also as shown in Table 44–2, the reabsorption of salt and
reabsorption of water occur in different parts of the loop. The
descending limb reabsorbs water but not sodium or chloride.
In contrast, the ascending limbs (both thin and thick) reabsorb
sodium and chloride but little water. As a whole, the loop reab-
sorbs some water and more salt, leaving a dilute fluid in the
lumen. The differences between the two limbs reveal that the
cells lining the descending and ascending regions have differ-
ent permeability properties. The basolateral membranes of all
renal cells are quite permeable to water due to the presence of
aquaporins. As a result, the cytosolic osmolality is always
close to that of the surrounding interstitium. But the apical
membranes do not always contain aquaporins. The descend-
ing limbs contain aquaporins, so water is reabsorbed there,
driven by the increasing osmolality of the medullary intersti-
tium. The ascending limbs do not express aquaporins in the
apical membranes, and the tight junctions are not permeable
to water. Therefore, even though an osmotic gradient exists
between the lumen (dilute) and interstitium (concentrated),
water does not move down the gradient, and water flowing
into the ascending limb remains there and is passed on to the
distal tubule.
LUMEN
INTERSTITIUM
+
Na+ Na Na+
2CI– ATP
Na+
K+ K+
K+
K+
Cl–
K+
Cl–
H2O
What are the mechanisms of sodium and chloride reabsorp-
tion by the ascending limbs? These are mainly passive in the
thin ascending limb and active in the thick ascending limb.
Water reabsorption in the descending limb concentrates lumi-
nal sodium somewhat. Then when tubular fluid, now contain-
ing an increased sodium concentration, reaches the epithelium
of the thin ascending limb, this gradient drives reabsorption,
probably by the paracellular route. As tubular fluid then enters
the thick ascending limb, the transport properties of the epithe-
lium change again, and active processes become dominant. As
shown in Figure 44–4, the major apical entry step for the
sodium and chloride in this segment is via the Na–K–2Cl sym-
porter (NKCC2 isoform). (The Na–K–2Cl symporter requires
that equal amounts of potassium and sodium be transported, a
topic we will address in Chapter 46.) The Na–K–2Cl symporter
is the target for a major class of diuretics collectively known as
the loop diuretics, which include the drugs furosemide (Lasix)
and bumetanide. The apical membrane of this segment also
has a Na–H antiporter isoform, which, like the isoform in the
proximal tubule, provides another mechanism for sodium
movement into the cell.
In addition to the active transcellular reabsorption of
sodium, a large percentage (approaching 50%) of total sodium
reabsorption in this segment occurs by paracellular diffusion.
There is a high paracellular conductance for sodium in the
thick ascending limb, and the luminal potential in this seg-
ment is positive, which is a significant driving force for cat-
ions. (We will see in later chapters that this paracellular
pathway also allows substantial reabsorption of potassium
and calcium.) However, none of this would work without the
continuous operation of the Na,K-ATPase in the basolateral
membrane.
To summarize the most important features of the loop of
Henle, the descending limb reabsorbs water but not sodium
chloride, whereas the ascending limb reabsorbs sodium chlo-
ride but not water. The crucial events occur in the thick ascend-
ing limb. By reabsorbing salt but not water, this assures that
the net for the loop as a whole is reabsorption of more salt than
 CHAPTER 44 Basic Renal Processes for Sodium, Chloride, and Water
LUMEN INTERSTITIUM
ATP
Na+
K+
Na+
Na+ K+
Cl–
Cl–
H2O
FIGURE 44–5 Major transport pathways for sodium and
chloride in the distal convoluted tubule. The apical membrane
contains the Na–Cl symporter (NCC), which is the target for inhibition
by thiazide diuretics. There is also some sodium reabsorption via
apical sodium channels. The apical membranes and tight junctions
have a very low water permeability. (Modified with permission from
Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical
Books/McGraw-Hill, Medical Pub. Division, 2009.)
water. The ascending limb is called a diluting segment (it
dilutes the tubular fluid), and fluid leaving the loop to enter
the distal convoluted tubule is hypo-osmotic (more dilute)
compared with plasma.
DISTAL CONVOLUTED TUBULE
The distal tubule continues to reabsorb sodium and chlo-
ride, the major luminal entry step being via the Na–Cl sym-
porter (Figure 44–5). This transporter differs significantly
from the Na–K–2Cl symporter in the thick ascending limb
and is sensitive to different drugs. In particular, the Na–Cl
symporter is blocked by the thiazide diuretics. Sodium
channels also permit sodium entry in the distal convoluted
tubule. Like the ascending limb of the loop of Henle, the
distal tubule is not permeable to water, so that it further
dilutes the already somewhat dilute fluid entering it from
the thick ascending limb.
COLLECTING DUCT SYSTEM
In the collecting ducts, there is a division of labor among sev-
eral different cell types. Reabsorption of sodium and water is
associated with principal cells (so called because they make
up approximately 70% of the cells; Figure 44–6). Reabsorption
of chloride occurs partially via paracellular pathways, but
active reabsorption is also associated with another class of col-
lecting duct cells, the intercalated cells (see Figure 47–3).
The principal cells reabsorb sodium, the luminal entry step
being via epithelial sodium channels. Regulation of this entry
443
LUMEN INTERSTITIUM
ATP
Na+
Na+
K+
K+
H2O H2O
ADH stimulates
Cl– Cl–
FIGURE 44–6 Major transport pathways for sodium,
chloride, and water in principal cells of the cortical collecting
duct. Sodium reabsorption is via apical sodium channels. Activity of
these channels is controlled by the hormone aldosterone (see
Chapter 45). Chloride reabsorption is passive via the paracellular
pathway. Water reabsorption is via aquaporins, the activity of which
is controlled by the antidiuretic hormone (ADH). (Modified with
permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY:
Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)
step is enormously important in controlling sodium excretion,
and we will expand on this topic in Chapter 45.
Some sodium chloride reabsorption continues in the med-
ullary collecting ducts, probably via some form of epithelial
sodium channels. Although with modern diets containing
excess sodium there is usually a substantial amount of sodium
in the final urine, it is possible to reabsorb virtually all of the
remaining sodium if dietary access to sodium is limited.
Principal cells in the collecting ducts are also the crucial
players in reabsorbing water. As indicated earlier, there is
always a substantial amount of dilute fluid entering the collect-
ing duct system, which reabsorbs variable amounts of the water.
The water permeability of the principal cells in the collecting
duct system—both the cortical and medullary portions—is
subject to physiological control by circulating antidiuretic
hormone (ADH; see Figure 44–6). The inner medullary col-
lecting duct has at least a finite water permeability even in the
absence of ADH, but the outer medullary and cortical regions
have a vanishingly low water permeability without ADH.
Depending on levels of ADH, therefore, water permeability
for most of the collecting duct system can vary from very low
to very high. When water permeability is very low (absence of
ADH), the hypo-osmotic fluid entering the collecting duct
system from the distal convoluted tubule remains hypo-
osmotic as it flows along the ducts. When this fluid reaches the
medullary portion of the collecting ducts, there is now a huge
osmotic gradient favoring reabsorption, which occurs to some
extent. That is, although there is little cortical water reabsorp-
tion without ADH, there is still a finite medullary absorption
because of the enormous osmotic gradient. However, because
444 SECTION VII Renal Physiology
so much water is not reabsorbed in the cortex, most of the
water entering the medullary collecting duct flows on to the
ureter. The result is the excretion of a large volume of very
hypo-osmotic (dilute) urine, or water diuresis.
What happens when the collecting duct system’s water perme-
ability is very high (plentiful ADH)? As the hypo-osmotic fluid
entering the collecting duct system from the distal convoluted
tubule flows through the cortical collecting ducts, most of the
water is rapidly reabsorbed. This is because of the large differ-
ence in osmolality between the hypo-osmotic luminal fluid and
the isosmotic (285 mOsm/kg) interstitial fluid of the cortex. In
essence, the cortical collecting duct is reabsorbing the large vol-
ume of water that did not accompany solute reabsorption in the
ascending limbs of Henle’s loop and distal convoluted tubule. In
other words, the cortical collecting duct reverses the dilution car-
ried out by the diluting segments. Once the osmolality of the
luminal fluid approaches that of the cortical interstitial fluid, the
cortical collecting duct then behaves analogously to the proxi-
mal tubule, reabsorbing approximately equal proportions of sol-
ute (mainly sodium chloride) and water. The result is that the
tubular fluid, which leaves the cortical collecting duct to enter
the medullary collecting duct, is isosmotic with cortical plasma,
but its volume is greatly reduced compared with the amount
entering from the distal tubule.
In the medullary collecting duct, solute reabsorption con-
tinues, but in the presence of ADH water reabsorption is pro-
portionally even greater. This is because the ADH has signaled
much of the medullary collecting duct epithelium to have high
water permeability, and the medullary interstitium is hyperos-
motic relative to normal plasma (for reasons discussed later).
Therefore, the tubular fluid becomes more and more hyperos-
motic, and reduced in volume.
How does ADH convert epithelial water permeability from
very low to very high? An alternative name for ADH is argin-
ine vasopressin (because the hormone can constrict arterioles
and thus increase arterial blood pressure), but the major renal
effect of ADH is antidiuresis, that is, “against a high urine vol-
ume” (see Chapter 61). ADH acts in the collecting ducts on the
principal cells, the same cells that reabsorb sodium, to recruit
vesicles containing aquaporins into the luminal membrane. In
the absence of ADH, the aquaporins are withdrawn from the
apical membrane by endocytosis. (As stated earlier, the water
permeability of the basolateral membranes of renal epithelial
cells is always high because of the constitutive presence of
other aquaporin isoforms; thus, the permeability of the lumi-
nal membrane is rate limiting.)
URINARY CONCENTRATION: THE
MEDULLARY OSMOTIC GRADIENT
The production of hypo-osmotic urine is, we hope by now, an
understandable process: the tubules (particularly the thick
ascending limb of Henle’s loop) reabsorb relatively more solute
than water, and the dilute fluid that remains in the lumen is
excreted. The production of hyperosmotic urine is also
TABLE 44–5 Composition of medullary interstitial
fluid and urine during the formation of a concentrated
urine or a dilute urine.
Interstitial Fluid at Tip of Urine (mOsm/L)
Medulla (mOsm/L)
Concentrated urine
Urea = 650 Urea = 700
+
Na + Cl − = 750 a
Nonurea solutes = 700 (Na+, Cl−, K+,
urate, creatinine, etc.)
Dilute urine
Urea = 300 Urea = 30–60
Na+ + Cl− = 350a Nonurea solutes = 10–40 (Na+, Cl−,
K+, urate, creatinine, etc.)b
a
Some other ions (e.g., K+) contribute to a small degree to this osmolarity.
b
Depending on the sodium balance state, sodium in the urine can vary between
undetectable and the majority of the osmolytes.
Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.
straightforward in that reabsorption of water from the lumen
into a hyperosmotic interstitium concentrates that luminal
fluid, leaving concentrated urine to be excreted. The question
is: how do the kidneys generate a hyperosmotic medullary
interstitium? Not only is the medullary interstitium hyperos-
motic, but there is also a gradient of osmolality, increasing
from a nearly isosmotic value at the corticomedullary border
to a maximum of greater than 1,200 mOsm/kg at the papilla.
This peak value is not constant and changes depending on
conditions. It is highest during periods of water deprivation
and dehydration, when urinary excretion is lowest, and is
“washed out” to only about half of that during excess hydration
and when urinary excretion is high (see Table 44–5).
The main components of the system that develops the med-
ullary osmotic gradient are (1) the addition of sodium to the
medullary interstitium by the thick ascending limb; (2) a vas-
culature that minimizes removal of that sodium, due both to
the unusual arrangement of descending components in close
apposition to ascending components and to a low rate of blood
flow, and (3) the recycling of urea between the medullary col-
lecting ducts and the deep portions of the loops of Henle (see
Figure 43–3). Some aspects of the process are still uncertain.
However, the essential points are clear, and it is these essential
points on which we now focus.
Let us begin with a condition in which there is no gradient
and follow its establishment. Assume that both the plasma enter-
ing the medulla and the medullary interstitium have a normal
sodium concentration (140 mEq/L) and that the medullary
interstitium is isosmotic with normal plasma. The reabsorption
of sodium and chloride by the thick ascending limb in the outer
medulla is the first step. As sodium is deposited in the intersti-
tium, the interstitial sodium concentration begins to increase
above 140 mEq/L. This drives the diffusion of sodium into
neighboring blood vessels. For those portions of the thick
 CHAPTER 44 Basic Renal Processes for Sodium, Chloride, and Water
ascending limb in the cortex, the reabsorbed sodium simply
mixes with material reabsorbed by the nearby proximal convo-
luted tubules. Because the cortex contains abundant peritubular
capillaries and a high blood flow, the reabsorbed material imme-
diately moves into the vasculature and returns to the general
circulation. However, in the medulla, the vascular anatomy and
blood flow are quite different, and reabsorbed sodium that is
deposited in the outer medullary interstitium is not immediately
removed, that is, it accumulates. The degree of accumulation is a
function of the arrangement of the vasa recta, their permeability
properties, and the volume of blood flowing within them.
VASA RECTA
As described in Chapter 40, blood enters and leaves the outer
medulla through parallel bundles of descending and ascend-
ing vasa recta. These vessels are permeable to sodium, and
they initially take up most of the sodium that is being trans-
ported by the thick ascending limbs into the interstitium of the
outer medulla. The ascending vessels return that sodium to
the general circulation, but the descending vessels carry it
down into the inner medulla, where it diffuses out across the
endothelia of the vasa recta and the interbundle capillaries
that they feed, thereby increasing the sodium concentration
(and osmolality) throughout the medulla. It is here that the
anatomy of the vasculature becomes particularly important. If
inner medullary blood with its somewhat elevated sodium
concentration simply flowed into a venous drainage system,
very little additional increase in interstitial sodium concentra-
tion would occur. However, the interbundle capillaries drain
into ascending vasa recta that lie right next to descending vasa
recta. The walls of the ascending vasa recta are fenestrated,
allowing rapid and thorough equilibration of water and small
solutes between plasma and interstitium. As the total sodium
content of the medulla increases, blood in the ascending ves-
sels acquires an increasingly higher sodium concentration.
Meanwhile, blood entering the medulla has a normal sodium
concentration of about 140 mEq/L. Thus, there is a gradient of
concentration between ascending and nearby descending ves-
sels. Accordingly, some of the medullary sodium begins to
recirculate, diffusing out of ascending vessels (containing an
elevated sodium concentration) and reentering nearby
descending vessels (containing a normal sodium concentra-
tion). The process of crossing between ascending and descend-
ing vessels is called countercurrent exchange. Over time, the
content of sodium in the ascending vessels and medullary
interstitium increases until a steady state is reached in which
the amount of new sodium pumped into the outer medulla
from thick ascending limbs matches the amount of extra
sodium leaving in ascending vasa recta and returning to the
general circulation. At its peak, the concentration of sodium in
the inner medulla may reach 300 mEq/L, which is more than
double its value in the general circulation. Since sodium is
accompanied by an anion, mostly chloride, the contribution of
salt to the medullary osmolality is about 600 mOsm/kg.
445
What happens to water in the medulla during this time?
Although solute can accumulate without a major effect on
renal volume, the amount of water in the medullary intersti-
tium must remain relatively constant; otherwise, the medulla
would undergo significant swelling or shrinking. The endothe-
lial cells of descending vasa recta, although not as leaky as the
fenestrated endothelium of ascending vasa recta, contain
aquaporins, allowing water to be drawn from the plasma into
the increasingly hyperosmotic medullary interstitium in a
manner similar to water being drawn out of tubular elements.
This loss of water from descending vasa recta decreases the
plasma volume of blood penetrating deeper into the medulla
and raises its osmolality, thereby reducing the tendency to
dilute the inner medullary interstitium. Water leaving descend-
ing vessels moves by bulk flow into nearby ascending vasa
recta and is removed from the medulla; thus, there is no accu-
mulation of water. Just as there is countercurrent exchange of
solute between descending and ascending vessels, there is
countercurrent exchange of water. In descending vessels water
leaves and solute enters, while in ascending vessels water enters
and solute leaves (see Figures 44–7 and 40–1). Water and salt
reabsorption in the thin regions of Henle’s loops also influ-
ences the osmotic gradient. While their quantitative contribu-
tion is not known, it is surely less than that of the thick
ascending limbs and vasa recta.
The magnitude of blood flow in the vasa recta is a crucial vari-
able. If blood flow is relatively high, water from the isosmotic
plasma entering the medulla in descending vasa recta dilutes the
hyperosmotic interstitium (“washes it out”), which occurs to
some extent during a water diuresis. But medullary blood flow is
lowest in conditions where medullary osmolality is highest.
Therefore, the diluting effect of water diffusing out of descending
vasa recta during periods of minimal blood flow is not great.
UREA
There is one additional major player involved in the develop-
ment of the medullary osmotic gradient—urea. As indicated
above, the peak osmolality in the renal papilla reaches over
1,200 mOsm/kg. About half of this is accounted for by sodium
and chloride, and most of the rest (500–600 mOsm/kg) is
accounted for by urea. To develop such a high concentration
of urea (remember that the normal plasma concentration is
only about 5 mmol/L), there must be a process of recycling.
This involves the tubules as well as the vasa recta.
We described this recycling process in Chapter 43 and review
the key points here. Urea is freely filtered, and about half is
reabsorbed in the proximal tubule. Urea is secreted in the loop
of Henle (thin regions), driven by the high urea concentration
in the medullary interstitium, thus restoring the amount of
tubular urea back to the filtered load. From the end of the thin
limbs to the inner medullary collecting ducts, little urea trans-
port occurs. Because the vast majority of water is reabsorbed
prior to the inner medullary collecting ducts (by the cortical
and outer medullary collecting ducts), the luminal urea
446 SECTION VII Renal Physiology

FIGURE 44–7 Renal water handling in states A

of maximum antidiuresis and maximum diuresis. 110
Numbers to the right indicate interstitial osmolality;
numbers in the tubules indicate luminal osmolality.
The dashed line indicates the corticomedullary CORTEX
border. Arrows indicate sites of water movement. In 300 300
both antidiuresis and diuresis, most (65%) of the MEDULLA
filtered water is reabsorbed in the proximal tubule
and another 10% in the descending loop of Henle.
500
The greater relative reabsorption of solute versus Vasa
water by the loop as a whole and distal tubule recta
results in luminal fluid that is quite dilute (110
mOsm) as it enters the collecting ducts. During 900
antidiuresis (A), most of the remaining water is
reabsorbed in the cortical collecting ducts, 1200 1200
stimulated by the actions of ADH, with some
additional reabsorption in the medullary collecting
ducts. The equilibration of tubular fluid with the
high medullary osmolality results in final fluid that is Maximum antidiuresis
very hyperosmotic (1,200 mOsm). During diuresis
(B), no water reabsorption occurs in the cortical B
110
collecting duct, but some occurs in the inner
medullary collecting duct. Despite the medullary
water reabsorption, continued medullary solute
reabsorption reduces solute content relatively more CORTEX
110 300
than water content, and the final urine is very dilute
(70 mOsm). In the parallel vasa recta, there is MEDULLA
considerable exchange of both solute and water, so
that plasma osmolality and solute concentrations 350
Vasa
equilibrate with the surrounding interstitium. The
recta
ascending vasa recta ultimately remove all the
solute and water reabsorbed in the medulla.
400
Because there is always some net volume
reabsorption in the medulla, the vasa recta plasma
flow out of the medulla always exceeds the plasma 70 600
flow in. (Modified with permission from Eaton DC,
Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange
Medical Books/McGraw-Hill, Medical Pub. Division, 2009.) Maximum diuresis

concentration increases up to 50 times its plasma value (i.e.,
500 mmol/L or more). In the inner medullary collecting ducts,
this drives urea reabsorption via specialized ADH-sensitive
urea uniporters, increasing the medullary interstitial concen-
tration close to the same high value as in the tubular lumen.
The concentrated urea remaining in the collecting ducts, typi-
cally about half the filtered load, is excreted. The combination
of a high urea concentration, along with the high sodium and
chloride, brings the medullary osmolality to a value exceeding
1,200 mOsm/kg H2O. The importance of urea in contributing
to the medullary osmotic gradient is emphasized in the case of
low protein intake, which results in a greatly reduced meta-
bolic production of urea. In this condition, the ability of the
kidneys to produce highly concentrated urine is reduced.
To summarize the generation of the renal osmotic gradient:
salt (without water) is deposited in the interstitium of the outer
medulla by the thick ascending limbs. That salt enters descend-
ing vasa recta and is distributed to the inner medulla. It accumu-
lates in the medullary interstitium because a combination of low
blood flow and countercurrent exchange between ascending and
descending vasa recta minimizes removal. Adding to the osmo-
lality of the medulla is urea, which recycles from the inner med-
ullary collecting ducts to the thin limbs of the loop of Henle.
Urea also participates in countercurrent exchange between
ascending and descending vasa recta for the same reasons that
salt does. The magnitude of the osmotic gradient is variable,
being greatest during states of dehydration and lowest during a
water diuresis (see Figure 44–8). Key controlling factors are levels
of ADH and the magnitude of medullary blood flow.
Let us conclude by addressing a common student question:
under conditions of high ADH, why does not the water being
reabsorbed from the medullary collecting ducts dilute the med-
ullary interstitium and destroy the osmotic gradient? The
answer is 2-fold. First, with high ADH most of the total water
reabsorbed from the tubule occurs in the cortex, and there sim-
ply is not very much water left to be reabsorbed in the medulla.
Second, the thick ascending limb keeps adding solute to the
medulla. Proportionally more sodium is added from the thick
ascending limb than water is added from the inner medullary
collecting ducts.
 CHAPTER 44 Basic Renal Processes for Sodium, Chloride, and Water 447

A
100%

Volume of remaining filtrate

75%

50% No ADH

25%

Maximum ADH

Proximal tubule Loop of Henle Cortical Medullary

collecting duct collecting duct

B
1200
Maximum ADH
Osmolality (mOsmol/kg)

900

600

300

No ADH

Proximal tubule Loop of Henle Cortical Medullary

collecting duct collecting duct
FIGURE 44–8 Volume of remaining filtrate (A) and tubular osmolality (B) at different sites along the tubule in conditions of
maximum ADH and no ADH. Under all conditions the majority of the filtered volume is reabsorbed in the proximal tubule. Additional
reabsorption occurs in the thin limbs of the loop of Henle, the exact amount depending on ADH because the interstitial osmolality varies with
ADH. In the absence of ADH no further reabsorption occurs until the inner medulla, whereas with maximal ADH most of the remaining volume
is reabsorbed in the cortical collecting ducts. The osmolality of the final urine is strongly dependent on ADH, as is the maximum osmolality in
the loop of Henle because the peak medullary interstitial osmolality also varies with ADH.

CLINICAL CORRELATION
A 19-year-old male college freshman is convinced by his
roommates to seek evaluation after noting his amazing
amounts of water drinking and urination. He said that he
has always consumed lots of water, and thought there was
nothing wrong other than the inconvenience of urinating a
lot. He only urinates once per night, and does not feel spe-
cial urgency, although he does urinate many times during
the day and seeks cold water to drink, sometimes in prefer-
ence to food. At the university clinic, a physical exam reveals
nothing unusual. He reports no family history of diabetes
mellitus. While in high school, he had a severe bout of vom-
iting and diarrhea, diagnosed as viral gastroenteritis, in
which he lost over 10 lb of body weight and showed signs of
severe dehydration, but recovered without ill effects. Blood
tests show normal levels of glucose, urea (BUN), creatinine,
calcium, and osmolality. A urine sample, in which he was
able to void a volume greater than 1 L, reveals no glucose
but it does have an unusually low osmolality of 62 mOsm/
kg. At this point, he was sent to the university hospital for a
pyelogram, consisting of administering contrast media
intravenously and taking serial digital radiographs of the
kidneys and urinary tracts. The contrast medium appears in
the renal cortex almost immediately and is freely filtered. In
another 10 minutes, it makes its way to the renal papilla.
Examination of the student’s radiographs revealed normal
kidneys, but rather enlarged ureters and bladder. He was
448 SECTION VII Renal Physiology
kept in the hospital and put on water deprivation overnight,
during which time he urinated a considerable volume and
lost 5 lb of body weight. His water deprivation was main-
tained during the morning, and he continued to produce
urine. His blood pressure was normal while sitting, but it
decreased considerably when he was standing (orthostatic
hypotension). A urine sample taken at this time yielded an
osmolality of 279 mOsm/kg, and his plasma osmolality was
301 mOsm/kg.
His physicians strongly suspected this to be a case of
diabetes insipidus. The fact that water loss continued well
into a state of dehydration ruled out nonosmotic causes
(e.g., psychogenic polydipsia) as a cause of the excessive
urination. Accordingly, he was given an intravenous injec-
tion of aqueous arginine vasopressin (ADH). Serial urine
measurements showed that the urine osmolality increased
to a peak value of over 500 mOsm/kg, demonstrating that
the kidneys were able to respond well to the ADH. This is
a case of diabetes insipidus due to a failure of adequate
ADH secretion by the posterior pituitary gland. In this
case, the cause of the patient’s decrease in posterior pitu-
itary function could not be ascertained from his medical
history. For more on diabetes insipidus, see Chapter 61.
CHAPTER SUMMARY
■ The reabsorption of most of the filtered water, anions, and
osmotic content is linked to the active reabsorption of sodium.
■ In all conditions, the vast majority of the filtered volume is
reabsorbed iso-osmotically in the proximal tubule in a manner
that is entirely dependent on active sodium reabsorption.
■ The capacity to generate urine with a variable osmolality depends
on “separating salt from water” in the diluting segments.
■ Reabsorption of water remaining in the lumen beyond the loop
of Henle depends on hydration status, allowing the kidneys to
excrete either a high-volume dilute urine, a low-volume
concentrated urine, or anything in between.
■ Levels of ADH determine whether the hypo-osmotic fluid
leaving the diluting segments is excreted largely as is or
whether most of this fluid is subsequently reabsorbed.
■ The existence of the medullary osmotic gradient depends on
(1) transport of salt without water into the medullary intersti-
tium by the thick ascending limb, (2) recycling of urea, and
(3) low-volume countercurrent blood flow in the vasa recta.
STUDY QUESTIONS
1. Chloride reabsorption parallels sodium reabsorption
mainly because
A) chloride is almost always transported via a symporter
with sodium.
B) chloride is the most abundant negatively charged species
available to balance the reabsorption of the positive charge
on sodium.
C) chloride has a very high passive permeability.
D) chloride and sodium are both part of the sodium chloride
molecule and cannot be separated.
2. The obligatory water loss in the kidney
A) is another name for insensible loss of water.
B) occurs because there is always at least some excretion of
waste solutes.
C) occurs because there is an upper limit to how fast
aquaporins can reabsorb water.
D) is the amount of water that accompanies salt excretion.
3. Which region of the tubule secretes water?
A) the descending thin limb
B) the cortical collecting duct
C) the medullary collecting duct (when ADH is absent)
D) no region secretes water
4. If the thick ascending limb stopped reabsorbing sodium, then
the final urine would be
A) isosmotic with plasma in all conditions.
B) dilute, depending on ADH.
C) concentrated, depending on ADH.
D) dilute or concentrated, depending on ADH.
5. If a healthy young person drinks a large amount of water, which
of the following is unlikely to happen?
A) an increase in medullary blood flow
B) an increase in water permeability in the medullary
collecting ducts
C) a decrease in interstitial osmolality at the tip of the
renal papilla
D) a decrease in the urea concentration in the final urine.
6. A healthy young person drinks a large amount of water. Over
the next several hours, most of the water entering the
glomerular filtrate is
A) excreted.
B) reabsorbed in the cortical collecting duct.
C) reabsorbed in the proximal tubule.
D) reabsorbed in the loop of Henle.
 45
C H A P T E R

Regulation of Sodium
and Water Excretion
Douglas C. Eaton and John P. Pooler

O B J E C T I V E S

■ Describe the relationship between renin and angiotensin II.

■ Describe the detectors that regulate renin secretion.
■ Define pressure natriuresis and diuresis.
■ Define tubuloglomerular feedback, and describe the mechanism for
tubuloglomerular feedback and autoregulation of glomerular filtration rate.
■ List the major factors that regulate sodium excretion.
■ State the tissue origin of aldosterone, its renal sites of action, and its effect
on sodium reabsorption.
■ State the origin of atrial natriuretic peptides, the stimulus for their secretion,
and their effect on sodium reabsorption and glomerular filtration rate.
■ Describe the origin of antidiuretic hormone and the two major reflex controls
of its secretion.
■ Distinguish between the reflex changes that occur when an individual has
suffered iso-osmotic fluid loss because of diarrhea as opposed to a pure
water loss (i.e., solute water loss as opposed to pure water loss).
■ Diagram in flow-sheet form the pathways by which sodium and water
excretions are altered in response to sweating, diarrhea, hemorrhage,
high-salt diet, and low-salt diet.
■ Describe the control of thirst.

GOALS
The excretion of sodium and water is regulated by an array of
signals, some originating within the kidneys themselves (intra-
renal signals) and some from other regions of the body. The
regulatory processes are complex, and it is imperative to grasp
the goals of regulation so that individual mechanisms fit into a
logical framework. A key concept is that the kidneys work in
partnership with the cardiovascular system. Together they
ensure that (1) there is enough blood volume to fill the vascular
tree, (2) enough pressure to drive blood flow through periph-
eral tissues, and (3) the blood, and therefore the cells through-
out the body, has the proper osmolality. One way or another, all
the regulatory mechanisms that control sodium and water
excretion exist for the purpose of meeting these goals. There is
also an indirect, but related goal. Variations in renal blood flow
(RBF) and glomerular filtration rate (GFR) are major means
of regulating sodium excretion. However, the kidneys cannot
allow blood flow and filtration to reach such extreme levels that
they compromise the metabolic health of the kidneys or inter-
fere with the excretion of substances other than sodium. Thus,
another goal is to limit the sodium-related changes in RBF and
GFR that might otherwise reach deleterious levels.
SODIUM EXCRETION: THE
CARDIOVASCULAR CONNECTION
The kidneys play a direct role in maintaining cardiac output,
first by ensuring that there is sufficient blood volume to allow
the heart to fill between beats, and second by contributing to

449

Ch45_449-462.indd 449 11/26/10 10:33:53 AM

450 SECTION VII Renal Physiology

the plasma and tissue interstitial space. Thus, maintenance of

Direct renal
influences
Blood cell Total peripheral
ECF volume
production resistance
Blood volume
FIGURE 45–1 Influence of the kidneys on the cardiovascular
system. The kidneys affect blood volume via their production of
erythropoietin, which stimulates red blood cell production, and via
their control of salt and water excretion. They also influence total
peripheral resistance via the actions on angiotensin II (see text for
details).
the control of total peripheral resistance (see Figure 45–1). Let
us examine the renal involvement in these cardiovascular
issues, with blood volume first.
Blood is composed primarily of red blood cells (about 45%)
and blood plasma (about 55%). The kidneys are crucial for
both parts—they secrete the hormone erythropoietin, which
stimulates production of red blood cells, and they regulate
the extracellular fluid (ECF) volume, of which blood plasma
is a significant part. Although not exact, there is an approxi-
mate proportionality between blood volume and total ECF
volume. Blood volume tends to increase and decrease as ECF
volume increases and decreases due to shifts of fluid between
blood volume is largely a matter of maintaining ECF volume.
It is obvious why water is crucial for ECF volume, but why is
sodium so important? The answer stems from two facts. First
ECF osmolality is tightly regulated, and second the osmotic
content of the ECF depends critically on its sodium content.
We can approximate ECF osmolality as follows:
ECF solute content
ECF osmolality = ______________ (1)
ECF volume
By rearrangement the above expression becomes:
ECF solute content
ECF volume = ______________ (2)
ECF osmolality
Furthermore, since almost all of the ECF solute is accounted
for by sodium and an equivalent number of anions (mostly
chloride and bicarbonate), the amount of ECF solute is approx-
imately twice the sodium content. We can write the previous
expression as follows:
2×ECF sodium content
ECF volume = ________________ (3)
ECF osmolality
Therefore, in the face of tightly controlled ECF osmolality,
ECF volume varies directly with sodium content.
This raises the following question: how do the kidneys know
how much sodium is present in the ECF? There is no mecha-
nism for the body to assay sodium content per se. Instead the
detection of sodium content is indirect, based mainly on vas-
cular pressures. That is, variations in vascular pressures are
interpreted by the body as variations in sodium content.
Vascular pressures are assessed by baroreceptors—cells
that deform in response to changes in local intravascular
pressure. Three sets of baroreceptors are important for con-
trolling sodium excretion (see Figure 45–2). Two have already
been described in Chapter 29. These are (1) the arterial

Total peripheral resistance

Brainstem
Arterial Cardiac performance
vasomotor
baroreceptors Sympathetic drive to kidney
center
Venous compliance

Brainstem Venous compliance

vasomotor Sympathetic drive to kidney
center Total peripheral resistance
Cardiopulmonary
Cardiac performance
baroreceptors
Hypothalamus ADH

Intrarenal Renin-angiotensin system

baroreceptors GFR, salt and water
reabsorption

FIGURE 45–2 Baroreceptors and the major processes they influence. Arterial baroreceptors sense pressures in the aorta and carotid
arteries and send afferent information to the brainstem vasomotor center, which then regulates cardiovascular and renal processes via
autonomic efferents. Cardiopulmonary baroreceptors sense pressure in the cardiac atria and pulmonary arteries, thereby being responsive to the
filling of the vascular tree. They send afferent information in parallel with the arterial baroreceptors. While there is overlap between the
influences of the two sets of baroreceptors, the cardiopulmonary baroreceptors have a particularly important influence on the hypothalamus,
which regulates secretion of ADH. The intrarenal baroreceptors have a major role in the renin–angiotensin system (see text for details). (Modified
with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)
 CHAPTER 45 Regulation of Sodium and Water Excretion
baroreceptors, nerve cells that mediate the classic barorecep-
tor reflex, and (2) the cardiopulmonary baroreceptors that are
also nerve cells and work in parallel with the arterial barore-
ceptors. The third set of baroreceptors consists of intrarenal
baroreceptors, which are not nerve cells. We will describe
their operation shortly, but first we briefly summarize the
neural baroreceptors as a review.
The medullary cardiovascular centers stimulate vascular
tone (vasoconstriction) throughout the body via the sympa-
thetic nervous system. In the arterioles of the peripheral vas-
culature this sympathetic tone maintains total peripheral
resistance, and in the peripheral venous system it maintains
central venous pressure via its influence on the compliance of
large veins. Arterial baroreceptors exert a tonic inhibition of
the medullary cardiovascular centers, resulting in a brake on
sympathetic drive. An increase in arterial pressure causes
greater firing of the baroreceptors, more inhibition, and there-
fore even less sympathetic drive to the periphery, while a
decrease in arterial pressure reduces firing in the barorecep-
tors and less inhibition, allowing more sympathetic drive. The
resulting changes in vascular tone alter total peripheral resis-
tance and help stabilize arterial pressure. The cardiopulmo-
nary baroreceptors act in the same way, but respond not to
arterial pressure, but rather to pressures in the cardiac atria
and pulmonary vessels. The medullary cardiovascular centers
also send both sympathetic stimulatory and parasympathetic
inhibitory signals to the heart in response to variations in
baroreceptor input.
The kidneys, being part of the peripheral vasculature,
respond to changes in sympathetic drive and contribute to
changes in total peripheral resistance. However, as we will
describe later, changes in sodium excretion in response to
sympathetic drive are even more important than the renal
contribution to total peripheral resistance.
RENAL CONTROL OF
VASCULAR RESISTANCE
If deviations in blood pressure are sustained, the kidneys are
capable of strongly reinforcing the effects of the vasomotor
centers on vascular resistance. How does this work? The major
detectors involved in the kidney’s ability to regulate vascular
resistance are the previously described neural baroreceptors,
and the intrarenal baroreceptors. The intrarenal baroreceptors
sense renal afferent arteriolar pressure. Anatomically, these
structures are not nerve cells and do not send signals to the
brainstem vasomotor center, but rather are specializations of
the cells of the afferent arteriole: granular cells (also called
juxtaglomerular cells) that form part of the juxtaglomerular
apparatus described in Chapter 40. They act entirely within
the kidney. Although granular cells acting as intrarenal barore-
ceptors do not send signals centrally, neural signals originat-
ing in the vasomotor centers (generated in response to neural
baroreceptors) reach the granular cells via the renal sympa-
451
thetic nerve. Thus, the activity of the granular cells is affected
both by direct sensing of pressure in the renal arterioles and by
pressures sensed by neural baroreceptors elsewhere in the
body
In response to changes in pressures sensed by baroreceptors,
a number of renal events are set in motion that have powerful
effects on total peripheral resistance, and, as we will see later,
on sodium excretion. The critical events are signaling path-
ways known as renin–angiotensin systems (RAS).
RENIN–ANGIOTENSIN SYSTEMS
An important hormone in the control of sodium excretion
and blood pressure is angiotensin II. It is a potent vasocon-
strictor, and also a mediator of multiple actions in the kidneys
that affect sodium excretion. Thus, it affects blood pressure
directly as a vasoconstrictor and indirectly via regulation of
renal sodium excretion and therefore blood volume.
There are many local RAS systems in individual tissues,
including the kidneys, brain, and the heart. There is also a
global or systemic RAS. All RAS systems, whether global or
local, consist of a large protein substrate called angiotensino-
gen, several enzymes, and several products. The key product is
angiotensin II. When angiotensin II binds to cell surface recep-
tors, it initiates actions that affect blood pressure and excretion
of sodium. The first key enzyme in all RAS systems is renin
(pronounced REE-nin). It acts upon angiotensinogen to pro-
duce a small (10-amino acid) product called angiotensin I.
Angiotensin I is acted upon by another enzyme, angiotensin-
converting enzyme (ACE), to produce the highly active eight-
amino acid peptide angiotensin II. In the global RAS system,
the source of angiotensinogen circulating in the blood is the
liver. The source of circulating renin is the granule cells in the
kidney. Renin is secreted both into the interstitium of the kid-
ney and into the lumen of the afferent arterioles, where it acts
on circulating angiotensinogen to produce circulating angio-
tensin I. ACE, which is expressed on the luminal surface of
endothelial cells in many parts of the vasculature, then con-
verts angiotensin I to angiotensin II (see Figure 45–3).
The major source of angiotensin II that affects the kidneys is
produced by a local RAS system within the kidneys them-
selves. Thus, the kidneys are regulated by both the global RAS
system and a local RAS system.
The circulating level of angiotensinogen in the global RAS
system is normally high and is not rate limiting. Furthermore,
ACE activity usually converts most of the angiotensin I into
angiotensin II. Therefore, the major controller of angiotensin II
production is the amount of angiotensin I produced by the
action of renin. Consequently, understanding angiotensin II
production requires an understanding of the regulation of renin
secretion. Two primary regulators of renin secretion have been
described: the first are the neural baroreceptors, which influ-
ence the activity of renal sympathetic nerves that stimulate
granular cell production of renin and vasoconstriction at the
same time. This occurs via a β1-adrenergic receptor–protein
452 SECTION VII Renal Physiology

Stimuli to renin

Liver

Kidney
Angiotensinogen
(453 aa)

Renin (enzyme)

Angiotensin I
(10 aa)

Angiotensin I
Angiotensin-converting Angiotensin-converting
enzyme enzyme
(endothelium) (endothelium)
Angiotensin II

Angiotensin II
(8 aa)

Adrenal
Cardiovascular cortex
system Aldosterone

Kidney

Salt and H2O

FIGURE 45–3 Major components of the global RAS. Vasoconstriction
retention
Angiotensin II acts on the vascular system as a vasoconstrictor
and stimulates adrenal production of aldosterone. It also acts
within the kidneys to promote sodium reabsorption (although
the major source of renal angiotensin II is the intrarenal RAS
system). (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Blood pressure
Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

kinase A-dependent process. The second regulators of renin
secretion are the intrarenal baroreceptors, that is, the very same
granular cells that respond to adrenergic stimulation also
deform in response to changes in afferent arteriolar pressure;
when the pressure decreases, renin production increases. Thus,
granular cells act as both detectors (of renal arteriolar pressure)
and signal generators (releasing renin) in response to changes
in pressure and sympathetic activity. The signals from the vaso-
motor system to the renin-producing granular cells ensure that
there is tight coordination between the rapid activity of the sys-
temic baroreceptor reflex and the slower-acting RAS. However,
the intrarenal pressure detector can function in the absence of
renal innervation (e.g., after a renal transplantation).
There is also a third detector mechanism that regulates renin
release. It is another component of the juxtaglomerular appa-
ratus (Figure 45–4) that monitors the amount of tubular
sodium chloride directly bathing the macula densa cells. This
amount of sodium chloride depends on both the rate of filtra-
tion (GFR) and the rate of sodium reabsorption in all the
nephron elements preceding the macula densa. When sodium
chloride delivery to the apical surface of macula densa cells
increases, renin production decreases, that is, high tubular
sodium loads inhibit renin production. The utility of this load
detector control of renin secretion is that in situations in which
the body contains excess sodium and is excreting sodium rap-
idly, it is advantageous not to produce very high quantities of
angiotensin II.
In review, three separate mechanisms regulate renin secre-
tion (neural signals, afferent arteriolar pressure, and NaCl at
the macula densa). The multiple controls reflect the importance
 CHAPTER 45 Regulation of Sodium and Water Excretion 453

Mesangial
cells

Glo
1. Renal sympathetic nerve
er

m
activity stimulates renin ulu
secretion from granular cells. s FIGURE 45–4 Control of renin secretion.
Three primary mechanisms regulate renin
secretion. First, renal sympathetic nerve activity
nt activates β1-adrenergic receptors on granular
ere
Aff riole cells of the afferent arteriole to stimulate renin
2. Changes in systemic e
art

Ef rter
secretion. Second, the granular cells also act as

fe iol
a
blood pressure deform
nin

re e
intrarenal baroreceptors, responding to changes

nt
membrances of granular cells Re R
en
to stimulate release of renin. in in pressure within the afferent arteriole, which,
Granular except in cases of renal artery stenosis, is a
cells reflection of changes in arterial blood pressure.
Deformation of the granular cells alters renin
Chemical transmitters secretion: when pressure falls, renin production
increases. Third, macula densa cells in the thick
ascending limb sense the delivery of tubular
sodium chloride, leading to the release of
Macula d
en chemical transmitters that alter renin secretion
sa
from the granular cells: when sodium chloride
3. Osmotic stretch in response to
changes in NaCI delivery deform
delivery increases, renin production decreases.
membranes to stimulate release of (Modified with permission from Eaton DC, Pooler JP: Vander’s
chemical messengers that reduce Renal Physiology, 7th ed. New York, NY: Lange Medical
renin secretion. Books/McGraw-Hill, Medical Pub. Division, 2009.)

of the RAS system and angiotensin II, in particular, in cardio-
vascular control. A significant action of circulating angiotensin
II produced by the global RAS system is general arteriolar
vasoconstriction. This vasoconstriction acts in parallel with
sympathetically mediated neural signals to increase total
peripheral resistance, thereby increasing blood pressure. The
importance of this system makes the RAS a natural target for
pharmacological intervention to reduce high blood pressure.
A number of blood pressure–lowering pharmacological agents
are aimed at components of the RAS systems, including ACE
inhibitors and angiotensin II receptor blockers (ARBs).
CONTROL OF SODIUM
EXCRETION
GLOMERULAR FILTRATION RATE
Many factors influence sodium excretion. One simple principle
to remember amid the complexities is that the amount of sodium
excreted is the difference between the filtered load and the
amount reabsorbed. Therefore, a major control over sodium
excretion is regulation of the filtered load via regulation of GFR.
As detailed in Chapter 40, GFR is a function of afferent arte-
riolar pressure (reflecting systemic arterial pressure) and the
resistances of the afferent and efferent arterioles. Changes in
resistance are produced by changes in renal sympathetic nerve
activity and levels of angiotensin II. In the face of a decrease in
blood pressure there is a decrease in GFR directly, and an
additional decrease due to increased renal sympathetic nerve
activity that is part of the neural baroreceptor reflex. These
actions all decrease sodium excretion. If the low pressure per-
sists, large amounts of renin are released and the subsequent
actions of angiotensin II reinforce these actions. All of this
makes logical sense: in the face of low arterial pressure, the
kidneys conserve sodium. On the other hand, if the sodium
content of the body increases significantly and plasma volume
is increased, or if there is an inappropriate increase in arterial
pressure, sympathetic vasoconstrictive activity is reduced,
RBF and GFR increase, and sodium excretion increases.
The filtered load of sodium is always enormous, and it is
imperative that the kidneys reabsorb the vast majority of it
under all conditions. Because even a small fractional change in
reabsorption results in a large change in the absolute amount
excreted, precise control over reabsorption is an essential
aspect of maintaining sodium balance. While GFR is an
important variable, most controls focus on reabsorption. As
with many other aspects of renal function, certain details of
this control system are still not understood. Thus, we empha-
size again that the most important goal of regulating sodium
balance, even if we do not know all of the mechanistic details,
is to regulate ECF volume.
ECF VOLUME
Dietary sodium loads always expand the ECF volume. Under
most circumstances, sodium loads are accompanied by water
loads, as when one eats pizza and beverage, thus accounting
454 SECTION VII Renal Physiology

for the increase in volume. But even if the load is the unusual
case of salt without water, the ECF still expands because the
added osmoles in the ECF increase its osmolality and draw
water from the intracellular space (see Figure 44–1). The kid-
neys respond to sodium loads by decreasing sodium reabsorp-
tion, thus allowing more sodium to be excreted. Much of the
decrease in reabsorption occurs as a result of decreased levels
of angiotensin II, via a mechanism described in the next sec-
tion. At least some of the signaling is via cardiopulmonary
baroreceptors that inhibit the medullary vasomotor centers
and lead to less sympathetic drive, which in turn leads to less
production of angiotensin II. In response, the kidneys permit
a large amount of sodium to be excreted. A pure water load,
which also expands the ECF volume, does not lead to increased
sodium excretion. This is partly because pure water loads are
excreted much more rapidly than salt loads and partly because
pure water loads simultaneously reduce plasma osmolality.
A major decrease in ECF volume, such as occurs with pro-
longed vomiting and diarrhea or a major hemorrhage, always
involves loss of sodium. The low volume sensed by cardiopul-
monary baroreceptors leads to strong sympathetic stimulation
of the kidneys, lower RBF, lower GFR, activation of the RAS,
and stimulation of tubular sodium reabsorption. These actions
reduce sodium excretion to low levels, thereby helping pre-
serve ECF volume. Figure 45–5 summarizes the multiple
responses to low ECF volume, of which reduction in sodium
excretion is a significant part.
ANGIOTENSIN II
As important as angiotensin II is to vascular resistance, it plays
an even more important role in regulating sodium reabsorp-
tion in the kidneys. It has direct tubular actions and it stimu-
lates the secretion of the hormone aldosterone from the
adrenal cortex, another major player in the connection
between sodium excretion and the cardiovascular system
(see Figure 45–3 and Chapter 65). Finally, angiotensin II acts
in a negative feedback manner to inhibit renin production by
acting directly on granular cells.
Angiotensin II affects blood pressure by altering peripheral
vascular resistance, but within the kidneys, angiotensin II
exerts significant sodium-retaining actions that begin by bind-
ing to G protein–coupled receptors and activating intracellu-
lar signaling cascades: (1) it constricts renal arterioles (as it
does arterioles elsewhere), thereby reducing RBF and GFR; (2)
it constricts glomerular mesangial cells, also reducing GFR;
and (3) it stimulates sodium reabsorption in the proximal
tubule. All of these actions reduce sodium excretion. The
number of functioning Na–H exchangers in the apical mem-
brane of proximal tubule cells is strongly influenced by angio-
tensin II. These proteins can shuttle back and forth between
locations where they are functioning and where they are inac-
tive. When angiotensin II is present, the Na–H exchangers
move to locations in the apical membrane where they trans-
port ions, thereby increasing the reabsorption of sodium.

Controlled
– LOW EFFECTIVE variable
CIRCULATING VOLUME

JUXTAGLOMERULAR LOW PRESSURE HIGH PRESSURE Sensors

APPARATUS BARORECEPTORS BARORECEPTORS

Renin

Mediators
RENIN-ANGIOTENSIN- ADH SYMPATHETIC NERVOUS
ALDOSTERONE AXIS SYSTEM

+ + + + +
Effectors
RENAL SODIUM
+ STARLING + VASOCONSTRICTION CARDIAC EXCITATION
& WATER
FORCES RETENTION
+ +

+ MEAN ARTERIAL
BLOOD PRESSURE

FIGURE 45–5 Responses to low vascular volume. Because adequate vascular volume is essential for the long-term maintenance of
arterial pressure, loss of volume, as occurs in prolonged diarrhea, vomiting, or hemorrhage, invokes multiple corrective responses. Following a
rapidly acting stimulation of the heart and peripheral resistance, the kidneys are stimulated to reduce excretion of sodium and water, thereby
preserving existing volume. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)
 CHAPTER 45 Regulation of Sodium and Water Excretion
Conversely, when the levels of angiotensin II decrease, the
Na–H exchangers are withdrawn to sites where they are inac-
tive, along with a concomitant reduction in activity of the
basolateral Na,K-ATPase, resulting in much less sodium reab-
sorption. Thus, variation in levels of angiotensin II is a very
powerful bidirectional response system. When the levels of
angiotensin II are high, the kidneys filter less sodium and
reabsorb more, thereby greatly reducing the amount excreted.
In contrast, when there is little angiotensin II, large amounts of
sodium remain in the tubule and are excreted.
PRESSURE NATRIURESIS
AND DIURESIS
Just as ECF volume exerts control over sodium excretion, so
does arterial pressure. Increased pressure in the renal artery
causes the kidneys to increase their excretion of sodium. This
phenomenon has been given the name pressure natriuresis
(and because natriuresis tends to increase water excretion, it
can be properly called pressure natriuresis and diuresis). It is
an entirely intrarenal phenomenon, that is, it is not activated
by external signals (although, as described later, it can be
severely attenuated, or even prevented by external signals).
Pressure natriuresis and diuresis serves as a backup system that
comes into play if fast-acting neural reflex systems of regulat-
ing blood pressure fail to completely correct large increases.
The mechanism of pressure natriuresis is a fascinating inter-
action between renal hemodynamics and intricate signaling
cascades. It begins when higher renal artery pressure drives
higher blood flow in the medulla. The medulla has relatively
poor autoregulation (compared with the highly effective auto-
regulation in the cortex); accordingly medullary blood flow
tends to vary in closer relation to renal artery pressure. The
higher medullary blood flow when pressure is high leads to
increased interstitial pressure that is transmitted throughout
the kidney. In turn, the higher interstitial pressure activates
intrarenal signals (arachidonic acid metabolites), which com-
mand the proximal tubule cells to reduce their transport capac-
ity. They do this by withdrawing Na–H antiporters (similar to
what happens when angiotensin II falls) and reducing Na,K-
ATPase activity. Together these events reduce sodium reab-
sorption and increase excretion. Higher interstitial pressure
may also increase backleak from the interstitium into later
portions of the tubule, further reducing reabsorption. If the
increased pressure is maintained, the RAS system is suppressed
and the production of angiotensin II is lowered, which aug-
ments and sustains the withdrawal of Na–H antiporters.
Although pressure natriuresis is an intrarenal process, it can
be overridden by external signals. When the ECF volume is
normal or high and pressure in the renal artery increases, pres-
sure natriuresis and diuresis are very effective in increasing
excretion of sodium and water and reducing blood volume.
On the other hand, if ECF volume is low and renal artery pres-
sure increases, there is much less salt and water loss. In effect,
it is more important to prevent further loss of volume than it is
455
to correct the elevated arterial pressure. Another example of
override occurs during exercise. Arterial pressure increases,
but sodium excretion decreases.
An implicit assumption about all the processes that control
sodium excretion is that there are parallel movements of water,
and therefore volume. This is indeed true, and maintaining
ECF volume is, as we have said, the most important reason for
regulating sodium excretion. While most of the time it is
appropriate that water accompany the movement of sodium,
it is not always true (because there are occasions when the
inputs of salt and water are not in parallel). Therefore, the kid-
neys possess ways of independently controlling water and
sodium excretion. Such independent controls are exerted in
regions of the nephron beyond both the proximal tubule and
loop of Henle, namely, in the collecting tubules and ducts. As
described in the next section, the chief player with respect to
independent control of sodium excretion is the hormone
aldosterone.
LONG-TERM CONTROL:
ALDOSTERONE REGULATION
OF SODIUM BALANCE
Aldosterone is a major stimulator of sodium reabsorption in
the distal nephron; that is, regions of the tubule beyond the
proximal tubule and loop of Henle. Aldosterone-stimulated
sodium retention is an effector system that is vital in correct-
ing prolonged reductions in body sodium, blood pressure, and
volume. The most important physiological factor controlling
secretion of aldosterone is the circulating level of angiotensin
II, which stimulates the adrenal cortex to produce aldosterone.
This targets the distal nephron to increase sodium reabsorp-
tion and thus increase total body sodium and blood volume to
produce a long-term correction to total body sodium content
and mean blood pressure.
Aldosterone stimulates sodium reabsorption mainly in the
cortical connecting tubule and cortical collecting duct, spe-
cifically by the principal cells. An action on this late portion of
the nephron is what one would expect for fine-tuning the out-
put of sodium, because more than 90% of the filtered sodium
has already been reabsorbed by the time the filtrate reaches the
collecting duct system.
The percentage of sodium reabsorption dependent on the
influence of aldosterone is approximately 2% of the filtered
load. Thus, all other factors remaining constant, in the com-
plete absence of aldosterone, a person would excrete 2% of the
filtered sodium, whereas in the presence of high plasma con-
centrations of aldosterone, virtually no sodium would be
excreted. Two percent of the filtered sodium may seem trivial
but is actually a significant amount because a large quantity of
sodium is filtered:
Total filtered Na per day = GFR × PNa =
(4)
180L per day × 145 mmol/L = 26,100 mmol per day
456 SECTION VII Renal Physiology
Thus, aldosterone controls the reabsorption of 0.02 × 26,100
mmol per day = 522 mmol per day. In terms of sodium chlo-
ride, the form in which most sodium is ingested, this amounts
to the control of approximately 30 g NaCl per day, an amount
considerably more than the average person consumes. There-
fore, by control of the plasma concentration of aldosterone
between minimal and maximal, the excretion of sodium can
be finely adjusted to the intake so that total body sodium
remains constant. We should emphasize that aldosterone
exerts control over sodium, but not water. While changes
in water excretion may accompany aldosterone-mediated
changes in sodium excretion, this is not always the case.
Aldosterone also stimulates sodium transport by other epi-
thelia in the body, namely, sweat and salivary ducts and the
intestine. The net effect is the same as that exerted on the kid-
ney: movement of sodium from lumen to blood. Thus, aldos-
terone is an all-purpose stimulator of sodium retention.
In the kidney, aldosterone acts like many other steroid hor-
mones to increase the genetic expression of key proteins
(see Chapter 65). The effect of these proteins is to increase the
activity or number of apical membrane sodium channels and
basolateral membrane Na,K-ATPase pumps to promote
increased reabsorption of sodium (Figure 45–6).
Angiotensin II produced by the global RAS system is the
main stimulator of aldosterone secretion, although there are
others, including elevated plasma potassium concentration, as
described in Chapter 46 in the context of the renal handling of
potassium. The atrial natriuretic factors (discussed later)
inhibit aldosterone secretion. Since levels of angiotensin II are
LUMEN INTERSTITIUM
Inactive 11ß-HSD Glucocorticoids
products
receptor Aldosterone
transcription
protein synthesis
ATP
Na+
Na+ K+
FIGURE 45–6 Mechanism of aldosterone action. Aldosterone
enters principal cells and interacts with cytosolic aldosterone
receptors. The aldosterone-bound receptors interact with nuclear
DNA to promote gene expression. The aldosterone-induced gene
products activate sodium channels in the apical membrane and
sodium pumps in the basolateral membrane, causing increased
sodium reabsorption. Glucocorticoids such as cortisol are also capable
of binding to the aldosterone receptor. However, they are inactivated
by 11β-hydroxysteroid dehydrogenase (11β-HSD). (Modified with
permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY:
Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)
controlled by renin, this emphasizes once again the impor-
tance of the global RAS system. Both renin and aldosterone
have relatively short plasma half-lives (~15 minutes), while the
half life of angiotensin II is very short (<1 minute). Therefore,
prolonged stimulation by aldosterone requires the continuous
stimulation of renin secretion. Figure 45–7 shows how
decreased plasma volume, via the RAS–aldosterone system,
leads to decreased volume excretion.
AUTOREGULATION REVISITED
The control of sodium excretion is mediated in part by changes
in RBF and GFR. However, if changes in these processes are
too large, there are negative consequences. In essence, the
body cannot allow controls of sodium excretion to “take over”
the kidneys to either the detriment of the metabolic health of
the kidneys or the excretion of other substances. Substantial
reductions in RBF severely compromise already oxygen-poor
regions of the kidney such as the medulla. Substantial increases
in glomerular capillary pressures are likely to damage the
glomeruli. In addition, the ability of the kidneys to regulate the
excretion of water and many substances other than sodium
depends on keeping tubular flow (i.e., GFR) within a certain
limited range. These goals are met by several processes that
collectively result in autoregulation of both RBF and GFR
(see Figure 40–7). While these processes do not exist, strictly
speaking, for the purpose of regulating sodium excretion, they
nevertheless do affect it.
Autoregulation involves the myogenic response described
in Chapter 40 and a rather complicated intrarenal signaling
system called tubuloglomerular feedback. This feedback
(from the tubule to the glomerulus) is associated with the
macula densa sodium chloride load detector (see Figure 45–4).
Earlier in this chapter, we described the actions of the macula
densa in the context of control over renin secretion, where we
said that in conditions when GFR is very high and therefore
filtering a large amount of sodium, it inhibits renin release.
And, as detailed below, the macula densa also reduces GFR
and RBF.
The macula densa cells at the end of the thick ascending
limb have Na–K–2Cl symporters that avidly take up Na, Cl,
and K when GFR, and hence, NaCl delivery is high. Sodium
also enters the macula densa cells via a Na–H antiporter. Since
the action of this antiporter causes the cells to lose a hydrogen
ion for every sodium ion entering, this increases intracellular
pH. A combination of cellular volume change, increased intra-
cellular chloride, and higher intracellular pH initiates intracel-
lular signaling processes that lead to the release of ATP from
the basolateral surface of the cells in close proximity to the
glomerular mesangial cells (see Figure 39–6). This ATP stimu-
lates purinergic P2 receptors on the mesangial cells and affer-
ent arteriolar smooth muscle cells. P2 receptor stimulation
increases calcium in these cells and promotes contraction.
Contraction of mesangial cells decreases the effective filtration
area, which decreases GFR. Contraction of the afferent
 CHAPTER 45 Regulation of Sodium and Water Excretion 457

Plasma volume

Activity of renal Arterial GFR, which causes

sympathetic nerves pressure flow to macula densa

Direct
effect
of less NaCl delivery
stretch to macula densa

Renal juxtaglomerular cells

Renin secretion

Plasma renin

Plasma angiotensin II

Adrenal cortex
Aldosterone secretion

Plasma aldosterone

FIGURE 45–7 Pathways by which low plasma volume Cortical collecting ducts
Sodium and H2O reabsorption
leads to increased aldosterone secretion and subsequent
reduction in salt and water excretion. (Reproduced with
permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology,
Sodium and H2O excretion
11th ed. McGraw-Hill, 2008.)

arteriolar smooth muscle cells increases afferent resistance

and decreases RBF and GFR. In addition, it is the increased
calcium in the afferent arteriolar cells that reduces renin secre-
tion. The ATP may also be metabolized to adenosine, which
can stimulate adenosine receptors that produce the same result
as the P2 receptors (in contrast to the vasodilatory actions of
adenosine in most other tissues). In addition to purinergic
agonists that mediate tubuloglomerular feedback, there are
other intrarenal signaling systems, specifically including nitric
oxide and arachidonic acid metabolites, that participate in
modulating the strength of the vasoconstrictive actions.
Because the actions of the sodium chloride load detector
and tubuloglomerular feedback are complicated, we summa-
rize them here. High salt content in the thick ascending limb
of a given nephron generates signals that reduce glomerular
blood flow and reduce filtration in that nephron, thus blunting
(but not eliminating) the increase in sodium excretion initi-
ated by other processes in conditions (e.g., volume expansion)
in which the appropriate overall response is increased sodium
excretion. The same signals that reduce filtration also reduce
the secretion of renin.
OTHER MECHANISMS FOR
CONTROLLING SODIUM BALANCE:
NATRIURETIC PEPTIDES
Although there are several other renal mechanisms for con-
trolling sodium balance independent of water balance, under
normal physiological circumstances, none are as important as
aldosterone. Only under certain pathophysiological conditions
do these other mechanisms contribute significantly to the reg-
ulation of sodium balance. Important among these are a family
of hormones called natriuretic peptides, so named because
they promote excretion of sodium in the urine. The key ones
are atrial natriuretic peptide (ANP) and brain natriuretic
peptide (BNP; named as such because it was first discovered
in the brain). The main source of both natriuretic peptides is
the heart. The natriuretic peptides have both vascular and
tubular actions. They relax the afferent arteriole, thereby pro-
moting increased filtration, and act at several sites in the
tubule. They inhibit release of renin, inhibit the actions of
angiotensin II that normally promote reabsorption of sodium,
458 SECTION VII Renal Physiology
and act in the medullary collecting duct to inhibit sodium
absorption. The major stimulus for increased secretion of the
natriuretic peptides is distention of the atria, which occurs
during plasma volume expansion. This is probably the stimu-
lus for the increased natriuretic peptides that occurs in persons
on a high-salt diet. Although most experts assume that these
peptides play some physiological role in the regulation of
sodium excretion in this and other situations in which plasma
volume is expanded, it is not currently possible to quantify
their contribution precisely, although it is surely less than
aldosterone. These peptides are greatly increased in patients
with heart failure and can serve as diagnostic indicators.
SUMMARY OF THE CONTROL
OF SODIUM EXCRETION
An array of signals, some originating in baroreceptors outside
the kidneys and some originating within the kidneys, alters
vascular resistances and transport proteins in order to control
sodium excretion, with the main goals of maintaining ECF
volume acutely and arterial pressure in the long term
(see Figure 45–8). In response to sodium loads and losses,
consequent changes in pressure are detected by neural and
intrarenal baroreceptors that directly or indirectly signal the
kidneys to modify sodium excretion, thereby excreting loads
or preserving existing sodium. GFR, which determines the fil-
tered load of sodium, is a function of arterial pressure and the
amount of smooth muscle contraction in renal arterioles.
Sodium reabsorption is controlled by a combination of signals
that affect transport proteins in the renal tubules. The main
controlling signals come from renal sympathetic nerves and
the RAS–aldosterone hormonal system. The latter is activated
both by sympathetic nerves and by low pressure at the
Dietary Arterial RAS
GFR
sodium pressure system
+ Angiotensin II
+ +
– do this by regulating how much water is reabsorbed in the col-
ECF +
volume + hypo-osmotic tubular fluid in the loop of Henle. Then as the
Sodium – Aldosterone
excretion
± +
Intrarenal Natriuretic
messengers peptides
FIGURE 45–8 Important variables that affect sodium
excretion. Increases in dietary sodium, particularly via the ensuing
rise in ECF volume, lead to increased sodium excretion. Increased
arterial pressure, increased GFR, and the actions of natriuretic
peptides also increase sodium excretion. Activation of the renin–
angiotensin system (RAS) decreases sodium excretion via the actions
of both angiotensin II and aldosterone. Intrarenal messengers,
depending on the specific messenger, can either increase or decrease
sodium excretion.
intrarenal baroreceptors. Elevated arterial blood pressure also
exerts direct effects on the kidneys (pressure natriuresis) via a
separate intrarenal signaling system.
When considering mechanisms of sodium excretion, it is
useful to consider two conceptually different categories of
mechanisms: (1) GFR and proximal tubule mechanisms that
lead to coupled changes in sodium and water excretion and (2)
distal nephron effects in which sodium can be reabsorbed
independently of water. The proximal mechanisms are pri-
marily involved in excreting excess ECF volume, whereas the
distal mechanisms alter sodium excretion when ingestion of
sodium is not balanced by ingestion of water. Both types of
mechanisms can alter blood pressure because of the intimate
relationship among total body sodium and water, blood vol-
ume, and blood pressure.
CONTROL OF WATER EXCRETION
As with sodium excretion, water excretion is regulated in part-
nership with the cardiovascular system. A central goal in regu-
lating both salt and water excretion is to preserve vascular
volume. It is also crucial to maintain plasma osmolality at a
level that is healthy for tissue cells. It is not surprising then that
signals related to osmolality and volume are the main regula-
tors of water excretion.
The relation between urinary water excretion, urinary sol-
ute excretion, and urine osmolality is shown in the following
expression (where, as before, we approximate osmolality sim-
ply as total moles divided by volume):
Urine solute excretion
Urine water excretion = ________________ (5)
Urine osmolality
At a given urine osmolality, water excretion varies directly
with urinary solute excretion. More solute excreted (due, e.g.,
to a higher GFR or reduced sodium reabsorption) means more
water excreted (because “water follows the osmoles”). This is
the basis for most diuretics, which promote sodium excretion,
and therefore water excretion. But the kidneys can also vary
the amount of water accompanying the excreted solute. They
lecting ducts. As we already know, the kidneys first generate
fluid subsequently flows through the collecting duct system,
variable amounts of water are reabsorbed by allowing the
tubular fluid to equilibrate to varying degrees with the sur-
rounding interstitium. The final osmolality, and hence final
volume, depends on the peak medullary osmolality and how
closely the tubular osmolality approaches that value. We also
know that equilibration with the interstitium is a function of
water permeability in the collecting ducts via aquaporins
under the control of the hormone ADH. Therefore, the regula-
tion of water excretion that is independent of solute excretion
focuses on controls over ADH secretion.
Antidiuretic hormone (ADH; arginine vasopressin [AVP]
in humans) is a small peptide (nine amino acids) produced by
 CHAPTER 45 Regulation of Sodium and Water Excretion
neurons in the hypothalamus. The cell bodies are located in the
supraoptic and paraventricular nuclei of the hypothalamus,
and their axons extend downward to the posterior pituitary
gland, from which ADH is released into the blood (for more
detail, see Chapter 61). There is normally a moderate rate of
ADH secretion, allowing considerable water reabsorption in the
renal collecting ducts and resulting in urine that is more con-
centrated than plasma. ADH secretion can increase or decrease
from this level, giving the control system a bidirectional respon-
siveness. And because the collecting ducts are very sensitive to
ADH, this allows the body to control water excretion rate over a
very wide range. There are many sources of synaptic input to the
ADH-secreting neurons. The most important signals originate
in osmoreceptors and cardiovascular baroreceptors.
OSMORECEPTOR CONTROL
OF ADH SECRETION
Plasma osmolality is one of the most tightly regulated vari-
ables in the body. It is set mainly by the ratio of ECF sodium
(plus its associated anions) to water. Other solutes (e.g., glu-
cose and potassium) make some contribution, but those other
solutes are regulated for reasons other than their osmolality.
Thus, except under unusual circumstances, variations in
plasma osmolality reflect variations in sodium concentration.
If the body keeps the inputs and outputs of sodium and water
matched in lock step, osmolality remains constant. But inputs
are often not matched. The major effect of gaining or losing
water or salt without corresponding changes in the other is a
change in the osmolality of the body fluids. When osmolality
deviates from normal, strong reflexes come into play to change
ADH secretion, and thus change the excretion of water. Key
receptors that initiate reflexes controlling ADH secretion are
osmoreceptors: neurons responsive to changes in osmolality.
Most osmoreceptors are located in tissues surrounding the
third cerebral ventricle. These tissues contain fenestrated cap-
illaries, which allow rapid adjustment of interstitial composi-
tion when plasma composition changes. The hypothalamic
cells that secrete ADH receive synaptic input from the osmore-
ceptors. Via these connections, an increase in osmolality
increases their rate of ADH secretion. In turn, this causes
water permeability of the collecting ducts to increase, water
reabsorption is maximal, and a very small volume of highly
concentrated (hyperosmotic) urine is excreted. By this means,
relatively less filtered water than solute is excreted, which low-
ers body fluid osmolality toward normal. Conversely, decreased
osmolality inhibits ADH secretion. For example, when a per-
son drinks pure water, the excess water lowers the body fluid
osmolality, which inhibits ADH secretion via the hypotha-
lamic osmoreceptors. As a result, water permeability of the
collecting ducts becomes very low, little water is reabsorbed
from these segments, and a large volume of extremely dilute
(hypo-osmotic) urine is excreted. In this manner, the excess
water is rapidly eliminated and plasma osmolality is increased
(see Figure 45–9).
459
Excess H2O ingested
Body fluid osmolarity
( H2O concentration)
Firing by hypothalamic
osmoreceptors
Posterior pituitary
Vasopressin secretion
Plasma vasopressin
Collecting ducts
Tubular permeability
to H2O
H2O reabsorption
H2O excretion
FIGURE 45–9 Mechanism for increased water excretion in
response to a pure water load. Decreased plasma osmolality leads,
via osmoreceptors, to decreased secretion of ADH (vasopressin), in
turn causing decreased collecting duct water reabsorption and more
water excretion. (Reproduced with permission from Widmaier EP, Raff H, Strang
KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
The osmoreceptor–ADH system is very sensitive, respond-
ing to an osmolality change of only 1 or 2 mOsm/kg. However,
common perturbations are often a good deal greater than this.
For example, if a 70-kg person consumes 1 L of pure water,
ECF osmolality is reduced by about 7 mOsm/kg. And exercise
for several hours on a warm day can increase ECF osmolality
by 10 mOsm/kg or more. Such routine perturbations result in
strong ADH responses that remain active until osmolality
returns to its previous value. ADH has a plasma half-life of
only a few minutes, so prolonged stimulation of water perme-
ability in the kidneys requires continuous stimulation of the
ADH-secreting neurons.
BARORECEPTOR CONTROL
OF ADH SECRETION
There is a second major influence on ADH secretion. This
originates in systemic baroreceptors (the same ones that influ-
ence sympathetic drive to the kidneys). A decreased extracel-
lular volume or major decrease in arterial pressure reflexively
460 SECTION VII Renal Physiology
Plasma volume
Venous, atrial, and arterial
pressures
Reflexes mediated
by cardiovascular
baroreceptors
Posterior pituitary
Vasopressin secretion
Plasma vasopressin
Collecting ducts
Tubular permeability
to H2O
H2O reabsorption
H2O excretion
FIGURE 45–10 Decreased water excretion in response to
decreased plasma volume. Low pressure sensed by neural
baroreceptors reduces inhibition of the hypothalamic cells whose
axons release ADH (vasopressin) from the posterior pituitary gland.
The subsequent increase in ADH increases water reabsorption in the
collecting ducts and helps preserve existing volume. (Reproduced with
permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed.
McGraw-Hill, 2008.)
activates increased ADH secretion. The response is mediated
by neural pathways originating in cardiopulmonary barore-
ceptors, and if arterial pressure decreases, from arterial barore-
ceptors (see Figure 45–10).
Decreased cardiovascular pressures cause less firing by the
baroreceptors, which relieves inhibition of stimulatory path-
ways and results in more ADH secretion. In effect, the low car-
diovascular pressures are interpreted as low volume, and the
response of increased ADH appropriately serves to minimize
loss of water (i.e., volume). Conversely, baroreceptors are stim-
ulated by increased cardiovascular pressures, interpreted as
excess volume, and this causes inhibition of ADH secretion.
The decrease in ADH results in decreased reabsorption of
water in the collecting ducts, and more excretion. The adap-
tive value of these baroreceptor reflexes is to help stabilize ECF
volume and, hence, blood pressure.
There is a second adaptive value to this reflex: large
decreases in plasma volume, as might occur after a major
hemorrhage, elicit such high concentrations of ADH—much
higher than those needed to produce maximal antidiuresis—
that the hormone is able to exert direct vasoconstrictor effects
on arteriolar smooth muscle. The result is increased total
peripheral resistance, which helps restore arterial blood pres-
sure independently of the slower restoration of body fluid vol-
umes. Renal arterioles and mesangial cells also participate in
this constrictor response, so a high plasma concentration of
ADH, quite apart from its effect on tubular water permeabil-
ity, may promote retention of both sodium and water by low-
ering GFR.
We have described two different major afferent pathways
controlling the ADH-secreting hypothalamic cells: one from
baroreceptors and one from osmoreceptors. These hypotha-
lamic cells are, therefore, true integrators, whose activity is
determined by the total synaptic input to them. Thus, a simul-
taneous increase in plasma volume and decrease in body fluid
osmolality causes strong inhibition of ADH secretion. Con-
versely, a simultaneous decrease in plasma volume and increase
in osmolality produces very marked stimulation of ADH
secretion. However, what happens when baroreceptor and
osmoreceptor inputs oppose each other (e.g., if plasma volume
and osmolality are both decreased)? In general, because of the
high sensitivity of the osmoreceptors, the osmoreceptor influ-
ence predominates over that of the baroreceptors when
changes in osmolality and plasma volume are small to moder-
ate. However, a dangerous reduction in plasma volume will
take precedence over decreased body fluid osmolality in influ-
encing ADH secretion; under such conditions, water is
retained in excess of solute even though the body fluids become
hypo-osmotic (for the same reason, plasma sodium concen-
tration decreases). In essence, when blood volume reaches a
life-threatening low level, it is more important for the body to
preserve vascular volume and thus ensure an adequate cardiac
output than it is to preserve normal osmolality.
The ADH-secreting cells also receive synaptic input from
many other brain areas. Thus, ADH secretion and, hence,
urine flow can be altered by pain, fear, and a variety of other
factors, including drugs such as alcohol, which inhibits ADH
release. However, this complexity should not obscure the gen-
eralization that ADH secretion is determined over the long
term primarily by the states of body fluid osmolality and
plasma volume.
Figure 45–11 summarizes the major factors known to con-
trol renal sodium and water excretion in response to severe
sweating. Sweat is a hypo-osmotic solution containing mainly
water, sodium, and chloride. Therefore, sweating causes both a
decrease in ECF volume and an increase in body fluid osmola-
lity. The renal retention of water and sodium helps preserve
existing water and salt that are depleted by sweating.
THIRST AND SALT APPETITE
Large deficits of salt and water can be only partly compensated
by renal conservation of these substances, and ingestion is the
ultimate compensatory mechanism. The centers that mediate
thirst are located in the hypothalamus (very close to those
areas that produce ADH). The subjective feeling of thirst,
which drives one to obtain and ingest water, is stimulated both
 CHAPTER 45 Regulation of Sodium and Water Excretion 461

Begin

Severe sweating

Loss of hypoosmotic
salt solution

Plasma volume Plasma osmolarity

( H2O concentration)

GFR Plasma Plasma vasopressin

Reflexes Reflexes
aldosterone

Sodium excretion H2O excretion

FIGURE 45–11 Coordinated response to severe sweating. A combination of decreased ECF volume and increased plasma osmolality
activates reflexes that preserve both salt and water. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed.
McGraw-Hill, 2008.)

by reduced plasma volume and by increased body fluid osmo-
lality. The adaptive significance of both is self-evident. Note
that these are precisely the same changes that stimulate ADH
production, and the receptors—osmoreceptors and the nerve
cells that respond to the cardiovascular baroreceptors—that
initiate the ADH-controlling reflexes are near those that initi-
ate thirst. The thirst response, however, is significantly less
sensitive than the ADH response.
There are also other pathways controlling thirst. For exam-
ple, dryness of the mouth and throat causes profound thirst,
which is relieved by merely moistening them. Also, when ani-
mals such as the camel (and humans, to a lesser extent) become
markedly dehydrated, they will rapidly drink just enough
water to replace their previous losses and then stop. What is
amazing is that when they stop, the water has not yet had time
to be absorbed from the gastrointestinal tract into the blood.
Some kind of metering of the water intake by the gastrointes-
tinal tract has occurred, but its nature remains a mystery. Neu-
ral afferents from the pharynx and upper gastrointestinal tract
are likely to be involved.
Angiotensin II is yet another factor that stimulates thirst: by
its direct effect on the brain. This hormone constitutes one of
the pathways by which thirst is stimulated when ECF volume
is decreased.
Salt appetite, which is the analog of thirst, is also an
extremely important component of sodium homeostasis in
most mammals. It is clear that salt appetite in these species is
innate and consists of two components: (1) hedonistic appetite
and (2) regulatory appetite. In other words, (1) animals like
salt and eat it whenever they can regardless of whether they are
salt deficient and (2) their drive to obtain salt is markedly
increased in the presence of deficiency.
The significance of these animal studies for humans, how-
ever, is unclear. Salt craving does seem to occur in humans
who are severely salt depleted, but the contribution of such
regulatory salt appetite to everyday sodium homeostasis in
healthy persons is probably slight. On the other hand, humans
do seem to have a strong hedonistic appetite for salt, as mani-
fested by almost universally large intakes of sodium whenever
it is cheap and readily available. Thus, the average American
intake of salt is 10–15 g per day even though humans can sur-
vive quite normally on less than 0.5 g per day. As pointed out
previously, a large salt intake may be a contributor to the
pathogenesis of hypertension in susceptible individuals.
CLINICAL CORRELATION
A 57-year-old man has a long history of smoking and
hypertension, but in prior years, has refused the use of any
medications for treatment. Six months ago, he suffered a
fall from a tractor and injured the right side of his back. He
recovered well, but 2 weeks ago, his blood pressure was
147/102, and his physician finally convinced him to start
on an ACE inhibitor. At this follow-up visit, his blood pres-
sure was only mildly increased, but he was feeling very tired
and agitated, without any specific symptoms. Laboratory
analysis of his blood revealed azotemia (high levels of crea-
tinine and urea), and he was referred to a nephrologist.
462 SECTION VII Renal Physiology
Further tests, after taking him off all medications, showed
activation of the RAS. When he was put back on the ACE
inhibitor, his renin levels increased markedly, but not his
aldosterone. At this point, a renal angiogram indicated
moderate left renal artery blockage and major right renal
artery blockage.
His diagnosis is renovascular hypertension, caused by
activation of the RAS system. He has generalized athero-
sclerosis, but the major problem is stenosis (narrowing) of
his right renal artery, perhaps exacerbated by trauma dur-
ing his accident 6 months prior. Decreased renal perfusion
pressure activates renin secretion from his right kidney, in
turn leading to increased angiotensin II and aldosterone.
This is causing a significant increase in blood pressure. The
high blood pressure and levels of angiotensin II suppress
secretion of renin from his left kidney, but this makes no
difference in the face of the high secretion from the right
kidney. The increased pressure in the left renal artery main-
tains total GFR sufficiently high to provide adequate excre-
tion of nitrogenous waste. However, after an ACE inhibitor
is given, his levels of angiotensin II and aldosterone
decrease. Consequently, his systemic and left renal artery
pressure decreases, resulting in a decrease in GFR and
excretion of nitrogenous waste, leading to the azotemia.
Furthermore, when he is given an ACE inhibitor and there
are decreased levels of angiotensin II, the suppressive effect
that the usually high angiotensin II is having on his left kid-
ney is removed, and renin secretion from the left kidney
rises markedly. Renal artery stenosis is sometimes treated
by renal artery angioplasty and placement of a stent to
maintain the patency of the renal artery.
CHAPTER SUMMARY
■ Sodium and water excretion are regulated primarily to meet
the needs of the cardiovascular system via preservation of
vascular volume, blood pressure, and plasma osmolality.
■ Baroreceptors at various sites inform the kidneys of vascular
pressures and volume status.
■ Angiotensin II, produced by local and systemic RAS, is a crucial
regulator of sodium excretion and blood pressure via its actions
in the kidneys, peripheral vasculature, and adrenal glands.
■ Sodium excretion is regulated by both the rate of filtration
(GFR) and rate of reabsorption.
■ ECF volume status is a major determinant of sodium excretion.
■ A major action of angiotensin II is to stimulate sodium reabsorp-
tion via Na–H antiporter activity in the proximal tubule.
■ Elevated renal artery pressure leads to increased sodium
excretion (pressure natriuresis) without external signals.
■ Long-term regulation of sodium excretion and, therefore,
blood pressure centers on the actions of aldosterone in the
distal nephron.
■ Water excretion tends to parallel solute excretion, but is also
regulated independently by controlling water reabsorption in
the collecting ducts.
■ ADH secretion is regulated by plasma osmolality via hypotha-
lamic osmoreceptors, and blood pressure, via the baroreceptor–
vasomotor center system.
STUDY QUESTIONS
1. Which of the following cell types are not nerve cells?
A) pituitary cells that secrete ADH
B) baroreceptors located in pulmonary vessels
C) baroreceptors located in the arch of the aorta
D) intrarenal baroreceptors
2. In the normal RAS system leading to the production of
aldosterone, the rate-limiting step is
A) the production of angiotensin I.
B) the production of angiotensinogen.
C) the activity of ACE.
D) the responsiveness of the adrenal gland to angiotensin II.
3. A person eats a large bag of very salty potato chips with no
beverage. Which response is most likely to ensue?
A) movement of aquaporins into the membrane of cortical
collecting duct principal cells
B) enhanced activity of Na–H antiporters in the proximal
tubule
C) enhanced activity of Na,K-ATPase pumps in collecting duct
principal cells
D) decreased levels of natriuretic peptides in the blood
4. In response to a major hemorrhage
A) GFR increases.
B) ADH secretion is reduced.
C) granular (juxtaglomerular) cells are stimulated by
neural input.
D) neural baroreceptor firing rate increases.
5. Tubuloglomerular feedback contributes to the regulation of
A) GFR.
B) sympathetic neural activity.
C) ADH secretion.
D) ACE activity.
 46
C H A P T E R

Regulation of
Potassium Balance
Douglas C. Eaton and John P. Pooler

O B J E C T I V E S

■ State the normal balance and distribution of potassium between cells and
extracellular fluid.
■ Describe how potassium moves between cells and the extracellular fluid,
and how, on a short-term basis, the movement protects the extracellular
fluid from large changes in potassium concentration.
■ Describe how plasma levels of potassium do not always reflect the status of
total body potassium.
■ State how insulin and epinephrine influence the cellular uptake of potassium,
and identify the situations in which these hormonal influences are most
important.
■ State the relative amounts of potassium reabsorbed by the proximal tubule and
thick ascending limb of Henle’s loop regardless of the state of potassium intake.
■ Describe how nephron segments beyond the thick ascending limb can
manifest net secretion or reabsorption; describe the role of principal cells
and intercalated cells in these processes.
■ List inputs that control the rate of potassium secretion by the distal nephron.
■ Describe the actions of renal outer medulla (ROMK) and BK potassium
channels in conditions of low, normal, and high potassium excretions.
■ Describe how changes in plasma potassium influence aldosterone secretion.
■ State the effects of most diuretic drugs and osmotic diuretics on potassium
excretion.
■ Describe the association between perturbations in acid–base status and the
plasma potassium level.

REGULATION OF POTASSIUM centration of potassium in the ECF is a closely regulated quan-

BETWEEN THE INTRACELLULAR
AND EXTRACELLULAR
COMPARTMENTS
Potassium, like all other important ions, is distributed between
the intracellular fluid and extracellular fluid (ECF) of the body.
The vast majority of potassium is intracellular, and only about
2% of total body potassium is in the ECF. This small fraction,
however, is absolutely crucial for body function, and the con-
tity. Major increases and decreases (called hyperkalemia and
hypokalemia) from the normal plasma values of 3.5–5 mEq/L
are cause for medical intervention. The importance of main-
taining this concentration relatively constant stems primarily
from the role of potassium in the excitability of nerve and
muscle, especially the heart (review Chapters 4 and 23).
Given that the vast majority of body potassium is within
cells, the extracellular potassium concentration is crucially
dependent on (1) the total amount of potassium in the body
and (2) the distribution of this potassium between the extra-
cellular and intracellular fluid compartments. Total body

463

Ch46_463-470.indd 463 11/26/10 10:34:08 AM

464 SECTION VII Renal Physiology
potassium is determined by the balance between potassium
intake and excretion. Healthy individuals remain in potassium
balance, as they do in sodium balance, by excreting an amount
of urinary potassium equal to the amount of potassium
ingested minus the small amounts eliminated in the feces and
sweat. Normally, potassium losses via sweat and the gastroin-
testinal tract are small, but very large quantities can be lost
from the digestive tract during vomiting or diarrhea. The con-
trol of renal potassium handling is the major mechanism by
which total body potassium is maintained in balance.
The fact that most body potassium is intracellular follows
strictly from the size and properties of the intracellular and
extracellular compartments. About two thirds of the body
fluids are intracellular (the collective cytosolic volume of all
the cells in the body), and typical cytosolic potassium con-
centrations are about 140–150 mEq/L. One third of the body
fluids are extracellular, with a potassium concentration of
about 4 mEq/L. In a clinical setting, only the extracellular
concentration can be measured (the intracellular potassium
is, in a sense, hidden behind the wall of the cell membrane).
Furthermore, the extracellular value does not necessarily
reflect total body potassium. A patient may, for example, be
hyperkalemic and yet at the same time be depleted of total
body potassium.
The high level of potassium within cells is maintained by the
collective operation of the Na,K-ATPase plasma membrane
pumps, which actively transport potassium into cells. Because
the amount of potassium in the extracellular compartment is
very small (40–60 mEq total), even very slight shifts of potas-
sium into or out of cells produce large changes in extracellular
potassium concentration. Similarly, a meal rich in potassium
(e.g., steak, potato, and spinach) could easily double the extra-
cellular concentration of potassium if most of that potassium
were not transferred from the blood to the intracellular com-
partment. It is crucial, therefore, that dietary loads be taken up
into the intracellular compartment rapidly to prevent major
changes in plasma potassium concentration. The tissue con-
tributing most to the sequestration of potassium is skeletal
muscle, simply because it contains the largest collective intra-
cellular volume. Muscle effectively buffers extracellular potas-
sium by taking up or releasing it and keeping the plasma
potassium concentration close to normal. On a moment-to-
moment basis, this is what protects the ECF from large swings
in potassium concentration. Major factors involved in these
homeostatic processes include insulin and epinephrine, both
of which cause increased potassium uptake by muscle (and
certain other cells) through stimulation of plasma membrane
Na,K-ATPases. Another influence is the GI tract, which con-
tains an elaborate neural network (the “gut brain”) that sends
signals to the central nervous system. It also contains a com-
plement of enteroendocrine cells that releases an array of
peptide hormones. Together these neural and hormonal sig-
nals affect many target organs, including the kidneys (see later
discussion) in response to dietary input.
The increase in plasma insulin concentration after a meal is
a crucial factor in moving ingested and absorbed potassium
into cells rather than allowing it to accumulate in the ECF.
This new potassium then slowly comes out of cells between
meals to be excreted. Moreover, a large increase in plasma
potassium concentration facilitates insulin secretion at any
time, and the additional insulin induces greater potassium
uptake by the cells, a negative feedback system for opposing
acute elevations in plasma potassium concentration. In the
natural order of things, insulin also stimulates glucose uptake
and metabolism by cells: a necessary source of energy to drive
the insulin-activated Na,K-ATPase responsible for moving
potassium into cells.
The effect of epinephrine on cellular potassium uptake is
probably of greatest physiological importance during exercise
when potassium moves out of muscle cells that are rapidly
firing action potentials. In fact, very intense intermittent
exercise such as wind sprints can transiently double plasma
potassium. However, at the same time, exercise increases
adrenal medullary secretion of epinephrine, which stimulates
potassium uptake by muscle and other cells. Similarly, trauma
causes loss of potassium from damaged cells, and epineph-
rine released due to stress stimulates other cells to take up
plasma potassium.
Still another influence on the distribution of potassium
between the intracellular fluid and ECF is the ECF hydrogen
ion concentration: an increase in ECF hydrogen ion concen-
tration (acidemia; see Chapter 47) is often associated with net
potassium movement out of cells, whereas a decrease in ECF
hydrogen ion concentration (alkalemia) causes net potassium
movement into them. It is as though potassium and hydrogen
ions were exchanging across plasma membranes (i.e., hydro-
gen ions moving into the cell during acidemia and out during
alkalemia and potassium doing just the opposite), but the pre-
cise mechanism underlying these “exchanges” has not yet been
clarified. However, like the effect of insulin, it probably involves
an inhibition (acidemia) or activation (alkalemia) of the Na,K-
ATPase.
RENAL POTASSIUM HANDLING
OVERVIEW
Although other tissues play an important role in the moment-
to-moment control of plasma potassium concentration, in the
final analysis, the kidney determines total body potassium
content. Therefore, understanding potassium handling by the
kidneys is the key to understanding potassium balance. Potas-
sium is freely filtered into Bowman’s space. Under all condi-
tions, almost all the filtered load (~90%) is reabsorbed by the
proximal tubule and thick ascending limb of the loop of
Henle. Then, if the body is trying to conserve potassium, most
of the rest is reabsorbed in the distal nephron and medullary
collecting ducts, leaving almost none in the urine. In contrast,
if the body is ridding itself of potassium, a large amount is
secreted in the distal nephron, resulting in a large excretion.
When secretion occurs at high rates, the amount excreted may
 CHAPTER 46 Regulation of Potassium Balance 465

TABLE 46–1 Summary of tubular potassium transport. loads are high. It is in these distal segments where most regula-
tion of potassium excretion is exerted. The distal nephron is
Low-potassium Diet composed of a number of segments, including the distal con-
Normal- or High- or Potassium voluted tubule, connecting tubule, initial collecting tubule,
Transport potassium Diet Depletion
and cortical collecting duct; that is, all of the tubule segments
Proximal tubule Reabsorption Reabsorption (55%) between the end of the thick ascending limb and the medul-
(60–80%) lary collecting duct. It is not possible to finely differentiate
Thick ascending limb Reabsorption Reabsorption (30%) between these segments in terms of function, although the
(5–25%) connecting tubule stands out as being particularly important
Distal convoluted Secretion Reabsorption in potassium handling because of its rich complement of
tubule transport elements. It appears that most of the potassium
Principal cells, Substantial Little secretion secretion occurs prior to segments where most of the water is
connecting tubule, and secretion (>15%) absorbed (cortical collecting duct). Finally, the medullary col-
cortical collecting duct lecting ducts reabsorb small amounts of potassium under all
H,K-ATPase-containing Reabsorption Reabsorption (10%) conditions. When the sum of upstream processes has already
intercalated cells, (10%) reabsorbed almost all the potassium, the medullary collecting
cortical collecting duct ducts bring the final urine excretion down to a few percent of
H,K-ATPase-containing Reabsorption Reabsorption (5%) the filtered load, for an excretion of about 10–15 mEq per day.
cells, medullary (5%) On the other hand, if upstream segments are secreting avidly,
collecting duct the modest reabsorption in the medullary collecting ducts
Percentages are in reference to the filtered load of potassium. H, hydrogen; K, does little to prevent an excretion that can reach 1,000 mEq
potassium; ATPase, adenosine triphosphatase.
per day. Figure 46–1A and B depicts the overall renal handling
Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009. of potassium in different tubule regions in conditions of high
and low potassium excretion.
A complication in the renal handling of potassium in all
exceed the filtered load. The chief means of regulation lies in regions, specifically including the proximal tubule and thick
control of secretion in parts of the nephron beyond the loop of ascending limb, is that its active transport is always coupled to
Henle. Let us look at potassium handling by various nephron the active transport of another solute. Active influx of potas-
segments and then address the issue of control. sium across the basolateral membrane via the ubiquitous
Since potassium is freely filtered, a normal plasma level of Na,K-ATPase is coupled to efflux of sodium, while influx of
4 mEq/L and GFR of 150 L per day or more results in a daily potassium across apical membranes via H–K antiporters is
filtered load of about 600 mEq per day. The subsequent events accompanied by efflux of protons. Thus, in describing the
in various tubule segments are summarized in Table 46–1. In renal handling of potassium in various segments, we always
the proximal tubule, about 65% of the filtered load is reab- have to keep in mind the fate of these other solutes. In the
sorbed, mostly via the paracellular route. Much of the flux is proximal tubule, the Na,K-ATPase in the basolateral mem-
driven by the concentration gradient set up when water is brane is very active in moving sodium from the cell to the
reabsorbed (thus concentrating all solutes remaining in the interstitium, necessitating that potassium be simultaneously
tubular lumen). Some may also move by entrainment with the taken up from the interstitium. Since we know that potassium
rapidly reabsorbed water (solvent drag). Either way, this is being put into the interstitium surrounding the proximal
accounts for major potassium absorption in an essentially tubule, this pumped potassium must therefore recycle right
unregulated manner. In the loop of Henle, there is additional back to the interstitium by passive flux through channels in
reabsorption. The major events take place in the thick ascend- the basolateral membrane.
ing limb, where the Na–K–2Cl multiporter in the apical In the thick ascending limb, the interaction with sodium is
membrane reabsorbs potassium (see Figure 44–3). Some of even more complicated. As mentioned above, potassium is
this potassium is returned to the lumen across the apical mem- actively transported into the cells across both membranes and
brane via potassium channels, and the rest exits the cells across exits the cells passively across both membranes. It is pumped
the basolateral membrane by a combination of passive flux into the epithelial cells from the tubular lumen with sodium
through channels and through symporters with chloride, via Na–K–2Cl antiporters and from the interstitium via the
resulting in net transcellular reabsorption. Some potassium is Na,K-ATPase. Since there is far less potassium than sodium in
also reabsorbed by the paracellular route in this segment, the lumen, potassium must recycle back to the lumen by pas-
driven by a lumen-positive voltage. Usually about 25% of the sive channel flux to keep a supply of potassium available to run
filtered load is reabsorbed in the thick ascending limb, so that the multiporter with sodium. Otherwise, sodium reabsorption
only about 10% is passed on to the distal nephron. would be limited only to the amount of potassium present in
In the distal nephron, there is continuous reabsorption if the tubular fluid. Quantitatively, the sum of all these transcel-
dietary loads are very small, but a major superimposed secre- lular and paracellular processes is net reabsorption of about
tion that greatly exceeds the amount reabsorbed when dietary 25% of the filtered load.
466 SECTION VII Renal Physiology

1 1
3 3
2 2

5 4 5 4

A B
FIGURE 46–1 Potassium transport at different locations of the tubule in conditions of low or high excretion. In low excretion (A)
the majority of filtered potassium is reabsorbed in the proximal tubule, mainly by the paracellular route (1). In the thick ascending limb (2)
most of the rest is reabsorbed, mostly by the transcellular route. In the cortical (3) and medullary collecting duct (4) there is some additional
reabsorption via intercalated cells. Some of the potassium reabsorbed into the medullary interstitium recycles back into the thin limbs of the
loop of Henle (5). In high excretion (B) the events in most regions of the tubule are the same as when there is little potassium excretion, but
in the distal nephron, particularly in the connecting tubule, there is major secretion (6) that in some cases is greater than the sum of the
reabsorptive processes. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill,
Medical Pub. Division, 2009.)

SECRETION IN THE DISTAL
NEPHRON AND ITS REGULATION
There are two cell types in the epithelium of the distal nephron:
principal cells (about 70% of the cells) and intercalated cells.
The intercalated cells are further subdivided into type A (more
numerous) and type B (sparse) intercalated cells. The princi-
pal cells secrete potassium at highly variable rates, while the
type A intercalated cells reabsorb potassium. The principles
governing both secretion and reabsorption are straightfor-
ward. Secretion of potassium by principal cells involves the
uptake of potassium from the interstitium via the Na,K-
ATPase and secretion into the tubular lumen through chan-
nels (Figure 46–2). Type A intercalated cells reabsorb
potassium via the H,K-ATPase in the apical membrane, which
actively takes up potassium from the lumen. They then allow
potassium to enter the interstitium across the basolateral
membrane via potassium channels.
Regulation of potassium excretion involves multiple con-
trols over the secretory processes in the distal nephron, some-
thing like a passenger van where everyone in it has an
accelerator and a brake pedal. As is the case with regulation of
sodium excretion, we cannot predict just how these controls
operate in every situation. Fortunately, with potassium as well
as sodium, the healthy kidneys do a remarkable job of increas-
ing potassium excretion in response to high dietary loads and
reducing excretion in the face of restricted diets. Much of the
regulation involves controlling the activity of potassium chan-
nels. The kidneys and other body organs express numerous
potassium channel species; for simplicity we do not usually
differentiate between types. However, in principal cells of the
distal nephron, two types of channels stand out as being those
that secrete potassium in a regulated manner: ROMK (stand-
ing for renal outer medulla, because that is where they were
first identified) and BK (since each channel has a “big” capac-
ity to secrete potassium, also called maxi-K). While ROMK
and BK channels both conduct potassium, they play different
roles and are regulated by quite different mechanisms. At very
low dietary loads of potassium, there is virtually no secretion
LUMEN INTERSTITIUM
amiloride
aldosterone
ATP
Na+ Na+ Na+ Na+
K+ K+
K+ K+ K+ K+
FIGURE 46–2 Generalized pathway for potassium
secretion by principal cells. Potassium secretion is tied to
sodium reabsorption via the Na,K-ATPase. The drug amiloride
inhibits sodium entry, and therefore inhibits potassium secretion.
Aldosterone stimulates both sodium and reabsorption and
potassium secretion at multiple points. (Modified with permission
from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange
Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)
 CHAPTER 46 Regulation of Potassium Balance 467

Low K excretion Normal K excretion High K excretion

ROMK BK ROMK BK ROMK BK

(sequestered) (closed) (open) (closed) (open) (open)

K K K
FIGURE 46–3 Activity of ROMK and BK potassium channels in principal cells under different conditions. When the body is
conserving potassium and little is being excreted, ROMK channels are mostly sequestered in intracellular vesicles and BK channels are closed;
thus, there is virtually no secretion. Under modest potassium loads (normal conditions), ROMK channels secrete potassium, while BK channels
remain closed. When potassium excretion is very high, as on a high-potassium diet, ROMK channel activity is maximized and BK channels are
open, allowing substantial secretion. (Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/
McGraw-Hill, Medical Pub. Division, 2009.)

by either kind of channel. ROMK channels are sequestered in
intracellular vesicles and BK channels are closed. At normal
potassium loads, ROMK channels are moved to the apical
membrane and secrete potassium. BK channels are still closed,
held in reserve and ready to respond to appropriate signals
when needed. At high excretion rates, both types of channel
are present in the luminal membrane and avidly secreting
potassium (Figure 46–3).
Figure 46–4 shows factors known to influence the secretion,
and thus the ultimate excretion of potassium. The following
provides a brief description of how specific factors affect
potassium excretion:
1. Plasma potassium. The role of plasma potassium is the
most understandable influence. First, the filtered load is
directly proportional to plasma concentration. Second,
the environment of the principal cells, that is, the cortical
interstitium, has a potassium concentration that is nearly
the same as in plasma. The Na,K-ATPase that takes up
potassium is highly sensitive to the potassium concentra-
tion in this space, and varies its pump rate up and down
when potassium levels in the plasma vary up and down.
Thus, plasma potassium concentration does exert an in-
fluence on potassium excretion, but is not the dominant
factor under normal conditions.
2. Aldosterone. We discussed the role of aldosterone in reg-
ulating sodium excretion in Chapter 45. Here we describe
its role in potassium excretion. One stimulator of aldos-
terone secretion is an increase in plasma potassium con-
centration. This is a direct action of potassium on the ad-
renal cortex and does not involve the renin–angiotensin
system. Aldosterone, as well as increasing expression of
the Na,K-ATPase, also stimulates expression of ROMK
channels in the distal nephron. Both actions have the ef-
fect of increasing potassium secretion. Greater pumping
by the Na,K-ATPase supplies more potassium from the
interstitium to the cytosol of the principal cells, and more
ROMK channels provide more pathways for secretion.
3. Delivery of sodium to the distal nephron. Any change in
sodium handling prior to the distal nephron determines
how much is sent on from the thick ascending limb, that is,
delivered to the distal nephron. Changes in upstream han-
dling of sodium include changes in filtered load and reab-

High flow rate

High Na delivery
High potassium in distal nephron
to distal nephron
diet

Aldosterone

Nonchloride anions High plasma

in distal nephron potassium
Potassium
secretion in
distal
nephron

FIGURE 46–4 Factors that increase secretion of potassium by principal cells as described in the text. (Modified with permission from Eaton
DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)
468 SECTION VII Renal Physiology
sorption in prior segments. Sodium delivery influences
potassium secretion because more sodium delivered means
more sodium taken up by principal cells, and therefore
more sodium pumped out by the Na,K-ATPase, in turn
causing more potassium to be pumped in. The increased
intracellular potassium can just recycle back to the intersti-
tium, but the usual result is more potassium secretion.
4. Distal nephron flow rate. The role of flow rate in regulat-
ing potassium secretion is a story by itself. Increased flow
is detected by mechanosensitive elements of the principal
cells. This includes bending of the central cilium that pro-
trudes from the apical surface into the tubule lumen.
Bending of the central cilium initiates intracellular release
of calcium and activation of BK channels. Under most
conditions, increased delivery of sodium is the chief cause
of increased flow, because the sodium is accompanied by
water. Thus, increased delivery of sodium implies in-
creased flow. Increased flow has another effect. By sweep-
ing away potassium that reaches the tubule by secretion,
luminal potassium concentration is kept low enough to
preserve a favorable concentration gradient for secretion.
5. Concentration of nonchloride anions. In order for princi-
pal cells to secrete potassium there must be a route (open
channels and/or functioning transporters) and driving forc-
es (electrochemical gradients). In addition to the majority
secretion via potassium channels, a smaller component in-
volves secretion via potassium-chloride symport. Under
conditions in which the luminal chloride concentration is
low due to replacement of luminal chloride with anions that
are not usually in high concentration, the effect is to increase
the electrochemical gradient for chloride secretion. In turn
this increases the normally modest secretion of potassium
via potassium-chloride symport.
6. Dietary potassium. The influence of dietary potassium
on renal function is both the most obvious regulator of
potassium excretion and the least understood. A major
task of the kidneys is to maintain potassium balance by
increasing and decreasing potassium excretion in parallel
with dietary load. The healthy kidneys do this very well.
The problem is in understanding the signaling—how do
the kidneys know how much potassium a person has con-
sumed? While very large potassium loads can increase
plasma potassium somewhat, the changes in excretion as-
sociated with diet do not seem to be accounted for on the
basis of changes in either plasma potassium or the other
identified factors. However, the previously mentioned
gastrointestinal signals influence not only the cellular up-
take of potassium absorbed from the GI tract, but also re-
nal handling of potassium, and seem to be one of the links
between dietary load and excretion. One of the manifesta-
tions of changing dietary loads is to regulate the distribu-
tion of ROMK channels between the apical membrane
and intracellular storage, that is, high-potassium diets lead
to insertion of apical channels and therefore higher potas-
sium secretion. In contrast, during periods of prolonged
low potassium ingestion, there are few ROMK channels in
the apical membrane. Another adaptation to prolonged
periods of low potassium ingestion is an increase in H,K-
ATPase activity in intercalated cells, resulting in even
more efficient reabsorption of filtered potassium.
PERTURBATIONS IN RENAL
HANDLING OF POTASSIUM
A potential problem in the renal handling of potassium that is not
a problem in healthy kidneys is the simultaneous balance of
sodium and potassium. Given that so much of the transport of
these ions is by coupled mechanisms, it is remarkable that the
kidneys can deal with every combination of dietary load: both
high, both low, one high, etc. This is all the more remarkable
when we consider that aldosterone is a regulator of both. If a per-
son is consuming very little sodium or potassium, we expect, in
order to preserve body stores of sodium, for aldosterone levels to
be high enough to stimulate avid reabsorption of sodium. But
this should also lead to avid secretion of potassium, which is an
unwanted action since the body is also trying to conserve potas-
sium. The answer is simply that potassium cannot be secreted
unless there are open apical channels. If the actions of intracellu-
lar signaling cascades have caused most of the ROMK channels
to be sequestered in intracellular vesicles, then potassium that is
taken up from the interstitium via the Na,K-ATPase recycles back
via basolateral channels to the interstitium and is not secreted.
Effects of Diuretics
Diuretics are agents that increase urine flow and reduce ECF
volume, usually by increasing the renal excretion of sodium.
Most diuretics have the unwanted side effect of simultaneously
increasing the renal excretion of potassium. Potassium excre-
tion is almost always increased in individuals undergoing
osmotic diuresis (high filtration of solute that is not reab-
sorbed) or treatment with diuretics that block sodium reab-
sorption in the proximal tubule, loop of Henle, or distal
convoluted tubule (i.e., sites that are upstream from the princi-
pal cells). All of these events increase flow rate past the
potassium-secreting principal cells, which is a major stimula-
tor of potassium secretion. The potassium loss may cause
severe potassium depletion (see Figure 46–5).
Let us integrate this information about diuretics with our
understanding of the action of aldosterone. High aldosterone
levels in individuals with heart failure or other diseases of sec-
ondary hyperaldosteronism generally do not cause potassium
hypersecretion because these patients simultaneously have
low fluid delivery to the distal nephron. However, consider
what happens when such persons are treated with diuretics to
eliminate their retained sodium and water. The diuretics
increase fluid delivery to the distal nephron, and now patients
have both increased aldosterone and increased flow. This
combination causes marked increases in potassium secretion
and excretion. To prevent the potassium loss, drugs that block
the renal actions of aldosterone may be given; such drugs are

Diuretics affecting proximal
tubule, loop of Henle, or
distal convoluted tubule
Inhibition of NaCI reabsorption
Inhibition of water reabsorption
Rate of fluid delivery to
cortical collecting duct
Potassium secretion
Potassium excretion
Potassium depletion
FIGURE 46–5 Pathway by which diuretic drugs affecting the proximal tubule, loop of Henle, or distal convoluted tubule cause
potassium depletion. The decrease in potassium reabsorption is a less important factor in causing the increased potassium excretion than the
increased secretion by the principal cells of the cortical collecting ducts. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)
weak diuretics because they block only the aldosterone-
stimulated fraction of sodium reabsorption with its small
amount of associated water reabsorption. However, unlike
most common diuretics, they are “potassium sparing” because
they simultaneously block aldosterone’s stimulation of potas-
sium secretion. Another class of “potassium-sparing” diuretics
blocks sodium channels in the principal cells of the cortical
collecting duct, preventing sodium entry from lumen to cell.
Therefore, the basolateral membrane Na,K-ATPase pumps
slow their uptake of potassium in exchange for sodium, and
potassium secretion across the apical membrane also slows.
To recapitulate the effects of diuretics: increased delivery of
sodium resulting from the filtration of osmotic diuretics or
from blocking sodium absorption upstream from the distal
nephron increases potassium secretion; however, blocking
sodium reabsorption in the distal nephron does not.
Effects of Acid–Base Changes
Primary acid–base disturbances are a major cause of second-
ary potassium imbalances (and, as discussed in Chapter 47,
imbalances in body potassium can perturb acid–base status).
The existence of an elevated plasma pH (alkalemia) is often
(i.e., frequently, but not always) associated with hypokalemia.
CHAPTER 46 Regulation of Potassium Balance 469
Inhibition of potassium
reabsorption
Similarly, low plasma pH (acidemia) is usually associated
with hyperkalemia. Whether these relations between acid–
base and potassium actually occur in a particular patient
depends on many factors, including the cause of the acid–
base disturbance.
There are two known reasons for the effects of acid–base
status on potassium. First, changes in the extracellular con-
centration of hydrogen ions lead to a de facto exchange of
these ions with cellular cations, the most important of which
is potassium. During an alkalemia, for example, the low extra-
cellular hydrogen ion concentration induces the efflux of
hydrogen ions that are normally bound to intracellular buffers.
The loss of the positively charged hydrogen ions is balanced
by the uptake of other cations, in this case potassium. Thus,
an alkalemia (with hydrogen ions leaving tissue cells to replen-
ish the loss from the ECF) induces cells to take up potassium,
causing a hypokalemia. Conversely, a low pH with a concom-
itant cellular uptake of hydrogen ions (“cellular buffering”)
often leads cells to dump potassium, causing a hyperkalemia.
In addition to these exchanges of potassium for hydrogen ions,
there is an effect of intracellular pH on cellular Na,K-ATPase and
potassium channel activity. Low intracellular pH inhibits pumps
everywhere, allowing potassium to escape from cells (particularly
muscle cells) and increase plasma potassium. Ordinarily, the
470 SECTION VII Renal Physiology
increase in plasma potassium would stimulate potassium uptake
by the Na,K-ATPase in principal cells, but low intracellular pH
also inhibits the pumps there as well as luminal membrane potas-
sium channels. Therefore, the principal cells respond inappropri-
ately and do not effectively secrete the excess plasma potassium
(paradoxical potassium retention). A high intracellular pH
reverses these effects and relieves this inhibition (effectively stim-
ulating the pump and the potassium channels). Alkalemia pro-
motes potassium loss and contributes to the production of a
hypokalemia. Thus, a patient suffering from alkalemia (induced,
for example, by excessive base input) will manifest increased uri-
nary excretion of potassium solely as a result of the alkalemia and
will, therefore, become potassium deficient.
Finally, it should be emphasized that although alkalemia is
often associated with hypokalemia, and acidemia is often asso-
ciated with hyperkalemia, there are exceptions when this is
not the case
CLINICAL CORRELATION
A 60-year-old African American woman has a history of
hypertension going back several decades, but blood pres-
sure medications have kept it under control and she has
generally been in good health. Recently, however, she has
been feeling fatigued and has occasional problems with
constipation. Furthermore, her blood pressure medications
no longer seem to be effective. Most recently, she has expe-
rienced shortness of breath (dyspnea) on several occasions.
On a visit to her physician, her blood pressure is 142/101.
Laboratory work shows a normal plasma sodium of 144
mEq/L and a low potassium of 2.9 mEq/L (clearly
hypokalemic). A disorder of aldosterone secretion is sus-
pected, and assays for plasma aldosterone and renin are
ordered. In the meantime, the patient is put on an angio-
tensin receptor blocker and the diuretic amiloride, which is
a potassium-sparing diuretic. Laboratory results reveal an
increased plasma aldosterone and low renin.
The reasons for the long-standing hypertension are
unknown, and the new symptoms were still too vague to per-
mit a definite diagnosis. However, given the clearly identified
hypokalemia, those symptoms are consistent with muscular
problems that are created by low plasma potassium. This
information, combined with the refractory hypertension,
points to an overabundance of aldosterone. The aldosterone
drives excessive distal nephron secretion of potassium,
accounting for the hypokalemia, and the excessive reabsorp-
tion of sodium leads to an upward creep in arterial pressure.
The combination of high aldosterone and low renin identi-
fies this as a case of primary hyperaldosteronism (high levels
of aldosterone in spite of low plasma renin; see Chapter 65).
The initial precautionary treatment with the angiotensin
receptor blocker did not correct the high aldosterone, indi-
cating that the high secretion is being driven by something
other than angiotensin II. The amiloride is helpful because it
promotes the excretion of sodium by blocking sodium chan-
nels in the distal nephron without simultaneously increasing
potassium excretion. Follow-up work finds hypersecretion
of aldosterone by the left adrenal gland due to a benign tumor
(adenoma), and the left adrenal gland is removed surgically.
CHAPTER SUMMARY
■ Only a small fraction of body potassium is extracellular, and
the extracellular concentration may not be a good indicator of
total body potassium status.
■ On a short-term basis, uptake and release of potassium by
tissue cells prevent large swings in extracellular potassium
concentration.
■ Overall renal handling is accomplished by reabsorbing nearly all
filtered potassium and then secreting an amount of potassium
that maintains balance between ingestion and excretion.
■ It is mainly the principal cells of the connecting tubule and
cortical collecting duct that alter rates of potassium secretion.
■ Potassium secretion (and thus excretion) is increased by high
sodium delivery to the distal nephron, particularly when this is
caused by diuretics acting upstream.
STUDY QUESTIONS
1. Potassium excretion is controlled mainly by controlling the rate of
A) potassium reabsorption in the proximal tubule.
B) potassium reabsorption in the distal nephron.
C) potassium secretion in the proximal tubule.
D) potassium secretion in the distal nephron.
2. In the thick ascending limb
A) the net amounts of potassium and sodium that are
reabsorbed are the same.
B) the major pathway for moving potassium from lumen to
cell is via the Na,K-ATPase.
C) most of the potassium that is absorbed into the cells leaks
back into the lumen via potassium channels.
D) the major pathway for moving potassium from cell to
interstitium is via the Na–K–2Cl multiporter.
3. For which substance is it possible to excrete more than is filtered?
A) sodium
B) potassium
C) chloride
D) it is not possible to excrete any of the above-mentioned ions
in amounts greater than the filtered loads
4. After a potassium-rich meal, the key action of insulin that
prevents a large increase in plasma potassium is to
A) decrease absorption of potassium from the GI tract.
B) increase uptake of potassium by tissue cells.
C) increase the filtered load of potassium.
D) increase tubular secretion of potassium.
5. A key role of “BK” potassium channels in the kidney is to
A) reabsorb potassium when the body is depleted of potassium.
B) recycle potassium in the thick ascending limb.
C) secrete potassium when distal nephron flow rate is very low.
D) help the body excrete potassium in response to very large loads.
 47
C H A P T E R

Regulation of
Acid–Base Balance
Douglas C. Eaton and John P. Pooler

O B J E C T I V E S

■ State the Henderson–Hasselbalch equation for the carbon dioxide–

bicarbonate buffer system.
■ State the major sources for the input of fixed acids and bases into the body,
including metabolic processes and activities of the gastrointestinal tract.
■ Describe how the input of fixed acids and bases affects body levels of
bicarbonate.
■ Explain why body levels of carbon dioxide are usually not altered by the input
of fixed acids and bases.
■ Explain why some low pH fluids alkalinize the blood after they are
metabolized.
■ Describe the reabsorption of filtered bicarbonate by the proximal tubule.
■ Describe how bicarbonate is excreted in response to an alkaline load.
■ Describe how excretion of acid and generation of new bicarbonate are linked.
■ Describe how the titration of filtered buffers is a means of excreting acid.
■ Describe how the conversion of glutamine to ammonium and subsequent
excretion of ammonium accomplishes the goal of excreting acid.
■ Describe how the kidneys handle ammonium that has been secreted in the
proximal tubule.
■ State how total acid excretion is related to titratable acidity and ammonium
excretion.
■ Define the four categories of primary acid–base disturbance and the
meaning of compensation.
■ Describe the renal response to respiratory acid–base disorders.
■ Identify nonrenal problems that may cause the kidneys to generate a
metabolic alkalosis.

OVERVIEW It is essential for the body to regulate the concentration of

Regulating acid–base balance is a key task of the body, and
perturbations of acid–base balance are among of the most
important problems confronting clinicians in a hospital set-
ting. Regulating blood levels of acids and bases is a partner-
ship between the kidneys and the respiratory system (see
Chapter 37).
free protons (hydrogen ions) in the ECF. While most sub-
stances regulated by renal processes exist at plasma levels in
the millimolar range or greater, the normal hydrogen ion con-
centration is a seemingly miniscule 40 nmol/L (1 nmol is one
millionth of a millimole). Even though very small, this level is
crucial for body function. As functional groups on membrane
proteins protonate and deprotonate, the resulting change in

471

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472 SECTION VII Renal Physiology
charge affects the shape, and therefore the behavior, of those
proteins. The plasma levels of hydrogen ions are constantly
being altered by a number of processes, including (1) metabo-
lism of ingested food, (2) secretions of the gastrointestinal (GI)
tract, (3) de novo generation of acids and bases from metabo-
lism of stored fat and glycogen, and (4) changes in the produc-
tion of carbon dioxide.
The essence of the physiological response to these changes
comes down to two processes: (1) matching the excretion of
acid/base equivalents to their input, that is, maintaining bal-
ance, and (2) regulating the ratio of weak acids to their conju-
gate bases in buffer systems. Buffer systems limit changes in pH
to a small range. The two processes of excreting acids and bases,
and regulating physiological buffer concentrations are inti-
mately related, but they are not identical. It is possible for them
to be in balance even though buffer ratios are inappropriate.
ACID–BASE FUNDAMENTALS
An acid, when dissolved in solution, dissociates into a hydro-
gen ion and the conjugate base of the acid, thereby increasing
the concentration of free hydrogen ions (decreasing the pH).
A base, when dissolved in solution, associates with existing
free hydrogen ions and decreases their concentration (increases
the pH). These processes are shown in equation (1). The addi-
tion of acids drives the reaction to the right; the addition of
bases drives it to the left. Strong acids such as hydrochloric
acid release all their hydrogen ions, whereas weak acids such
as acetic acid keep most of the hydrogen ions bound and
release only a small fraction. However, weak acids strongly
affect plasma levels of free hydrogen ions. A weak acid present
at a millimolar concentration, even if it released just a few per-
cent of its hydrogen ions, would completely overwhelm the
existing nanomolar level of free hydrogen ions if buffering sys-
tems did not intervene:
→ Conjugate base + H+
Acid ← (1)
A buffer system consists of a mixture of a weak acid and its
conjugate base. It limits the change in pH on addition of other
acids or bases. When another acid is added, most of the hydro-
gen ions released by that acid combine with the base of the buf-
fer system, greatly restricting the increase in free hydrogen ions.
Similarly, when another base is added, most of the free hydro-
gen ions removed by the base are replaced by hydrogen ions
that dissociate from the acid of the buffer system. In any buffer
system, the ratio of the acid to its conjugate base fixes the free
aqueous concentration of hydrogen ion (which is only a trivial
fraction of the concentration of the acid and base), as shown in
equation (2), or in the more familiar pH form (the Henderson–
Hasselbalch equation), as shown in equation (3):
[Acid]
[H+] = K _____ (2)
[Base]
Base
[Acid]
pH = pK + log ____ (3)
We should emphasize that buffers do not eliminate added acid
or base equivalents, but only limit the effect of the equivalents
on blood pH. In the face of persistent imbalance between input
and output, the acid or base component of the buffer is gradu-
ally reduced in concentration as it is converted to the other
component. Eventually acid or base equivalents added to the
body, even though transiently associated with blood buffers,
must be excreted by the kidneys to maintain balance.
Buffers exist in the extracellular fluid, the intracellular fluid
(the cytosol of the various cells in the body), and the matrix of
bone. Although these buffers are in different compartments,
they communicate with each other. Phosphate and albumin
are important buffers in the ECF. Hemoglobin in red blood
cells is an important intracellular buffer, since changes in
plasma pH lead to uptake or release of protons from red blood
cells. For several reasons, the most important buffer system in
the body turns out to be the CO2–bicarbonate buffer system.
Fortunately, we can understand acid–base balance by looking
at this single buffer system alone and ignore the others, because
all buffer systems must have ratios of weak acid to conjugate
base that result in the same pH.
One property that sets the CO2–bicarbonate buffer system
apart from other buffer systems is that the concentrations of
CO2 and bicarbonate are regulated independently of each
other. Because the concentrations of both components are
regulated, the ratio of their concentrations is regulated. There-
fore, this regulates pH.
In the CO2–bicarbonate buffer system, CO2 is not a weak
acid per se, but it acts like a weak acid because it readily com-
bines with water to form carbonic acid. (CO2 is often called a
volatile acid because it can evaporate. All other acids, for
example, sulfuric and lactic, are called fixed acids.) Carbonic
acid dissociates like any other weak acid into a proton and its
conjugate base, which is bicarbonate [equation (4a)]. Consid-
ered this way, and given the ubiquitous presence of water in
our body, it is clear that carbon dioxide is effectively an acid.
The concentration of carbonic acid in our blood is trivial
(about 3 μmol/L), and at first glance it appears that this system
has little effective buffering capacity. However, the supply of
CO2 is effectively infinite because it is being produced contin-
uously (over 10 mol per day). Any carbonic acid consumed in
a reaction is immediately replaced by new generation from
existing CO2:
→ H CO ←
CO2 + H2O ← → HCO – + H+ (4a)
2 3 3
(carbonic anhydrase)
→ HCO – + H+
CO2 + H2O ← (4b)
3
The reaction on the left side of equation (4a) to form carbonic
acid is rather slow, but most tissues express one or several iso-
forms of the enzyme, carbonic anhydrase, intracellularly,
extracellularly, or both. This enzyme greatly speeds the reac-
tion between CO2 and water to form bicarbonate and a hydro-
gen ion. In so doing it actually skips the step of forming
carbonic acid, as shown in equation (4b). However, as with all
enzyme-catalyzed reactions, the enzyme increases the velocity

of the reaction but not the equilibrium concentrations of reac-
tants and products.
Unlike the other buffer systems in the body, where addition
or loss of hydrogen ions changes the concentration of the weak
acid, in the CO2–bicarbonate system, the concentration of the
weak acid (CO2) is held essentially constant. This is because
the partial pressure of arterial CO2 (Paco2) is regulated by our
respiratory system to be about 40 mm Hg (see Chapters 37
and 38). This partial pressure corresponds to a CO2 concentra-
tion in blood of 1.2 mmol/L. Any change in Pco2 resulting from
the addition or loss of hydrogen ions or change in metabolism
is sensed by the arterial chemoreceptors and chemorecep-
tors in the brainstem (see Chapter 38), which alter the rate of
ventilation to restore the concentration. There are times when
the Pco2 does indeed differ from 40 mm Hg, but this reflects
changes in the activity of the respiratory system, not a change
in Pco2 in response to addition or loss of hydrogen ions.
Although adding or removing hydrogen ions from a source
other than CO2 does not change Pco2, such changes do alter
the concentration of bicarbonate. Adding hydrogen ions
drives the reaction in equations (4a) and (4b) to the left and
reduces bicarbonate on a nearly mole-for-mole basis. We say
nearly because the other blood buffers also take up some of
the load. Removing hydrogen ions drives the reaction to the
right and increases bicarbonate in the same way. There are
many ways of adding or removing hydrogen ions, but, regard-
less of the process, the result is to change the concentration of
bicarbonate.
Be aware that, from the acid–base perspective, any meta-
bolic process or reaction that produces hydrogen ions is iden-
tical to the one that removes bicarbonate, because in both
cases the end result is loss of bicarbonate. The same logic
applies to processes that remove hydrogen ions. A reaction in
which a hydrogen ion is a reactant is equivalent to one in
which bicarbonate is a product, that is, in both cases the end
result is an increase in bicarbonate.
From the foregoing, we conclude that the task of maintain-
ing hydrogen ion balance really becomes one of maintaining
bicarbonate balance (again assuming that the respiratory sys-
tem keeps Pco2 constant). When hydrogen ions are added
(or bicarbonate is removed), the body has to generate new
bicarbonate to replace that which was lost. Analogously, the
removal of hydrogen ions (or addition of base) increases bicar-
bonate, and the extra bicarbonate has to be excreted. Excretion
and generation of new bicarbonate is the responsibility of the
kidneys.
Before moving on, let us clarify a common misconception.
Students sometimes get the impression that somehow fixed
acid equivalents can be converted to CO2 and excreted by
exhalation, or that CO2 can be converted to acids that are
excreted in the urine. Neither is true: fixed acid equivalents
can only be excreted by the kidneys, and CO2 can only be
removed from the body via the lungs. Fixed acids consume
bicarbonate and generate CO2, but just exhaling the CO2 does
not restore the bicarbonate that disappeared when the acid
was added. Without actual renal excretion of those acid equiv-
CHAPTER 47 Regulation of Acid–Base Balance 473
alents, continuous acid input would soon reduce plasma bicar-
bonate to zero. Similarly, no more than a few millimoles of
CO2 are dissolved in the urine, and there is far less carbonic
acid. If somehow the kidneys could convert the acid equiva-
lents of CO2 to fixed acid and excrete those acid equivalents, it
would require excreting over 10,000 mmol of fixed acids per
day—clearly an impossibility.
SOURCES OF ACIDS AND BASES
METABOLISM OF DIETARY PROTEIN
Although the oxidative metabolism of most foodstuff is acid–
base neutral, protein contains some amino acids that contrib-
ute acid or base. When sulfur-containing amino acids and
those with cationic side chains are metabolized to CO2, water,
and urea, the end result is addition of fixed acid. Phosphory-
lated proteins also contribute to an acid load. Similarly, the
oxidative metabolism of amino acids with anionic side chains
adds base (consumes hydrogen ions). Depending on whether
a person’s diet is high in either meat or fruit and vegetables, the
net input can be acid or base. For typical American diets, the
input is usually acidic.
METABOLISM OF DIETARY WEAK ACIDS
Fruits and vegetables, particularly citrus fruit, contain many
weak acids and the salts of those acids (i.e., the conjugate base
plus a cation, usually potassium). We all know that citrus juice
is acidic, with some fruit juices having a pH below 4.0. Inter-
estingly, metabolism of these acidic substances alkalinizes the
blood, sometimes called the fruit juice paradox. The com-
plete oxidation of the protonated form of an organic acid
(e.g., citric acid) to CO2 and water is acid–base neutral, no dif-
ferent in principle than the oxidation of glucose. However, the
complete oxidation of the base form adds bicarbonate to the
body, that is, organic anions are precursors of bicarbonate.
One can think of the metabolic process as taking a hydrogen
ion from the body fluids to protonate the base, converting it to
the acid, and then oxidizing the acid. The loss of the hydrogen
ion, as emphasized above, adds bicarbonate. Acidic fruits and
vegetables contain a mixture of organic acids in the protonated
form and base form. Although the pH is low, there is far more
base than free hydrogen ions. Before oxidation, the mixture is
acidic, but on complete oxidation to CO2 and water, the result
is addition of base.
GI SECRETIONS
The GI tract, from the salivary glands to the colon, is lined with
an epithelium and glands that can secrete hydrogen ions, bicar-
bonate, or a combination. In addition, the major exocrine secre-
tions of the pancreas and liver that flow into the duodenum
contain large amounts of bicarbonate. To accomplish these
474 SECTION VII Renal Physiology

tasks, the GI tract (and the kidneys as we discuss later) uses the
CO2–bicarbonate system in an ingenious way. When we gener-
ate bicarbonate and protons from CO2 and water in a given
medium, say in the blood or in a cell, the result is always acidifi-
cation, because the concentration of protons rises. However,
cells of the GI tract separate the protons from the bicarbonate.
They transport protons out of the cell into one medium (e.g., the
lumen of the GI tract), and bicarbonate into another (the inter-
stitium bathing the basolateral surface). Therefore, the lumen
becomes acidified, and the surroundings (and therefore the
blood leaving the tissue) become alkalinized (see Figure 47–1).
In other regions of the GI tract, the cells reverse the direction of
these processes, that is, they transport bicarbonate into the
lumen (alkalinizing it) and protons into the surroundings. Thus,
different regions of the GI acidify and alkalinize the blood. Nor-
mally, the sum of GI tract secretions is nearly acid–base neutral
(i.e., the secretion of acid in one site, e.g., the stomach, is bal-
anced by the secretion of bicarbonate elsewhere, e.g., the
pancreas). Typically, there is a small net secretion of bicarbonate
into the lumen of the GI tract, resulting in addition of protons to
the blood. However, in conditions of vomiting or diarrhea, one
kind of secretion may vastly exceed the other, resulting in a
major loss of acid or base to the outside world complete with a
major retention of base or acid in the blood.
ANAEROBIC METABOLISM
OF CARBOHYDRATE AND FAT
The normal oxidative metabolism of carbohydrate and fat is
acid–base neutral. Both carbohydrate (glucose) and triglycer-
ides are oxidized to CO2 and water. Although there are inter-
mediates in the metabolism (e.g., pyruvate) that are acids or
bases, the sum of all the reactions is neutral. However, some
conditions lead to production of fixed acids. The anaerobic
metabolism of carbohydrate produces a fixed acid (lactic
acid). In conditions of poor tissue perfusion, this can be a
major acidifying factor, and the metabolism of triglyceride to
β-hydroxybutyrate and acetoacetate also adds fixed acid
(ketone bodies). These processes normally do not add much
of an acid load but can add a huge acid load in unusual meta-
bolic conditions (e.g., severe uncontrolled diabetes mellitus).
INTRAVENOUS SOLUTIONS:
LACTATED RINGER’S
Another way in which acid–base loads can enter the body is via
intravenous solutions. Hospitalized patients receive a variety of
intravenous solutions, a common one being lactated Ringer’s
solution, a mixture of salts that contains lactate at a concentra-
tion of 28 mEq/L. The pH is about 6.5. However, this is an alka-
linizing solution for the same reason described as the fruit juice
paradox earlier. Lactate is the conjugate base of lactic acid, and
when oxidized to CO2 and water, it takes a hydrogen ion from
the body fluids, thereby producing bicarbonate. Lactated
Ringer’s should not be confused with lactic acidosis associated
with strenuous exercise or certain forms of shock. In these situ-
ations, the body produces equal numbers of hydrogen ions and
lactate, and the result is to acidify the body fluids.
RENAL HANDLING
OF ACIDS AND BASES
A simplified overview of the renal processing of acids and
bases is as follows: the kidneys reabsorb most of the filtered
bicarbonate in the proximal tubule, thus conserving plasma

LUMEN INTERSTITIUM
H2O CO2

Carbonic
anhydrase

H+ H+ HCO3– HCO3–

H-secreting cell

H2O CO2

FIGURE 47–1 Generic model of hydrogen ion secretion

Carbonic
(upper cell) and bicarbonate secretion (lower cell). The source of anhydrase
secreted ions is CO2 and water. Every hydrogen ion moved out
of a cell across one membrane must be accompanied by the
HCO3– HCO3– H+ H+
transport of a bicarbonate ion out of the cell across the other
membrane. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal HCO3–secreting cell
Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical
Pub. Division, 2009.)

TABLE 47–1 Normal contributions of tubular
segments to renal hydrogen ion balance.
Proximal tubule
Reabsorbs most filtered bicarbonate (normally about 80%)a
Produces and secretes ammonium
Thick ascending limb of Henle’s loop
Reabsorbs second largest fraction of filtered bicarbonate
(normally about 10–15%)a
Distal convoluted tubule and collecting duct system
Reabsorbs virtually all remaining filtered bicarbonate as well
as any secreted bicarbonate (type A intercalated cells)a
Produces titratable acid (type A intercalated cells)a
Secretes bicarbonate (type B intercalated cells)
a
Processes achieved by hydrogen ion secretion.
Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.
bicarbonate. The proximal tubule also secretes limited amounts
of organic bases or weak organic acids and acid equivalents.
Then, in the distal nephron (mostly the collecting tubules), the
kidneys secrete either protons or bicarbonate to balance the
net input into the body (summarized in Table 47–1).
The first task is to reabsorb most of the filtered bicarbonate.
Bicarbonate is freely filtered at the renal corpuscles. Reabsorp-
tion is an active process, but it is not accomplished in the con-
ventional manner of importing bicarbonate across the apical
membrane and exporting it across the basolateral membrane.
Rather, the mechanism involves the tubular secretion of hydro-
gen ions. An enormous amount of hydrogen ion secretion
occurs in the proximal tubule, with additional secretion in the
thick ascending limb of Henle’s loop and collecting duct sys-
tem. The basic pattern is illustrated in the upper part of
Figure 47–1 without indicating any specific transporters.
Within the cells, hydrogen ions and bicarbonate are generated
from CO2 and water, catalyzed by carbonic anhydrase. The
hydrogen ions are actively secreted into the tubular lumen,
LUMEN
Filtered H2O CO2
HCO3–
Carbonic
anhydrase
– –
H+ H+ 3HCO3
+
Carbonic Na Na+
anhydrase ATP
H2O CO2
CHAPTER 47 Regulation of Acid–Base Balance 475
where they combine with filtered bicarbonate to form water
and carbon dioxide; thus, the filtered bicarbonate “disappears.”
At the same time, the cellular bicarbonate is transported across
the basolateral membrane into the interstitial fluid and then
into the peritubular capillary blood. The overall result is that
the bicarbonate filtered from the blood at the renal corpuscle
is converted to CO2 and water, replaced by bicarbonate that is
generated inside the cell. Thus, no net change in plasma bicar-
bonate concentration occurs. It is also important to note that
the hydrogen ion that was secreted into the lumen is not
excreted in the urine. It has been incorporated into water. Any
secreted hydrogen ion that combines with bicarbonate in the
lumen does not contribute to the urinary excretion of hydro-
gen ions, but only to the conservation of bicarbonate.
Specific transporters are required for these transmembrane
movements of hydrogen ions and bicarbonate. First, particu-
larly prominent in the apical membrane of the proximal tubule
is the Na–H antiporter (NHE3) as described in Chapter 44
and shown in Figure 47–2. This transporter is the major means
not only of hydrogen ion secretion, but also of sodium uptake
from the proximal tubule lumen. The same NHE3 antiporter
also mediates hydrogen ion secretion in the thick ascending
limb. Second, a primary active H-ATPase exists in all the
hydrogen ion–secreting distal tubular segments. The type A
intercalated cells of the collecting duct system possess this pri-
mary active H-ATPase as well as a primary active H,K-ATPase,
which simultaneously moves hydrogen ions into the lumen
and potassium into the cell, both actively (Figure 47–3).
The basolateral membrane exit step for bicarbonate gener-
ated when H ions are secreted is via Cl–HCO3 antiporters or
Na–HCO3 symporters (Figures 47–2 and 47–3), depending
on the tubular segment. In both cases, the movement of bicar-
bonate is down its electrochemical gradient (i.e., the exit step
is passive). Symport with sodium is the dominant means of
extruding bicarbonate in the proximal tubule and is particu-
larly interesting because the efflux of sodium is up its electro-
chemical gradient. This is a rare case of sodium active transport
INTERSTITIUM
FIGURE 47–2 Predominant proximal tubule mechanism
3HCO3
for reabsorption of bicarbonate. Hydrogen ions and bicarbonate
are produced intracellularly. The hydrogen ions are secreted via a
+ Na–H antiporter (member of the NHE family), while the bicarbonate
Na
is transported into the interstitium via an Na–3HCO3 symporter
K+
(member of the NBC family). Because more sodium enters via the
Na–H antiporter than leaves via the Na–3HCO3 symporter,
additional sodium is removed via the Na,K–ATPase. (Modified with
permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York,
NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)
476 SECTION VII Renal Physiology

LUMEN INTERSTITIUM

H2O CO2

Carbonic
anhydrase
ATP
+ + – –
H H HCO3 HCO3
ATP Cl–
H+ H+
K+

Cl–
A

LUMEN INTERSTITIUM

FIGURE 47–3 Type A and type B intercalated cells. H2O CO2

A) Predominant collecting tubule mechanisms in type A
intercalated cells for the secretion of hydrogen ions that Carbonic
result in formation of titratable acidity. The apical membrane anhydrase
ATP
contains H-ATPases and H,K-ATPases, which transport
+
hydrogen ions alone or in exchange for potassium. B) The – – H
HCO3 HCO3
type B intercalated cell secretes bicarbonate and Cl– ATP
simultaneously transports hydrogen ions into the H+
interstitium. The difference between this cell type and the K+
type A cell and those in the proximal tubule is that the
location of the transporters for hydrogen ions and Cl–
bicarbonate are switched between apical and basolateral B
membranes. (Modified with permission from Eaton DC, Pooler JP:
Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/
McGraw-Hill, Medical Pub. Division, 2009.)

that does not use ATP as the energy source, but uses the gradi-
ent of another ion. (However, this process can only occur if the
Na,K–ATPase sets up the Na gradient that powers the removal
of hydrogen ions via Na–H exchange in the apical mem-
brane.)
Through its secretion of hydrogen ions, the proximal
tubule reabsorbs 80–90% of the filtered bicarbonate. The
thick ascending limb of Henle’s loop reabsorbs another 10%,
and almost all the remaining bicarbonate is reabsorbed by
the distal convoluted tubule and collecting duct system
(although this depends on diet and other conditions; see later
discussion).
Throughout the tubule, intracellular carbonic anhydrase
is involved in the reactions generating hydrogen ion and
bicarbonate. In the proximal tubule, carbonic anhydrase is
also located in the lumen-facing surface of apical cell mem-
branes, and this carbonic anhydrase catalyzes the intralu-
minal generation of CO2 and water from the large quantities
of secreted hydrogen ions combining with filtered bicar-
bonate.
RENAL EXCRETION
OF ACID AND BASE
Acid or base loads generated from the processes described ear-
lier result in changes in plasma bicarbonate. In essence, an
acid or base load, regardless of original source, is turned into
an excess or deficit of bicarbonate. In response to base loads,
the process is relatively straightforward: we reabsorb most
of the filtered bicarbonate, but excrete just enough bicarbonate
in the urine to match the input. The kidneys do this in two
ways: (1) allow some filtered bicarbonate to pass through to
the urine and (2) secrete bicarbonate via type B intercalated
cells. The type B intercalated cells, which are found only in the
cortical collecting duct, do indeed secrete bicarbonate. In
essence, the type B intercalated cell is a “flipped-around” type
A intercalated cell (Figure 47–3B). Within the cytosol, hydro-
gen ions and bicarbonate are generated via carbonic anhy-
drase. However, the H-ATPase pump is located in the
basolateral membrane, and the Cl–HCO3 antiporter is in the

apical membrane. Accordingly, bicarbonate moves into the
tubular lumen and hydrogen ion is actively transported out of
the cell across the basolateral membrane and enters the blood,
where it combines with a bicarbonate ion and reduces plasma
bicarbonate. Thus, the overall process achieves the disappear-
ance of excess plasma bicarbonate and the excretion of bicar-
bonate in the urine.
How do the kidneys excrete an acid load, which always gener-
ates a bicarbonate deficit? First, they reabsorb all the filtered
bicarbonate. Then they secrete additional hydrogen ions that
attach to buffers in the tubular fluid other than bicarbonate. The
now protonated buffer is excreted. Meanwhile, the bicarbonate
generated in the cell is transported into the blood, replacing the
bicarbonate lost when the acid load entered the body. It is
important to realize that both parts of this process must occur,
that is, new bicarbonate and excretion of hydrogen ions on buf-
fers. If there were no new bicarbonate, plasma levels would not
be restored, and if hydrogen ions were not excreted, they would
react with and remove the bicarbonate just generated.
HYDROGEN ION EXCRETION
ON URINARY BUFFERS
We see that the identical transport process of hydrogen ion
secretion achieves both reabsorption of bicarbonate (without
new bicarbonate) and acid excretion, with addition of new
bicarbonate to the blood. At first glance, this seems like a con-
tradiction: how can the same process produce two different
end results? The answer lies in the fate of the hydrogen ion
once it is in the lumen. For secreted hydrogen ions that com-
bine with bicarbonate, we are simply replacing bicarbonate that
would have left the body. In contrast, when secreted hydrogen
ions combine with a nonbicarbonate buffer in the lumen, the
hydrogen ion is excreted, and the bicarbonate produced in the
cell and transported across the basolateral membrane is new
bicarbonate, not a replacement for filtered bicarbonate.
LUMEN INTERSTITIUM
Filtered
HPO42– H2O CO2
Carbonic
anhydrase
H+ H+ 3HCO3– 3HCO3–
H2PO4– Na + Na+
excreted
H2PO4–
CHAPTER 47 Regulation of Acid–Base Balance 477
There are two sources of tubular nonbicarbonate buffers:
filtration and synthesis. Normally, the most important filtered
buffer is phosphate, while ammonia is the most important
synthesized buffer. Ammoniagenesis is crucial to renal acid
excretion because its rate can be greatly increased in the face of
large acid loads, whereas the availability of filtered buffers,
while somewhat variable, is not regulated for purposes of acid
excretion. Figure 47–4 illustrates the sequence of events that
achieves hydrogen ion excretion on filtered phosphate and the
addition of new bicarbonate to the blood. It must be empha-
sized also that neither filtration per se nor excretion of free
hydrogen ions makes a significant contribution to hydrogen
ion excretion. First, the filtered load of free hydrogen ions,
when the plasma pH is 7.4 (40 nmol/L/H+), is less than 0.1
mmol per day. Second, there is a minimum urinary pH—
approximately 4.4—that can be achieved. This corresponds to
a free hydrogen ion concentration of 0.04 mmol/L. With a
typical daily urine output of 1.5 L, the excretion of free hydro-
gen ions is only 0.06 mmol per day, a tiny fraction of the nor-
mal 50–100 mmol of hydrogen ion ingested or produced every
day. To excrete these additional amounts of protons, they must
associate with tubular buffers.
PHOSPHATE AND ORGANIC
ACIDS AS URINARY BUFFERS
Free plasma phosphate exists in a mixture of monovalent
(acid) and divalent forms (base). In the following equation,
monovalent dihydrogen phosphate (on the left) is a weak acid,
and divalent monohydrogen phosphate (on the right) is its
conjugate base:
→ HPO 2– + H+
H2PO4– ← (5)
4
We can write the above equation in the form of the
Henderson–Hasselbalch equation:
FIGURE 47–4 Excretion of hydrogen ions on filtered
phosphate. Divalent phosphate (base form) that has been filtered
and not reabsorbed reaches the collecting tubule, where it
combines with secreted hydrogen ions to form monovalent
phosphate (acid form), which is then excreted in the urine. The
bicarbonate entering the blood is new bicarbonate, not merely a
replacement for filtered bicarbonate. (Modified with permission from
Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange
Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)
478 SECTION VII Renal Physiology
[HPO 2–]
pH = 6.8 + log _______
4
[H PO –]
(6)
2 4
At the normal plasma pH of 7.4, we find that about 80% of the
plasma (and filtered) phosphate is in the base (divalent) form
and 20% is in the acid (monovalent) form. As the tubular fluid
is acidified in the collecting ducts, most of the base form takes
up secreted hydrogen ions. Depending on final urine pH, most
of the base (HPO42−) has been protonated to acid (H2PO4−).
The secreted hydrogen ions that combined with the base form
are excreted, and the bicarbonate that was generated intracel-
lularly enters the blood. How much phosphate is available for
this process? The amount is somewhat variable, depending on
a number of factors (see Chapter 48), but a typical plasma
concentration is about 1 mmol/L, of which about 90% is free
(the rest being loosely bound to plasma proteins). At a GFR of
180 L per day, the total filtered load of phosphate is about
160 mmol per day. The fraction reabsorbed is also variable:
from 75% to 90%. Thus, unreabsorbed divalent phosphate
available to take up secreted hydrogen ions amounts to roughly
40 mmol per day. In other words, the kidneys can excrete acid
loads using the phosphate buffer system at a rate of about 40
mmol per day. However, the availability of phosphate cannot
be easily increased to increase acid excretion.
HYDROGEN ION EXCRETION
ON AMMONIUM
Ordinarily, hydrogen ion excretion associated with phosphate
and other filtered buffers is not sufficient to balance the nor-
mal hydrogen ion production of 50–100 mmol per day nor can
it take care of any unusually high (usually pathological) pro-
duction of acid loads. To excrete the rest of the hydrogen ions
and achieve balance, there is a second means of excreting
hydrogen ions that involves ammoniagenesis and excretion of
hydrogen ions as ammonium. Quantitatively, far more hydro-
gen ions can be excreted by means of ammonium than via fil-
tered buffers. There are many nuances to hydrogen ion
excretion via ammonium, but the basic concepts are straight-
forward.
As described in Chapter 43, the catabolism of protein and
oxidation of the constituent amino acids by the liver generates
CO2, water, urea, and some glutamine. Although the metabo-
lism of the side chains of amino acids can lead to addition of
acid or base, the processing of the core of an amino acid—the
carboxyl group and amino group—is acid–base neutral. After
many intermediate steps, processing of the carboxyl group of
the amino acid produces bicarbonate, and processing of the
amino group produces ammonium. Processing does not stop
there, however, because ammonium in more than minuscule
levels is quite toxic. Ammonium is further processed by the
liver to either urea or glutamine. In both cases, each ammo-
nium consumed also consumes a bicarbonate. Thus, the bicar-
bonate produced from the carboxyl group is just an intermediate,
consumed as fast as it is made, and the process as a whole is
acid–base neutral. We can write this process as follows:
2 amino acids (+oxygen) 2NH4+ + 2HCO3–
(7)
Urea or glutamine (+ CO2 and water)
When the urea (or glutamine) is excreted, the body has com-
pleted the catabolism of protein in a manner that promotes
total body nitrogen balance, and is acid–base neutral.
The renal handling of urea is somewhat complicated from
the osmotic point of view, as described in earlier chapters, but
is acid–base neutral. Glutamine, however, is different.
Although the production of glutamine by the liver is acid–base
neutral, it is important to recognize that glutamine can be
thought to contain the two components from which it was
synthesized: a base component (bicarbonate) and an acid
component (ammonium). Ammonium is the protonated form
of ammonia. It is an acid because it contains a dissociable pro-
ton as shown in equation (8). The pK of ammonium is near
9.2, making it an extremely weak acid (i.e., only at high pH will
it release its proton), but it is an acid nevertheless. At physio-
logical pH, over 98% of the total exists as ammonium, and less
than 2% exists as ammonia. For renal acid–base purposes, this
is a good thing because virtually all excreted ammonia is in the
protonated form and takes a hydrogen ion with it:
→ H+ + NH
NH4+ ← (8)
3
Glutamine released from the liver is taken up by proximal
tubule cells, both from the lumen (filtered glutamine) and
from the renal interstitium. The cells of the proximal tubule
then convert the glutamine back to bicarbonate and NH4+, in
essence reversing what the liver has done. The NH4+ is secreted
into the lumen of the proximal tubule, and the bicarbonate
exits into the interstitium and then into the blood
(Figure 47–5A). This is new bicarbonate, just like the new
bicarbonate generated by titrating nonbicarbonate buffers.
Further processing of the NH4+ is complicated, but eventually
the ammonium is excreted (Figure 47–5C).
The ammonium ion has interesting chemical properties in
that it can masquerade as other ions, in some cases as a hydro-
gen ion and in other cases as a potassium ion. This is because
some transporters and some channels are not completely
selective for the species they usually move compared with
ammonium. As the concentration of ammonium rises, there is
an increasing tendency for ammonium to substitute for these
other ions and “sneak” its way across membranes.
Also, whenever ammonium is present in body fluids, a small
fraction (2% at physiological pH) always exists as ammonia
because the dissociation, although limited in extent, is nearly
instantaneous. Ammonium, being a small hydrated ion, is
essentially impermeant in lipid bilayers and must be handled
by channels or transporters if it is to move across membranes,
but the neutral ammonia has a finite permeability. In terms of
cellular handling, cells sometimes transport ammonium as
such and at other times transport ammonia and a proton in
parallel, the end result being the same in both cases.
It would “make sense” if the ammonium secreted into the
proximal tubule simply stayed in the lumen and was excreted,
but the kidneys have a more complicated way of doing
 CHAPTER 47 Regulation of Acid–Base Balance 479

LUMEN INTERSTITIUM LUMEN INTERSTITIUM

NH4+

Filtered
glutamine
glutamine 2CI– NH3 NH4+
H+
Na+
NH4+ HCO3
–
HCO3
– Na+
NH4+
Na+ NH4 +
Na+
K+
NH4+ NH4+
Na+
NH4+
(to thick
A ascending B
limb)

LUMEN INTERSTITIUM

ATP
Na+
ATP
K+ NH3 NH4+

H+ H+ H+

+ NH3
NH4 NH3
NH3 NH3

C (excretion)

FIGURE 47–5 Ammoniagenesis and excretion. A) Ammonium production from glutamine. Glutamine is originally synthesized in
the liver from NH4+ and bicarbonate. When glutamine reaches the proximal tubule cells, it is converted via several intermediate steps (not
shown) back to NH4+ and bicarbonate. B) Ammonium reabsorption in the thick ascending limb. Ammonium reaches the thick ascending
limb from two sources. Most comes as a result of secretion in the proximal tubule. Some also enters the thin limbs from the medullary
interstitium in the form of neutral ammonia and is subsequently reprotonated in the lumen (ammonium recycling). Ammonium is
reabsorbed in the thick ascending limb by several mechanisms, the predominant one being entrance via the NKCC multiporter (where
ammonium substitutes for potassium). C) Ammonium secretion in the inner medulla. Several mechanisms are involved. A prominent one
involves uptake and secretion of neutral ammonia via specific transporters in parallel with hydrogen ion secretion, resulting in reformation
of ammonium in the lumen. In the innermost medulla, the high interstitial ammonium concentration allows ammonium to substitute for
potassium on the Na,K–ATPase. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/
McGraw-Hill, Medical Pub. Division, 2009.)

things. An array of channels and transporters participates in
moving ammonium or ammonia into or out of the tubule in
various segments. So long as all the ammonium produced
from glutamine and secreted in the proximal tubule ends up
being excreted, the process accomplishes the goal of excret-
ing acid, even if ammonium is transported as such in some
places and moved as H+ and NH3 separately in other places.
But if ammonium is returned to the circulation, it is metab-
olized by the liver back to urea, consuming bicarbonate in
the process, thereby nullifying the renal generation of bicar-
bonate.
Most of the ammonium synthesized from glutamine in the
proximal tubule is secreted via the NHE3 antiporter in exchange
for sodium (with ammonium substituting for a hydrogen ion);
but some may also diffuse into the lumen as ammonia and then
combine with a secreted hydrogen ion. The next major trans-
port event occurs in the thick ascending limb (Figure 47–5B).
In this segment about 80% of the tubular ammonium is reab-
sorbed, mostly by the Na–K–2Cl multiporter (with ammo-
nium now substituting for potassium). In the medullary
portions of the thick ascending limb, this reabsorption results
in accumulation of ammonium (and therefore some ammonia)
480 SECTION VII Renal Physiology

in the interstitium, with the concentration progressively increas- TABLE 47–2 Renal contribution of new bicarbonate
ing toward the papilla, analogous to the osmotic gradient. The to the blood in different states.
high interstitial concentration surrounding the loops of Henle
leads to some secretion of ammonia into the thin descending Alkalosis Normal State Acidosis
limbs, where the ammonia becomes protonated in the lumen.
Titratable acid 0 20 40
Therefore, there is a certain amount of recycling, with the con- (mmol per day)
sequence that a considerable amount of ammonium is trapped
Plus NH4+ excreted 0 40 160
in the medullary interstitium (similar to the situation with (mmol per day)
urea). Finally, in the medullary collecting ducts, there is secre-
tion, mainly by parallel transport of hydrogen ions and ammo- Minus HCO3− 80 1 0
excreted (mmol
nia. Thus, the ammonium that was reabsorbed in the thick per day)
ascending limb and accumulated in the medullary interstitium
Total (mmol per day) –80 (lost 59 (added 200 (added
is now put back into the tubule and excreted. from body) to body) to body)

Urine pH 8.0 6.0 4.6

QUANTIFICATION OF RENAL Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

ACID–BASE EXCRETION
We can now quantify the excretion of acid/base equivalents by
looking at three quantities in the urine: (1) the amount of
titratable acidity, (2) the amount of ammonium, and (3) the
amount of bicarbonate, if any. Titratable acidity can be mea-
sured by titrating the urine with strong base (NaOH) to a pH
of 7.4. (The amount of NaOH required to increase the pH back
to 7.4 must equal the amount of hydrogen ion that was secreted
and combined with phosphate and organic buffers.) Urinary
ammonium equals the urinary volume times the urinary
ammonium concentration. (Ammonium does not contribute
to titratable acidity because with a pK of 9.2, few hydrogen
ions are removed by titration to pH 7.4.) Similarly, urinary
bicarbonate equals the urinary volume times the urinary
bicarbonate concentration.
Thus, we can write the net acid excretion as:
Net acid excretion =
(9)
Titratable acid excreted + NH4+ excreted – HCO3– excreted
Note that there is no term for free hydrogen ion in the urine
because, even at a minimum urine pH of 4.4, the number of
free hydrogen ions is trivial.
Typical urine data for the amounts of bicarbonate contrib-
uted to the blood by the kidneys in three potential acid–base
states are given in Table 47–2. Note that in response to acido-
sis, as emphasized previously, increased production and excre-
tion of NH4+ is quantitatively much more important than
increased formation of titratable acid.
REGULATION OF THE RENAL
HANDLING OF ACIDS AND BASES
Renal acid–base processing is regulated in response to different
body conditions. The key regulatory signals are the concentra-
tions of free hydrogen ions and CO2 in the fluids to which the
various transport elements are exposed, that is, the pH and Pco2
of the interstitium and cytosol within renal cells. There are no
known neural or hormonal signals conveying acid–base infor-
mation to the kidneys. In effect, the kidneys act as “pH meters”
and Pco2 detectors and adjust their transport of hydrogen ion
and ammonium excretion accordingly. Hydrogen ion transport
is also stimulated independently by aldosterone.
An increase in Pco2, as occurs during respiratory acidosis
due to hypoventilation, produces a decrease in plasma pH
and, thereby, signals an increased tubular hydrogen ion secre-
tion. A decrease in Pco2, as occurs during respiratory alkalosis
due to hyperventilation, causes a decrease in secretion.
Because the tubular membranes are quite permeable to CO2,
an altered arterial Pco2 causes an equivalent change in Pco2
within the tubular cells. In turn, this causes altered intracel-
lular hydrogen ion concentration by driving the reactions
shown in equations (4a) and (4b) to the right or left. This
change in intracellular pH, along with signals generated in
response to altered Pco2 at the basolateral surface, adjusts the
rate of hydrogen ion secretion.
We can see that these renal responses are appropriate. If the
Pco2 is high (causing a decrease in plasma pH), the increased
hydrogen ion secretion increases plasma bicarbonate, thereby
increasing plasma pH closer to normal (despite the continued
high Pco2). Similarly, if the pH is low because of low bicarbon-
ate, the new bicarbonate restores the bicarbonate (and, there-
fore, the pH) toward normal.
CONTROL OF RENAL GLUTAMINE
METABOLISM AND AMMONIUM
EXCRETION
In addition to regulating hydrogen ion secretion per se, there
are several homeostatic controls over the production and
tubular handling of NH4+. First, the generation of glutamine
by the liver is increased by low plasma pH. In this case, the
liver shifts some of the disposal of ammonium ion from urea
to glutamine. Second, the renal metabolism of glutamine is

TABLE 47–3 Summary of processes that acidify or
alkalinize the blood.
Nonrenal mechanisms of acidifying the blood
Consumption and metabolism of protein (meat) containing acidic
or sulfur-containing amino acids
Consumption of acidic drugs
Metabolism of substrate without complete oxidation (fat to ketones
and carbohydrate to lactic acid).
GI tract secretion of bicarbonate (puts acid in blood)
Nonrenal mechanisms of alkalinizing the blood
Consumption and metabolism of fruit and vegetables containing
basic amino acids or the salts of weak acids
Consumption of antacids
Infusion of lactated Ringer’s solution
GI tract secretion of acid (puts bicarbonate in the blood)
Renal mechanisms of acidifying the blood
Allow some filtered bicarbonate to pass into the urine
Secrete bicarbonate (type B intercalated cells)
Renal means of alkalinizing the blood
Secrete protons that form urine titratable acidity
(type A intercalated cells)
Excrete NH4+ synthesized from glutamine
GI, gastrointestinal.
Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,
7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.
also subject to control by extracellular pH. A decrease in extra-
cellular pH stimulates renal glutamine oxidation by the proxi-
mal tubule, whereas an increase does just the opposite. Thus,
an acidosis that lowers plasma pH, by stimulating renal glu-
tamine oxidation, causes the kidneys to contribute more new
bicarbonate to the blood, thereby counteracting the acidosis.
This pH responsiveness increases over the first few days of an
acidosis and allows the glutamine–NH4+ mechanism for new
bicarbonate generation to become the predominant renal pro-
cess for opposing the acidosis. Conversely, an alkalosis inhibits
glutamine metabolism, resulting in little or no renal contribu-
tion of new bicarbonate via this route.
Table 47–3 provides a summary of the processes of adding
acids and bases to the body fluids. The unifying and, therefore,
simplifying principle is that all processes of acid or base addi-
tion boil down to addition or loss of bicarbonate. All processes
that acidify the blood end up removing bicarbonate, and all
processes that alkalinize the blood end up adding bicarbonate.
ACID–BASE DISORDERS
AND THEIR COMPENSATION
In this section we briefly address the topic of acid–base disorders
in the context of the kidney. This topic is covered more thor-
oughly in the context of the respiratory system in Chapter 37.
Acid–base disorders develop when either arterial Pco2, bicar-
bonate, or both deviate from their normal range. Clinicians
CHAPTER 47 Regulation of Acid–Base Balance 481
assign acid–base disorders to the following four categories: (1)
high Pco2 is a respiratory acidosis, (2) low Pco2 is a respiratory
alkalosis, (3) low bicarbonate is a metabolic acidosis, and (4)
high bicarbonate is a metabolic alkalosis:
[Bicarbonate]
pH = 6.1 + log __________
0.03 P (10)
co2
It should be clear from the Henderson–Hasselbalch equation
[equation (10)] for the CO2–bicarbonate buffer system that
changing either the Pco2 or the bicarbonate concentration
increased or decreases the pH. If only one of these is changed,
it is called a primary uncompensated disorder. In most cases
the situation is more complicated because there is at least
some, and usually considerable, compensation. Compensa-
tion exists when either Pco2 or bicarbonate levels remain altered
for a period of time and the body changes the other variable in
the same direction. For example, if the Pco2 is abnormally low,
renal compensation consists of reducing plasma bicarbonate.
Similarly, if bicarbonate is abnormally low, respiratory com-
pensation consists of reducing arterial Pco2. The compensatory
changes bring the ratio of bicarbonate to Pco2 closer to a nor-
mal value, and therefore minimize the change in pH. However,
compensation for an acid–base disorder is not correction,
because even if the compensation has returned the pH to the
normal range, both Pco2 and bicarbonate values are still abnor-
mal. Consider a case where the Pco2 is too high (respiratory
acidosis) due to hypoventilation (review Chapter 37). The
body compensates by increasing bicarbonate. If bicarbonate is
increased high enough, this restores pH to the normal range;
however, it does not correct the original respiratory problem
that resulted in an increased Pco2 . The same logic applies to any
other acid–base disorder.
The astute reader may recognize a potential problem in the
interpretation of acid–base disorders. When any acid–base
disorder is well compensated, that is, the degree of compen-
sation is such that the pH is in the normal range, both the
Pco2 and bicarbonate are increased or decreased in the same
direction. Suppose both the Pco2 and bicarbonate are high.
Is this a respiratory acidosis with renal compensation, or is
it a metabolic alkalosis with respiratory compensation?
Fortunately in a clinical setting it would be rare not to have
additional information. For example, the high Pco2 of chronic
bronchitis patient is, in all likelihood, a respiratory acidosis
resulting from impaired ventilation, not a compensation for
a metabolic alkalosis. Nevertheless, in real life there are often
mixed acid–base disorders that indeed present a challenge in
the clinic.
RENAL RESPONSE TO RESPIRATORY
ACIDOSIS AND ALKALOSIS
In a respiratory acidosis, the low alveolar ventilation causes
an increase in Pco2, in turn causing a decrease in pH. The pH
would be restored to normal if the bicarbonate were increased
to the same degree as Paco2. The normal kidneys respond to the
482 SECTION VII Renal Physiology
increased Pco2 by contributing new bicarbonate to the blood in
the manner previously described.
The renal compensation in response to respiratory alkalosis is
just the opposite. Respiratory alkalosis is the result of hyperven-
tilation, as occurs at high altitude (see Chapter 71), in which the
person transiently eliminates carbon dioxide faster than it is pro-
duced, thereby decreasing Pco2 and increasing pH. The decreased
Pco2 and increase in extracellular pH signal reduced tubular
hydrogen ion secretion and increased bicarbonate secretion.
Bicarbonate is lost from the body, and the loss results in decreased
plasma bicarbonate and a return of plasma pH toward normal.
There is no titratable acid in the urine (the urine is alkaline in
these conditions), and there is little or no NH4+ in the urine
because the alkalosis inhibits NH4+ production and excretion.
RENAL RESPONSE TO
METABOLIC ACIDOSIS
There are many possible causes of metabolic acidosis, includ-
ing the kidneys themselves. These include (1) increased input
of acid by ingestion, infusion, or production; (2) decreased
renal production of bicarbonate, as in renal failure; or (3)
direct loss of bicarbonate from the body, as in diarrhea. The
result is the same regardless of whether there is loss of bicar-
bonate or addition of hydrogen ions: that is, a lower concen-
tration of bicarbonate and a lower plasma pH. The renal
response (if the kidneys are not the cause) is to produce more
bicarbonate, thereby returning pH toward normal. (Note that
this is a response, not compensation, because the primary
problem is not a respiratory change in Pco2.) To do this, the
kidneys must reabsorb all the filtered bicarbonate and contrib-
ute more new bicarbonate through increased formation and
excretion of NH4+ and titratable acid. This is precisely what
healthy kidneys do in the case of any acid load, but if the acid
load is too great or the problem is in the kidneys themselves,
the bicarbonate concentration will remain low.
FACTORS CAUSING THE KIDNEYS
TO GENERATE OR MAINTAIN A
METABOLIC ALKALOSIS
The normal kidneys are able to excrete large amounts of bicar-
bonate. However, in some situations, the kidneys fail to do
this, and thereby either generate a metabolic alkalosis or main-
tain a metabolic alkalosis that originates from another cause.
Recall that secretion of hydrogen ions, after all filtered bicar-
bonate has been reabsorbed, generates new bicarbonate. Also
recall that secretion of hydrogen ions is coupled to the reab-
sorption of sodium in the proximal tubule and thick ascend-
ing limb, and that some is coupled to the reabsorption of
potassium in the distal nephron. Some conditions that signal
strong reabsorption of sodium or potassium ions have the
undesired effect of causing the secretion of too many hydro-
gen ions. The most important situations in which this occurs
are (1) volume contraction, (2) chloride depletion, and (3) the
combination of aldosterone excess and potassium depletion.
In any metabolic alkalosis, by definition the plasma bicarbon-
ate concentration is elevated. This problem is not a defect in the
ability of the kidneys to excrete bicarbonate; if a person is fed a
large load of bicarbonate, the kidneys can excrete the load with-
out a major increase in bicarbonate levels. The problem seems to
be in regulation of bicarbonate excretion. The key event in all
these situations is oversecretion of hydrogen ion (and sometimes
of NH4+ as well), either producing a metabolic alkalosis or fail-
ing to respond as usual to an existing metabolic alkalosis.
INFLUENCE OF EXTRACELLULAR
VOLUME CONTRACTION
The presence of total body volume contraction because of salt
loss stimulates sodium reabsorption, and also hydrogen ion
secretion because the transport of these ions is linked via the
Na/H antiporters in the proximal tubule. In addition, the renin–
angiotensin system (RAS) is usually activated, resulting in
stimulation of aldosterone secretion. Besides stimulating
sodium reabsorption, aldosterone stimulates hydrogen ion
secretion by type A intercalated cells. The net result is that all
the filtered bicarbonate is reabsorbed so that the already ele-
vated plasma bicarbonate associated with the preexisting meta-
bolic alkalosis is locked in, and the plasma pH remains high.
The urine, instead of being alkaline, as it should be when the
kidneys are normally responding to a metabolic alkalosis, is
somewhat acid. The generation or maintenance of a metabolic
alkalosis in volume contraction may also occur when the vol-
ume is normal or high but the body “thinks” volume is low, spe-
cifically in congestive heart failure and advanced liver cirrhosis.
INFLUENCE OF CHLORIDE DEPLETION
We referred to extracellular volume contraction without dis-
tinguishing between sodium and chloride losses as the cause
because loss of either of these ions will lead to extracellular vol-
ume contraction. However, we emphasize that specific chloride
depletion, in a manner independent of and in addition to extra-
cellular volume contraction, helps maintain metabolic alkalo-
sis by stimulating hydrogen ion secretion. The most common
reasons for chloride depletion are chronic vomiting and heavy
use of diuretics. The result is that bicarbonate excretion remains
essentially zero, and the metabolic alkalosis is not corrected.
INFLUENCE OF ALDOSTERONE
EXCESS AND SIMULTANEOUS
POTASSIUM DEPLETION
As noted, aldosterone stimulates hydrogen ion secretion.
Potassium depletion, by itself, also weakly stimulates tubu-
lar hydrogen ion secretion and NH4+ production. However,
 CHAPTER 47 Regulation of Acid–Base Balance 483

Extensive use of
diuretics

Extracellular-
volume contraction Potassium depletion

Renin secretion

Plasma renin
(Helps maintain the alkalosis)

Plasma angiotensin II

Aldosterone secretion

Plasma aldosterone

FIGURE 47–6 Pathway by which overuse

Tubular secretion of hydrogen ion
Reabsorption of all filtered bicarbonate and
contribution of new bicarbonate to blood
Generation of metabolic alkalosis
of diuretics leads to a metabolic alkalosis. NH4+
production and excretion are increased by the
presence of a high aldosterone and potassium
depletion. The extracellular volume contraction,
via both aldosterone and as yet unidentified
nonaldosterone mechanisms, helps to maintain
the alkalosis once it has been generated. If the
diuretics have also caused chloride depletion, this
too will contribute to the maintenance of the
metabolic alkalosis (not shown). (Modified with
permission from Eaton DC, Pooler JP: Vander’s Renal
Physiology, 7th ed. New York, NY: Lange Medical Books/
McGraw-Hill, Medical Pub. Division, 2009.)

the combination of potassium depletion of even moderate diuretic use for weight loss) that can generate a metabolic
degree and high levels of aldosterone stimulates tubular alkalosis (Figure 47–6).
hydrogen ion secretion markedly (NH4+ production also
increases significantly). As a result, the renal tubules not
only reabsorb all filtered bicarbonate, but also contribute
inappropriately large amounts of new bicarbonate to the CLINICAL CORRELATION
body, thereby causing metabolic alkalosis. Note that there
A 7-year-old boy is brought by his mother to his pediatri-
may have been nothing wrong with the acid–base balance to
cian. The boy has been vomiting on and off for over a day
start with: the alkalosis is actually generated by the kidneys
and has not been able to eat or drink anything. He seems
themselves. Of course, if alkalosis were already present, this
jittery and complains of tingling around his mouth. His
high aldosterone–potassium depletion combination would
blood pressure is 107/77, and his heart rate is 89. After the
not only prevent the kidneys from responding appropriately,
pediatrician notes signs of dehydration, he directs them to
but would also make the alkalosis worse. This phenomenon
a local hospital ER. At the hospital, blood gas analysis
is important because the combination of a markedly elevated
shows an arterial pH of 7.52 and Pco2 of 45 mm Hg, for a
aldosterone and potassium depletion occurs in a variety of
calculated bicarbonate of 36 mEq/L, which is high. Analy-
clinical situations, the most common of which is the exten-
sis of his urine, which is scant, yields a chloride of 17 mEq/L,
sive use of diuretic drugs (e.g., from extensive, inappropriate
484 SECTION VII Renal Physiology
which is low. He is given intravenous normal saline (0.9%
NaCl) and an antiemetic to reduce the vomiting.
The boy has lost a lot of hydrogen ions, chloride, and
water, resulting in hypovolemia and a metabolic alkalosis.
The relatively rapid development of the alkalosis leads to a
transient hypocalcemia (see Chapter 48), in turn leading to
hyperexcitability of peripheral neurons, tending to produce
muscle spasms and perioral tingling. His slightly high Pco2
represents a partial compensation for the alkalemia. His
body responds to the volume depletion by decreasing the
excretion of salt and water via decreased GFR and activa-
tion of the RAS, which stimulates sodium reabsorption.
Given the elevated plasma bicarbonate, the kidneys should
begin excreting bicarbonate, but it is difficult for them to
do so in the face of the volume depletion. First, aldosterone
is stimulating the type A intercalated cells to secrete hydro-
gen ions, just the opposite of what is needed. Second, it is
difficult for the type B intercalated cells to increase their
secretion of bicarbonate, a process that is accomplished by
exchanging cellular bicarbonate for luminal chloride via an
antiporter. Less luminal chloride is available to exchange
with bicarbonate due to upstream reabsorption. Since there
is no renal pathology per se, and the vomiting is transient,
his case can be treated by replacing fluid loss and restoring
chloride.
CHAPTER SUMMARY
■ Plasma pH is regulated by controlling the concentrations of
CO2 (Pco2) and bicarbonate.
■ Fixed acid or base loads are turned into excesses or deficits of
bicarbonate in the body.
■ Fixed acids and bases can enter the body via GI processes,
metabolism, intravenous infusions, and renal processes.
■ Under all conditions, the kidneys must recover virtually all
filtered bicarbonate.
■ The kidneys excrete acid by means of filtered or synthesized
urinary buffers.
■ Phosphate is the most important filtered urinary buffer.
■ The kidneys excrete acid by converting glutamine to bicarbon-
ate and ammonium, excreting the ammonium, and returning
the bicarbonate to the blood.
■ Primary acid–base disorders that change either Pco2 or
bicarbonate can be compensated by changing the other variable
in the same direction, thereby preserving the ratio of bicarbon-
ate to Pco2.
■ Some situations, including volume contraction and aldosterone
excess, can cause the kidneys to excrete too much acid,
generating a metabolic alkalosis.
STUDY QUESTIONS
1. A patient excretes 2 L of alkaline (pH 7.6) urine having a
bicarbonate concentration of 28 mmol/L. What do we know
about titratable acid excretion?
A) It is 56 mmol.
B) There is negative titratable acidity.
C) Titratable acid plus ammonium sums to 56 mmol.
D) We cannot determine without data for ammonium and
phosphate.
2. Which of the following is an acid load per se or becomes an acid
load after metabolism?
A) eating a large steak
B) eating unsweetened grapefruit juice
C) eating sweetened grapefruit juice
D) intravenous infusion of sodium lactate
3. How does the proximal tubule handle filtered bicarbonate?
A) Bicarbonate is taken up by the tubular cells on a symporter
with sodium.
B) Bicarbonate is taken up by the tubular cells via antiport with
small base anions (e.g., formate).
C) Bicarbonate is taken up by the tubular the cells via antiport
with chloride.
D) Bicarbonate combines with a proton in the lumen and is
converted to carbon dioxide and water.
4. In which situation(s) would you expect to see decreased or no
renal excretion of acid equivalents?
A) during a major metabolic acidosis such as diabetic
ketoacidosis
B) during a time when the pancreas is secreting a high amount
of bicarbonate-rich fluid into the GI tract
C) in response to consuming a large number of antacid tablets
D) all of the above situations
5. What is the fate of ammonium secreted in the proximal tubule?
A) It flows through to the urine.
B) It is mostly reabsorbed in the collecting ducts.
C) It is mostly reabsorbed in the thick ascending limb and
secreted again in the collecting ducts.
D) It is mostly reabsorbed in the thick ascending limb and
combined with bicarbonate to form urea.
6. A person develops a decreased arterial Pco2 because of
hyperventilation. If this condition persists, what kind of response
would we expect by the kidneys?
A) more urinary titratable acidity
B) more urinary bicarbonate
C) more urinary ammonium
D) a decreased urinary pH
 48
C H A P T E R

Regulation of Calcium
and Phosphate Balance
Douglas C. Eaton and John P. Pooler

O B J E C T I V E S

■ State the normal total plasma calcium concentration and the fraction that is
free.
■ Describe the distribution of calcium between bone and extracellular fluid
and the role of bone in regulating extracellular calcium.
■ Describe and compare the roles of the gastrointestinal tract and kidneys in
calcium balance.
■ Describe and compare bone remodeling and calcium buffering by bone.
■ Describe the role of vitamin D in calcium balance.
■ Describe how the synthesis of the active form of vitamin D (calcitriol)
is regulated.
■ Describe the regulation of parathyroid hormone secretion, and state the
major actions of parathyroid hormone.
■ Describe renal handling of phosphate.
■ Describe how parathyroid hormone changes renal phosphate excretion.

OVERVIEW to complex with phosphate is a key aspect of the normal for-

Calcium plays a key role in a multitude of physiological pro-
cesses. Therefore, it is essential to regulate both the total
amount of calcium in the body and its plasma concentration.
Regulation is accomplished by the cooperative effort of several
organ systems, including the gastrointestinal (GI) tract (Chap-
ter 52), the endocrine system (Chapter 64), and the kidneys.
The importance of calcium centers on its being (1) a structural
component of bone, (2) an intermediate in intracellular sig-
naling cascades, and (3) a regulator of the conformation of
membrane proteins. These functions derive largely from the
chemical properties of the calcium cation. Unlike sodium,
potassium, and magnesium, calcium is “sticky,” meaning that
it avidly binds to anionic sites on proteins and readily forms
complexes with small anions such as phosphate and citrate.
These associations have consequences for physiological func-
tion. When calcium binds and unbinds from membrane pro-
teins, this alters the net charge, and hence the conformation of
those proteins. In the case of voltage-gated channels, this
affects membrane excitability (see Chapter 2). The propensity
mation and maintenance of bone structure. Furthermore,
when levels of calcium and/or small anions such as phosphate
are increased, they approach the solubility limit of the com-
plexes, leading to pathologies such as the formation of stones
in the urinary tract and deposition of calcium complexes in
soft tissue. For these reasons, the body possesses elaborate
means to regulate plasma calcium.
While calcium obeys the principles of input–output balance
as do the other substances we have discussed, its regulation is
fundamentally different. First, whole body calcium balance is
regulated predominantly by input rather than output. Control
of input from the GI tract is a crucial determinant of whole
body calcium. Output by the kidneys plays an important, but
secondary, role.
Second, moment-to-moment regulation of plasma calcium
is achieved by shifting calcium in and out of bone. Bone stores
of calcium are an enormous buffer system that keeps plasma
calcium nearly constant regardless of whole body balance.
Thus, ordinary variations in ingestion and excretion have little
effect on plasma levels because of this tight buffering.

485

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486 SECTION VII Renal Physiology
The long-term regulation of total calcium in bone is, of course,
important for bone growth during childhood and bone integ-
rity in adult life. Here the kidneys play an important but indi-
rect role because they (1) excrete calcium in the urine and (2)
are involved in forming the active form of vitamin D, which is
a major controller of GI input.
Normal levels of plasma calcium are about 10 mg/dL
(2.5 mmol/L or 5 mEq/L). This calcium exists in three general
forms. First, almost half is in the free ionized (Ca2+) form. This
is the only form that is biologically active in target organs.
Second, about 15% is complexed to anions with relatively low
molecular weights, such as citrate and phosphate. Third, the
remaining 40% is reversibly bound to plasma proteins.
EFFECTOR SITES
FOR CALCIUM BALANCE
GI TRACT
Most dietary calcium simply passes through the GI tract to the
feces. The amount absorbed depends on many factors, includ-
ing the quantity of calcium in the diet. Some of the calcium
that is absorbed moves by a regulated active transcellular pro-
cess in the duodenum, while the majority is absorbed by
unregulated paracellular diffusion in the rest of the small
intestine. In the active transport system calcium enters duode-
nal cells passively through calcium-selective channels, binds
reversibly to mobile cytosolic calcium-binding proteins (called
calbindins), and is then actively transported out the basolat-
eral side via a Ca-ATPase and to some extent by a Na–Ca anti-
porter. Calbindins contain multiple binding sites for calcium
and are free to diffuse throughout the cytosol. They act as ferry
boats for calcium, permitting large amounts of calcium to
move from place to place within a cell, in this case from apical
to basolateral membrane, all the while keeping the concentra-
tion of free calcium at a low level (see Figure 48–1).
KIDNEYS
The kidneys handle calcium by filtration and reabsorption.
The free component of plasma calcium is freely filterable.
Most of the filtered calcium is reabsorbed in the proximal
tubule (about 60% of the filtered load) and the remainder in
the thick ascending limb of Henle’s loop, distal convoluted
tubule, and collecting duct system. Overall reabsorption is
normally 97–99%, leaving only a few percent of the filtered
load to be excreted.
Calcium reabsorption in the proximal tubule and thick
ascending limb of Henle’s loop is largely passive and paracel-
lular, and the electrochemical forces driving it are dependent
directly or indirectly on sodium reabsorption as they are for so
many other substances. In contrast, calcium reabsorption in
the more distal segments is active and transcellular. It uses the
same general mechanism as in the GI tract; that is, entrance
Lumen Interstitium
ATP
Calbindin Ca
Ca Ca
Ca
Ca Ca
Na
Ca
FIGURE 48–1 Generic method for transcellular calcium
transport in the GI tract and kidney. In all body cells the free
intracellular calcium concentration must be kept to minuscule levels
to prevent formation of insoluble complexes and activation of
deleterious signaling pathways, even though the concentrations of
calcium at the two external surfaces of the cells are thousands of
times higher. The epithelial cells accomplish this by using diffusible
calbindins. As calcium enters the cells through channels in the
luminal surface, the calcium concentration in the microenvironment
near the channels is slightly raised, thus promoting the binding of
calcium to calbindins. At the basolateral surface active extrusion of
calcium via ATPases and sodium–calcium antiporters lowers the
calcium concentration in the local microenvironment, promoting
dissociation of calcium from the calbindins. Ion charge symbols (Ca2+
and Na+) omitted for clarity.
via calcium-specific channels, diffusion bound to calbindins,
and active exit across the basolateral membrane by a combina-
tion of Ca-ATPase and Na–Ca antiport activity (Figure 48–2).
Endocrine control of renal calcium handling is exerted in the
distal tubule.
The amount of calcium excreted in the urine, when averaged
over time, is equal to the net addition of new calcium to the
body via the GI tract; thus, the kidneys help maintain a stable
balance of total body calcium. However, the change in renal
excretion in response to changes in dietary input is much less
than the equivalent responses to dietary sodium, water, or
potassium. For example, only about 5% of an increment in
dietary calcium appears in the urine, whereas virtually all of an
increased ingestion of water or sodium soon appears in the
urine. The reason is that most of the dietary increment never
gains entry to the blood because it fails to be absorbed from the
GI tract. In contrast, when dietary intake of calcium is reduced
to extremely low levels, there is a slow reduction of urinary
calcium, but some continues to appear in the urine for weeks.
What determines renal calcium excretion? First, calcium is not
secreted. Second, while the filtered load is highly variable, being
the product of free plasma calcium and GFR, the GFR is regu-
lated mainly to meet the needs of sodium balance, not calcium.
In fact, an increase in urinary calcium excretion can be induced
simply by administering salt. This feature is used clinically as an
emergency procedure when calcium levels in the blood get

Lumen
Interstitium
Na ATP
Cl Thiazides
block
PTH
stimulates
Ca Ca
Ca Na
Ca Ca
FIGURE 48–2 Mechanism of calcium reabsorption in the
distal convoluted tubule, which is the major site for regulated
reabsorption. Ca enters via apical Ca channels, under the control of
PTH, and is actively transported across the basolateral membrane via
Na–Ca antiport and via a Ca-ATPase. The apical membrane also
contains the Na–Cl symporter (NCC), which is the target for inhibition
by thiazide diuretics. Interestingly, inhibition of NCC with thiazide
diuretics promotes calcium reabsorption (probably by enhancing
the basolateral sodium gradient and increasing Na–Ca exchange).
Thus, thiazides may reduce the calcium loss associated with
osteoporosis. Ion charge symbols (Ca2+, Cl–, K+, and Na+) omitted for
clarity. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal
Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub.
Division, 2009.)
alarmingly high, the treatment consisting of administering large
amounts of saline, with the consequence that large amounts of
calcium-containing fluid pass through the kidneys to the urine.
Thus, we are left with changes in the active reabsorption in the
distal nephron as the means of exerting independent control of
calcium excretion. We will describe this control shortly.
BONE
Bone serves as the powerful short-term calcium-buffering sys-
tem that prevents large swings in plasma calcium. About 0.5 g
of calcium passes back and forth between bone and the blood
plasma each day. Bone is also the repository of calcium that
keeps blood supplied with calcium during times of negative
whole body calcium balance.
The calcium in bone exists in the form of crystalline
hydroxyapatite (see Chapter 64). Calcium can move back and
forth between blood and hydroxyapatite in the inner recesses
of bone via an interconnected cellular network of osteocytes.
The equilibrium between crystalline hydroxyapatite and its
dissolved components is highly labile, dependent on the con-
centrations of calcium, phosphate, hydrogen ions, and specific
noncollagenous proteins in the immediate environment. The
formation and dissolution of hydroxyapatite protects the blood
plasma from short-term swings in calcium concentration.
This process does not require hormonal signals. However, the
CHAPTER 48 Regulation of Calcium and Phosphate Balance 487
set point for plasma calcium concentration maintained by the
rapid movement of calcium in and out of bone is critically
regulated by hormonal control, as discussed later.
The slow remodeling process in bone described in Chapter 64
Na is important for bone integrity and calcium stores on a much
K slower time scale, but this action has little effect on plasma cal-
cium levels.
Ca HORMONAL CONTROL
OF EFFECTOR SITES
The regulation of calcium is achieved mostly through the
actions of two hormones: the active form of vitamin D (1,25-
(OH)2D; calcitriol) and parathyroid hormone (PTH). The
chemistry and production of these hormones is described in
Chapter 64 along with the actions of calcitonin, which plays
an extremely minor role, if any. Briefly, calcitriol is synthe-
sized through a series of steps beginning with cholesterol and
culminating in the kidney, where a crucial hydroxylation step
creates the active form. PTH is a small peptide that is synthe-
sized by parathyroid glands lying behind the thyroid gland.
Simply stated, the active form of vitamin D regulates what
comes into the body and PTH regulates what is in the ECF.
VITAMIN D
The major action of calcitriol is to increase active absorption of
calcium and phosphate by the duodenum. A key mechanism is
to stimulate synthesis of the proteins involved in the steps
described earlier. In addition, vitamin D has some independent
actions on bone that are not entirely clear. Vitamin D also stim-
ulates the renal tubular reabsorption of calcium and phosphate,
again by increasing the synthesis of the protein components in
the transport pathway. The influences of vitamin D on bone
and the kidney are far less important than its actions on the GI
tract to stimulate absorption of calcium and phosphate.
PTH
PTH secretion is acutely regulated by levels of free plasma cal-
cium in a reciprocal manner—a decrease in plasma calcium
stimulates secretion, and an increase inhibits secretion. Phos-
phate also affects PTH secretion: increased plasma phosphate
stimulates PTH secretion by stimulating the capacity of the
parathyroid gland to synthesize PTH, so that chronically high
levels of phosphate lead to increased PTH.
PTH exerts at least four distinct effects on calcium homeo-
stasis (summarized in Figure 48–3 showing the response to
hypocalcemia and discussed in detail in Chapter 64):
1. PTH actions on bone normally increase the movement
of calcium from bone into the ECF. They do this by
favoring the dissolving of hydroxyapatite into its
components.
488 SECTION VII Renal Physiology
Rapid
Renal
FIGURE 48–3 Physiological responses to Ca reabsorption
reduced plasma calcium concentration.
Reduced plasma calcium stimulates secretion of
PTH. In response, the bone matrix immediately
releases calcium from hydroxyapatite into the ECF.
PTH also stimulates renal calcium reabsorption.
On a slower time scale PTH stimulates osteoclastic
bone resorption and increased synthesis of
calcitriol (vitamin D) in the kidney, leading to
increased absorption of dietary calcium from the
GI tract.
2. PTH stimulates the activation of an intermediate form of
vitamin D to calcitriol. The major control point is the sec-
ond hydroxylation step that occurs in the kidneys. This
step is stimulated by PTH. If plasma calcium decreases
acutely, the subsequent increase in PTH immediately
stimulates calcium release from bone, thus restoring plas-
ma calcium levels, and also stimulates calcium uptake (via
calcitriol from the GI tract, on a slower time scale). This
ensures that enough new calcium will enter the body to
replace that “borrowed” from bone.
3. PTH increases renal–tubular calcium reabsorption,
mainly by an action on the distal convoluted tubule and
connecting tubule. At these locations, it acts rapidly
through activation of kinases that phosphorylate regula-
tory proteins on a short-term basis. It also acts, on a slow-
er time scale, to increase synthesis of all the components
of the transport pathway. The increased uptake of calcium
from the tubular lumen stimulates basolateral extrusion
(by a combination of Ca-ATPase activity and Na–Ca
antiporter activity) and thus decreases urinary calcium
excretion.
4. PTH reduces the proximal tubular reabsorption of phos-
phate, thereby increasing urinary phosphate excretion
and decreasing extracellular phosphate concentration.
The adaptive values of the first three effects all result in a
higher extracellular calcium concentration and thus compen-
Plasma calcium
PTH
Synthesis of
1,25 (OH)2-vit D
Rapid Slow Slow
dissolution of Osteoclastic Intestinal
hydroxyapatite bone resorption Ca absorption
Restoration of
plasma calcium
sate for the lower calcium concentration that originally stimu-
lated PTH secretion. Regarding the fourth effect, when PTH
acts on bone, both calcium and phosphate are released into the
blood. Similarly, calcitriol enhances the intestinal absorption
of both calcium and phosphate, so that the processes that are
restoring calcium to its normal level are simultaneously acting
to increase the plasma phosphate above normal. But this is an
unwanted action because of the tendency to form insoluble
precipitates of calcium phosphate. Under the influence of
PTH, plasma phosphate does not actually increase, because of
PTH’s inhibition of tubular phosphate reabsorption. Indeed,
this effect is so potent that plasma phosphate may actually
decrease when PTH levels are high.
All of the above describes the effects of an increase in PTH
induced by a decrease in plasma calcium. An increase in extra-
cellular calcium concentration reduces PTH secretion, thereby
producing increased urinary and fecal calcium loss and net
movement of calcium from the ECF into bone.
There are nuances to the actions of PTH on bone that have
important clinical implications. The response of bone to PTH
depends on the pattern of its plasma concentration over time.
PTH can either promote resorption of hydroxyapatite (its
usual action) or, if administered intermittently, promote depo-
sition. Primary hyperparathyroidism, resulting from a
primary defect in the parathyroid glands (usually a hormone-
secreting tumor), generates a continuous excess hormone
level and causes enhanced bone resorption. This leads to bone
 CHAPTER 48 Regulation of Calcium and Phosphate Balance
thinning and the formation of completely calcium-free areas
or cysts. In this condition, plasma calcium often increases and
plasma phosphate decreases, the latter caused by increased uri-
nary phosphate excretion. A seeming paradox is that urinary
calcium excretion is increased despite the fact that tubular cal-
cium reabsorption is enhanced by PTH. The reason is that the
increased plasma calcium concentration induced by the effects
of PTH causes the filtered load of calcium to increase even
more than it increases the reabsorptive rate. Because the fil-
tered load is so great, there is also an increased amount not
reabsorbed (i.e., excreted). This result nicely illustrates the
necessity of taking both filtration and reabsorption (and secre-
tion, if relevant) into account when analyzing excretory
changes of any substance. And, as mentioned earlier, the high
urinary calcium content promotes the formation of stones.
In contrast to what happens with the continuous presence of
elevated PTH that accelerates bone resorption and release of
calcium, intermittent increases (produced by injections once
per day) actually increase deposition of calcium in bone. Inter-
mittent injection of PTH is used therapeutically to increase
bone density in osteoporosis patients.
OVERVIEW OF RENAL
PHOSPHATE HANDLING
Normally, approximately 75% of the filtered phosphate is
actively reabsorbed, almost entirely in the proximal tubule in
symport with sodium. Reabsorption is a tubular maximum–
limited (Tm) system, and the normal filtered load is just a little
higher than the Tm. Thus, while most filtered phosphate is
reabsorbed, some always spills into the urine. (Recall that this
phosphate is responsible for accepting hydrogen ions in the
collecting duct and is the primary ion responsible for titratable
acidity.) Since the reabsorptive capacity is saturated at normal
filtered loads, any increase in filtered load simply adds to the
amount excreted. This occurs when plasma phosphate con-
centration increases for any reason, such as increased dietary
phosphate intake or release of phosphate from bone. Systemic
acidosis promotes release of calcium and phosphate from
bone. The increase in plasma phosphate and the consequent
increase in filtered load of phosphate provides more titratable
buffer in the collecting tubule to help remove the excess hydro-
gen ion that promoted the phosphate release.
Much of the physiology we have described is illustrated by
the case of chronic renal failure, in which a low glomerular
filtration rate limits the ability of the kidneys to excrete a num-
ber of substances, specifically including phosphate. An almost
universal complication of chronic renal failure is increased
plasma phosphate (hyperphosphatemia). Another common
finding is increased levels of PTH, due in part to the high
plasma phosphate. The PTH stimulates excessive bone resorp-
tion, leading to osteoporosis. This is an example of secondary
hyperparathyroidism (because the pathology is not in the
gland itself, but in the signals that drive it). One goal in the
489
treatment of hyperphosphatemia associated with chronic renal
failure is reduction of phosphate absorption from the GI tract.
This is accomplished by encouraging the ingestion of high
doses of calcium. The calcium forms complexes with phos-
phate in the GI tract, reducing the availability of absorbable
phosphate. The high levels of PTH in a healthy patient should
signal the kidneys to form more calcitriol, but in chronic renal
failure a further complication is a reduced ability to synthesize
calcitriol in the kidney. Another clinical intervention in this
case is to provide exogenous calcitriol. This hormone sup-
presses expression of the PTH gene in the parathyroid gland.
The calcitriol increases GI absorption of phosphate, the very
thing we are trying to inhibit, but its ability to lower the syn-
thesis of PTH is the more important action because this
reduces the excessive resorption of bone stimulated by PTH.
Thus, administering vitamin D or its active metabolite calcit-
riol is a useful clinical tool.
CLINICAL CORRELATION
A 53-year-old African American male is hospitalized with
major vomiting, diarrhea, dehydration, and confusion, and
the physicians are unable to obtain a history. His heart rate is
84, and blood pressure is 122/63. Temperature is 36.7°C.
His blood work is normal, except for his calcium and phos-
phate. Calcium is high at 15 mg/dL, and phosphate is low at
1.6 mg/dL. He is given intravenous saline to replace fluid loss,
and then additional saline and a loop diuretic to induce
excretion of calcium. After a day, this procedure has brought
his serum calcium down to 11.5 mg/dL (still somewhat high).
His physicians suspect primary hyperparathyroidism, which
is usually caused by a parathyroid adenoma producing too
much PTH and causing his high calcium and low phosphate.
Measurement of plasma PTH however shows a suppressed
intact PTH concentration. If the parathyroid glands are nor-
mal and the hypercalcemia is due to some other cause, the
production of intact PTH should be very low, because secre-
tion should be suppressed by the elevated blood calcium. On
the other hand, if he has primary hyperparathyroidism, the
PTH levels should be much higher than what was measured.
His physicians are unsure of a diagnosis, so they look for
causes other than primary hyperparathyroidism.
They realize that this patient is showing the presence of
something that is acting like intact PTH and binding to the
PTH receptor throughout the body, but has a different
enough amino acid sequence so that it is not detected in the
clinical assay for authentic intact PTH produced by the para-
thyroid glands. Further workup eventually reveals a carci-
noma of the right kidney that is the source of this PTH
receptor agonist—it is called PTH-related peptide (PTHrP)
and is a common cause of humoral hypercalcemia of malig-
nancy, which is what the patient has. The right kidney is
removed surgically. On the third postsurgical day, the serum
calcium and phosphate have returned to the normal range.
490 SECTION VII Renal Physiology
CHAPTER SUMMARY
■ Moment-to-moment regulation of plasma calcium primarily
involves calcium flux between bone and plasma.
■ Calcium has a strong tendency to associate with small anions
and anionic sites on proteins.
■ The most important action of vitamin D is to ensure adequate
absorption of calcium from the GI tract.
■ PTH is essential both to maintain proper calcium flux between
bone and plasma and to maintain adequate levels of vitamin D.
■ Keeping phosphate levels in the normal range allows normal
calcium retrieval from bone.
STUDY QUESTIONS
1. The most important action of calcitriol is to stimulate
A) calcium deposition in bone.
B) calcium resorption from bone.
C) calcium absorption from the GI tract.
D) calcium reabsorption from the renal tubules.
2. Why does prolonged excessive PTH lead to high urinary levels of
calcium?
A) PTH inhibits calcium renal calcium reabsorption in the
proximal tubule, allowing more to be excreted.
B) PTH stimulates resorption of calcium from bone, which
raises plasma calcium and increases the filtered load.
C) PTH inhibits renal calcium reabsorption in the distal
nephron, allowing more to be excreted.
D) PTH stimulates renal calcium secretion in the distal
nephron.
3. In response to a sudden decrease in plasma calcium, what is the
source for most of the calcium that restores plasma levels?
A) bone
B) the GI tract
C) the renal tubules
D) the organelles of tissue cells
4. Compared with other common plasma cations such as
magnesium and potassium, calcium is unusual because
it tends to
A) form complexes with small anions and negative groups
on proteins.
B) form precipitates of elemental metal.
C) substitute for other ions on transporters.
D) diffuse passively through lipid bilayers.
5. In a case of acute hypercalcemia, one can rapidly lower plasma
calcium and increase urinary calcium excretion by
A) feeding large amounts of phosphate
B) withholding phosphate from the diet
C) injecting PTH
D) giving large amounts of saline
6. Which condition(s) would directly or indirectly increase urinary
excretion of phosphate?
A) the actions of PTH on bone
B) the actions of osteoclasts in bone
C) the actions of PTH on the kidneys
D) all of the above would increase urinary phosphate excretion
 SECTION VIII GI PHYSIOLOGY

49
Overview of the GI C H A P T E R

System—Functional
Anatomy and Regulation
Kim E. Barrett

O B J E C T I V E S

■ Understand the basic functions of the gastrointestinal system and the design
features that subserve these.
■ Describe the functional layers of the gastrointestinal tract and the
specializations that contribute to function.
■ Identify the segments of the gastrointestinal tract and the specialized
functions attributed to each.
■ Understand the circulatory features of the intestine and variations that occur
after meals.
■ Understand the integrated response to a meal and the need for mechanisms
that regulate the function of the gastrointestinal tract as a whole.
■ Describe modes of communication in the gastrointestinal tract.
■ Understand principles of endocrine regulation.
■ Understand the design of the enteric nervous system and neurocrine
regulation.
■ Describe immune and paracrine regulatory pathways.

OVERVIEW OF THE
GASTROINTESTINAL SYSTEM
AND ITS FUNCTIONS
DIGESTION AND ABSORPTION
The gastrointestinal system exists primarily to convey nutri-
ents and water into multicellular organisms. Most nutrients in
a normal human diet are macromolecules and thus not readily
permeable across cell membranes. Likewise, nutrients are not
usually taken predominantly in the form of solutions, but
rather as solid food. Thus, in addition to the food uptake, the
intestine serves to physically reduce the meal into a suspension
of small particles mixed with nutrients in solution. These are
then chemically altered, resulting in molecules capable of tra-
versing the intestinal lining. These processes are referred to as
digestion, and involve gastrointestinal motility as well as the
influences of pH changes, biological detergents, and enzymes.
The final stage in the assimilation of a meal involves move-
ment of digested nutrients out of the intestinal contents, across
the intestinal lining, and into either the blood supply to the gut
or the lymphatic system, for transfer to more distant sites in the
body. Collectively, this directed movement of nutrients is
referred to as absorption. The efficiency of absorption may vary
widely for different molecules in the diet, as well as those

491

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492 SECTION VIII GI Physiology
supplied via the oral route with therapeutic intent, such as drugs.
The barriers to absorption encountered by a given nutrient will
depend heavily on its physicochemical characteristics, and par-
ticularly on whether it is hydrophilic (such as the products of
protein and carbohydrate digestion) or hydrophobic (such as
dietary lipids). Generally, the gastrointestinal tract does not rely
solely on diffusion to provide for uptake, but rather has evolved
active transport mechanisms that take up specific solutes with
high efficiency. There is also significant excess capacity in the
systems for both digestion and absorption of a meal, including
an excess of enzymes and other secreted products as well as an
excess in the surface area available for absorption in healthy
individuals. Thus, assimilation of nutrients is highly efficient,
assuming adequate amounts are presented to the lumen.
EXCRETION
The gastrointestinal system also serves as an important organ
for excretion of substances out of the body. This excretory
function extends not only to the nonabsorbable residues of the
meal, but also to specific classes of substances that cannot exit
the body via other routes. Thus, in contrast to the renal sys-
tem, which handles predominantly water-soluble waste prod-
ucts, the intestine works together with the biliary system to
excrete hydrophobic molecules, such as cholesterol, steroids,
and drug metabolites.
HOST DEFENSE
The inner surface of the intestinal tract exists in continuity with
the exterior of the body. This, of course, is essential to its func-
tion of bringing nutrients from the environment into the body:
however, this also implies that the intestine, like the skin and
respiratory system, is a potential portal into the body for less
desirable substances. Indeed, we exploit this property to deliver
drugs via the oral route. In addition, the intestine is potentially
vulnerable to infectious microorganisms that can enter the gut
with the ingestion of food and water. To protect, itself and the
body, the intestine has evolved a sophisticated system of
immune defenses. The gastrointestinal immune system is
characterized by specific functional capabilities, most notably
by being able to distinguish between “friend” and “foe”: mount-
ing immune defenses against pathogens while being tolerant of
dietary antigens and beneficial commensal bacteria.
ENGINEERING CONSIDERATIONS
Given the functions of the gastrointestinal system discussed
earlier, we will now consider the anatomic features needed to
support these functions. In this discussion, the gastrointesti-
nal system can be thought of as a machine (Figure 49–1) in
which distinct portions conduct the various processes needed
for assimilation of a meal without uptake of significant quanti-
ties of harmful substances or microorganisms.
Chopper
Blender
Acid sterilizer
Reservoir
Reaction vessel
Enzyme supplier
Detergent Neutralizer
supplier
Catalytic and
absorptive surface
Residue combuster
Dessicator and pelleter
Emission control device
FIGURE 49–1 The gastrointestinal system as a machine that
conducts digestive, absorptive, immune, and excretory functions.
(Modified with permission from Barrett KE, Barman SM, Boitano S, Brooks H:
Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
DESIGN OF HOLLOW ORGANS
The gastrointestinal tract is a long muscular tube stretching
from mouth to anus. Within the lining of this tube, blind-
ended glandular structures invaginate into the wall of the gut
and empty their secretions into the lumen, defined as the cav-
ity within the gut. At various points along the length of the
gastrointestinal tract, more elaborate glandular organs are also
attached to the intestine and are connected to the intestinal
lumen via ducts, allowing secretions to drain into the intestine
where they can be mixed with intestinal contents. Examples of
such organs include the pancreas and salivary glands. Glands
in general can be considered as structures that convert raw
materials from the bloodstream into physiologically useful
secretions, such as acid and enzyme solutions.
In general, the glands have a common structure. Specialized
secretory cells form blind-ended structures known as acini
where a primary secretion is produced. Clusters of such acini,
which can be likened to a bunch of grapes, then empty into
tubelike ductular structures, with larger ducts collecting the
secretions from a group of smaller ones until a main collecting
duct is reached that connects directly to the gut lumen. The
liver, which will be considered in this section as a critical par-
ticipant in gastrointestinal function overall, has a highly spe-
cialized structure that will be discussed in detail in Chapter 55.
For now, suffice to say that the liver is designed not only to
secrete substances into the gastrointestinal lumen via the bil-
iary system, but also to receive absorbed substances from the
intestine that travel first to the liver via the portal circulation
before being distributed to the body as a whole.
 CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation 493

Lumen

Epithelium
Basement membrane
Mucosa
Lamina propria

Muscularis mucosa

Submucosa

Circular muscle

Muscularis
Myenteric plexus propria

Longitudinal muscle FIGURE 49–2 Organization of the wall

of the intestine into functional layers. (Adapted
with permission from Madara J. and Anderson J.: Textbook
of Gastroenterology, 4th ed., pp. 151–165. Copyright
Mesothelium (Serosa) Lippincott Williams and Wilkins, Philadelphia, 2003.)

CELLULAR SPECIALIZATION before succumbing to programmed cell death (or apoptosis)

and being shed into the lumen or engulfed by their neighbors.
The tube that comprises the gastrointestinal tract is made Epithelial cells arise from stem cells that are anchored perma-
up of functional layers composed of specialized cell types nently in specific positions in the gut lining, located at the base
(Figure 49–2). The first layer encountered by an ingested of crypts in the intestine and in the middle of gastric glands in
nutrient is the epithelium, which forms a continuous lining the fundic region of the stomach. Following several cycles of
of the entire gastrointestinal tract as well as lining the glands
and organs that drain into the tube. The epithelium must
provide for the selective uptake of nutrients, electrolytes,
and water while rejecting harmful solutes. The surface area Small intestine
of the intestinal epithelium is amplified by being arranged LUMEN
into crypt and villus structures (Figure 49–3). The former
are analogous to the glands discussed earlier, whereas villi
are fingerlike projections that protrude into the intestinal
Villus
lumen, which are covered by epithelial cells. In the large
intestine, only crypts are seen, interspersed with surface epi-
thelium between the crypt openings.
The majority of the gastrointestinal epithelium is columnar
in nature, where a single layer of tall, cylindrical cells separates Crypt
the gut lumen from the deeper layers of the wall of the gut. The
structure of the columnar epithelium can be compared to a six
packs of soda cans, with the cans representing the cells and the Colon
plastic holder that links them as a series of intercellular junc- LUMEN Surface
tions that provide a barrier to passive movement of solutes
around the cells. However, in the first part of the intestinal
tube, known as the esophagus, the epithelial lining is a strati-
fied squamous epithelium. In this site, the epithelium forms Crypt
a multilayer reminiscent of the structure of the skin, with cells
migrating toward the lumen from a basal germinal layer.
The epithelium of the gut as a whole is subject to constant FIGURE 49–3 Comparison of the morphology of the
renewal, unlike the majority of tissues in the adult body. Gas- epithelial layers of the small intestine and colon. (Modified with
trointestinal epithelial cells turn over every 3 days or so in permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical
humans, undergoing a cycle of division and differentiation Books/McGraw-Hill, Medical Pub. Division, 2006.)
494 SECTION VIII GI Physiology
division, epithelial cells also differentiate into specialized cell
types with specific functions in the digestive process.
In the stomach, some epithelial cells migrate downwards
deeper into the gland, and become chief or parietal cells
that contribute specific products to the gastric juice, or
endocrine cells that regulate the function of the latter secre-
tory cell types. The remaining gastric epithelial cells migrate
upwards to become cells capable of secreting mucus and
bicarbonate ions.
In the intestine, some stem cells give rise to Paneth cells,
which remain in the crypt base and secrete antimicrobial pep-
tides. The majority of the daughter cells that arise from stem
cell divisions migrate upwards toward the villus (or surface
epithelium in the colon), and of these, most are destined to
differentiate into absorptive epithelial cells with the capacity
for the final steps of nutrient digestion and uptake. A few
cells, however, differentiate into goblet cells, which produce
mucus, or enteroendocrine cells that respond to luminal con-
ditions, and regulate the functions of the other epithelial cell
types as well as those of more distant organs.
Beneath the epithelium is a basement membrane, overlying
a layer of loose connective tissue known as the lamina pro-
pria. This contains nerve endings and blood vessels, as well as
a rich assortment of immune and inflammatory cells. Taken
together, the epithelium and lamina propria are referred to as
the mucosa. The mucosa also contains a thin layer of smooth
muscle known as the muscularis mucosae. Beneath this layer,
there is a plexus of nerve cell bodies known as the submucous
(or submucosal) plexus, designed to relay information to and
away from the mucosa, including the epithelial cells. Then,
beyond the mucosa are the smooth muscle layers that provide
for overall gut motility. These are arranged circumferentially
around the outer side of the intestinal tube.
Closest to the mucosa is a layer of circular muscle that
reduces the diameter of the intestinal lumen when it contracts.
On the outer side of the gut, a layer of smooth muscle in which
the fibers are arranged longitudinally along the axis of the tube
provides for intestinal shortening. Working together, these
two outer muscle layers can provide for complex motility pat-
terns that subserve specific gut functions, as will be described
in more detail later. Sandwiched between the circular and lon-
gitudinal muscle layers, the myenteric plexus of nerves regu-
lates their function.
DIVISION OF INTESTINE INTO
FUNCTIONAL SEGMENTS
Movement of the meal along the length of the intestine is a reg-
ulated process, and involves selective retention in specific sites
to promote optimal digestion and absorption. This is accom-
plished by specialized smooth muscular structures known as
sphincters, whose function is also coordinated with that of the
system as a whole (Figure 49–4). For example, the pylorus,
which controls outflow from the stomach, retains the meal in
the gastric lumen and releases it slowly to match the availability
Esophagus Upper and lower
esophageal sphincters
Stomach
Liver
Pylorus
Sphincter of Oddi
Pancreas
Gallbladder
Colon
Small intestine
Internal and external
Ileocecal valve anal sphincters
FIGURE 49–4 Overall anatomy of the gastrointestinal
system and division of the GI tract into functional segments
by sphincters and valves. (Modified with permission from Barrett KE:
Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical
Pub. Division, 2006.)
of nutrients to the capacity of the enzymes required for diges-
tion and the absorptive surface area. Similarly, the ileocecal
valve retains the majority of the gastrointestinal flora within
the colon, opening only intermittently to permit the residues
of the digested meal, along with water and cellular debris, to
enter the large intestine. Finally, the sphincter of Oddi relaxes
in conjunction with a meal to allow the outflow of both biliary
and pancreatic secretions into the lumen.
Most gastrointestinal sphincters are under involuntary
control, and perform their normal cycles of relaxation and
contraction without conscious input. Many may also func-
tion in a manner that is largely autonomous of the central
nervous system (CNS), being controlled instead by the
enteric nervous system. On the other hand, the external
anal sphincter can be controlled voluntarily, a skill learned
during toilet training in infancy, and the esophageal sphinc-
ters are regulated by the CNS.
ORGANS AND SYSTEMS
INVOLVED IN THE RESPONSE
TO A MEAL
Several intestinal and extraintestinal tissues cooperate to
respond appropriately to the ingestion of a meal. Collectively,
these tissues can sense, signal, and respond to meal ingestion
with altered function. Moreover, the tissues and their func-
tions are interactive and highly efficient, and redundancy
 CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation
exists among the majority of GI regulatory mechanisms. In
this section, we will introduce the functions of each segment
of the gastrointestinal tract and the structural features that
underlie these. More detailed discussions will be provided in
subsequent chapters. Specific features of the circulatory sys-
tems designed to carry absorbed nutrients away from the gut,
and the neuromuscular system that provides for motility and
regulation, will also be considered.
ORAL CAVITY AND ESOPHAGUS
The oral cavity is concerned with initial intake of food and
with shaping and lubricating the bolus of ingested materials
such that it can be swallowed. The teeth reduce large portions
of food into sizes suitable for passage through the esophagus.
Salivary glands, which drain into the oral cavity, supply an
aqueous environment and also mucus that coats the surface of
the bolus and thus aids in swallowing. The aqueous environ-
ment also permits diffusion of taste molecules to specific
receptors on the tongue that relay information centrally as to
whether the meal is palatable. Salivary secretions also reduce
microbial contamination of the oral cavity. Finally, the struc-
tures of the oral cavity are also intimately involved in swallow-
ing. The esophagus transfers the bolus from the mouth to the
stomach. Its upper third is surrounded by striated muscle
overlaid by a thick submucous elastic and collagenous net-
work. The muscle then transitions to smooth muscle that
works in concert with the swallowing reflex to propel the bolus
toward the stomach.
Toward the lowest portion of the esophagus, the smooth
muscle gradually thickens and interacts with neurogenic and
hormonal factors, as well as the diaphragm, to serve function-
ally as a lower esophageal sphincter. The higher pressure in
this segment prevents excessive backflow, or reflux, of the gas-
tric contents into the esophageal lumen. Failure of this process
leads to gastroesophageal reflux disease (GERD), where
refluxed contents of the stomach can cause damage to the
esophageal epithelium. GERD is one of the most common
gastrointestinal disorders.
STOMACH
The stomach is a muscular bag that functions primarily as a res-
ervoir, controlling the rate of delivery of the meal to more distal
segments of the gastrointestinal tract. Anatomically, it is divided
into three regions, the cardia (which overlaps with the lower
esophageal sphincter), fundus, and antrum, each with distinctive
structures that subserve specific functions (Figure 49–5).
The cardia begins where the squamous epithelium of the
esophagus gives way to the columnar epithelium of the remain-
der of the gastrointestinal tract; it functions mostly to secrete
mucus and bicarbonate to protect the luminal surface from the
corrosive gastric contents. At the microscopic level, the sur-
face area of the stomach is amplified by pits, which represent
the entrances to deep gastric glands. The specific structures of
495
Lower esophageal sphincter—
prevention of reflux
Cardia
ure
Secretion Fundus and body
at
v
ur
ture
rc Reservoir
s se
urva
Le
c
ter
Mixing
ea
Grinding Gr
Antrum
Pylorus—
control of emptying
FIGURE 49–5 Functional regions of the stomach. (Modified
with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange
Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
these glands differ in the three regions of the stomach; they are
shallowest in the cardia, intermediate (though with deep pits)
in the antrum, and deepest in the fundus.
The fundic (or gastric) glands contain specific secretory cells
that produce the characteristic components of gastric juice—
acid and pepsin—that are products of parietal and chief cells,
respectively. Thus, the fundus is a secretory region. On the other
hand, the antrum (also referred to as the pyloric zone) engages
in extensive motility patterns, mixing the gastric contents and
grinding and sieving ingested particles. Eventually, the meal is
gradually emptied into the small intestine via the pylorus.
The stomach also undergoes receptive relaxation. The gas-
tric musculature relaxes as it is stretched during filling, ensur-
ing that the pressure in the stomach does not increase
significantly as its volume expands. This response ensures that
the meal is not forced back into the esophagus, and is integral
to the reservoir function of the stomach. An individual lacking
a significant portion of his or her stomach cannot tolerate
large meals due to the loss of this reservoir function, making
gastric restriction a treatment for obesity.
DUODENAL CLUSTER UNIT
The first segment of the small intestine immediately distal to
the pylorus, approximately 12 in in length, is referred to as the
duodenum. Together with the pancreas and biliary system,
the duodenum makes up the duodenal cluster unit. This seg-
ment of the gastrointestinal system acts as a critical regulator
of digestion and absorption. Endocrine cells within the wall of
the duodenum, as well as chemosensitive and mechanosensi-
tive nerve endings, monitor the characteristics of the luminal
contents and emit signals that coordinate the function of more
distant regions of the gastrointestinal tract to ready them for
496 SECTION VIII GI Physiology
the arrival of the meal, or to retard the flow of contents from
the stomach. The exocrine pancreas and gallbladder also drain
into the duodenum with egress of secretions controlled by
opening of the sphincter of Oddi.
SMALL INTESTINE
The remainder of the small intestine consists of the jejunum
and ileum. The jejunum serves as the site of the majority of
nutrient absorption in the healthy individual, and has a mark-
edly amplified surface area due to the presence of surface folds
and tall, slender villi. The surface area of the jejunum is
also amplified considerably by an abundance of microvilli on
the apical surface of villus epithelial cells. More distally, the
ileum has fewer folds and shorter, sparser villi, and is less actively
engaged in nutrient absorption other than for specific solutes
such as conjugated bile acids, which are exclusively salvaged by
transporters expressed in the terminal ileum. However, if jeju-
nal absorption is impaired, the ileum represents an anatomic
reserve that can be called on for absorption. As a result, the
small intestine has excess capacity for both digestion and absorp-
tion, and thus malabsorption is a relatively rare event.
COLON
The colon, or large intestine, serves as a reservoir for the stor-
age of wastes and indigestible materials prior to their elimina-
tion by defecation. In general, colonic epithelial cells (or
colonocytes) do not express absorptive transporters for con-
ventional nutrients such as monosaccharides, peptides, amino
acids, and vitamins but may be actively involved in the uptake
of other luminal constituents. As its name implies, the large
intestine is of a considerably larger diameter than the small
intestine, with a thicker wall and folds known as haustrations.
The colon is divided into several regions: the ascending, trans-
verse, descending, and sigmoid colon, which are defined ana-
tomically but may also subserve different functions (Figure 49–6).
For example, in the ascending and transverse colon, there is an
emphasis on reclamation of fluid as well as salvage of other
dietary byproducts, such as absorption of short-chain fatty acids
produced by the bacterial fermentation of dietary fiber. The
smooth muscle of the colon, under the influence of the enteric
nervous system, produces mixing motility patterns that maxi-
mize the time for reabsorption of fluid and other useful solutes.
Other luminal solutes, such as bile acids and bilirubin, are also
modified in the colon by bacterial metabolism. In fact, the
healthy colon contains an abundant ecosystem comprised pri-
marily of anaerobic bacteria, and these symbionts are important
contributors to whole body nutritional status.
The descending colon serves primarily as the storage reser-
voir for fecal wastes. When these are propelled through the
sigmoid colon into the rectum, stretch receptors initiate a
reflex relaxation of the internal anal sphincter and also send
afferent impulses to the CNS indicating a need to defecate.
Defecation can, however, be postponed to a convenient time
Splenic flexure
Transverse colon
Hepatic flexure
Descending
colon
Tenia
Ascending
colon
coli
Ileum
Haustra
Cecum
Appendix Sigmoid colon
Internal anal
Rectum
External sphincter
FIGURE 49–6 Anatomy of the large intestine comprised of
the cecum, colon, rectum, and anus. (Reproduced with permission from
Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology,
23rd ed. McGraw-Hill Medical, 2009.)
by contraction of the external anal sphincter and levator ani
muscles, which are under voluntary control. Compared with
other segments of the gastrointestinal tract, propulsive motil-
ity in the colon is relatively sluggish until a reflex sufficient to
trigger mass peristalsis and defecation occurs, and contents
may remain in the colon for days.
SPLANCHNIC CIRCULATION
AND LYMPHATICS
Blood supply to the intestines is vitally important in carrying
away absorbed nutrients, particularly those that are water sol-
uble, to sites of usage elsewhere in the body. Likewise, most
lipids enter the lymphatic drainage of the gut initially, because
they are packaged in particles (chylomicrons) too large to pass
through the pores between capillary endothelial cells. Lymph
fluid containing absorbed lipids is emptied into the blood-
stream via the thoracic duct.
The circulation of the gastrointestinal tract is unusual because
of its anatomy (Figure 49–7). Unlike venous blood draining
from other organs of the body, which returns directly to the
heart, blood flow from the intestine flows first to the liver via
the portal vein. Conversely, the liver is unusual in receiving a
considerable portion of its blood supply not as arterial blood,
but as blood that has first perfused the intestine. This anatomic
arrangement ensures that substances absorbed from the gut
flow first to the hepatocytes where they can be detoxified if
necessary. Gastrointestinal blood flow is also notable for the
range of its dynamic regulation. Even in the fasting state, the
splanchnic circulation receives blood flow (25% of cardiac
 CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation 497

Vena cava myenteric plexus. Many of these fibers are contained in

Hepatic vein
Hepatic
sinusoids
Hepatic artery
Intestinal artery
(from mesentery)
Portal vein
Liver
Intestinal capillaries
Intestine
FIGURE 49–7 Schematic anatomy of the splanchnic
circulation. (Modified with permission from Barrett KE: Gastrointestinal Physiology.
New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
output) that is disproportionate to the mass of the organs per-
fused (5%). Under these circumstances, the liver receives
approximately 65% of its blood flow via the portal system. In
the postprandial period, blood is diverted from the skeletal
muscles and other body systems, and flow through vessels per-
fusing the intestine can increase more than 5-fold. Under these
circumstances, the liver receives more than 85% of its blood
supply via the portal system. These dramatic changes in blood
distribution are produced by hormonal and neurogenic stimuli
occurring secondary to the ingestion of a meal.
the vagus nerve, which follows blood vessels to innervate the
stomach, small intestine, cecum, and ascending and transverse
colon. The remainder of the colon receives parasympathetic
innervation via the pelvic nerve.
The most striking aspect of intestinal neurophysiology is the
enteric nervous system contained wholly within the gut wall.
This system consists of neurons with their cell bodies in the
myenteric or submucosal plexuses. The anatomy of the enteric
nervous system and its relationship to other gut structures is
shown in Figure 49–8.
The enteric nervous system serves as a relay station to con-
duct and interpret information supplied by extrinsic auto-
nomic afferents carrying impulses that originate centrally,
and also to pass information from sensory efferents that have
their endings in the epithelium or smooth muscle. Thus, the
enteric nervous system can ultimately cause changes in motil-
ity and/or secretory behavior in response to centrally medi-
ated signals. The enteric nervous system can also function
autonomously and mediate reflexes that do not involve the
CNS at all.
Myenteric plexus
Circular muscle
Deep muscular plexus
Submucosal
plexus
Longitudinal
muscle
Submucosal
Mucosa
Muscularis artery
A mucosae

Paravascular nerve Perivascular nerves

NEUROMUSCULAR SYSTEM
The motility functions of the gastrointestinal tract are essen- Subserous nerve Mesentery
tial to propel ingested nutrients along the length of the alimen- Myenteric plexus
tary canal, and also to control the length of time available for
digestion and absorption. The motility patterns of the intes-
tine are brought about by the integrated control of the contrac-
tion and relaxation of the circular and longitudinal muscle
layers. Extrinsic innervation of the gut occurs via both sympa-
Deep muscular
thetic and (more prominently) parasympathetic pathways. plexus
Sympathetic innervation primarily involves postganglionic Submucosal
plexus Mucosal plexus
adrenergic nerves originating in prevertebral ganglia. These
nerves synapse mainly with others in the enteric nervous sys- B
tem, discussed later, but a few may directly innervate secretory FIGURE 49–8 Plexuses of the enteric nervous system and
cells in various glands (especially the salivary glands) or the their relationship to the other functional layers of the gut wall.
smooth muscle cells of blood vessels, leading to vasoconstric- Panel A shows intact tissue while Panel B is a transverse section.
tion. Parasympathetic innervation, on the other hand, is via (Adapted with permission from Furness J. and Costa M. Neuroscience 1980;5:1–20.
preganglionic nerve fibers that synapse with cell bodies in the Copyright Pergamon Press.)
498 SECTION VIII GI Physiology

REGULATION OF
GASTROINTESTINAL FUNCTION
For nutrient assimilation to occur, specific tissues and
regions of the gastrointestinal system must sense, signal,
and respond to the ingestion of a meal (Figure 49–9). To
conduct the business of the gastrointestinal system most
efficiently, the various segments must also communicate.
Thus, the activities of the gastrointestinal tract and the
organs that drain into it are coordinated temporally via the
action of a series of chemical mediators, with the system
being referred to collectively as neurohumoral regulation,
implying the combined action of soluble and neuronal path-
ways. The integrated regulation of gastrointestinal function
underlies the efficiency of the system and its ability to pro-
vide for the effective uptake of nutrients even when they are
in short supply.
Nutrients
COMMUNICATION
IN THE GI TRACT
GENERAL FEATURES OF
NEUROHUMORAL REGULATION
Communication that depended simply on diffusion of
locally released signals would not be adequate for the timely
transfer of information from one intestinal segment to
another. Likewise, the gastrointestinal tract also needs to
communicate its status to organs that drain into it, such as
the pancreas and gallbladder. Thus, the system has evolved
mechanisms for communication over significant distances,
although local messengers also play a role in fine-tuning
information delivery or, in some cases, amplifying or
antagonizing it. Overall, information is carried between the
various sites by chemical entities possessing specific physi-
cochemical properties. Another general principle underly-
ing communication is that of functional redundancy. Several
different mediators may often produce the same physiologic
response, and single mediators may alter the function of
more than one system.

Special Chemo/mechanosensitive CHARACTERISTICS OF

senses nerve endings CHEMICAL SIGNALS
Neurohumoral regulation is effected by several classes of
Higher chemical messengers including peptides, derivatives of amino
centers
acids, small molecule neurotransmitters, and lipid mediators.
The gastrointestinal messengers that have been assigned defi-
nite physiologic roles are listed in Table 49–1.
Dorsal
Vagus ENS
vagal
nerve
complex
SPECIFIC MODES OF
Stomach
Intestines
COMMUNICATION
Pancreas Four modes of communication are recognized within the
Gallbladder
Sphincters gastrointestinal system—endocrine, neurocrine, paracrine
(of which autocrine is a special case), and juxtacrine regula-
tion, most often ascribed to cells of the immune system. A
Changes in diagrammatic representation of each of these is provided in
secretion Figure 49–10.
and motility

FIGURE 49–9 Overview of neural control of the ENDOCRINE COMMUNICATION

gastrointestinal system. Nutrients activate both special senses
(smell, taste) and specific sensory nerve endings that exist within
the wall of the gut. These responses are conveyed via the autonomic
nervous system and enteric nervous system (ENS) to alter the
function of the gastrointestinal tract and organs draining into it,
resulting in changes in secretion and motility. Such functional
changes may additionally feed back on neural control to allow for
appropriate homeostasis of the system. (Modified with permission from
Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill,
Medical Pub. Division, 2006.)
Because of its ability to regulate multiple sites in an essentially
simultaneous fashion, endocrine regulation is critical to the
integrated function of the gastrointestinal system in response
to a meal. The intestine is extremely well supplied with cell
types containing endocrine mediators (hormones); in fact, if
all of the endocrine cells within the gut were assembled as a
single structure, they would make up the largest endocrine
organ in the body.
 CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation 499

TABLE 49–1 Major physiologic neurohumoral regulators of gastrointestinal function.

Endocrine Neurocrine Paracrine Immune/Juxtacrine

Gastrin Acetylcholine Histamine Histamine

Cholecystokinin Vasoactive intestinal polypeptide Prostaglandins Cytokines

Motilin Substance P Somatostatin Reactive oxygen species

Secretin Nitric oxide 5-Hydroxytryptamine Adenosine

Glucose-dependent insulinotropic peptide Cholecystokinin

5-Hydroxytryptamine

Somatostatin

Calcitonin gene-related peptide

Endocrine hormones are packaged within secretory gran-
ules and released in response to nervous activity, as well as
chemical and mechanical signals coincident with food inges-
tion. The endocrine cells of the gut have been identified with
letters to describe their hormonal contents; gastrin, secretin,
cholecystokinin (CCK), and glucose-dependent insulino-
tropic peptide (also referred to as gastric inhibitory peptide,
Endocrine Paracrine (autocrine)
Neurocrine Immune/Juxtacrine
or GIP) are stored in G, S, I, and K cells, respectively. Cells
containing motilin have not been named, and indeed, there is
some debate as to whether this peptide is stored in endocrine
cells or nerve endings.
Some endocrine cells may have processes that contact the
luminal contents and are activated to release their mediators in
response to specific features of luminal composition, such as
acidity, osmolarity, or nutrients such as amino acids and free
fatty acids. In other cases, hormone release in response to
changes in luminal composition can also be activated by a reflex
arc that first involves activation of a sensory enteric nerve end-
ing, with subsequent release of specific neurotransmitters close
to the surface of the endocrine cell to stimulate exocytosis. Yet
other endocrine cells are designed to respond to conditions
existing in the interstitium. The hormones that are released
from endocrine cells diffuse into the lamina propria and thence
into the portal circulation. From there, they travel to target
organs and modify secretion, motility, and cell growth. All of
the currently known GI hormones are peptides, but not all pep-
tides isolated from the gastrointestinal tract are hormones.
The GI hormones are synthesized in various segments of the
gastrointestinal tract (Figure 49–11), but only gastrin appears
to be present in the stomach of healthy individuals. The
remaining hormones are present in greatest amounts in the
duodenum and jejunum, with tapering expression of CCK and
secretin into the ileum. However, under normal conditions,
most of the release of gastrin occurs in the stomach, and of the
other hormones in the duodenum and to some extent the jeju-
num. Ileal expression of some hormones, therefore, represents
another example of the “reserve capacity” of the intestine that
can be called upon to regulate gastrointestinal function if
required. Further, in health, there appears to be little, if any,
expression of gastrointestinal hormones in the colon.

FIGURE 49–10 Modes of communication in the

gastrointestinal system. Information is conveyed by endocrine,
neurocrine, paracrine, and immune/juxtacrine routes. Autocrine
regulation is a special class of paracrine regulation. (Modified with
permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical
Books/McGraw-Hill, Medical Pub. Division, 2006.)
NEUROCRINE REGULATION
Neurocrine regulation is mediated by specific nerve endings
of both the enteric and central nervous systems. Neurotrans-
mitters stored in these nerve endings are released on receipt
500 SECTION VIII GI Physiology
FIGURE 49–11 Sites of production of the
five gastrointestinal hormones along the length
of the gastrointestinal tract. The width of the bars
reflects the relative abundance at each location.
(Modified with permission from Barrett KE, Barman SM, Boitano
S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed.
McGraw-Hill Medical, 2009.)
of an electrical signal, and diffuse across synaptic clefts to
alter secretomotor function in the gastrointestinal system.
These neurotransmitters thus provide information exchange
that is exquisitely spatially specific, and because of their rela-
tive instability, there is very little spillover of information
conveyed by neurotransmitters even to immediately adjacent
sites. Some endocrine mediators may also convey informa-
tion among the various parts of the gastrointestinal system
by activating nerve endings in addition to their ability to
circulate to distant sites; the most classic example of this
mode of communication is mediated by CCK, for which
receptors exist on sensory nerve endings in the small
intestinal mucosa.
PARACRINE COMMUNICATION
Some substances are designed to act only in the immediate
area of their release, and yet are released from cell types
other than nerves. This paracrine communication provides
an important additional layer of control for gastrointestinal
secretomotor function, particularly in response to changes
in local conditions. Paracrine regulators, like neurotrans-
mitters, are readily metabolized or retaken up to limit
the duration of their activity. A special case of paracrine
regulation is labeled autocrine, which involves the release
of a substance that then acts on its cell of origin. Intesti-
nal epithelial cells may engage in autocrine regulation
since they are capable of releasing growth factors that influ-
ence their proliferation and/or migration along the crypt–
villus axis.
Gastrin CCK Secretin GIP Motilin
Fundus
Antrum
Duodenum
Jejunum
Ileum
Colon
IMMUNE COMMUNICATION
A final class of communication in the gastrointestinal system is
mediated by the release of substances by cells of the mucosal
immune system. These cells are activated by antigenic sub-
stances or products of pathogenic microorganisms, and release
a variety of chemical mediators including amines (such as his-
tamine), prostaglandins, and cytokines. Immune regulation is
important in changing the function of the secretomotor sys-
tems of the gastrointestinal tract during times of threat- for
example, invasion of the mucosa by pathogens. Immune medi-
ators may also be responsible for intestinal dysfunction in the
setting of inflammation or conditions such as food allergies,
where inappropriate immune responses to substances that
would normally be innocuous may be deleterious for the host.
Finally, immune cell types may be activated by endogenous
substances such as bile acids in the lumen, or by specific pep-
tide neurotransmitters. Immune regulation thus contributes to
gastrointestinal regulation not only under pathological circum-
stances, but also in response to normal physiologic events.
PRINCIPLES OF ENDOCRINE
REGULATION
ESTABLISHED GI HORMONES
As noted above, five gastrointestinal peptides have fulfilled the
criteria to be named as hormones (Table 49–2). These fall into
three groups based on structural and signaling similarities.
 CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation
TABLE 49–2 Factors influencing release of gastrointestinal hormones.
Gastrin CCK
Proteins/amino acids ↑ ↑
Fatty acids ↔ ↑
Glucose ↔ ↔
Acid ↓ ↔
Neural stimulation ↑ ↑
Stretch ↑ ↔
Peptide-releasing factors ↔ ↑
a
Motilin release is reduced by feeding, but the precise mechanism is unclear.
GASTRIN/CCK FAMILY
Gastrin and CCK occur in the gastrointestinal system in vari-
ous forms, and are structurally related peptides that also bind
to closely related receptors known as CCK-A and CCK-B.
CCK and gastrin share a common C-terminal pentapeptide,
which is amidated as a final step in processing in I and G cells,
respectively. Amidation is believed to increase the stability of
these hormones by blocking carboxypeptidase activity.
The major biologically active forms of gastrin are 17- and
34-amino-acid peptides, which may or may not be sulfated;
this posttranslational modification is of unknown function.
CCK also occurs as a family of peptides of decreasing length
(CCK-58, CCK-39, CCK-33, and CCK-8), but unlike gastrin,
all of the released peptides are sulfated. The sulfation of CCK
peptides appears critical for their high-affinity interaction
with their receptor (CCK-A).
CCK was named for its ability to contract (-kinin) the gall-
bladder (cholecysto-), but it also affects the function of numer-
ous other tissues and cell types, and can be considered as the
master regulator of the duodenal cluster unit. It has also been
shown to signal the CNS to indicate satiety, or fullness. CCK
also appears to cooperate with a major systemic regulator of
food intake—leptin—that is released by adipocytes to signal
the status of fat stores throughout the body.
CCK-A and CCK-B receptors are G protein–coupled recep-
tors that signal via increases in cytoplasmic calcium. The spec-
ificity of CCK and gastrin for these receptors is defined by
their structures. Gastrin is highly specific for CCK-B, whereas
CCK binds to both CCK-A and (with lower affinity) CCK-B,
giving it a broader activity that may overlap to some extent
with that of gastrin.
SECRETIN FAMILY
The secretin family of gastrointestinal peptides includes not only
the hormones secretin and GIP, but also a systemic hormone,
glucagon, as well as a neuropeptide, vasoactive intestinal poly-
peptide (VIP). Although there is some homology among the
amino acid sequences of these peptides, each is believed to bind
501
Secretin GIP Motilin
↔ ↔ ↓a
↑ ↑ ↓a
↔ ↑ ↓a
↑ ↔ ↔
↔ ↔ ↑
↔ ↔ ↔
↔ ↔ ↔
to distinct receptors on target cells. All of the receptors for these
family members, however, share the common property of signal-
ing predominantly via associated G proteins of the Gs class, and
thus via increasing intracellular levels of cAMP.
Secretin itself is a 27-amino acid peptide that is synthesized
by S cells located predominantly in the duodenal mucosa, and
is released in response to a low intraluminal pH. This accords
nicely with the major known biological action of secretin,
which is to stimulate secretion of bicarbonate by the cells lin-
ing the pancreatic and biliary ducts, as well as the duodenal
epithelial cells themselves. Up to 80% of the bicarbonate secre-
tory response that occurs in the course of digesting and absorb-
ing a meal is likely due to the direct influence of secretin.
GIP, or glucose-dependent insulinotropic peptide (formerly
known as gastric inhibitory peptide, which fortuitously has
the same initials), is released from intestinal K cells in response
to all of the major components of a meal—carbohydrates, pro-
tein, and fat. Its primary physiologic actions are to inhibit gas-
tric acid secretion and to amplify glucose-stimulated release of
insulin from the endocrine pancreas, making it an incretin.
The former action represents an example of a feedback regula-
tory event that contributes to the termination of gastric secre-
tory function once the bulk of the meal has moved into the
small intestine. The latter action represents a feedforward sig-
nal from the gut to the insulin-secreting cells of the endocrine
pancreas such that the insulin response to absorption of glu-
cose is amplified (see Chapter 66).
MOTILIN
Human motilin is a 22-amino acid linear peptide that is
released cyclically from the gut in the fasting state, and is
responsible for stimulating a specific pattern of gastrointesti-
nal motility known as the migrating motor complex that will
be discussed in detail in Chapter 54. A closely related peptide,
ghrelin, is predominantly produced in the stomach, and its
plasma concentrations are increased by fasting and reduced by
feeding. Ghrelin may be an important mediator of signaling
between the intestine and hypothalamus to increase metabolic
efficiency at times when nutrient supplies are limited.
502 SECTION VIII GI Physiology
CANDIDATE GI HORMONES
As mentioned earlier, the gastrointestinal tract is a rich source
of stored peptides, and several peptides have received atten-
tion for their potential physiologic roles. The most compelling
evidence exists for three such peptides—enteroglucagon,
pancreatic polypeptide, and peptide YY (tyrosine–tyrosine).
Enteroglucagon is a member of the secretin family, whereas
the other two peptides are related to each other, but not to any
of the other hormone families thus far discussed. While none
of these peptides have yet fulfilled all of the criteria needed to
classify them as a hormone, it is possible that they may do so
in the future.
Intestinal L cells make peptides that are closely related to
pancreatic glucagon, and arise from differential processing of
the same gene. One of these peptides, glucagonlike peptide-1,
is a 30-amino acid peptide that inhibits gastric secretion and
emptying, and also potently augments the secretion of insulin
in response to glucose (making it another incretin). The
enteroglucagons are released in response to luminal sugars,
and thus may contribute to the axis by which circulating glu-
cose concentrations are regulated during the period of glucose
absorption after a meal, by coordinating the activities of the
intestine and endocrine pancreas. As such, these presumed
enteroglucagons act in concert with GIP.
Cells of the pancreatic islets synthesize pancreatic polypep-
tide as a 36-amino acid linear peptide and release it in response
to ingestion of a meal, although the signals between the gut
and pancreas have not been defined. Likewise, although the
peptide can be shown to inhibit pancreatic enzyme and bicar-
bonate secretion, the physiologic significance of this is unclear
because infusion of an antibody to neutralize the actions of
pancreatic polypeptide during meal digestion and absorption
had no effect on the extent of pancreatic secretion. Thus, the
precise role of this peptide remains elusive.
Finally, peptide YY is synthesized and released by enteroen-
docrine cells in the distal small intestine and colon in response
to the presence of fat in the ileal lumen. Its actions are largely
inhibitory, reducing gastrointestinal motility as well as gastric
acid secretion and secretion of chloride by the intestinal epithe-
lium. Some have proposed that peptide YY can be considered
Sensory
neuron
FIGURE 49–12 Schematic diagram of the enteric
nervous system (ENS) and its interactions with the central
nervous system (CNS). PC, program circuit; IC, integration
circuit. (Reproduced with permission from Barrett KE: Gastrointestinal
Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub.
Division, 2006.)
an ileal brake, that is, a substance that acts to slow propulsive
motility and reduce luminal fluidity if nutrients remain unab-
sorbed by the time the meal reaches the ileum, thereby maxi-
mizing contact time and ability to absorb nutrients.
PRINCIPLES OF NEUROCRINE
REGULATION
“LITTLE BRAIN” MODEL OF
THE ENTERIC NERVOUS SYSTEM
The enteric nervous system is often referred to as the “little
brain” (as opposed to the “big brain” of the CNS) because
many of its responses are autonomous of central input. The
gastrointestinal system is unique in being the only organ sys-
tem outside the CNS with such an extensive system of intrinsic
neural circuits. The various neurons of the enteric nervous
system can be considered to perform functions in two primary
areas (Figure 49–12). First, program circuits receive inputs
regarding the physiologic status of the intestine, and translate
these into appropriate changes in function. Second, integra-
tion circuits relay such information to the CNS, and in turn
integrate information derived from the CNS with that sup-
plied from intrinsic circuits to modify functional outcomes.
As discussed earlier, the intrinsic nerves of the gastrointesti-
nal system are arranged into two plexuses—myenteric and
submucosal. Within these plexuses, the neurons can be subdi-
vided according to their functions (Table 49–3). In the myen-
teric plexus, inhibitory and excitatory nerves control the
function of the circular and longitudinal muscle layers. There
are also ascending and descending interneurons that relay
information through the myenteric plexus along the length of
the gastrointestinal tract. In the submucosal plexus, secreto-
motor neurons, some of which also innervate blood vessels to
promote vasodilatation, regulate the secretion of fluid and
electrolytes and contractions of the muscularis mucosa. The
plexuses also contain cell bodies of primary afferent nerves
with projections to the mucosa designed to sense the physio-
logic environment.
Epithelium
Secretomotor neuron
Smooth muscle
PC IC
CNS
ENS
 CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation 503

TABLE 49–3 Classification of enteric nerves.
Type
Myenteric neurons
Stimulatory motor neurons
Inhibitory motor neurons
Ascending and descending
interneurons
Sensory neurons
Submucosal neurons
Noncholinergic secretomotor
neurons
Cholinergic secretomotor
neurons
On the other hand, painful sensations are conveyed via spinal
afferents that pass through the dorsal root ganglia.
Primary Neurotransmitters Vagal communication is largely mediated through the
enteric nervous system and involves cholinergic transmission.
Parasympathetic vagal input and vagovagal reflexes play a crit-
Acetylcholine
ical role in regulating numerous gut functions, particularly
Nitric oxide during the early phases of response to a meal. The pelvic nerve
Acetylcholine, plays an analogous role in the distal colon and rectum. On the
5-hydroxytryptamine other hand, sympathetic innervation to the intestine, medi-
ated by norepinephrine, is relatively limited in its extent and
Substance P
implications under physiologic circumstances. Instead, it
seems likely that sympathetic regulation is called upon to over-
Vasoactive intestinal polypeptide ride the normal control of gut function, by slowing motility
and inhibiting secretion, as a defense mechanism during times
Acetylcholine of threat to whole body homeostasis.

Sensory neurons Substance P

PARACRINE AND
IMMUNE REGULATION
ENTERIC NEUROTRANSMITTERS
IMPORTANT MEDIATORS
Most, if not all, enteric neurons store multiple neurotransmit-
ters, but not all of the transmitters in a given nerve may be Paracrine and immune regulation of gastrointestinal function
equally important in terms of information transfer. Some gen- both involve the release of substances from nonexcitable cell
eral patterns are also apparent. Thus, excitatory nerves depend types, including enteroendocrine cells, enterochromaffin
largely on cholinergic neurotransmission. The actions of ace- and enterochromaffinlike (ECL) cells, and immune elements
tylcholine in muscarinic stimulatory pathways for either mus- in the lamina propria, which then act on neighboring cell types
cle contraction or secretory functions may be amplified by in the immediate environment. Important paracrine/immune
coreleased tachykinins such as substance P and neuroki- mediators are summarized, along with their major sources of
nin A. Acetylcholine also serves to deliver information from origin, in Table 49–4.
the parasympathetic branch of the autonomic nervous system, Note that some paracrines are also stored in nerves, and
largely via the vagus nerve, to the enteric neurons, although in thus play a dual role in signaling in the gut. For example,
this case it acts via nicotinic receptors. somatostatin, an important inhibitory peptide in the gut, is
Inhibitory nerves in the myenteric plexus, on the other synthesized by enteroendocrine D cells as well as being stored
hand, exert their effects predominantly via the release of nitric in interneurons of the enteric nervous system. Other para-
oxide, although several other neurotransmitters also play vary- crines may also derive from multiple cell sources. Thus, hista-
ing roles depending on the species and the segment of intes- mine is released from ECL cells in the gastric glands as a classic
tine being considered. These additional inhibitory
neurotransmitters include VIP, ATP, and pituitary adenylate
cyclase activating peptide (PACAP). VIP is also a critical TABLE 49–4 Important paracrine and immune
neurotransmitter for noncholinergic neurons in the submu- mediators in the gastrointestinal tract.
cosal plexus that function to stimulate secretomotor function
as well as vasodilation. Mediator Major Sources Selected Functions
Interneurons in the myenteric plexus utilize various neu- Histamine 1. ECL cells 1. Gastric acid secretion
rotransmitters to deliver information along the vertical axis, 2. Mast cells 2. Intestinal chloride
but one common transmitter in such nerves is serotonin secretion
(5-hydroxytryptamine [5-HT]). Other interneurons contain- 5-Hydroxytryptamine Enterochromaffin Response to luminal
ing acetylcholine and somatostatin have been implicated in cells nutrients
the generation of a motility pattern known as the migrating
Somatostatin D cells Various inhibitory effects
motor complex (see Chapter 54). Finally, the intrinsic primary throughout GI tract
afferents that relay information to the enteric program and
Prostaglandins Subepithelial Intestinal secretion;
integration circuits utilize tachykinins for sensory transmis- myofibroblasts vascular regulation
sion. These neurons ultimately control intestinal movements,
blood flow, and secretion in response to distension, luminal Adenosine Various cell types Intestinal secretion;
vascular regulation
chemistry, and mechanical deformation of the mucosal surface.
504 SECTION VIII GI Physiology
paracrine, but also from mucosal mast cells in response to
antigenic stimulation, where it acts as an immune mediator.
MECHANISMS OF ACTIVATION
Paracrine and immune regulators are primarily responsible
for fine-tuning physiologic responses that are set into motion
by hormonal and neural regulation, and as such are usually
released in response to triggers that also act in the immediate
environment. Thus, both the endocrine and immune cells
that release these substances can be considered as the gut
equivalent of the taste buds in the tongue that sample various
components of ingested food and send information about its
palatability. More distally, therefore, enteroendocrine cells are
triggered in response to specific meal components, or by
potentially injurious solutes in the lumen in the case of
immune cells.
In some cases, the cells responsible for releasing paracrine
and/or immune effectors also receive neural input, and/or
are sensitive to the actions of circulating gastrointestinal
hormones. The gastric ECL cell in the fundic region is an
excellent example of this, releasing histamine in response to
both acetylcholine released from enteric nerve endings and
gastrin traveling through the bloodstream from the gastric
antrum.
INTEGRATION OF
REGULATORY SYSTEMS
There is considerable cross-talk between the regulatory sys-
tems discussed in this chapter, as well as functional redundancy.
Moreover, communication mediated by one mode, for exam-
ple, endocrine, may secondarily activate other modes of com-
munication to amplify the eventual physiologic responses in
target organs. An example of this is seen with the GI hormone
CCK. On release from the gastrointestinal mucosa, CCK not
only travels through the bloodstream to activate secretory and
motor responses in other sites, but also binds to receptors on
primary efferent nerve endings within the intestinal wall that
can transmit vagovagal reflexes to propagate additional signal-
ing. Conversely, a neurocrine messenger, gastrin-releasing
peptide, acts on G cells to release a hormone that then can dis-
tribute the signal more broadly.
Finally, the existence of multiple inputs to many of the cell
types involved in the integrated response to a meal not only
provides functional redundancy, underscoring the importance
of gastrointestinal function for whole body homeostasis, but
also permits synergism, or potentiated responses, at the level
of the target cell type. Synergism, or a greater than additive
physiologic response, can be predicted to occur if the two (or
more) messengers in question activate their target cell by dif-
ferent intracellular signaling cascades.
Integration of intestinal responses also involves the trans-
mission of negative, or inhibitory, signals. Such feedback
inhibition controls the rate of delivery of nutrients such that
this is matched with digestive and secretory capacity. Feed-
back mechanisms also terminate gut secretory responses
when they are no longer needed to assimilate a meal, to con-
serve resources and, in some cases, minimize possible adverse
consequences of overly prolonged exposure to gastrointestinal
secretions.
CHAPTER SUMMARY
■ The GI system fulfills the functions of digestion and absorp-
tion, excretion, and host defense.
■ The GI system reflects a complex and cooperative network
of various organs.
■ Cellular specialization underlies the various functional
responses required of the GI system.
■ The GI system is highly efficient, interactive, and redundant.
■ The circulatory features of the GI tract and liver set them apart
from other organs.
■ Communication between the various segments of the GI tract,
as well as the organs that drain into it, is vital for the integrated
response to a meal.
■ Communication is achieved via the endocrine, neurocrine,
paracrine, and immune mediators that act at sites distant from
the site of stimulation and locally.
■ The enteric nervous system serves to regulate the motility and
secretory responses of the gut, and to integrate this regulation
with information from the CNS.
■ Stimulatory and inhibitory nerves and neurotransmitters
are involved in the communication and regulation of the
information.
■ Paracrine and immune messengers act locally to modulate
endocrine and neurocrine signaling.
STUDY QUESTIONS
1. A patient receiving chemotherapy for a prostate tumor develops
severe abdominal pain and diarrhea. Following the treatment,
his or her gastrointestinal symptoms subside. The resolution of
his or her symptoms most likely reflects repair of which of the
following cell types?
A) epithelial cells
B) smooth muscle cells
C) lymphocytes
D) enteric nerves
E) Paneth cells
2. A pharmaceutical scientist trying to develop a new drug for
hypertension gives a candidate compound orally to rats. He or
she determines that the drug is adequately absorbed from the
intestine, but levels in the systemic circulation remain below
the therapeutic range. The drug is most likely metabolized
by which organ?
A) small intestine
B) kidney
C) lung
D) liver
E) spleen
 CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation 505

3. A mouse is genetically engineered to lack CCK-B receptors. This 5. In a study of the secretion of gastrointestinal hormones, their
animal would be expected to display increased circulating levels concentrations in the portal vein are measured during luminal
of which of the following hormones? perfusion of the small intestine with solutions of various pH
A) gastrin levels. Which hormone will increase in the portal vein plasma
B) motilin during perfusion with a buffered solution of pH 3?
C) secretin A) CCK
D) CCK B) gastrin
E) insulin C) GIP
4. An experiment was conducted in which a balloon was inflated D) motilin
inside the stomach of a human volunteer and gastric pressures E) secretin
measured. Despite the increase in gastric volume, gastric
pressures remained relatively constant. This remarkable
pressure–volume relationship could be abolished by which of
the following pharmacological agents?
A) adrenergic agonist
B) inhibitor of the enzyme responsible for nitric oxide synthesis
C) cholinergic agonist
D) CCK
E) an antibody to gastrin
This page intentionally left blank
 50
C H A P T E R

Gastric Secretion
Kim E. Barrett

O B J E C T I V E S

■ Understand the physiological role of gastric acid secretion, as well as that of

other gastric secretory products.
■ Identify the regions of the stomach and cell types from which the various
gastric secretions originate.
■ Understand how gastric secretion is initiated in response to anticipation of a
meal, and how secretion is amplified once the meal has been ingested.
■ Define cephalic, gastric, and intestinal phases of the secretory response.
■ Describe how secretion is terminated once the meal has left the stomach.
■ Define the cellular basis for acid secretion and the morphological changes
that take place in parietal cells to achieve this.

BASIC PRINCIPLES
OF GASTRIC SECRETION
ROLE AND SIGNIFICANCE
The stomach is a muscular reservoir into which the meal
enters after being swallowed. While limited digestion may
begin in the oral cavity as a result of enzymes contained in
saliva, the gastric juices represent the first significant source of
digestive capacity. However, the digestive functions of the
stomach are not necessary for assimilation of a mixed meal,
and indeed, surgical removal of the majority of the stomach
usually allows adequate nutrition. However, some degree of
gastric secretory function is required for the absorption of an
essential vitamin, B12, and gastric acid may also be important
in the absorption of dietary nonheme iron. Gastric secretions
also serve to sterilize the meal.
GASTRIC SECRETORY PRODUCTS
The functions outlined in the previous section are subserved
by a number of products secreted by the stomach (Table 50–1).
The most characteristic secretory product of the stomach is
hydrochloric acid. The acidity of the gastric secretions begins
the digestive process via simple hydrolysis and is also antimi-
crobial. Enzymatic digestion of the meal also occurs as a result
of gastric secretions. A proteolytic enzyme, pepsin, is secreted
as an inactive precursor, pepsinogen, and autocatalytically
cleaved at the low pH existing in the stomach lumen. Pepsin is
specialized for its role in mediating protein digestion in the
stomach because it exhibits optimum activity at low pH. The
gastric juice also contains intrinsic factor, synthesized by pari-
etal cells, and lipase, that contributes to the initial digestion of
triglycerides. Intrinsic factor binds to vitamin B12, also known
as cobalamin, and is required for the eventual absorption of
this vitamin more distally in the intestine. The stomach also
secretes products important in protecting the mucosa from the
harsh effects of the luminal mixture of acid and enzymes.
Throughout the stomach, the surface cells are covered with a
layer of mucus. Mucus consists of a mixture of mucin glyco-
proteins, surface phospholipids that endow hydrophobic prop-
erties on the surface of the mucus layer, and water. The stability
of this layer is additionally enhanced by the activity of small
peptides, known as trefoil factors, which interact with the car-
bohydrate side chains of mucin molecules. Bicarbonate ions
are also secreted into the base of this mucus layer and protect
the gastric surface from excessively low and potentially injuri-
ous pH via simple neutralization. Finally, the stomach secretes
a number of products into the mucosa that play critical roles in

507

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508 SECTION VIII GI Physiology

TABLE 50–1 Important gastric secretory products.

Product Source Functions

Hydrochloric acid Parietal cell Hydrolysis; sterilization of meal

Intrinsic factor Parietal cell Vitamin B12 absorption

Pepsinogen Chief cell Protein digestion

Mucus, bicarbonate Surface mucous cells Gastroprotection

Trefoil factors Surface mucous cells Gastroprotection

Histamine ECL cells Regulation of gastric secretion

Gastrin G cells Regulation of gastric secretion

Gastrin-releasing peptide Nerves Regulation of gastric secretion

Acetylcholine (ACh) Nerves Regulation of gastric secretion

Somatostatin D cells Regulation of gastric secretion

regulating the secretory and motility functions of the stomach,

including gastrin, histamine, and prostaglandins. The roles of Acid, intrinsic factor, pepsinogen
these factors will be discussed in more detail later.

Mucus layer

ANATOMICAL CONSIDERATIONS
FUNCTIONAL REGIONS
Surface mucous cells
OF THE STOMACH (mucus, trefoil peptide,
bicarbonate secretion)
The stomach lies between the esophagus and the duodenum,
and is delimited by the lower esophageal sphincter and the Cell migration Mucous neck cells
pylorus, respectively (Figure 49–5). The wall of the stomach (stem cell compartment)
contains thick vascular folds known as rugae, and the surface
epithelium is invaginated with a series of gastric pits. Each pit
opens to four to five blind-ended gastric glands. The stomach Parietal cells
(acid, intrinsic factor
can also be divided into three major regions by both structure
secretion)
and function. Most proximal is the cardia that represents
approximately 5% of the gastric surface area, and is a transi-
tional zone where the stratified squamous epithelium of the
esophagus gives way to the columnar epithelium that lines the ECL cell
remainder of the stomach and intestinal tract. The fundus or (histamine secretion)
body of the stomach contains approximately 75% of the gastric
glands, and in this region the oxyntic glands consist of spe-
cialized cell types from which arise the characteristic secre-
tions of the stomach (Figure 50–1). Finally, the antrum of the Chief cells
(pepsinogen secretion)
stomach, immediately proximal to the pylorus, is responsible
for the secretion of gastrin, the primary regulator of postpran-
dial gastric secretion. The antrum also fulfills important motil-
ity functions that will be described in Chapter 54.

FIGURE 50–1 Structure of a gastric gland from the fundus

GASTRIC CELL TYPES
The oxyntic, or parietal, glands found in the gastric fundus
contain a variety of specific cell types (Figure 50–1). These
include parietal cells, which are specialized to secrete acid and
and body of the stomach. These acid – and pepsinogen-producing
glands are referred to as “oxyntic” glands in some sources. Notice the
mitotic figures in several mucous neck cells indicating rapid cell
turnover. (Adapted with permission from Barrett KE: Gastrointestinal Physiology.
New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
 CHAPTER 50 Gastric Secretion 509

A B
Golgi complex Golgi
complex
Intracellular
canaliculus

Tubulovesicular
membrane
Intracellular Mitochondria
canaliculus
Tubulovesicular
membrane
Basal folds Mitochondria
Basal folds Intracellular
Basement lamina
canaliculus
Basement lamina

Parietal cell (Nonsecreting)

Parietal cell (secreting)

FIGURE 50–2 A) Ultrastructural appearance of a resting parietal cell. Note the elaborate system of intracellular membranes and a large
number of mitochondria. B) Ultrastructural appearance of a parietal cell during active secretion. The apical membrane is massively amplified by
fusion of tubulovesicles and the secretory canaliculi. (Modified with permission from Ito S: Functional gastric morphology. In: Physiology of the Gastrointestinal Tract,
2nd ed. Johnson LR (editor). New York: Raven Press, 1987.)

intrinsic factor, and chief cells, which store pepsinogen in api- tionally significant communication with the gastric lumen.
cal granules that can release their contents via exocytosis. The D cells, which secrete somatostatin, are also present.
glands also contain endocrine cells that are responsible for
releasing products that regulate gastric function, particularly
the enterochromaffin-like (ECL) cells that synthesize hista- INNERVATION
mine. Toward the top of the gland where it joins with the gas-
Nerves carried through the parasympathetic vagus nerve,
tric pit, and moving out onto the gastric surface, the gland
with both efferent and afferent pathways, richly innervate the
contains surface mucous cells that secrete mucus. In the isth-
stomach. Vagal afferents convey information from the dorsal
mus and neck region of the gland lie the mucus neck cells,
vagal complex, which is integrated with that coming from
which are the precursors for all of the other differentiated cell
higher centers, such as the hypothalamus, to set the overall
types in the gland. These anchored stem cells give rise to
level of secretory function at any given moment. Visceral
daughter cells, which migrate downward to become parietal,
inputs also contribute to gastric regulation. Notably, the out-
chief, or endocrine cells, or upward to become surface mucous
put of taste receptors travels to a brain region called the
cells. The surface mucous cells turn over every 1–3 days in
nucleus tractus solitarius, where this information is again
adult humans.
translated into signals that regulate secretion and other gastric
The parietal cells are remarkable for their secretory capac-
functions. The enteric nerve plexuses throughout the gastro-
ity and energetic requirements. These cells secrete acid against
intestinal tract also encircle the walls of the stomach. These
a concentration gradient of more than 2.5 million–fold, from
allow for some degree of autonomous function, in addition to
the cytoplasmic pH of 7.2 to a luminal pH of less than 1 when
transmitting effects of central input.
secretion is maximally activated. To sustain such massive rates
The dorsal vagal complex represents an important site
of secretion, the parietal cell is packed with mitochondria,
where the various influences that can alter gastric secretion are
which are estimated to take up about 30–40% of the cell’s vol-
integrated. Thus, the dorsal vagal complex receives central
ume. The resting parietal cell also contains numerous mem-
input from the hypothalamus, as well as visceral input from
branous compartments known as tubulovesicles, as well as a
the nucleus tractus solitarius.
central canaliculus that deeply invaginates the apical mem-
brane (Figure 50–2A). This morphology changes dramatically
on cell stimulation (Figure 50–2B) as will be described more
fully later. REGULATION OF
In the antral mucosa, the glands do not contain parietal or GASTRIC SECRETION
chief cells, but instead are composed of both mucus-secreting
cells and enteroendocrine cells that regulate gastric function. Control of the secretion of the characteristic products of the
Particularly, the glands contain G cells, which synthesize and cell types lining the stomach represents a paradigm for control
release gastrin across their basolateral poles, and have func- of gastrointestinal function as a whole. Thus, the secretory
510 SECTION VIII GI Physiology
capacity of the stomach is closely integrated with signals coin-
cident with the ingestion of a meal, and modulated as the meal
moves through the gastrointestinal tract to provide optimum
digestion. There are many mechanisms, therefore, whereby
the function of the stomach is controlled.
REGULATORY STRATA
Short and Long Reflexes
Neural input provides an important mechanism for regulation
of gastric secretion (Figure 50–3). Reflexes contribute to both
the stimulation and inhibition of secretion. For example, dis-
tension of the stomach wall activates reflexes that stimulate
acid secretion at the level of the parietal cell. These may be
short reflexes, which involve neural transmission contained
entirely within the enteric nervous system. In addition, long
reflexes involve the activation of primary afferents that travel
through the vagus nerve, which in turn are interpreted in the
dorsal vagal complex and trigger vagal outflow via efferent
nerves that travel back to the stomach and activate parietal cells
or other components of the secretory machinery. These long
reflexes are also called vagovagal reflexes. Acetylcholine
(ACh) is an important mediator of both short and long reflexes
Dorsal
vagal complex
Vago-vagal
reflex
Acid Oxyntic
Pepsin gland
ENS
reflex
Stretch
G receptor
cell
GRP
Gastrin
Blood stream
FIGURE 50–3 Neural regulation of gastric secretion in
response to gastric distension. Stretch of the stomach wall
increases acid secretion via both intrinsic reflexes and vagovagal
reflexes. (Modified with permission from Barrett KE: Gastrointestinal Physiology.
New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
in the stomach. It participates in the stimulation of parietal,
chief, and ECL cells, as well as the synapses between nerves
within the enteric nervous system. In addition, a second impor-
tant gastric neurotransmitter is gastrin-releasing peptide
(GRP). GRP is released by enteric nerves in the vicinity of gas-
trin-containing G cells in the gastric antrum.
Humoral Control
The gastric secretory response is also regulated by soluble fac-
tors that originate from endocrine and other regulatory cell
types, such as ECL cells (Figure 50–4). The primary endocrine
regulator of gastric secretion is gastrin, which travels through
the bloodstream to stimulate parietal and ECL cells via their
cholecystokinin (CCK)-B receptors.
Gastric secretion is also modified by paracrine mediators. His-
tamine is released from ECL cells under the combined influence
of gastrin and acetylcholine, and diffuses to neighboring parietal
cells to activate acid secretion via histamine H2 receptors. At one
time, histamine was thought to be the final common mediator of
acid secretion, based in part on the clinical observation that his-
tamine H2 receptor antagonists can profoundly inhibit acid
secretion. However, it is now known that parietal cells express
receptors for not only histamine, but also acetylcholine (muscar-
inic m3) and gastrin (CCK-B) (Figure 50–5). Because histamine
H2 receptors are linked predominantly to signaling pathways that
involve cAMP, while ACh and gastrin signal through calcium,
when the parietal cell is acted upon simultaneously by all three
stimuli, a potentiated, or synergistic, effect on acid secretion
results. The physiological implication of this potentiation, or syn-
ergism, is that a greater level of acid secretion can be produced
with relatively small increases in each of the three stimuli. The
pharmacological significance is that simply interfering with the
action of any one of them can significantly inhibit acid secretion.
In fact, synergism is a common theme in the control of several
different functions throughout the gastrointestinal system.
Acid secretion is also subject to negative regulation by spe-
cific mediators. Specifically, somatostatin is released from
D cells in the antral mucosa when luminal pH decreases below 3,
and inhibits the release of gastrin from G cells. Elsewhere in the
stomach, somatostatin can also exert inhibitory influences on
ECL, parietal, and chief cells.
Luminal Regulators
Specific luminal constituents also modulate gastric secretion
indirectly. The example of pH is described earlier, but acid
output, at least, is also increased by components of the meal.
Short peptides and amino acids, derived from dietary protein,
are capable of activating gastrin release from G cells.
REGULATION OF SECRETION
IN THE INTERDIGESTIVE PHASE
Between meals, the stomach secretes acid and other secretory
products at a low level, perhaps to aid in maintaining the
 CHAPTER 50 Gastric Secretion 511

ANTRUM FUNDUS
Peptides/amino acids

GRP
H+
G cell ACh
H+ −
Parietal cell FIGURE 50–4 Regulation of gastric acid
and pepsin (P) secretion by soluble mediators
D cell
P and neural input. Gastrin is released from
Gastrin G cells in the antrum and travels through the
SST Chief cell circulation to influence the activity of ECL cells
ACh and parietal cells. The specific agonists of chief
? ?
cells are not well understood. Gastrin release is
Histamine
negatively regulated by luminal acidity via the
ACh release of somatostatin from antral D cells. SST;
Circulation ECL cell somatostatin. (Adapted with permission from Barrett KE:
Gastrointestinal Physiology. New York: Lange Medical Books/
Nerve ending McGraw-Hill, Medical Pub. Division, 2006.)

sterility of the stomach. However, because no food is present,
and thus no buffering capacity of the gastric contents, the low
volume of secretions produced nevertheless has a low pH—
usually around 3.0. Basal acid output in the healthy human is
in the range of 0–11 mEq/h, and is believed to reflect the
combined influences of histamine and ACh, released from
ECL cells and nerve endings, respectively. Gastrin secretion
during the interdigestive period, on the other hand, is mini-
mal. This is because gastrin release is suppressed by a luminal
pH of 3 or below.
REGULATION OF
POSTPRANDIAL SECRETION
In conjunction with a meal, gastric acid secretion occurs in
three phases—cephalic, gastric, and intestinal—and increases
to 10–63 mEq/h. The major portion of secretion occurs dur-
ing the gastric phase, when the meal is actually present in the
stomach. Secretion of other gastric products usually parallels
that of acid.
Cephalic Phase
Even before the meal is ingested, the stomach is readied to
receive it by the cephalic (i.e., related to the head) phase of
secretion. In fact, during the cephalic phase, several gastroin-
testinal systems in addition to the stomach become activated,
including the pancreas and gallbladder. Higher brain centers
respond to the sight, smell, taste, and even the thought of food,
and relay information to the dorsal vagal complex. In turn,
vagal outflow initiates both secretory and motor behavior in
the stomach and more distal segments. Gastric secretion
occurring during the cephalic phase readies the stomach
to receive the meal. Vagal outflow activates enteric nerves
that in turn release GRP and ACh. Release of GRP in the vicin-

Resting Secreting
Canaliculus

Tubulo- H+, K+ ATPase FIGURE 50–5 Parietal cell receptors

vesicle and schematic representation of the
morphological changes depicted in Figure
50-2. Amplification of the apical surface area
is accompanied by an increased density of
H+,K+-ATPase molecules at this site. Note that
Ca++ Ca++
M3 acetylcholine (ACh) and gastrin signal via
cAMP CCK−B calcium, whereas histamine signals via cAMP.
ACh
M3 CCK−B Gastrin (Adapted with permission from Barrett KE:
H2 H2 Gastrointestinal Physiology. New York: Lange Medical
Histamine Books/McGraw-Hill, Medical Pub. Division, 2006.)
512 SECTION VIII GI Physiology
ity of antral G cells releases gastrin that travels through the
bloodstream to activate parietal and chief cells in an endocrine
fashion.
Gastric Phase
The gastric phase of secretion is quantitatively the most
important. In addition to vagal influences continuing from the
cephalic phase, secretion is now amplified further by mechan-
ical and chemical stimuli that arise from the presence of the
meal in the lumen. These include the luminal signals discussed
earlier, and signals arising from stretch receptors embedded in
the wall of the stomach. Thus, as the stomach distends to
accommodate the volume of the meal, these receptors initiate
both short and long reflexes to further enhance secretory
responses either directly, via the release of acetylcholine in the
vicinity of parietal cells, or indirectly, via the activation of ECL
or G cells. The gastric phase also involves changes in motility
and is accompanied by a marked increase in gastric blood flow,
which supplies the metabolic requirements of the actively
secreting cell types.
Due to the combined influence of neurocrine and endocrine
signals, further amplified by histamine release from ECL cells,
secretory cells of the stomach are highly active during the gas-
tric phase. Moreover, pepsinogen released by chief cells is rap-
idly cleaved to pepsin in an autocatalytic reaction that occurs
optimally at pH 2, and this pepsin then acts on ingested pro-
tein to release short peptides and amino acids that further
enhance gastrin release. Moreover, many dietary substances,
including proteins, are highly effective buffers. Thus, while
acid secretory rates remain high, the effective pH in the bulk
of the lumen may increase to pH 5. This ensures that the rate
of acid secretion during the gastric phase is not attenuated by
an inhibition of gastrin release due to somatostatin.
Intestinal Phase
As contents move out of the stomach into the duodenum, the
buffering capacity of the lumen is reduced and the pH begins
to decrease. At around pH 3, somatostatin release is triggered
from D cells, and acts to suppress gastrin release. D cells them-
selves may be capable of responding to luminal acidity. There
is also evidence for a neural pathway, involving the activation
of chemoreceptors sensitive to pH, which in turn leads to
release of the neuropeptide calcitonin gene-related peptide
(CGRP). This peptide may then act on the D cells to induce
release of somatostatin. Other signals also limit the extent of
gastric secretion when the meal has moved into the small
intestine. For example, the presence of fat in the small intes-
tine is associated with a reduction in gastric secretion. This
feedback response is believed to involve several endocrine and
paracrine factors, including GIP.
Nevertheless, a portion of gastric secretion occurs once the
meal is in the intestine. The mediators of this response are largely
unknown, although CCK may play a role since the CCK-B
receptors on parietal cells do not discriminate markedly between
gastrin and CCK. The intestinal phase of secretion may serve to
ready the stomach for its next meal. Of course, there is also over-
lap between the gastric and intestinal phases of secretion since
the meal moves only gradually into the duodenum.
CELLULAR BASIS OF SECRETION
ACID SECRETION
The basolateral membrane of the parietal cell contains recep-
tors for histamine, gastrin, and ACh (Figure 50–5). The down-
stream targets of the signaling pathways linked to receptor
occupancy are presumed to include cytoskeletal elements, ion
channels, and the receptors themselves, the latter representing
a mechanism of negative feedback. Cytoskeletal rearrange-
ments are implied by the dramatic morphological changes that
occur as parietal cells transition from rest to secretion. At rest,
the cytoplasm is filled with the tubulovesicles and intracellular
canaliculi. When the parietal cell is stimulated, the canaliculi
fuse with the apical plasma membrane (Figure 50–5). The
intracellular tubulovesicles, in turn, fuse to the canaliculi, mas-
sively amplifying the surface area of the apical membrane that
is in contact with the gland lumen by a factor of approximately
5–10-fold. At rest, the tubulovesicles are the site for storage of
the majority of a membrane-bound transporter, H+,K+-ATPase,
or proton pump, where it is therefore sequestered from the
lumen. Following fusion of the tubulovesicles and canaliculi,
the density of proton pumps in the apical pole of the cell is
massively increased (Figure 50–5). These pumps are the sites of
active pumping of protons into the gastric lumen.
Protons are generated adjacent to the apical membrane as a
result of the activity of the enzyme carbonic anhydrase II
(Figure 50–6). This enzyme generates protons and bicarbonate
ions from the reaction of water and carbon dioxide. Protons are
then pumped out of the cell across the apical membrane in
exchange for potassium ions, with the consumption of cellular
energy. The potassium ions also originate from the cell cytosol,
where they are maintained at levels above their chemical equi-
librium by the activity of Na+,K+-ATPase. They can therefore
readily exit across the apical membrane through potassium
channels that are also localized to the tubulovesicles, and which
are opened when the parietal cell is stimulated. Specialized
chloride channels are also present in this site, and serve to allow
the apical exit of chloride ions to match the protons pumped
from the cell. Thus, the final secretory product is actually
hydrochloric acid. The overall mechanism should also remind
you of absorption of bicarbonate by the renal tubule, as was
discussed in Chapter 47.
A bicarbonate ion is generated for every proton that is
secreted, and if these were allowed to accumulate in the cyto-
sol, deleterious effects on cellular metabolism would result
from the resulting increase in pH. Thus, as the protons are
secreted apically, the parietal cells also discharge bicarbonate
ions across the basolateral membrane to maintain cytosolic
pH within narrow limits. At least a portion of this bicarbonate

Lumen
+
2K
Potassium
channel
H2O + CO2
H+
C.A.II
K+
+ +
H , K ATPase
H+ H+ + HCO3
Cl Cl
ClC
Chloride
channel
Apical
transport occurs in exchange for the chloride ions that are
needed for apical secretion, via a chloride–bicarbonate
exchanger. Some bicarbonate is likely also lost secondary to
pumping into intracellular vesicles (distinct from the tubulo-
vesicles) that then move to the basolateral membrane and fuse
with it, discharging their contents. The bicarbonate leaving the
cell is then picked up by the bloodstream. The arrangement of
the microvasculature in the gastric mucosa carries a portion of
this bicarbonate up to the basolateral pole of surface epithelial
cells, which secrete bicarbonate to defend themselves against
the potentially injurious effects of acid and pepsin. This move-
ment of bicarbonate into the bloodstream during gastric secre-
tion is referred to as the alkaline tide.
The transport mechanisms that exist in parietal cells are
depicted in Figure 50–6. In addition to those already men-
tioned earlier, the basolateral membrane contains a sodium–
hydrogen exchanger, NHE-1, which expels protons from the
cell in exchange for sodium ions, a process driven secondarily
by the low intracellular sodium concentration established by
the Na+,K+-ATPase. At first blush, this may seem counterin-
tuitive, since basolateral fluxes of protons would be predicted
to oppose the normal secretion of acid across the apical mem-
brane. However, the role of NHE-1 is not to participate in acid
secretion, but to fulfill “housekeeping” functions, namely to
allow for the efflux of protons generated in resting cells by
ongoing metabolic activities. A basolateral potassium channel
that has also been identified in parietal cells likely also plays a
similar homeostatic role.
OTHER PRODUCTS
The stomach also secretes a number of additional products
that are important in gastrointestinal physiology. Here, we
CHAPTER 50 Gastric Secretion 513
Blood Stream
Na+, K+ ATPase
3Na+
Na+
NHE-1
HCO3
FIGURE 50–6 Ion transport proteins of
parietal cells. Protons are generated in the
HCO3
cytosol via the action of carbonic anhydrase II
(C.A.II). Bicarbonate ions are exported from
Cl /HCO3 the basolateral pole of the cell either by
vesicular fusion or via a chloride/bicarbonate
exchanger
exchanger. NHE-1, sodium–hydrogen
exchanger (Adapted with permission from Barrett KE:
Gastrointestinal Physiology. New York: Lange Medical
Basolateral Books/McGraw-Hill, Medical Pub. Division, 2006.)
will briefly review how the secretion of these products is con-
trolled at the cellular level, although it should be noted that
considerably less information exists on this topic than for
gastric acid.
Intrinsic factor is synthesized and released by parietal cells,
presumably via a process of exocytosis, and activated by
the same secretagogues that initiate acid secretion. However,
while intrinsic factor is usually secreted in parallel with acid,
these processes are not dependent on each other. Thus, proton
pump inhibitors have no inhibitory effect on the secretion of
intrinsic factor. Pepsinogen is secreted by chief cells via a clas-
sical process of compound exocytosis, and is thereafter acti-
vated to its catalytic form in the presence of a low pH. The
active enzyme is inactivated if the pH increases above 5 (i.e.,
soon after the meal has moved into the duodenum, in healthy
individuals). As for other cell types that release their products
via exocytosis, calcium is a key intracellular mediator effecting
the secretory response, and ACh and GRP, both agents that
elevate intracellular calcium, are known to be important chief
cell secretagogues. The precise roles of gastrin and histamine,
on the other hand, remain controversial. One additional secre-
tagogue that may be important, however, is secretin, especially
during the intestinal phase of gastric secretion. Surface epithe-
lial cells throughout the stomach secrete mucus and bicarbon-
ate. The viscosity of mucus may limit diffusion of acid through
the plane of the gel via a mechanism known as viscous finger-
ing. Thus, acid secreted under hydrostatic pressure from the
gastric glands may emerge as a discrete stream through the gel,
restricting access of the acid to the gastric surface. Mucus-
secreting cells also package phospholipids that are secreted
concurrently with mucins, in a manner analogous to the secre-
tion of surfactant in the lung. These phospholipids may
limit the back-diffusion of apical solutes, such as protons,
toward the epithelium. Secretion of the components of the
514 SECTION VIII GI Physiology
mucus layer is increased by a variety of secretagogues, and is
presumed to be under the control of both cholinergic and gas-
trin-dependent signaling pathways, as well as local reflexes
that may involve CGRP and tachykinins. Likewise, prostaglan-
dins are potent mucus secretagogues, providing a partial
explanation as to why nonsteroidal anti-inflammatory drugs
(NSAIDs), which prevent prostaglandin synthesis, predispose
the gastric mucosa to injury and ulceration.
CLINICAL CORRELATION
A 55-year-old man is referred to a gastroenterologist for
evaluation of a persistent burning sensation in his upper
abdomen that has occurred intermittently for several
months. The pain begins 2–3 hours after eating, often
awakens him at night, and is lessened by a meal. His history
reveals that he smokes one pack of cigarettes per day and
ingests half a bottle of red wine every night with dinner.
Initially, over-the-counter antacids reduced his symptoms
to some extent, but recently they have provided little, if any,
relief. The physician refers the patient for an upper endos-
copy procedure, which shows several eroded areas of the
duodenal mucosa. A test for Helicobacter pylori infection
is also positive. A diagnosis of peptic ulcer disease is made,
and the patient is started on a triple regimen of two antibi-
otics and a proton pump inhibitor. The doctor also advises
him to stop smoking and reduce his intake of alcohol, and
over the next 2 months, the patient’s symptoms resolve and
do not recur.
Peptic ulcer disease, so called because its pathogenesis is
related to the injurious effects of gastric acid and pepsin,
involves erosions through the epithelial lining of the stom-
ach or duodenum that may ultimately lead to bleeding from
mucosal blood vessels. For duodenal ulcer disease, at least,
a failure in mucosal defense mechanisms seems more likely
to be the underlying pathogenic defect. There are two major
exogenous causes of both gastric and duodenal ulcers: gas-
tric colonization with a gram-negative, spiral-shaped bac-
terium known as H. pylori and ingestion of NSAIDs. In the
absence of NSAID use, the vast majority of all ulcer patients
can be shown to be infected with H. pylori, which is special-
ized to colonize the gastric niche because it secretes large
amounts of the enzyme, urease. This product converts urea
to ammonium ions in the vicinity of the bacteria, thereby
protecting them from the deleterious effects of gastric acid-
ity. In genetically susceptible individuals, infection with
H. pylori can have profound effects on both gastric and
duodenal physiology. NSAID-induced ulcers, on the other
hand, likely arise because the drugs suppress the synthesis
of prostaglandins that normally protect the mucosa via
their effects on mucus and bicarbonate secretion as well as
blood flow. Acid also contributes to ulcer pathogenesis,
even if secreted in normal amounts, due to its role in sus-
taining the activation of pepsin, and, in the case of duode-
nal ulcers, the direct injurious effects of protons on the
epithelial cells in this site. In fact, a clinical adage, “no acid,
no ulcer,” also gives clues as to possible treatments. Patients
with ulcer disease are treated typically with drugs that sup-
press acid secretion, thereby giving the mucosa the oppor-
tunity to heal itself. In the past, this was accomplished
primarily with H2 antihistamines. However, more recently,
profound acid suppression—essentially total in nature—
has been accomplished with proton pump inhibitors. In
addition to acid suppression, ulcer patients who can be
demonstrated to be infected with H. pylori usually receive
antibiotics to eradicate the microorganism, a treatment that
markedly reduces the risk of any relapse.
CHAPTER SUMMARY
■ Gastric secretion plays important roles in digestion, absorption
of specific nutrients, and host defense.
■ Acid secretion occurs in phases that correspond temporally to
the ingestion of a meal.
■ Regulation of acid secretion involves neurocrine, paracrine,
and endocrine components.
■ The stomach secretes other important products such as
pepsinogen, intrinsic factor, mucus, and bicarbonate and trefoil
peptides.
■ Various disease states can result from, or are associated with,
abnormal gastric secretory function.
STUDY QUESTIONS
1. A 40-year-old man comes to his physician complaining of
epigastric pain. An upper endoscopy reveals duodenal erosions,
and a test of gastric secretory function reveals markedly elevated
levels of basal acid secretion that are increased only modestly by
intravenous infusion of a gastrin analog. What is the most likely
diagnosis?
A) Zollinger–Ellison syndrome (a gastrin-secreting tumor)
B) H. pylori infection
C) gastroesophageal reflux disease
D) gastroparesis (impaired gastric motility)
E) achalasia (failure of the lower esophageal sphincter to relax)
2. In an experiment, rabbits are administered a cholinergic agonist,
pentagastrin, or histamine intravenously, and gastric acid
secretion measured. Which treatment, when coadministered
with each of these agents, would be expected to block gastric acid
secretion produced by any of the stimuli?
A) histamine H2 antagonist
B) antibodies to gastrin
C) anticholinergic drug
D) histamine H1 antagonist
E) proton pump inhibitor
 CHAPTER 50 Gastric Secretion 515

3. A patient suffering from anemia comes to his physician 6. A patient who is being treated for long-standing osteoarthritis
complaining of frequent bouts of gastroenteritis. A blood test with a NSAID also takes a drug that inhibits acid secretion to
reveals circulating antibodies directed against gastric parietal reduce the toxicity of her NSAID treatment. She comes to her
cells. His anemia is ascribable to hyposecretion of which of the physician complaining of recurrent bouts of diarrhea during a
following gastric secretory products? series of business trips to Guatemala. The apparent increase in
A) histamine her sensitivity to infections acquired by the oral route is most
B) gastrin likely due to reduced secretory function of which of the
C) pepsinogen following?
D) hydrochloric acid A) stomach
E) intrinsic factor B) pancreas
4. Two medical students studying for their physiology final decide C) gallbladder
to take a break for a lunchtime hamburger. Before reaching the D) salivary glands
cafeteria, nervous impulses from the dorsal vagal complex will E) lymphocytes
initiate gastric acid secretion by triggering release of which
neurotransmitter from the enteric nervous system?
A) norepinephrine
B) vasoactive intestinal polypeptide
C) substance P
D) GRP
E) nitric oxide
5. Compared to the cephalic phase, the gastric phase of gastric acid
secretion is characterized by which of the following patterns?

Somatostatin
Acid Secretion Gastrin Secretion Secretion

A) Increased Increased Increased

B) Increased Increased Decreased

C) No change Increased No change

D) Decreased Decreased Increased

E) Decreased Decreased Decreased

F) No change Decreased No change

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 51
C H A P T E R

Pancreatic and
Salivary Secretion
Kim E. Barrett

O B J E C T I V E S

■ Understand the role played by the pancreas in digestion and absorption of a

mixed meal.
■ Understand the structure of the exocrine pancreas and the cell types that give
rise to proteinaceous and fluid components of the pancreatic juice.
■ Identify the key constituents of the pancreatic juice and the enzymes that are
secreted in inactive forms.
■ Describe the factors that regulate the release of secretin and the role of this
hormone in stimulating pancreatic ductular secretion.
■ Understand the role of CCK and other factors in regulating pancreatic acinar cells.
■ Identify the signaling events activated in pancreatic acinar cells by
secretagogues.
■ Compare and contrast the structure of the salivary glands with that of the
exocrine pancreas.
■ Identify the functions of saliva and the constituents responsible for these.
■ Define the ion transport pathways that modify salivary composition.
■ Define the regulatory pathways for saliva production.

BASIC PRINCIPLES PANCREATIC SECRETORY PRODUCTS

OF PANCREATIC SECRETION
ROLE AND SIGNIFICANCE
The exocrine pancreas is the source of the majority of enzymes
required for digestion of a mixed meal (i.e., carbohydrate,
protein, and fat). Pancreatic enzymes are produced in great
excess, underscoring their importance in the digestive process.
However, unlike the digestive enzymes produced by the stom-
ach and in the saliva, some level of pancreatic function is nec-
essary for adequate digestion and absorption. In general,
nutrition is impaired if production of pancreatic enzymes
decreases below 10% of normal levels, or if outflow of the pan-
creatic juice into the intestine is physically obstructed.
The exocrine pancreas is largely the site of synthesis and
secretion of enzymes. These fall into four main groups—
proteases, amylolytic enzymes, lipases, and nucleases—as
shown in Table 51–1. In addition, other proteins are produced
that modulate the function of pancreatic secretory products,
such as colipase and trypsin inhibitors. Finally, the pancreas
secretes monitor peptide, which represents an important
feedback mechanism linking pancreatic secretory capacity
with the requirements of the intestine for digestion. Almost
80% (w/w) of the proteins secreted by the exocrine pancreas
are proteases. Of the proteases, trypsinogen, the inactive pre-
cursor of trypsin, is the most abundant. This likely reflects a
central role for trypsin in initiating the digestion of proteins,
which will be discussed further in Chapter 58.

517

Ch51_517-526.indd 517 12/7/10 9:56:58 PM

518 SECTION VIII GI Physiology

TABLE 51–1 Pancreatic acinar cell secretory products.

Amylolytic
Proteases Enzyme Lipases Nucleases Others

Trypsinogena Amylase Lipase Deoxyribonuclease Procolipasea

Chymotrypsinogena Nonspecific esterase Ribonuclease Trypsin inhibitors

Proelastasea Prophospholipase A2a Monitor peptide

Procarboxypeptidase Aa

Procarboxypeptidase Ba
a
Stored and secreted in inactive forms.

Like pepsinogen in the stomach, pancreatic proteases are exocytosis and fuse with each other and the apical membrane,
packaged and stored as inactive precursors. This is also true thereby discharging their contents into the lumen.
for at least one lipolytic enzyme, prophospholipase A2. The
need to store these enzymes in their inactive forms relates to
the toxicity of the active products toward the pancreas. Under DUCTULAR CELLS
normal circumstances, therefore, the pancreas does not
digest itself. The cells lining the intercalated ducts of the pancreas also play
an important role in modifying the composition of the pan-
creatic juice. They are classical columnar epithelial cells, com-
parable to those lining the intestine itself. When stimulated,
ANATOMIC CONSIDERATIONS these cells transport bicarbonate ions into the pancreatic juice,
IN PANCREAS with water following paracellularly. Thus, the effect of the duct
cells is to dilute the pancreatic juice and to render it alkaline.
Endocrine functions of the pancreas are restricted to cells
located in the islets of Langerhans, which are scattered
throughout the pancreatic parenchyma (see Chapter 66). The
Endocrine cells
exocrine functions, on the other hand, are conducted by a of pancreas
series of blind-ended ducts that terminate in structures known Exocrine cells
as acini (Figure 51–1). Many such acini, arranged like clusters (secrete
of grapes, disgorge their products into a branching ductular enzymes)
system that empties into larger and larger collecting ducts,
eventually reaching the main pancreatic duct or Wirsung’s
duct. A minor part of the pancreas is drained by an accessory
collecting duct, known as the duct of Santorini. Pancreatic Duct cells
(secrete
juice mixed with bile from the liver (see Chapter 56) enters bicarbonate)
the duodenum a short distance distal to the pylorus, under
Gallbladder Pancreas
the control of the sphincter of Oddi. Both the acinar and
ductular cells contribute distinct products to the pancreatic
juice, and both are regulated during the course of responding
to a meal.

ACINAR CELLS
Pancreatic duct
Pancreatic acinar cells are the source of the majority of the
proteinaceous components of the pancreatic juice. Their baso-
lateral membrane faces the bloodstream and contains recep-
tors for a variety of neurohumoral agents responsible for
regulating pancreatic secretion. The apical pole of the cell, on Common bile
Duodenum duct from gallbladder
the other hand, is packed at rest with large numbers of zymo-
gen granules that contain the digestive enzymes and other FIGURE 51–1 Structure of the pancreas. (Reproduced with
regulatory factors. When the cell is stimulated by secret- permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology,
agogues, the granules undergo a process of compound 11th ed. McGraw-Hill, 2008.)

REGULATION OF
PANCREATIC SECRETION
PHASES OF SECRETION
Pancreatic secretory activity related to meal ingestion occurs
in phases. The majority of the secretory response (approxi-
mately 60–70%) occurs during the intestinal phase, but there
are also significant contributions from the cephalic (20–25%)
and gastric (10%) phases. During the cephalic and gastric
phases, secretions are low in volume with high concentrations
of digestive enzymes, reflecting stimulation primarily of aci-
nar cells. This stimulation arises from cholinergic vagal input
during the cephalic phase, and vagovagal reflexes activated by
gastric distension during the gastric phase. During the intesti-
nal phase, on the other hand, ductular secretion is strongly
activated, resulting in the production of high volumes of pan-
creatic juice with decreased concentrations of protein, although
the total quantity of enzymes secreted during this phase is
actually also markedly increased. Ductular secretion during
this phase is driven primarily by the endocrine action of secre-
tin on receptors localized to the basolateral pole of duct epi-
thelial cells. The inputs to the acinar cells during the intestinal
phase consist of cholecystokinin (CCK) as well as neurotrans-
mitters including acetylcholine (ACh) and gastrin-releasing
peptide (GRP). The large magnitude of the intestinal phase is
also attributable to amplification by so-called enteropancreatic
reflexes transmitted via the enteric nervous system.
ROLE OF CCK
CCK can be considered a master regulator of the duodenal
cluster unit and especially the pancreas (Figure 51–2). It is a
potent stimulus of acinar secretion, acting both directly on
CCK
Gallbladder Pancreas Stomach
Contraction Acinar Reduced
secretion emptying
• Protein, carbohydrate, lipid absorption and digestion
• Matching of nutrient delivery to digestive and absorptive capacity
FIGURE 51–2 Multiple effects of cholecystokinin (CCK) in
the duodenal cluster unit. CCK serves to coordinate nutrient
delivery to match intestinal capacity. (Reproduced with permission from
Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill,
Medical Pub. Division, 2006.)
CHAPTER 51 Pancreatic and Salivary Secretion 519
CCK-A receptors localized to the basolateral membranes of aci-
nar cells and via stimulation of vagal afferents evoking vagova-
gal reflexes that stimulate acinar cell secretion through
cholinergic and noncholinergic neurotransmitters. CCK can
also modulate the activity of other neurohumoral regulators on
the pancreas in a synergistic fashion. Notably, while CCK is a
weak agonist of pancreatic ductular secretion of bicarbonate by
itself, it markedly potentiates the effect of secretin on this trans-
port mechanism. During the integrated response to a meal,
therefore, it is likely that the ability of secretin to evoke pancre-
atic bicarbonate secretion is amplified by occurring against the
background of a CCK “tone.” Nevertheless, CCK predominantly
affects acinar cell secretion. Thus, during the initial response to
a meal (i.e., the cephalic and gastric phases), pancreatic secre-
tions are low in volume with a high concentration of enzymes
and enzyme precursors. The output of pancreatic enzymes, but
not that of bicarbonate, that occurs in response to a meal can
essentially be reproduced by the intravenous administration of
postprandial concentrations of CCK. This situation should be
contrasted with secretory flows occurring in the intestinal
phase, where secretin also plays a role, as discussed later.
Factors Causing CCK Release
CCK is synthesized and stored by “I” cells, endocrine cells
located predominantly in the duodenum (Figure 51–3). Con-
trol of CCK release is carefully regulated to match needs for
CCK bioactivity. In part, this is accomplished by the activity of
two luminally active CCK-releasing factors, which are small
peptides. One is derived from the duodenum, and called CCK-
releasing peptide (CCK-RP). It is released in response to fatty
acids and aromatic amino acids. The other luminal peptide that
controls CCK secretion is monitor peptide, which is a product
of pancreatic acinar cells. Release of monitor peptide can be
neurally mediated, including by the release of ACh and GRP
during the cephalic phase, and mediated by subsequent vago-
vagal reflexes during the gastric and intestinal phases of the
response to a meal. Likewise, once CCK release has been stimu-
lated by CCK-RP, it too can cause monitor peptide release.
The significance of factors that regulate CCK release lies in
their ability to match pancreatic secretion of proteolytic
Sphincter enzymes to the need for these enzymes. When meal proteins
and peptides are present in the lumen in large quantities, they
of Oddi
compete for the action of trypsin and other proteolytic
enzymes, meaning that CCK-RP and monitor peptide are
Relaxation
degraded only slowly. Thus, CCK release is sustained, causing
further secretion of pancreatic juice. On the other hand, once
the meal has been fully digested and absorbed, CCK-RP and
monitor peptide will be degraded by the pancreatic proteases
leading to the termination of CCK release, and thus a marked
reduction in the secretion of pancreatic enzymes.
ROLE OF SECRETIN
The other major regulator of pancreatic secretion is secretin,
released from duodenal S cells. When the meal enters the
520 SECTION VIII GI Physiology

Ach
GRP
as
Protein cre
− Pan
Trypsin
LUMEN
Amino acids
− −
Fatty acids
CCK−RP Monitor peptide

FIGURE 51–3 Mechanisms responsible for controlling I cell

cholecystokinin (CCK) release from duodenal I cells. CCK-RP, EPITHELIUM
CCK-releasing peptide; ACh, acetylcholine; GRP, gastrin-
releasing peptide. Solid arrows represent stimulatory effects
while dashed arrows indicate inhibition. (Reproduced with CCK
permission from Barrett KE: Gastrointestinal Physiology. New York: Lange
BLOODSTREAM
Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

small intestine, the volume of pancreatic secretions increases
rapidly, shifting from a low-volume, protein-rich fluid to a
high-volume secretion. As the secretory rate increases, the pH
and bicarbonate concentration in the pancreatic juice increases,
with a reciprocal decrease in the concentration of chloride
(Figure 51–4). These latter effects on the composition of the
pancreatic juice are mediated predominantly by the endocrine
mediator, secretin.
Factors Causing Secretin Release
The S cells can be considered to act functionally as pH meters,
sensing the acidity of the luminal contents (Figure 51–5). As
the pH decreases, due to the entry of gastric acid, secretin is
released into the blood and binds to receptors on pancreatic
duct cells. These cells, in turn, secrete bicarbonate, thus causing
an increase in pH that will eventually shut off secretin release.
pH 7.2
The threshold for secretin release appears to be a luminal pH of
less than 4.5. The mechanism by which the S cells sense the
change in luminal acidity is currently unclear. Nevertheless,
subjects who are unable to secrete gastric acid also fail to release
secretin postprandially no matter what type of meal is given.
CELLULAR BASIS OF
PANCREATIC SECRETION
ACINAR CELLS
Pancreatic acinar cells synthesize the proteinaceous compo-
nents of pancreatic juice and package them into zymogen gran-
ules that are stored in the apical pole of the cell. The contents of
these granules are discharged into the lumen of the acinus via a
process of compound exocytosis. The pancreatic enzymes are
then rapidly resynthesized and repackaged into granules, with
pH 8.0

160
Na+
Concentration (mEq/L)

140 Stomach
HCO3
120
100 −
Acid HCO3−
80
60
Pancreatic
Duodenum
40 ducts
Cl
20
K+
Secretin
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
Flow rate (mL/min)
FIGURE 51–5 Function of secretin. Secretin is released from
the duodenum in response to reduced pH, and travels through the
FIGURE 51–4 Ionic composition of the pancreatic juice as a bloodstream to evoke bicarbonate secretion from the pancreatic
function of its flow rate. Note that the pancreatic juice becomes ducts (as well as from the biliary ducts and the duodenal mucosa,
alkaline at high rates of secretion. (Reproduced with permission from Barrett not shown), thereby neutralizing gastric acid in the duodenal lumen.
KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York:
Pub. Division, 2006.) Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

Enzymes washed
into duodenum
by ductular secretion
VIP
cAMP
Secretin
Phosphorylation
of structural
and regulatory
proteins
GRP
Ca++
ACh Fusion of granules
m3
with apical membrane
CCK and discharge of contents
CCK−A
BASOLATERAL APICAL
the process taking less than an hour, leaving the cell ready to
respond to the next meal. Evidence exists that the synthetic pro-
cess is regulated by CCK and also by other hormones, such as
insulin. In the long term, moreover, the rate of synthesis of spe-
cific classes of enzymes can be regulated in response to changes
in the diet. For example, an increase in carbohydrates will even-
tually result in increased expression of amylase as a proportion
of the total pancreatic enzymes. Corresponding changes occur
in the hydrolytic enzymes responsible for digestion of each of
the major classes of nutrients (carbohydrates, fats, and proteins)
in response to increased or decreased ingestion.
On their basolateral membranes, acinar cells express recep-
tors for CCK as well as for neural regulators of secretion, includ-
ing ACh, GRP, and vasoactive intestinal polypeptide (VIP)
(Figure 51–6). All of the receptors are G protein–coupled
receptors, and link to various downstream effectors such as
phospholipase C and adenylyl cyclase. In general, the phospho-
lipase C-dependent pathway, which is utilized by the receptors
for CCK, ACh, and GRP and results in increases in cytoplasmic
calcium, is the most quantitatively significant for acinar secre-
tion, with cAMP-dependent signaling playing a subsidiary role.
DUCTULAR CELLS
In contrast to acinar cells that secrete their characteristic prod-
ucts via exocytosis, the ductular cells are classical polarized
epithelial cells that conduct vectorial ion transport. As seen
elsewhere in the gastrointestinal tract, while exocytic secretion
predominantly involves calcium-dependent signaling with
cAMP playing a modulatory role, the membrane transport
events that underlie ductular secretion are predominantly
driven by cAMP, with calcium playing the subsidiary role.
The primary stimulus of duct cell secretion is secretin, which
binds to a basolateral receptor that links to adenylyl cyclase.
The primary target is protein kinase A, which phosphorylates
the cystic fibrosis transmembrane conductance regula-
CHAPTER 51 Pancreatic and Salivary Secretion 521
FIGURE 51–6 Receptors of the pancreatic acinar
cell and the regulation of secretion. The block arrow
indicates that calcium-dependent signaling pathways
play the most prominent role in enzyme secretion. VIP,
vasoactive intestinal polypeptide; GRP, gastrin-releasing
peptide; ACh, acetylcholine; CCK, cholecystokinin.
(Reproduced with permission from Barrett KE: Gastrointestinal
Physiology. New York: Lange Medical Books/McGraw-Hill, Medical
Pub. Division, 2006.)
tor (CFTR) chloride channel localized to the apical membrane
of the cell. This channel allows outflow of chloride ions, which
can exchange for bicarbonate across an apical chloride/
bicarbonate exchanger to provide for movement of bicarbon-
ate ions into the duct lumen (Figure 51–7). Water and sodium
ions follow paracellularly. CFTR itself may also be permeable
to bicarbonate ions under certain circumstances. The bicar-
bonate required for the transport mechanism derives from
two sources. Some is generated intracellularly via the activity
of carbonic anhydrase. Other bicarbonate ions are taken up
from the bloodstream via a basolateral sodium–bicarbonate
cotransporter (NBC). Circulating bicarbonate is derived from
the “alkaline tide” that is a byproduct of gastric acid secretion.
The bicarbonate transported by the duct cells, along with the
fluid secretion that this transport mechanism drives, is impor-
tant to wash the proteinaceous components of the gastric juice
into the intestinal lumen. Moreover, the alkaline nature of this
secretion is critically important in neutralizing gastric acid. The
pancreatic digestive enzymes are optimally active at neutral pH,
as opposed to the acidic pH optimum of gastric pepsin.
PANCREATIC PATHOPHYSIOLOGY
The hydrolytic enzymes secreted by the pancreas are produced
in quantities that are vastly in excess of those needed to digest
a normal intake of nutrients. It has been calculated that pan-
creatic enzyme output needs to decrease below 10% of normal
levels before effects on nutrient absorption are observed. Thus,
pancreatic insufficiency is not common. However, under spe-
cific conditions, it can occur, manifesting as maldigestion and
malabsorption. Fat absorption is usually the first affected by
alterations in pancreatic output of enzymes and bicarbonate,
perhaps due to a relatively limited supply of lipase and because
pancreatic lipase is most sensitive to inactivation by low pH.
Thus, steatorrhea, or fat in the stool, may be an early sign of
pancreatic dysfunction.
522 SECTION VIII GI Physiology

Duct lumen Basolateral

CO2 + H2O
C.A H+
− −
NHE-1
HCO3 HCO3 + H+ Na+
− −
Cl /HCO3 −
2HCO3
Exchanger NBC
Na+

3Na+
Na+, K+
FIGURE 51–7 Ion transport pathways
+ ATPase
present in pancreatic duct cells. C.A, carbonic 2K
Cl−
anhydrase; NHE-1, sodium/hydrogen
+ K+ channel
exchanger-1; NBC, sodium–bicarbonate
cotransporter. (Adapted with permission from Barrett cAMP
CFTR
KE: Gastrointestinal Physiology. New York: Lange Medical
Books/McGraw-Hill, Medical Pub. Division, 2006.)

BASIC PRINCIPLES (known as a bolus) that is suitable for swallowing. However, it

OF SALIVARY SECRETION
We consider salivary secretion here because of analogies
between this process and that of pancreatic secretion
(Figure 51–8). Thus, a primary salivary secretion arises in
acini, and is modified as it flows through ducts. Thus, it is
instructive to compare and contrast these two processes, and
an understanding of one permits understanding of the other.
ROLE AND SIGNIFICANCE
Saliva plays a number of roles in gastrointestinal physiology
(Table 51–2). Its primary function is to lubricate ingested food,
and to thereby permit formation of a smooth, rounded portion
also performs additional roles. For example, the ability of
saliva to solubilize molecules in the meal allows these to dif-
fuse to taste buds on the tongue, affecting appetite and food
intake. Salivary secretion can also begin the digestive process
and plays important roles in host defense. It contains a variety
of antibacterial substances that serve to protect the oral cavity
from microbial colonization. Saliva is also slightly alkaline.
This property is important in clearing any refluxed gastric acid
from the esophagus, thus acting to prevent esophageal ero-
sions and injury. Finally, saliva aids in speech.
SALIVARY SECRETORY PRODUCTS
The protein components of saliva include digestive enzymes.
Saliva begins the digestion of carbohydrates via the action of

Smell
Taste
Sound
Sight

Higher
centers

Parotid ACh Otic Pressure

gland ganglion in mouth

Parasympathetics Salivatory
nucleus of
medulla
Submandibular ACh Submandibular −
gland ganglion
Sleep
Fatigue
FIGURE 51–8 Regulation of salivary Increased Fear
secretion by the parasympathetic nervous salivary
system. ACh, acetylcholine. (Adapted with secretion
via effects on
permission from Barrett KE: Gastrointestinal Physiology.
• Acinar secretion
New York: Lange Medical Books/McGraw-Hill, Medical Pub.
Division, 2006.)
• Vasodilation

TABLE 51–2 Constituents of saliva and their
functions.
Constituent Functions
Water Facilitates taste and dissolution of
nutrients; aids in swallowing and
speech
Bicarbonate Neutralizes refluxed gastric acid
Mucins Lubrication
Amylase Starch digestion
Lysozyme, lactoferrin, IgA Innate and acquired immune
protection
Epidermal and nerve growth Assumed to contribute to mucosal
factors growth and protection
salivary amylase. This latter enzyme is not required for adequate
digestion of starch in healthy adults, but may assume greater
importance in neonates, where there is a developmental delay in
the expression of pancreatic amylase. Salivary enzymes are
“backups” that are only required for digestion if other sources
are reduced. In patients with pancreatic insufficiency, for exam-
ple, salivary enzyme synthesis may be modestly increased.
Salivary lysozyme and other antibacterial peptides limit
colonization of the oral cavity by microbes. Lactoferrin
sequesters iron, thereby inhibiting the growth of bacteria that
require this substance. Saliva also contains significant quanti-
ties of secretory IgA, which contribute to immune defense.
In terms of the lubricating and solubilizing functions of
saliva, the most important constituents are mucins and water.
Mucin molecules are large glycoproteins with viscoelastic prop-
erties. Water is the main component of saliva and is secreted at
very high rates. At maximal rates of secretion, the volumes pro-
duced by salivary glands can exceed 1 mL/min/g of gland tis-
sue, necessitating high rates of blood flow to supply this fluid.
In an adult, approximately 500 mL of saliva is produced daily.
Saliva also contains a variety of inorganic solutes, including
calcium and phosphate, that are important for tooth formation
and maintenance. The primary secretion from the salivary acini
has an ionic composition that is comparable to plasma. However,
as the secretion moves along the ducts, the composition is mod-
ified by active transport processes as will be described later.
SALIVARY GLAND ANATOMY
Like the pancreas, the salivary glands are made up of grape-
like clusters of acini that drain into a system of intercalated
and intralobular (striated) ducts, and eventually into interlob-
ular ducts that drain into the oral cavity. The individual acini
and associated ducts are also surrounded by a sheath of myo-
fibroblasts, which are contractile cells that may be important
in providing a hydrostatic force that expels saliva from the
gland, thereby contributing to high rates of secretion. The
CHAPTER 51 Pancreatic and Salivary Secretion 523
salivary glands also receive extensive sympathetic and para-
sympathetic innervation. Sympathetic efferents originate in
the salivatory center adjacent to the dorsal vagal complex,
whereas parasympathetics come from the salivatory nuclei.
ACINAR CELLS
The salivary glands are heterogenous in their specific struc-
ture and function. The acini of the parotid glands, which
drain into the upper part of the mouth via the parotid duct,
consist entirely of serous cells, and thus are responsible for
providing the protein constituents of saliva. The sublingual
gland, under the tongue, has predominantly mucous acini
responsible for secreting mucus and water, but also a scatter-
ing of serous acini as well. The submandibular gland, below
the jaw, has a mixture of serous and mucous acini.
DUCTULAR CELLS
As the saliva makes its way out of the acini, it passes through a
ductular system. The intercalated ducts, linked directly to the
acini, serve predominantly to convey the saliva out of the aci-
nus and to prevent backflow. Cells of the striated intralobular
ducts, on the other hand, are polarized epithelial cells with
specialized transport functions. The epithelial cells of the
intralobular ducts, moreover, have well-developed intercellu-
lar tight junctions that significantly limit the permeability of
this segment of the gland relative to the leaky acinus.
REGULATION OF
SALIVARY SECRETION
NEURAL REGULATION
The salivary glands are unusual in the gastrointestinal system
in that their regulation appears to be exclusively mediated by
neurocrine pathways and not by gastrointestinal hormones, at
least in the short term. The salivary glands are also unusual in
that they are positively regulated by both the parasympathetic
and sympathetic branches of the autonomic nervous system.
However, quantitatively, the predominant regulation of secre-
tory rate and composition is via parasympathetic pathways
with sympathetic efferents playing only a modifying role.
Parasympathetic and
Sympathetic Regulation
The parasympathetic nervous system initiates salivary secre-
tion and sustains secretion at high rates. The nerves originate
in the salivatory nucleus of the medulla, and receive input
from higher centers interpret the need for changes in salivary
secretion under both physiological or pathophysiological cir-
cumstances Conditioned reflexes, such as smell and taste, as
524 SECTION VIII GI Physiology
well as pressure reflexes transmitted from the oral cavity mark-
edly stimulate parasympathetic outflow, whereas fatigue, sleep,
fear, and dehydration suppress neurotransmission. Nausea
also strongly stimulates salivation, presumably to protect the
oral cavity and esophagus from the injurious effects of vom-
ited gastric acid and other intestinal contents. Parasympathetic
input to the salivary glands is mediated by ACh acting at mus-
carinic receptors. In addition to effects on the acinar cells and
ducts of the glands, parasympathetic innervation causes dila-
tion of the blood vessels supplying the gland, thereby provid-
ing both the fluid and metabolic requirements needed to
sustain high rates of secretion.
Efferents of the sympathetic nervous system passing
through the superior cervical ganglion also terminate at the
salivary glands. These nerves are not thought to be capable of
initiating or sustaining secretion independently, but can
potentiate the effects of parasympathetic regulation via the
release of norepinephrine and beta-adrenergic receptors.
CELLULAR BASIS OF
SALIVARY SECRETION
ACINAR CELLS
Acinar cells release their protein and mucus contents via a
process of exocytosis, analogous to enzyme release from the
pancreatic acini. These responses involve mobilization of
intracellular calcium downstream of the muscarinic receptor
for ACh. Acinar cells also actively secrete chloride, bicarbon-
ate, and potassium ions into the primary salivary secretion.
Because the acini are relatively leaky, sodium and water follow
paracellularly via the tight junctions and the initial secretion
has an ionic composition comparable to plasma.
DUCTULAR CELLS
As we learned for the pancreas, the duct cells in the salivary
glands modify the composition of the saliva as it passes by
them. The ionic composition of saliva changes as its flow rate
increases (Figure 51–9). At low rates of secretion, saliva is
hypotonic with respect to plasma and has higher concentra-
tions of potassium than sodium, the opposite of the situation
in plasma. The chloride concentration is also much lower than
that found in plasma. These changes in ionic content are
brought about by active transport events taking place in the
duct cells (Figure 51–10). Sodium and chloride are reabsorbed
across the apical membrane, in exchange for protons and bicar-
bonate, respectively. Protons are recycled to transfer potassium
into the duct lumen. At the basolateral membrane, the driving
force for sodium uptake is provided by a sodium–potassium
ATPase, and a potassium channel supplies potassium for secre-
tion into the saliva. Because the ductular epithelium has a low
passive permeability, water cannot flow across the tight junc-
tions fast enough at moderate rates of salivary secretion to
160
140
Concentration (mEq/L)
120
100
Na+
80
HCO3−
60
Cl−
40
20 K+
0 1 2 3 4
Flow of saliva (mL/min)
FIGURE 51–9 Ionic composition of saliva as a function of
its flow rate. Note that saliva becomes less hypotonic as flow rates
increase. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology.
New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
keep pace with the active reabsorption of sodium and chloride,
and thus saliva becomes hypotonic. Moreover, due to secretion
of bicarbonate into the lumen without an accompanying pro-
ton, the pH of saliva increases progressively to approximately
8 as the saliva enters the mouth.
At very high rates of salivary secretion, the concentrations
of sodium and potassium more closely resemble those in
plasma. The concentration of chloride also increases as the
flow rate of saliva increases. These changes in composition are
due to the fact that the residence time of the saliva in the ducts
is too short for the cells to be able to modify salivary composi-
tion significantly.
CLINICAL CORRELATION
A Caucasian couple brings their two-month old infant to a
pediatrician for a well-baby check. It is noted that the baby is
underweight, and his mother notes frequent coughing, some
episodes of vomiting after feeding, and a salty taste to the
child’s skin. After administering the muscarinic agonist,
pilocarpine, to stimulate secretion by the sweat glands, chlo-
ride concentrations in the sweat are found to be markedly
increased. Genetic testing later reveals that both parents are
heterozygous for a mutation that results in the deletion of the
phenylalanine residue at position 508 of CFTR, and a diag-
nosis of cystic fibrosis is made. The child’s condition improves
with supplementation of the diet with an oral preparation of
pancreatic enzymes as well as physical therapy designed to
dislodge thickened respiratory secretions, but recurrent lung
infections often require antibiotic therapy.
Respiratory complications due to failure to clear the thick-
ened mucus from the airways, are usually the most significant
cause of morbidity and mortality in cystic fibrosis. Pancreatic

DUCT LUMEN
Cl−/HCO3− HCO3−
Exchanger
Cl−
3Na+
Na+
NHE
2K+
H+
H+
H+/K+ K+
Exchanger
H2O
Tight junctions restrict osmotic reabsorption of water
function can also be altered in the genetic disorder of cystic
fibrosis, where mutations lead to abnormal function of the
CFTR chloride channel. Indeed, the disease was named for
characteristic cystic histological abnormalities observed in the
pancreas in affected patients. Although pancreatic enzyme
synthesis and secretion are normal in patients with cystic
fibrosis, the relative inability of the ducts to secrete bicarbon-
ate and water means that the enzymes cannot be flushed prop-
erly from the organ, and limited quantities reach the intestinal
lumen. Moreover, the enzymes that do reach the lumen are
inactive because of the failure to neutralize gastric acid. These
findings underscore the role of the duct cells in normal pan-
creatic function. In fact, in patients with severe CFTR muta-
tions causing a marked reduction in channel function, the
exocrine pancreas may be largely destroyed during fetal life,
due to the action of retained proteolytic enzymes that become
inappropriately activated and damage the tissue. Such patients
are said to have pancreatic insufficiency and are treated with
oral supplements of pancreatic enzymes, along with antacids,
to allow for adequate nutrition. Patients with milder muta-
tions may retain some degree of pancreatic function, at least
early in life, but are then at greater risk for the development of
inflammation of the pancreas (pancreatitis) with aging.
CHAPTER SUMMARY
■ Pancreatic secretion provides for digestion of meals.
■ Pancreatic acini supply enzymes, whereas ducts supply fluid;
major regulators of each cell type are CCK and secretin,
respectively.
■ Pancreatic secretion is initiated during the cephalic phase,
but is most prominent when the meal is in the duodenum.
CHAPTER 51 Pancreatic and Salivary Secretion 525
BASOLATERAL
Cl− channel
Cl−
Na+, K+
ATPase
K+
K+ channel
FIGURE 51–10 Ion transport pathways
in salivary duct epithelial cells. NHE, sodium/
hydrogen exchanger (Reproduced with permission
from Barrett KE: Gastrointestinal Physiology. New York: Lange
Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
■ The pancreas has several lines of defense to protect against
autodigestion. When these lines fail, pancreatitis results.
■ Salivary secretion shares several parallels with pancreatic
secretion.
■ Salivary secretion is predominantly mediated by parasympa-
thetic input arising from higher brain centers. Hormonal
regulation is much less important.
STUDY QUESTIONS
1. A 4-year-old boy is brought to the pediatrician for an evaluation
because of failure to thrive and frequent diarrhea characterized
by pale, bulky, foul-smelling stools. Sweat chloride concentrations
are measured and found to be elevated. Diminished secretion of
which pancreatic product is most likely to be the primary cause of
the patient’s apparent fat malabsorption?
A) lipase
B) procolipase
C) monitor peptide
D) cholecystokinin
E) bicarbonate
2. In an experiment, recordings are made of electrical activity in
afferent nerves originating in the small intestinal mucosa during
sequential luminal perfusion with saline, a solution of hydrolyzed
protein, and a solution of intact protein. Rates of neuronal firing
were shown to increase markedly during the period when intact
protein was infused compared with the other two. Firing in these
nerves was most likely stimulated by an increase in the mucosal
concentration of which of the following?
A) gastrin
B) secretin
C) somatostatin
D) ACh
E) cholecystokinin
526 SECTION VIII GI Physiology

3. A 50-year-old man with a history of alcohol abuse presents at the 5. A 50-year-old female patient who has suffered for several years
emergency room with severe, colicky abdominal pain and a fever. from severe dryness of her eyes due to inadequate tear
A blood test reveals increased levels of serum amylase and an production is referred to a gastroenterologist for evaluation of
endoscopic imaging procedure reveals a narrowed pancreatic chronic heartburn. Endoscopic examination reveals erosions and
duct. Pain in this patient is likely predominantly ascribable to scarring of the distal esophagus just above the lower esophageal
premature activation of pancreatic enzymes capable of digesting sphincter. Reduced production of which of the following salivary
which of the following nutrients? components most likely contributed to the tissue injury?
A) triglyceride A) lactoferrin
B) phospholipids B) mucus
C) protein C) IgA
D) starch D) bicarbonate
E) nucleic acids E) amylase
4. A researcher conducts a study of the regulation of salivary
secretion in a group of normal volunteers under various
conditions. Which of the following conditions was associated
with the lowest rates of secretion?
A) chewing gum
B) undergoing a mock dental exam
C) sleep
D) exposure to a nauseating odor
E) resting control conditions
 52
C H A P T E R

Water and Electrolyte

Absorption and Secretion
Kim E. Barrett

O B J E C T I V E S

■ Understand the physiological significance of the regulation of luminal water

content and daily fluid balance.
■ Describe the functional anatomy of the intestinal epithelium that permits it
to function as a regulator of fluid movement.
■ Define the pathways via which electrolytes can be transferred across
epithelial barriers.
■ Describe how a limited collection of membrane transport pathways is
arranged to assemble transepithelial transport mechanisms.
■ Identify the major electrolyte transport pathways of the small and large
intestines and their intracellular mechanisms of regulation.
■ Identify how subepithelial elements and other regulatory systems impact on
epithelial transport function.
■ Understand how transport function is integrated with intestinal motility.
■ Define major pathogenic alterations in intestinal electrolyte transport and
their consequences.

BASIC PRINCIPLES OF
INTESTINAL FLUID TRANSPORT
ROLE AND SIGNIFICANCE
Control of the amount of fluid in the intestinal lumen is criti-
cal for normal intestinal function. This fluid environment per-
mits contact of digestive enzymes with food particles, and in
turn the diffusion of digested nutrients to their eventual site of
absorption. The fluidity of the intestinal contents also provides
for their transit along the length of the gastrointestinal tract
without damage to the lining epithelium.
Large volumes of fluid are handled by the intestine during
the digestion and absorption of meals. Most of this fluid is
supplied by the intestine and the organs that drain into it. The
daily fluid load approximates 9 L in normal adults (Figure 52–1).
In health, this large volume is later reclaimed by the intestine
to avoid dehydration. Both the small and large intestines also
have a large reserve capacity for absorption, and it is only when
this is exceeded that excessive water loss to the stool occurs,
seen clinically as diarrhea.
ELECTROLYTES INVOLVED
Epithelial cells express several specialized properties that allow
them to control fluid movement. Most important are the intra-
cellular tight junctions that restrict the passive flow of solutes
and backflow of these once either secreted or absorbed. Water is
transported passively across the intestinal epithelium in response
to osmotic gradients established by the active transport of elec-
trolytes and other solutes. In common with those in other trans-
porting epithelia, such as in the nephron, active electrolyte
transport pathways share a number of defining characteristics
(Table 52–1). These transport pathways move a solute across a
single membrane in a polarized epithelial cell. Transepithelial
transport mechanisms, in turn, move solutes across the entire
epithelium. Furthermore, both absorption and secretion can
occur simultaneously in any given segment of the intestinal

527

Ch52_527-534.indd 527 11/26/10 10:34:53 AM

528 SECTION VIII GI Physiology

Oral intake TABLE 52–2 Small intestinal ion transport

2000 mL
mechanisms.
Bicarbonate secretion
Saliva Sodium-coupled nutrient absorption
1500 mL
Proton-coupled nutrient absorption
Gastric
juice Electroneutral NaCl absorption
2500 mL
Chloride secretion
Bile Pancreatic
juice Sodium-coupled bile acid absorption
500 mL
1500 mL Calcium and iron absorptiona
a
Intestinal Not major determinants of fluid transport.
secretion
1000 mL
ANATOMICAL CONSIDERATIONS
AMPLIFICATION OF
Small INTESTINAL SURFACE AREA
intestinal
absorption The capacity of the intestine for large volumes of water trans-
7000 mL port is related to its massively amplified surface area. In fact, the
(78%) Colonic surface area of the adult small intestine alone exceeds that of a
absorption
1900 mL
doubles tennis court. The intestine is not a simple cylinder, but
(21%) instead is amplified first by folds in the mucosa, then by the
Stool presence of crypts and villi, and finally by the presence of
100 mL (1%) microvilli on the apical poles of individual epithelial cells. Over-
FIGURE 52–1 Daily water balance in the healthy adult human all, the surface area is increased 600-fold by these physical struc-
gastrointestinal tract. The amount of oral intake varies among tures. This amplification of the surface area not only allows for
individuals depending on the types of meals taken. Note that even in handling of the large volumes of fluids required for normal
health there is a significant secretory flux of fluid from the intestine. functioning of the intestine, but also provides the reserve capac-
(Modified with permission from Barrett KE. and Dharmsathaphorn K: Transport of ity for fluid absorption in disease. However, the surface amplifi-
water and electrolytes in the gastrointestinal tract: physiological mechanisms, cation, particularly in the crypts, also carries a liability in that
regulation and methods for study. In: Maxwell and Kleeman’s Clinical Disorders of Fluid there is a corresponding reserve capacity for intestinal fluid
and Electrolyte Metabolism, 5th ed. Narins RG (editor). McGraw-Hill, New York, 1994.) secretion. If such secretion is extensive and prolonged, it can
rapidly lead to serious dehydration if left untreated.
tract. This is primarily because most of the cells of the villi (or
surface cells in the colon) are absorptive, whereas crypt epithe-
lial cells are secretory. In general, absorptive mechanisms for INNERVATION AND
fluid center on the active movement of sodium, whereas secre- REGULATORY CELLS
tory fluxes of fluid in the intestine are driven mostly by the elec-
trogenic movement of chloride ions, although bicarbonate As we learned in earlier chapters, the intestinal epithelium
secretion may assume significance in particular segments. rests on a lamina propria that is a rich source of potential regu-
Moreover, the transport mechanisms that are expressed in the latory factors. In addition to endocrine regulators, epithelial
small intestine and colon differ, due to the relative paucity of electrolyte transport is controlled by paracrine mediators sup-
nutrients in the latter segment (Tables 52–2 and 52–3). plied by local enteroendocrine cells, immune mediators, and

TABLE 52–1 Characteristics of active membrane TABLE 52–3 Colonic ion transport mechanisms.
transport pathways.
Electrogenic sodium absorption
Mediate uphill transport against an electrochemical gradient
Electroneutral NaCl absorption
Effective at low luminal concentrations
Short-chain fatty acid absorption
Demonstrate saturable kinetics
Chloride secretion
Require cellular energy
Potassium absorption/secretiona
Demonstrate high ionic specificity a
Not a major determinant of fluid transport.
 CHAPTER 52 Water and Electrolyte Absorption and Secretion
neurocrines released from secretomotor efferent nerves origi-
nating predominantly in the submucosal plexus of the enteric
nervous system. The epithelial cells themselves may also pro-
duce autocrine factors that regulate their transport function.
The regulatory systems that mediate changes in epithelial
transport do not act in isolation. Rather, there is significant
crosstalk between the various modes of communication. For
example, some immunologic mediators may have both direct
effects on epithelial cells and others that are mediated second-
arily via the activation of enteric nerves. Crosstalk between the
various regulatory systems also provides for coordinated regu-
lation of transport and motility functions.
REGULATION OF WATER AND
ELECTROLYTE TRANSPORT
REGULATORY STRATA
Much of our knowledge of the control of intestinal fluid move-
ment comes from studies of the factors that regulate fluid secre-
tion, which is driven primarily by the secretion of chloride ions.
Fluid absorption, particularly in the postprandial period, is more
of a passive response that is driven by the presence of nutrients,
and not highly subject to regulation by intracellular and intercel-
lular mechanisms. On the other hand, in the absence of nutri-
ents, the intestine absorbs fluid to balance secretory pathways via
the absorption of sodium and chloride ions. These nutrient-
independent pathways for fluid absorption are subject to both
intracellular and intercellular regulation. In general, regulatory
pathways that stimulate chloride secretion inhibit sodium chlo-
ride absorption, and vice versa. However, this does not apply to
nutrient-coupled absorption, which can continue unopposed
even under circumstances that lead to the stimulation of chloride
secretion. This last point underlies the efficacy of so-called oral
rehydration solutions, which are used to treat the dehydration
accompanying severe diarrheal diseases, such as cholera, when
intravenous fluids are not available.
Short and Long Reflexes
Intestinal epithelial transport is regulated by neurotransmitters
originating from nerve endings of the enteric nervous system.
The most potent effectors in this regard include acetylcholine
(ACh) and vasoactive intestinal polypeptide (VIP), both of
which can directly stimulate epithelial cells to secrete chloride.
Some neural input to the control of intestinal transport almost
certainly originates in the central nervous system, and this input
is then interpreted and integrated with local information to
impinge ultimately on the activity of secretomotor neurons. In a
similar fashion, vagovagal reflexes likely match intestinal trans-
port function to conditions that result from the physical state of
luminal contents, such as via the activation of stretch receptors.
In addition to these “long” reflexes, however, “short” or local
reflexes can be initiated by stroking the mucosa, which models
529
the local passage of a food bolus. In turn, this releases
5-hydroxytryptamine from local enterochromaffin cells, fol-
lowed by activation of cholinergic efferents that stimulate a cor-
responding burst of chloride, and thus fluid, secretion. This
reflex may be important in protecting the epithelium from
physical damage by the passing meal components.
Humoral Control
Although there appears to be a relatively limited role for clas-
sical endocrine hormones in mediating changes in intestinal
transport function, at least in the short term, other soluble
effectors have clear effects and are largely derived from para-
crine or immune sources. For example, local production of
prostaglandins, likely predominantly by subepithelial myofi-
broblasts, plays an important role in stimulating the secretion
of both chloride and bicarbonate. Similarly, histamine,
released by mast cells residing in the lamina propria, has been
shown to be an effective chloride secretagogue, although its
effect is transient. Indeed, immune effector cells that release
substances capable of regulating the epithelium can be consid-
ered specialized “sensory” cells that alter transport function in
response to specific conditions pertaining in the lumen, such
as the presence of food substances to which an individual is
allergic. These and other putative humoral regulators of intes-
tinal secretion and/or absorption are listed in Table 52–4.
Humoral regulators of intestinal transport typically bind to
receptors localized to the basolateral pole of intestinal epithe-
lial cells. It should be emphasized, however, that such effectors
can alter epithelial function not only via such direct binding,
but also via the secondary activation of other subepithelial ele-
ments. In this way, intestinal secretory and/or absorptive func-
tion can be better integrated with other physiological functions
of the gut such as motility and blood flow. In turn, agonists
that alter these latter functions may have indirect effects on
intestinal secretion and absorption. The net rate of movement
of any substance across the intestinal epithelium will reflect
not only the “east–west” vector of absorption/secretion, but
also the “north–south” vector of movement along the length of
the gastrointestinal tract (Figure 52–2). Thus, if motility is
increased, hastening the transit of substances along the intes-
tine, there will be less time for absorption to take place (or,
conversely, for active secretion to add to luminal fluid loads).
If transit is slowed, absorption can catch up with the presented
TABLE 52–4 Major endogenous regulators of
intestinal ion transport.
Cyclic Nucleotide-dependent Calcium-dependent
Vasoactive intestinal polypeptide (VIP) Acetylcholine (ACh)
Prostaglandins Histamine
Guanylin (cGMP) 5-Hydroxytryptamine
5′AMP/adenosine Bile acids
530 SECTION VIII GI Physiology

pendent of the presence of a meal, notably as stimulated by

Oral
input from the central nervous system at times of threat or
stress. In either case, while both secretion and absorption
occur simultaneously, in health, the absorptive vector
predominates overall, and most of the fluid used for digestion
and absorption is recycled (Figure 52–3).
Neurotransmitters released from enteric secretomotor neu-
rons, as well as paracrine effectors from local enteroendocrine
cells or other subepithelial elements, alter the functional
EAST-WEST capacity of transporting epithelial cells to conduct transport
VECTOR across their apical and basolateral membranes. Acutely, sec-
Influenced ond messenger pathways evoked by neurohumoral regulators
by surface alter the activation status of the transporters and/or redistrib-
area
ute transporters within the epithelial cells themselves. Deliv-
ery of additional, preformed transporters to the membrane
will increase transport capacity, whereas endocytic retrieval
will reduce it.

NaCl, nutrients
Anal NORTH-SOUTH VECTOR
Influenced by
motility → transit time

FIGURE 52–2 Integration of influences on fluid movement

in the intestine. Overall fluid fluxes depend on the surface area Villus
Health
available for ion transport and residence time in the lumen. (Modified
with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange
Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

fluid volume. This last principle underlies the efficacy of sev-

eral antidiarrheal medications, and particularly opiate drugs Crypt
such as loperamide.

NaCl
Luminal Regulators Cl−
The epithelium is also positioned to respond to substances
present in the intestinal lumen, and expresses a number of
apical receptors for such agents. Guanylin is a peptide regu-
lator of epithelial chloride secretion that is synthesized by
enteroendocrine cells and released into the lumen. The phys-
iological role of this substance may be to coordinate salt han-
dling by the small and large intestines with that of the Villus
Diarrheal
kidneys. Bile acids, which are synthesized by the liver to aid disease
in fat digestion and absorption, are also apical stimuli of
chloride secretion in the colon. Under normal circumstances,
however, bile acids are reabsorbed in the terminal ileum
when they are no longer needed to solubilize the products of Crypt
Nutrient absorption
fat digestion, and so bile acid–induced diarrhea is only largely normal
observed in the setting of disease.
Cl−
ACUTE REGULATION FIGURE 52–3 Balance between absorption and secretion in
health and in secretory diarrheal disease. Note that small intestinal
Acute regulation of intestinal fluid and electrolyte transport nutrient absorption is usually largely normal in the setting of secretory
occurs to match needs for luminal fluidity on a minute-to- diarrhea. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New
minute basis. Altered intestinal transport can also occur inde- York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
 CHAPTER 52 Water and Electrolyte Absorption and Secretion
CHRONIC ADAPTATION
The bowel is also capable of altering its ability to conduct water
and electrolyte transport in a chronic fashion (over days to
weeks), in order to adapt to changes in whole body electrolyte
status.
The hormone, aldosterone, is an important regulator of
sodium transport in the intestine in addition to similar roles in
the renal system (see Chapters 45 and 65). When the diet is low
in salt, aldosterone is released and increases the expression of
transporters required for sodium absorption in the colon. The
net effect is active sodium retention by the colon. Analogous
processes allow for increased or decreased intestinal retention
of other important electrolytes. For example, a decrease in
plasma calcium increases levels of 1,25-dihydroxyvitamin D,
which stimulates the expression of proteins needed for calcium
absorption in the small intestine. Conversely, levels of trans-
porters involved in intestinal iron absorption are decreased in
patients suffering from the disease of hemochromatosis, which
is associated with overloading of the body’s stores of iron.
CELLULAR BASIS OF TRANSPORT
ABSORPTIVE MECHANISMS
Absorptive mechanisms expressed in the small intestine and
colon are summarized in Tables 52–2 and 52–3. Throughout
the length of the small intestine, sodium is taken up in con-
junction with a variety of nutrients as exemplified by glucose-
coupled sodium absorption (Figure 52–4). This, and related
transport mechanisms such as those driven by specific amino
acids, relies on the low intracellular sodium concentration
established by the active, basolateral Na,K-ATPase. Apical
Glucose
GLUT-2
SGLT-1
Glucose
2Na+ 2K+
3Na+
Na+,K+–
ATPase
Cl–
FIGURE 52–4 Sodium-coupled nutrient absorption
exemplified by the uptake of glucose from the intestinal lumen.
(Used with permission from Montrose M.H. et al: Secretion and absorption: small
intestine and colon. In: Textbook of Gastroenterology, 4th ed. Yamada T, Alpers DH,
Kaplowitz N, Laine L, Owyang C, Powell DW (editors). Philadelphia, PA: Lippincott
Williams and Wilkins; 2003.)
531
uptake of sodium and glucose (or galactose) is a coupled pro-
cess that occurs via a cotransporter, SGLT-1. By tying the
movement of glucose to that of sodium, glucose can be moved
against its concentration gradient, even when luminal concen-
trations of this nutrient are low. Glucose thus absorbed is then
utilized by the enterocyte, or is transported to the bloodstream
via a facilitated diffusion pathway (GLUT-2). Anions (largely
chloride) and water follow passively via the tight junctions.
Sodium-coupled transport also allows for the active uptake of
conjugated bile acids, although in this case the transport
mechanism is restricted to the terminal ileum. In the colon,
where luminal glucose is largely absent, a similar mechanism
allows for the electrogenic uptake of sodium by replacing
SGLT-1 with the epithelial sodium channel (ENaC) (Figure
52–5).
Short peptides that are products of digestion of dietary pro-
teins are absorbed via an apical transporter known as PepT1,
coupled to proton uptake. PepT1 is a remarkable transporter
in that it can accommodate a wide range of substrates, includ-
ing dipeptides, tripeptides, and perhaps even tetrapeptides
made up of various combinations of the 20 naturally occurring
amino acids. As we will see in Chapter 58, some amino acids,
including essential ones that cannot be synthesized by the
body, are only efficiently absorbed in peptide form due to a
relative lack of relevant amino acid transporters.
Between meals, when nutrients are not available in the
lumen, fluid absorption can still continue via a mechanism
that involves the coupled absorption of both sodium and chlo-
ride (Figure 52–6). Coupled ion exchangers on the apical
membrane carry sodium and chloride into the cell in exchange
for protons and bicarbonate ions, respectively, and both
exchange processes require the activity of the other. Notably,
the NHE3 sodium–hydrogen exchanger isoform that partici-
pates in this transport mechanism is inhibited by cAMP;
therefore, the overall transport process can likewise be inhib-
ited by this second messenger.
EN
aC
Na+ K+
2K+
3Na+
Na+,K+ -
ATPase
Cl−
FIGURE 52–5 Electrogenic sodium absorption in the colon.
Sodium enters the epithelial cells via epithelial sodium channels
(ENaC). (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks
H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
532 SECTION VIII GI Physiology
2K+
NHE-3?
Na+
H+ NHE-2? Na+,K+ -
ATPase
Cl−
KCC1
CLD ?
HCO3–
FIGURE 52–6 Electroneutral NaCl absorption in the small
intestine and colon. NaCl enters across the apical membrane via the
coupled activity of a sodium/hydrogen exchanger (NHE) and a
chloride/bicarbonate exchanger (CLD). The route of basolateral
chloride exit remains speculative. (Reproduced with permission from Barrett
KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed.
McGraw-Hill Medical, 2009.)
The small intestine also absorbs iron and calcium in their ionic
forms, although the small quantities of these ions that are han-
dled do not contribute in a major way to fluid handling.
Calcium absorption is possible along the length of the small
intestine depending on whole body demands, whereas the major-
ity of iron absorption occurs in the proximal small intestine due
to specific expression of the membrane transporters required to
facilitate iron movement. Dietary iron is also handled differently
depending on whether it is in the form of heme (derived from
meat), from which it is released by lysosomal enzymes following
uptake of the intact heme molecule, or in its ionized form.
The colon also conducts an additional absorptive transport
process that reclaims an important byproduct of waste metab-
olism. Dietary fiber and other complex carbohydrates that
cannot be digested by mammalian enzymes are degraded in
the colon by the resident bacterial flora, and generate short-
chain fatty acids such as acetate, propionate, and butyrate that
are taken up by colonic epithelial cells.
SECRETORY MECHANISMS
Secretory mechanisms in the gastrointestinal tract center
around the active transport of chloride ions. The mechanism
for secretion of chloride itself is depicted in Figure 52–7. Chlo-
ride is taken up across the basolateral membrane of crypt epi-
thelial cells via a sodium/potassium/2 chloride cotransporter
called NKCC1. This transporter conducts secondary active
uptake of chloride into the cell cytosol by taking advantage of
the favorable gradient for sodium movement established by the
basolateral Na,K-ATPase. Potassium that is cotransported is
recycled across the basolateral membrane via channels that may
be activated by either cAMP or calcium. Chloride thus accumu-
lates in the cytosol, ready to exit the cell across the apical mem-
brane when chloride channels are opened in response to second
messenger pathways. The quantitatively most significant path-
Na+ _
3Na+ 2CI
TR
CF K+ NKCC1
Cl− Na+
2K+ 3Na+
+ +
Na , K -
K+
ATPase
Cl−
K+
FIGURE 52–7 Chloride secretion in the small intestine and
colon. Chloride uptake occurs via the sodium/potassium/2 chloride
cotransporter, NKCC1. Chloride exit is via the cystic fibrosis
transmembrane conductance regulator (CFTR) chloride channel, as
well as perhaps via additional chloride channels (not shown).
(Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H:
Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
way for chloride exit is the CFTR channel; there is some evi-
dence also to suggest an accessory role played by additional
chloride channels. The net effect is the electrogenic movement
of chloride from the bloodstream to the lumen; water and
sodium follow passively via the tight junctions to maintain neu-
trality. In response to agonists such as VIP or prostaglandins,
cAMP levels are increased in the crypt cell cytosol, which in
turn result in activation of PKA. This enzyme can phosphory-
late and thereby open the CFTR chloride channel, resulting in
an initial burst of chloride secretion (Figure 52-8). cAMP-
dependent agonists of this process are additionally notable for
the fact that they evoke sustained secretory responses. On the
other hand, agonists such as ACh, histamine, and likely bile
acids evoke chloride secretion by increasing cytosolic calcium
concentrations. In this case, the primary locus for regulation is
a basolateral potassium channel. As potassium leaves the cell,
the driving force for chloride exit increases, allowing chloride to
flow across the apical membrane via the small proportion of
CFTR channels that may be open at any given time. The cal-
cium-dependent chloride secretory response is smaller and
more transient than that evoked by cAMP elevation. This may
imply a physiological need to be able to call upon both brief and
sustained secretory responses under specific circumstances
during the digestion and absorption of a meal. Moreover, when
crypt epithelial cells are simultaneously exposed to a combina-
tion of agonists acting via cyclic nucleotides and calcium, a syn-
ergistic enhancement of secretion results.
The intestine is also capable of active bicarbonate secretion
(Figure 52–9). This mechanism is particularly prominent in
the proximal duodenum, which must defend itself from the
potentially injurious effects of the acidic gastric juice, and is
analogous to pancreatic secretion of this ion as discussed
in the previous chapter. Like chloride secretion, the overall
process of bicarbonate secretion can be stimulated by intracel-
lular increases in cAMP, cGMP, or calcium, with prostaglan-
 CHAPTER 52 Water and Electrolyte Absorption and Secretion 533

Cl−

APICAL
CFTR 2K+ 3Na+

CFT
R Na+,K+–
Phosphorylation ATPase
P Cl– Cl–
channel
opening
AE1?
CLD? Na+
R NHE-1
C
C HCO3– + H+ H+
HCO3–
Protein CA
CO2 + H2O
kinase A
cAMP 3Na+
2K+
Na+,K+–
Cytoskeleton R? ATPase
CFT
Vesicle
trafficking HCO3–

Gs Na+
NHE-1
A.C. HCO3– + H+ H+
NKCC1 CA
CO2 + H2O
K+ Na+
BASOLATERAL
2Cl
VIP
PGE2
FIGURE 52–9 Bicarbonate secretion in the duodenum. The
FIGURE 52–8 Regulation of chloride secretion by cAMP-
two models depicted differ in the pathway for bicarbonate exit across
dependent agonists such as vasoactive intestinal polypeptide (VIP)
the apical membrane. Both models are likely to be important,
and prostaglandins. These agonists activate adenylyl cyclase (A.C.) via a
although the anion exchanger involved in the upper mechanism has
stimulatory G protein (Gs), leading to an increase in intracellular cAMP.
not been conclusively identified. CA, carbonic anhydrase; AE1/CLD,
This in turn activates the cAMP-dependent protein kinase (protein kinase
anion exchangers; NHE-1, sodium/hydrogen exchanger-1. (Used with
A), causing dissociation of its catalytic (C) subunits from the regulatory
permission from Montrose et al: Secretion and absorption: small intestine and colon.
(R) subunits. The catalytic subunits are thereby freed to phosphorylate
In: Textbook of Gastroenterology, 4th ed. Yamada T, Alpers DH, Kaplowitz N, Laine L,
CFTR leading to channel opening, and to stimulate the insertion of
Owyang C, Powell DW (editors). Philadelphia: Lippincott, Williams and Wilkins; 2003.)
additional NKCC1 cotransporter molecules into the basolateral
membrane. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology.
New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

dins, guanylin, and ACh representing physiologically important

secretagogues that utilize each respective second messenger.
The primary physiological stimulus for duodenal bicarbon-
ate secretion appears to be the presence of an acidic pH in
the lumen.
CLINICAL CORRELATION
Following a tsunami disaster in which the supply of clean
drinking water is disrupted, hundreds of adults and chil-
dren are brought to emergency medical personnel suffer-
ing from profuse, watery diarrhea. The children, in
particular, show signs of severe dehydration. Because of
the prevailing conditions and a lack of trained personnel,
it is not possible to resuscitate patients with intravenous
fluids. Instead, patients are placed on cots that allow fecal
fluid losses to be measured over time. Many patients who
receive oral solutions of glucose and sodium chloride in
volumes equivalent to their fecal losses recover from their
acute diarrheal illness and survive. Later microbial analy-
ses reveal that stool samples contain large numbers of a
bacterial pathogen.
Diarrhea can result when intestinal chloride secretion
is stimulated excessively, and the resulting luminal fluid
load exceeds the absorptive capacity of the small and large
intestines (Figure 52–3). The prototypic disease state in
which this occurs is cholera, in which Vibrio cholerae bac-
teria in the intestinal lumen secrete a toxin. The active
subunit of this toxin translocates to the basolateral mem-
brane of intestinal epithelial cells where it irreversibly
activates the stimulatory Gs G-protein, resulting in a mas-
sive accumulation of cAMP and stimulation of down-
stream signaling pathways. This produces uncontrolled
and sustained chloride secretion, inhibition of electroneu-
tral NaCl absorption, and an outpouring of fluid into the
534 SECTION VIII GI Physiology
lumen. Stool volumes of up to 20 L per day are not uncom-
mon in this disorder, which can rapidly lead to death due
to the complications of dehydration if left untreated.
Active intestinal secretion may also underlie diarrhea
caused by a number of other enteric pathogens, including
rotavirus and Salmonella. Clostridium difficile is a patho-
gen that is often acquired in hospital settings, particularly
in patients whose normal enteric flora has been disrupted
by the administration of antibiotics. It secretes toxins that
provoke chloride secretion via calcium-dependent path-
ways in addition to damaging the barrier function of the
epithelium. Finally, the endogenous peptide regulator of
chloride secretion, guanylin, shows homology to a heat-
stable toxin produced by certain strains of pathogenic
E. coli, which is the major cause of traveler’s diarrhea. Secre-
tory diarrhea can also occur in noninfectious settings. In
particular, when the epithelium is exposed to a barrage of
immune and inflammatory mediators, such as in the
inflammatory bowel diseases of Crohn’s disease and
ulcerative colitis, there is both a stimulation of chloride
secretion and an inhibition of sodium and chloride absorp-
tion, seen clinically as diarrhea, which is the most frequent
symptom of these conditions. Diarrheal diseases continue
to represent a major public health problem, particularly in
developing countries where sanitation is inadequate and
represent an important cause of infant mortality in such
countries, second only to respiratory infections. Diarrheal
diseases also have a major impact in developed countries,
though more frequently in terms of discomfort, inconve-
nience, and lost productivity than mortality. Nevertheless,
thousands of deaths from diarrheal diseases occur each
year even in the United States, and many of these take
place even after the patient has reached a health facility
due to an underappreciation of how rapidly diarrhea can
cause dehydration and metabolic disturbances.
CHAPTER SUMMARY
■ The intestine handles large volumes of fluid in fulfilling its
physiological functions.
■ Dysfunction can rapidly impact whole body electrolyte
homeostasis.
■ Water is moved passively in response to active electrolyte
transport.
■ Transport mechanisms are heterogeneous along the length of
the intestine and between crypt and villus cells.
■ Transport mechanisms consist of the asymmetrical arrange-
ment of a limited number of electrolyte transport pathways.
■ Certain pathogens can cause diarrheal disease by hijacking
normal cellular signaling pathways.
■ Diarrheal disease remains a major health problem in both
developed and developing countries.
STUDY QUESTIONS
1. Individuals housed in a camp in Southeast Asia following a
natural disaster develop widespread watery diarrhea. Increased
activity of which of the following transport proteins might be
exploited therapeutically to reduce fluid losses?
A) SGLT-1
B) CFTR
C) NHE3
D) Na,K-ATPase
E) NKCC1
2. A 50-year-old man on a business trip to a developing county
develops severe diarrhea and begins taking the opiate drug
Imodium (loperamide) in an attempt to lessen his symptoms.
Any relief he obtains can most likely be ascribed to an increase in
which of the following?
A) intestinal transit time
B) mucosal blood flow
C) chloride secretion
D) peristalsis
E) epithelial proliferation
3. A 30-year-old woman with Crohn’s disease undergoes a surgical
resection of her terminal ileum. After recovering from the
surgery, she develops chronic diarrhea, with a daily stool output
10× normal. Which of the following substances is/are most likely
primarily responsible for her symptoms?
A) prostaglandins
B) inflammatory cytokines
C) VIP
D) bile acids
E) short-chain fatty acids
4. An infant develops chronic diarrhea and failure to thrive.
Tests reveal glucosuria (increased glucose in the urine).
Further studies show that urinary excretion of a nondigestible
disaccharide given orally, as well as uptake of oral alanine, is
comparable to that seen in a normal child, whereas oral galactose
absorption is markedly impaired. Diarrhea in this child is most
likely due to a mutation in which of the following proteins?
A) CFTR
B) ENaC
C) NHE3
D) PepT1
E) SGLT-1
5. In a healthy adult, the volume of fluid presented to the intestine
on a daily basis is approximately 8 L. Assuming a normal diet,
reabsorption of the bulk of this fluid in the small intestine is
driven primarily by which of the following?
A) nutrient-coupled electrogenic sodium absorption
B) electroneutral NaCl absorption
C) nutrient-coupled proton absorption
D) potassium absorption
E) electrogenic sodium absorption via ENaC channels
 53
C H A P T E R

Intestinal Mucosal
Immunology and Ecology
Kim E. Barrett

O B J E C T I V E S

■ Understand the role played by the mucosal immune system in protecting

the host from infections acquired via the oral route while not responding
to innocuous antigens.
■ Identify the cell populations that contribute to immunity in the gut and
where they are located
■ Describe the immune responses that occur to antigens encountered in the gut.
■ Understand the origins, makeup, and physiological importance of microbial
populations that exist in the normal intestine.
■ Define the consequences of abnormal immune responses in the intestine.

BASIC PRINCIPLES OF cells known as M cells. M cells overlie organized lymphoid

MUCOSAL IMMUNOLOGY
CONCEPT OF A MUCOSAL
IMMUNE SYSTEM
The surface of the gastrointestinal tract represents a vast frontier
that can potentially serve as a portal of entry into the body.
Indeed, the intestine is challenged to distinguish between poten-
tially harmful microorganisms, against which it must defend
itself, and the innocuous antigens that occur in food. This con-
stant exposure has driven the development of a highly special-
ized branch of the immune system, referred to as the mucosal
immune system, which encompasses the mucosa-associated
lymphoid tissues, or MALT. In fact, the intestine represents the
largest immunological compartment of the body, and has also
evolved nonimmunological barriers to invasion by pathogens.
SPECIAL FEATURES OF THE IMMUNE
SYSTEM OF THE INTESTINE
The lymphocytes that traffic to mucosal sites encounter anti-
gens in a controlled fashion. This is accomplished by limiting
the uptake of particulate antigens predominantly to specific
sites within the epithelial monolayer, via specialized epithelial
aggregates known as Peyer’s patches. The lymphocytes in these
structures are immunologically naive and represent the affer-
ent arm of the mucosal immune system. After they have been
stimulated by their cognate antigen, they traffic back to the
lamina propria. During this migration, the lymphocytes mature
and differentiate, and then represent an efferent arm of the sys-
tem, capable of effector functions in the mucosa. In addition to
T cells, the humoral aspects of mucosal immunity are predom-
inantly served by secretory immunoglobulin (IgA) molecules,
and the intestinal mucosa can also be considered to be con-
stantly in a state of “physiological” inflammation, even in
health. Presumably this reflects the constant stimulation the
system receives, and renders the intestine armed and ready to
respond rapidly at times of threat by pathogens.
FUNCTIONAL ANATOMY OF
THE MUCOSAL IMMUNE SYSTEM
CELLULAR MEDIATORS
OF INNATE IMMUNITY
The innate arm of the mucosal immune system is designed to
mount rapid responses to pathogens, via the expression of
pattern recognition receptors that recognize molecules that are

535

Ch53_535-542.indd 535 11/26/10 10:35:05 AM

536 SECTION VIII GI Physiology
important to broad classes of pathogenic microbes. These
receptors are prominently expressed on macrophages as well as
on cells not classically considered to be immune effector cells,
such as those in the epithelium. Pattern recognition receptors
include the Toll-like receptors, and proteins that may respond
to pathogen molecules presented intracellularly such as Nod2.
In general, activation of the innate immune response generates
chemotactic molecules that stimulate the influx and activation
of more inflammatory cells, including monocytes and neutro-
phils. Collectively, these cells can effect microbial killing.
CELLULAR MEDIATORS
OF ADAPTIVE IMMUNITY
Adaptive immunity involves the exquisitely specific recogni-
tion of literally millions of discrete antigenic sequences via spe-
cific receptors expressed on T and B cells. T cells recognize
peptides derived from antigenic sequences via a heterodimeric,
variable cell surface T-cell receptor. The peptides are presented
bound to major histocompatibility complex (MHC) mole-
cules on antigen-presenting cells. The binding of antigen to a
specific T-cell receptor then drives the expansion of a clone of
cells expressing that receptor; some of these differentiate into
effector T cells; others remain as memory cells to jump-start an
adaptive immune response if the same antigen is encountered
again. T cells in the mucosal immune system can be subdivided
into those expressing the differentiation marker CD4 and those
expressing CD8. The former cell population recognizes extra-
cellular antigens displayed on the surface of antigen-presenting
cells, likely including components of pathogenic microorgan-
isms. CD8-positive T cells, on the other hand, recognize abnor-
mal intracellular proteins and provide important protection
against potentially harmful intracellular events, such as viral
infection or malignant transformation. Adaptive immunity is
also mediated by B cells, which secrete antibodies specific for a
given antigen under the influence of T cell–derived cytokines.
ORGANIZATION
OF LYMPHOID TISSUES
It is also important to appreciate how lymphoid tissues are orga-
nized in the intestine. As mentioned earlier, in the small intes-
tine, the afferent arm of the system (i.e., the arm that responds
initially to a threat) occurs in Peyer’s patches, as shown dia-
grammatically in Figure 53–1. In the colon, these aggregates of
lymphocytes are more loosely organized, but analogous in func-
tion. Naive T and B cells from the bloodstream are targeted to
migrate into Peyer’s patches because they recognize a specific
type of endothelial cell that is found in these lymphoid struc-
tures. The other important components of the Peyer’s patch
include the M cell, and dendritic cells and macrophages, which
process and present antigens to the T and B cells. Once stimu-
lated, activated T and B cells migrate out of the lymphoid follicle
and eventually back to the lamina propria.
Follicle-associated epithelium
M cell
T cell area
B cell area
FIGURE 53–1 Structure of a Peyer’s patch in the small
intestinal mucosa. The follicle-associated epithelium contains M, or
microfold, cells that have a subapical pocket in which antigens can be
presented to immune cells. Lymphocytes are aggregated underneath
the epithelium with T and B lymphocytes restricted to distinct areas.
Peyer’s patches also contain dendritic cells (not shown) that can
present antigens to lymphocytes. (Reproduced with permission from Barrett
KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical
Pub. Division, 2006.)
A final class of organized lymphoid cells in the intestine
consists of lymphocytes anchored to the epithelial layer via
specific adhesion molecules. These are called intraepithelial
lymphocytes, and appear predominantly to consist of mem-
ory T cells capable of responding to only a subset of luminal
antigens. They likely function primarily to secrete cytokines
involved in the regulation of the epithelium, and may also par-
ticipate in immune surveillance for emerging malignancies.
SECRETORY IgA SYSTEM
Seventy to 90% of the B cells in the intestinal lamina propria
secrete IgA, with the remainder largely making IgM, and a few
cells making IgE. Very few cells in the lamina propria make
IgG. In fact, given the large numbers of lymphocytes that nor-
mally reside in the gut, the daily synthesis of IgA exceeds that
of all other immunoglobulins.
STRUCTURAL ASPECTS OF IgA
IgA plasma cells in the lamina propria secrete two IgA mole-
cules that are bound together by a short polypeptide sequence
known as the J (or joining) chain. J chain is also a component
of other polymeric immunoglobulins, such as IgM. The other
critical component of secretory IgA that is found in the lumen
of the intestine derives from intestinal epithelial cells
(Figure 53–2). Thus, dimers of IgA plus J chain are taken up at
the basolateral surface of the epithelium by binding to a struc-
ture known as the polymeric immunoglobulin receptor
(pIgR). The complex of IgA plus pIgR is internalized and
translocated across the epithelial cell. At the apical membrane,
the IgA dimer is released into the lumen bound to a cleaved
 CHAPTER 53 Intestinal Mucosal Immunology and Ecology
LUMEN Secretory component
Secretory
lgA
Lysosomal
degradation
Epithelial cell
plgR
J chain
Dimeric lgA
lgA plasma cell
FIGURE 53–2 Secretion of IgA across the intestinal
epithelium. IgA is secreted by plasma cells in the lamina propria as a
dimer, with two IgA molecules linked by a J, or joining, chain. J chain is
recognized by the polymeric immunoglobulin receptor (pIgR)
expressed on the basolateral membrane of epithelial cells, and once
bound, the complex is internalized and trafficked across the cytosol to
the apical membrane. Apical proteases cleave the extracellular portion
of pIgR, which remains associated with the IgA dimer as secretory
component. The remnant of the pIgR is internalized and degraded.
(Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York:
Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
portion of pIgR, known as secretory component. Secretory
component further stabilizes the IgA dimer against proteolytic
cleavage by either the digestive juices or bacterial proteases.
MECHANISMS OF
PROTECTIVE EFFECTS
Secretory IgA exerts protection in the intestine via several
mechanisms. In the lumen, it can bind microbial antigens,
food antigens, and viruses to prevent their uptake by intestinal
epithelial cells. There is also evidence for a second line of
defense that takes place within epithelial cells themselves.
Thus, if any antigens are internalized by these cells, they
537
encounter vesicles bearing IgA bound to pIgR that are des-
tined for the apical membrane. The IgA in these vesicles can
bind the foreign antigen and traffic it back to the apical mem-
brane, thus resulting in its elimination. Finally, some IgA mol-
ecules may function to sequester antigens that are able to
penetrate to the lamina propria.
IgA has an additional specialization relative to other anti-
body classes that particularly suits it to function in the gut.
Thus, the antibody is not capable of fixing complement via the
classical pathway, rendering it relatively noninflammatory on
antigen binding. This is likely an important consideration
given the vast antigenic load that is presented to the intestine,
representing the combined influences of potentially antigenic
food proteins along with microbial products.
PHYSIOLOGICAL FUNCTIONS
The secretory IgA response protects the body from potentially
injurious substances that might otherwise stimulate a more
generalized immune/inflammatory reaction in the periphery.
Note that the IgA system is not well developed in newborns. In
the breast-fed infant, protection can be obtained via IgA anti-
bodies in the mother’s milk. This is one benefit of the common
mucosal immune system, discussed earlier, where lympho-
cytes activated by antigens encountered in the intestine also
traffic to other mucosal sites, including the mammary glands.
The IgA system becomes mature in the child by the age of 5–6
months.
IMMUNE RESPONSE
TO ENTERIC ANTIGENS
There are three potential outcomes when the adaptive immune
system encounters an antigen in the intestine. The specific
outcome that occurs depends, in part, on the type of antigen
that is encountered and its quantity. A localized response can
occur, such as the stimulation of antigen-specific IgA produc-
tion. The antigen can also, at least theoretically, drive a sys-
temic immune response with the production of circulating
antibodies plus expansion of antigen-specific T cells. However,
it is clear that this would be an undesirable outcome under
normal circumstances, given the number of antigens encoun-
tered by the intestine on a daily basis and the deleterious con-
sequences of systemic reactions to these. Thus, an additional
response to orally delivered antigens has also evolved in the
mucosal immune system, which limits these adverse conse-
quences in the systemic immune system. This specialized
response is referred to as oral tolerance.
ORAL TOLERANCE
Oral tolerance refers to a mucosal immune response where local
IgA is produced, yet there is no detectable immune response in
538 SECTION VIII GI Physiology
the periphery. Oral tolerance is the most frequent outcome for
antigens that are presumably innocuous, such as from food. The
determination as to whether oral tolerance will occur depends
on the type of antigen, the amount given, the frequency of expo-
sure, and host factors, including the age of the recipient. The
lack of response in the periphery apparently requires active sup-
pressive mechanisms, and is highly specific, extending only to
the substance that is fed and not to other antigens. The phenom-
enon of oral tolerance is being exploited for the experimental
treatment of some systemic autoimmune diseases.
IMMUNE RESPONSIVENESS
Under different circumstances, it may be appropriate for the
intestine to respond to an antigen and additionally for this
response to spread to the periphery. This is particularly the
case for immune responses to pathogens. Generalized immune
responses to otherwise innocuous antigens can also be driven
by administering these in the presence of an adjuvant. This
latter approach might ultimately prove useful in exploiting the
oral route to vaccinate people against disease-related antigens.
Generalized immune responses can also be deleterious to
the host under specific circumstances. For example, if the bar-
rier function of the epithelium is compromised, it is possible
to generate both local and systemic immune responses to the
normal commensal flora of the gut, which in turn can lead to
tissue injury.
AUTOIMMUNITY
During the development of immunity, clones of T and B cells
capable of reacting to self-antigens are actively deleted. How-
ever, even in healthy individuals, a few such lymphocytes are
thought to remain in the mucosal immune system, and may be
needed to respond to microbes that express antigens that
resemble proteins of the host, in an attempt to evade immunity.
Under normal circumstances, these autoreactive clones are
likely held in check by active suppressive mechanisms, includ-
ing those mediated by regulatory T cells and inhibitory cyto-
kines. Likewise, self-antigens may be presented in the absence
of appropriate costimulatory molecules, which results in anergy
(the lack of an immune reaction) rather than an immune
response. On the other hand, under pathologic conditions, this
regulation may be lost with the resulting emergence of autore-
activity and tissue inflammation and injury. These mechanisms
may be important in contributing to disease in conditions such
as inflammatory bowel diseases (Crohn’s disease and ulcer-
ative colitis), celiac disease, and atrophic gastritis.
INTESTINAL MICROECOLOGY
The gastrointestinal tract also represents a unique body com-
partment with respect to the lifelong, reciprocally beneficial rela-
tionship it establishes with a resident microbial community,
known as the enteric flora or microbiota. The species that make
up this flora are referred to as commensal microorganisms.
DEVELOPMENT OF
INTESTINAL MICROBIOTA
At birth, the intestinal tract is sterile. However, by the age of
1 month, the infant acquires a rich flora, derived from the
environment in an oral-to-anal direction.
Indigenous Populations
The entire gastrointestinal tract can be shown to be colonized
by bacteria, but the types of bacteria and their numbers vary
along the gastrointestinal tract. The stomach and the majority
of the small intestine contain relatively few bacteria, and lack
anaerobes. On the other hand, beginning in the distal small
intestine, the numbers of bacteria increase sharply, and anaer-
obes also appear. The largest numbers of bacteria, by far, occur
in the colon, where anaerobes vastly outnumber aerobic bacte-
ria (Table 53–1).
The flora in the colon is complex, likely containing at least
400 different bacterial species. However, the precise propor-
tions of each species tend to differ between individuals, while
remaining relatively constant in a given individual over time in
the absence of events that alter the flora (see later). This has led
to the concept that the bacterial flora of a given subject is essen-
tially equivalent to a “fingerprint,” representing the interplay
between host and bacterial factors. The major anaerobic spe-
cies include Bacteroides, bifidobacteria, clostridia, Eubacteria,
and anaerobic streptococci. Likewise, important aerobes
include enterobacteria such as E. coli, streptococci, and staphy-
lococci.
Factors Controlling Microbiota
The bacterial colonization of the upper gastrointestinal tract is
kept in check by a number of physical and humoral factors.
Many gastrointestinal secretions contain substances that are
toxic to bacteria, including gastric acid, bile acids, small anti-
microbial peptides known as defensins, and lysozyme. In the
small intestine, moreover, the overall bacterial burden is kept
TABLE 53–1 Enteric bacterial populations.
Cecum/
Stomach Jejunum Ileum Colon
Total bacteria/g 0–103 0–104 104–108 1010–1012
Aerobes and 0–103 0–104 104–105 102–109
facultative
anaerobes/g
Anaerobes/g 0 0 103–108 1010–1012
pH 3 6–7 7.5 6.8–7.3
 CHAPTER 53 Intestinal Mucosal Immunology and Ecology
in check by the combined influences of motility (especially
peristalsis) and the secretion of fluid and electrolytes that can
wash bacteria out of the lumen. Secretion of IgA may also limit
the growth of some commensals.
In the colon, on the other hand, the relatively slow motility
permits the growth of large numbers of bacteria. These are
largely retained in the large intestine by the action of the ileo-
cecal valve. Upwards of 1012 bacteria can be found per gram of
colonic luminal contents, and the majority of the formed mass
of the stool, after water, consists of dead bacteria. Indeed, the
number of colonic bacteria in the average person is greater
than the total number of cells in the human body. The makeup
of the colonic flora is relatively insensitive to diet, although a
diet rich in fiber, which constitutes a fuel for anaerobic bacte-
ria, may result in an increase in overall bacterial numbers.
Conversely, intestinal colonization can be dramatically reduced
in patients taking broad-spectrum antibiotics. In this setting,
there is sometimes also overgrowth of harmful bacteria that
can cause disease, such as Clostridium difficile, commonly
acquired in hospitals, because there are fewer commensals to
compete with the harmful bacteria for nutrients.
PHYSIOLOGICAL FUNCTIONS
OF THE MICROBIOTA
Experiments in animals reveal that the intestinal microflora is
not essential to life. Thus, animals that are raised in a totally
sterile environment from birth are apparently healthy and
reproduce normally. Nevertheless, the flora clearly has mea-
surable effects on the host. First, in germ-free animals, the
mucosal immune system is poorly developed, illustrating the
critical role of luminal stimuli in driving the development and
TABLE 53–2 Metabolic effects of enteric bacteria.
Substrate Enzymes
Endogenous substrates
Urea Urease
Bilirubin Reductases
Primary bile acids Dehydroxylases
Conjugated bile acids Deconjugases
Exogenous substrates
Carbohydrates (fiber) Glycosidases
Amino acids Decarboxylases and
deaminases
Cysteine, methionine Sulfatases
a
SCFA, short-chain fatty acid.
539
maturation of intestinal lymphoid populations. Second, epi-
thelial proliferation and differentiation are slowed.
Colonic bacteria, in particular, also supply unique metabolic
functions, divided into effects on endogenous substances and
those on substances that originate outside the body. Colonic
bacteria convert bilirubin, a product of heme metabolism that
is secreted in the bile, into urobilinogen. This compound
undergoes some passive absorption across the wall of the colon
and appears in the urine. Bacterial dehydroxylases also act on
primary bile acids to generate secondary bile acids that enter
the enterohepatic circulation, and bacterial enzymes are also
responsible for deconjugating any conjugated bile acids that
escape active reabsorption in the terminal ileum, to then permit
their passive reuptake across the colonic mucosa (Table 53–2).
Bacterial enzymes also salvage nutrients that cannot be
degraded by pancreatic or other digestive enzymes (Table 53–2).
This is particularly important for dietary fiber, a form of carbo-
hydrate that is resistant to breakdown by amylase. Breakdown of
fiber occurs via a metabolic process known as fermentation,
and requires a strict anaerobic environment. Fermentation can
also break down any carbohydrates that escape digestion and
absorption in the small intestine. The products of fermentation
are the short-chain fatty acids, which can be absorbed by colonic
epithelial cells and used as fuel. Fermentation also yields energy
for the bacteria and the gases hydrogen, carbon dioxide, and
methane. Bacteria can also act on other dietary components to
yield byproducts, although these are usually quantitatively less
significant than the products of carbohydrate fermentation. A
final, and likely critical, role of the microflora is to increase the
resistance of the intestinal mucosa to colonization by pathogenic
microorganisms (Table 53–3). Germ-free animals are exquisitely
sensitive to enteric pathogens, succumbing to infection with
only a few pathogenic bacteria presented orally compared to the
Products Disposition
Ammonia Passive absorption or
excretion as NH4+
Urobilinogen, stercobilins Passive reabsorption
Excreted
Secondary bile acids Passive reabsorption
Unconjugated bile acids Passive reabsorption
SCFAsa Active absorption
H2, CO2, CH4 Expired in breath or excreted
in flatus
Ammonia, HCO3− Reabsorbed or excreted
(for ammonia) as NH4+
Hydrogen sulfide Excreted in flatus
540 SECTION VIII GI Physiology

TABLE 53–3 Selected important intestinal pathogens and their pathophysiological mechanisms.
Luminal (Toxigenic) Pathogens Adherent Pathogens Invasive Pathogens Viral Pathogens

V. cholerae Giardia Salmonella spp. Rotavirus

Enterotoxigenic E. coli Enteropathogenic E. coli Shigella Norwalk virus

H. pylori Campylobacter

Listeria

millions needed to cause disease in a normal animal. Likewise,

the enteric flora protects the host from overgrowth of bacteria
that are innocuous when present in low numbers, but can cause
disease if allowed to dominate the flora.
GENERATION OF
GAS IN THE INTESTINE
The intestinal flora is also the source of the majority of the gas
that originates in the gastrointestinal tract. While large vol-
umes of air may be swallowed with meals, most of this is
expelled from the stomach by belching. That which remains is
supplemented by carbon dioxide that is generated when gastric
acid is neutralized by bicarbonate; the majority of the carbon
dioxide can diffuse across the wall of the bowel and is excreted
via the lungs. The gas that remains in the intestine is moved
back and forth by motility patterns, resulting in bowel sounds—
borborygmi—that can be heard through a stethoscope and
sometimes even by the naked ear as a “rumbling stomach.” The
absence of such bowel sounds is a reliable indicator that bowel
motility has been inhibited, which happens commonly (and
usually reversibly) after abdominal surgery. More distally,
fermentation and other metabolic pathways promoted by bac-
terial enzymes in the colon result in the formation of large vol-
umes of gas on a daily basis, even in normal individuals. The
volume of gas produced by a healthy individual is likely to aver-
age 1 L per day. However, there is considerable variation among
individuals, and the amount of gas also depends on the quan-
tity of fermentable residues that depends, in turn, on the diet.
Most of the gases present in flatus are nonodorous, with the
majority consisting of nitrogen and hydrogen (Figure 53–3).
The amount of methane produced varies considerably among
individuals. On the other hand, the gases that are responsible
for the odor of flatus are present in very small, or trace,
amounts. These include hydrogen sulfide, indole, and skatole.
she is found to be hypotensive, with a red, itchy rash and
severe laryngeal edema that is starting to impair her breath-
ing. The physician immediately administers epinephrine as
well as an antihistamine, and the symptoms begin to sub-
side. As she starts to recover, she tells the physician that as
a child she was unable to eat peanuts but thought she had
grown out of the problem; one of her friends then points
out that one of the dishes she had tried contained ground
peanuts in the sauce. The physician discharges her with a
prescription for an epinephrine self-injector, and advice to
make an appointment with an allergist for further testing
and to carefully avoid ingesting peanuts in the future.
In certain individuals, likely as a result of a genetic predis-
position, the intestinal immune system inappropriately gen-
erates IgE antibodies to food proteins or other components
of the diet, such as nucleic acids. These antibodies bind to
mast cells that reside in the lamina propria, which are then
Major gases
H2
20%
CO2
10%
N2
65% CH4
O2 3%
2%

CLINICAL CORRELATION Trace gases:

Hydrogen sulfide
A 30-year-old woman is out for dinner with friends when Odorous
Indole
she notices a tingling sensation in her mouth and around Skatole (3-methyl indole)
her lips. Initially, she ignores the symptoms, but when her
face starts to swell and she begins to feel light-headed, her FIGURE 53–3 Composition of normal intestinal flatus.
(Reproduced with permission from Barrett KE: Gastrointestinal Physiology.
friends take her to a nearby emergency room. On arrival,
New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
 CHAPTER 53 Intestinal Mucosal Immunology and Ecology 541

said to be “sensitized.” The sensitization process also results STUDY QUESTIONS

in upregulation of pathways that permit transfer of the 1. A scientist interested in gut ecology studies intestinal responses in
offending protein across intestinal epithelial cells. The net germ-free mice. Compared with normally housed animals, what
result is that the next time the person eats the protein in combination of findings would be expected in the colonic lumen?
question, it is transferred rapidly across the epithelium and
cross-links IgE antibodies on the surface of mast cells, caus- Secondary Short-chain
ing cell activation and release of a host of potent chemical sIgA Bile Acids Fatty Acids
mediators. These mediators can increase intestinal chloride A) Increased Increased Decreased
secretion and alter motility, which can be observed clinically
B) Decreased Decreased Decreased
as diarrhea. Stimulation of enteric nerve endings by mast cell
mediators may further amplify these responses. In a seri- C) Increased Decreased Increased
ously allergic subject, the antigen may also gain access to the D) Decreased Increased Increased
circulation from which it can trigger reactions in extraintes-
E) Increased Increased Increased
tinal sites, such as the skin and airways, or cause the general-
ized allergic reaction throughout the body known as systemic
anaphylaxis. Food allergies can be life-threatening. 2. A biotechnology company attempts to develop an oral vaccine
Certain foods are more commonly seen as triggers of aller- for use in developing countries by expressing a viral protein in
transgenic bananas. However, clinical trials reveal that consumption
gic responses, perhaps reflecting the relative stability of com-
of the bananas fails to confer protective immunity against the viral
ponent proteins during the digestive process. Such foods infection. What immune response likely accounts for this failure?
include peanuts, eggs, certain fruits, and shellfish. Unless an
A) IgA secretion
individual is allergic to multiple foods, the best treatment for B) phagocytic uptake
food allergy is to avoid the food in question, especially if very C) oral tolerance
severe allergic reactions occur. However, it may not always be D) T-cell sensitization
a simple matter to avoid a given food, particularly outside the E) Toll-like receptor activation
home, and for this reason, those who are seriously affected by 3. In a diagnostic test conducted in a patient with suspected
food allergies are usually advised to carry a self-injector con- Giardia infection, fecal samples are screened for the presence
taining epinephrine, which can counter serious symptoms. of antibodies reactive with giardial antigens. Assuming such
antibodies are found, what is their likely class?
A) monomeric IgG
B) monomeric IgA
CHAPTER SUMMARY C) dimeric IgA
■ The mucosal immune system is uniquely specialized to D) monomeric IgM
protect the vast interface between the host and environment E) pentameric IgM
represented by the GI tract. 4. A patient with a severe lung infection is treated with a broad-
■ Mucosal immune responses are shared among several mucosal spectrum antibiotic. Shortly after beginning this treatment, she
sites beyond the intestine. develops severe diarrhea. Stool samples are most likely to reveal
■ The intestine can be considered to be “physiologically evidence of overgrowth with which of the following organisms?
inflamed,” even in health, priming it to respond promptly A) Shigella dysenteriae
to invaders. B) Vibrio cholerae
■ Secretory IgA provides important humoral protection against C) Lactobacillus acidophilus
infections in the gut. D) Campylobacter jejuni
E) C. difficile
■ Presentation of antigens via the oral route often leads to a
response known as oral tolerance, where a local immune 5. A scientist working to develop a new diagnostic test administers
response exists in the face of systemic unresponsiveness. a solution of lactulose (a disaccharide that is not digested by host
enzymes, but can be broken down by bacterial enzymes) orally to
■ Oral tolerance may protect us from inappropriate reactions
a group of volunteers as well as to a patient with symptoms of
to food antigens. This response may also be exploited for
malabsorption. She then measures the concentration of
therapeutic benefit in autoimmune diseases.
hydrogen in expired breath from each group. Hydrogen is
■ The intestine maintains a lifelong, reciprocally beneficial present in negligible amounts in both groups prior to lactulose
relationship with a complex microflora that is predominantly administration, and increases in the control group only after a
contained in the colon. 1–2-hour lag period. However, in the patient, breath hydrogen
■ Colonic bacteria supply metabolic functions, especially levels begin to rise almost immediately. What is the most likely
fermentation, and contribute to intestinal gas production. cause of this more rapid appearance?
■ Commensal bacteria may provide important protection against A) celiac disease
colonization by pathogens. B) cystic fibrosis
■ Derangements in intestinal physiology occur when immune C) Crohn’s disease
responses are inappropriately stimulated in the intestine, or D) small bowel bacterial overgrowth
when defenses fail to protect us from infection with pathogens. E) H. pylori infection
This page intentionally left blank
 54
C H A P T E R

Intestinal Motility
Kim E. Barrett

O B J E C T I V E S

■ Understand how the motility functions of the esophagus, stomach, and

intestines contribute to the integrated response to a meal.
■ Describe the functional anatomy of the esophagus, stomach, intestines, and
related structures, and their innervation.
■ Understand the roles played by the oral cavity, pharyngeal structures,
esophagus, and esophageal sphincters in transferring food from the mouth
to the stomach during swallowing.
■ Describe receptive relaxation and mixing/grinding patterns of motility and
their regulation.
■ Understand how the stomach is emptied, and how this is coordinated with
the function of downstream segments.
■ Define the motility patterns that characterize movements of the small and
large intestines under fed and fasted conditions and their control
mechanisms.
■ Distinguish between mixing patterns and those that propel contents along
the length of the intestine.
■ Describe reflexes that coordinate the motility functions of the small intestine
and colon with the function of the stomach.
■ Understand the process whereby undigestible residues of the meal are
eliminated from the body.

This chapter reviews the processes that move the meal along
the length of the gastrointestinal tract and provide for its dis-
persion, as well as mixing with digestive secretions. Because
there are segmental differences in the types and functions of
the motility processes of the alimentary tract, we will consider
in turn the motility of the esophagus, stomach, small intestine,
and colon. Each segment has a specific role to play in handling
the meal, but all depend on the properties of the smooth mus-
cle layers that surround the mucosa. It may therefore be help-
ful to review the basic properties of smooth muscle as explained
in Chapter 11.
BASIC PRINCIPLES OF
ESOPHAGEAL MOTILITY
ROLE AND SIGNIFICANCE
The esophagus is a muscular tube that transfers food from the
mouth to the stomach. Under normal circumstances, food
resides in the esophagus for only a few seconds. The move-
ments of the esophagus and related oral and pharyngeal struc-
tures must also be carefully regulated to avoid misdirection of

543

Ch54_543-558.indd 543 11/26/10 10:33:41 AM

544 SECTION VIII GI Physiology
esophageal
Striated muscle
Smooth muscle
FIGURE 54–1 Functional anatomy and innervation of
the esophagus. Note that the mode of innervation differs
between the portions of the esophagus made up of smooth
versus striated muscle. (Reproduced with permission from Barrett KE:
Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill,
Medical Pub. Division, 2006.)
the food into the respiratory tract, or inspired air into the diges-
tive system. At rest, the esophagus is a relaxed structure that is
closed off at both ends by sphincters—the upper esophageal
sphincter and lower esophageal sphincter (LES). These
sphincters not only cooperate in the act of swallowing, or
deglutition, but also prevent backflow of gastric contents into
the esophageal lumen or oral cavity. However, under specific
circumstances, the esophagus does allow for retrograde move-
ment. This occurs normally for air swallowed with the meal, in
the process of belching, or abnormally during vomiting. Dur-
ing retrograde movement in humans and most mammals, the
esophagus itself is a passive conduit, that is, there are no spe-
cific motility functions that propel vomitus or air along the
length of the tube. Swallowing can be initiated voluntarily, but
thereafter reflects an automatic reflex that involves, sequentially,
impulses from the brainstem, processing of this information
through vagal centers in the central nervous system, direct
effects of parasympathetic vagal efferents on esophageal muscle
layers, and relay of information via the enteric nervous system
(Figure 54–1). Movement of materials along the length of the
esophagus is aided by gravity, but predominantly depends on a
coordinated series of muscle contractions and relaxations that
make up the propulsive motility pattern known as peristalsis.
FUNCTIONAL ANATOMY OF THE
ESOPHAGEAL MUSCULATURE
MUSCLE LAYERS
The esophagus is 18–25-cm long in adult humans. Like the
remainder of the gastrointestinal tract, it is surrounded by two
muscle layers: the innermost (i.e., closest to the lumen) oriented
Swallowing
Glossopharyngeal
center
+ vagal afferents
Pharynx
(S)
Outflow:
Upper
• Somatic nerves (S)
sphincter regulate striated
(S) muscle directly
• Autonomic nerves (A)
regulate smooth
muscle via
enteric nervous
system or directly
(A)
(A)
Lower
esophageal
sphincter
Stomach
in a circular fashion and the outer oriented longitudinally.
However, unlike the exclusive occurrence of smooth muscle in
all more distal segments of the gastrointestinal tract, the esoph-
agus contains striated (or skeletal) muscle in its upper third,
both striated and smooth muscle in its middle third, and exclu-
sively smooth muscle in its most distal third. The distinction
between muscle types also corresponds approximately to dif-
ferent types of neural control, as discussed later.
Other structures associated with the esophagus are impor-
tant in swallowing and normal esophageal function. We have
already mentioned the upper esophageal sphincter and LES,
which occlude both ends of the esophagus at rest. The esopha-
gus is situated within the low-pressure thorax, and thus the
presence of these sphincters is important to prevent the entry
of air and gastric contents. The pharynx, which connects the
nose and mouth to both the esophagus and trachea, is also
critically involved in swallowing. It segregates food and air as
they pass through this region.
INNERVATION
The function of the pharynx is controlled by the central ner-
vous system, via outflow from a region known as the central
swallowing center (Figure 54–1). The pharynx thereby per-
mits complex coordination of voluntary swallowing with func-
tions such as respiration and speech. Central input also
controls the contractile function of the upper one third of the
esophagus. The somatic nerves that innervate these structures
have motor end plates that terminate directly on the striated
muscle fibers. They originate in brain regions of the medulla
known as the nucleus retrofacialis and the nucleus ambiguus
and release acetylcholine (ACh), which acts via nicotinic
receptors.

The smooth muscle of the esophagus is innervated predom-
inantly by the vagus nerve. The vagal efferents synapse with
myenteric neurons via ACh and with the smooth muscle
directly via ACh and substance P. Sensory afferents located in
the esophagus likewise project via the vagus to the brain region
of the medulla known as the nucleus tractus solitarius in the
dorsal vagal complex. Cell bodies in this region also project
to the motor neurons in the nucleus ambiguus, which control
a pattern generator for the oral and pharyngeal components of
swallowing. This neural circuitry ensures that control of the
muscle groups involved in deglutition is linked to the function
of more distal regions of the esophagus, as well as to the regu-
lation of opening of the LES.
The esophagus is also richly supplied with enteric neurons.
These clearly contribute to both sensing the presence and
nature of esophageal contents and coordinating local reflexes
that supplement central control of swallowing and esophageal
peristalsis. This network of enteric neurons can produce sec-
ondary peristalsis of the smooth muscle portion of the esopha-
gus even in the absence of vagal input.
FEATURES OF
ESOPHAGEAL MOTILITY
The motility functions consist of sequential movement of food
from the mouth into the esophagus itself, propulsion along the
length of the esophagus via peristalsis, and relaxation of the
LES to permit entry of the food bolus into the stomach. In
health, these components of deglutition are tightly integrated,
but for simplicity we will consider each in turn here.
SWALLOWING
Although the term swallowing can refer to the entire process
required to move food from the mouth to stomach, here we
will consider it to include only those motility events that move
the bolus beyond the upper esophageal sphincter, as well as
their regulatory controls. As noted earlier, swallowing is initi-
ated when we sense that food particles in the mouth have been
reduced in size sufficiently to permit their passage into the
esophagus. While we consider this to be a voluntary response,
during its course it in fact becomes an involuntary reflex
involving significant input from a pattern recognition center
in the brainstem. This recognizes a food bolus as suitable
for swallowing and generates the required neuromuscular
response. However, it is possible to override this recognition
system voluntarily, such as in the case of swallowing a pill or
capsule. But in either case, the subsequent events that contrib-
ute to swallowing are entirely involuntary.
First, the tongue shapes and lubricates the bolus and moves
it backward in the mouth. Subsequently, a rapid series of pha-
ryngeal effects occur, initiated by mucosal mechanoreceptors
in the pharynx that activate afferent nerves traveling via the
glossopharyngeal nerve to the swallowing center. In turn,
efferent motor nerves run through the vagi to control the
CHAPTER 54 Intestinal Motility 545
contractile state of the pharyngeal muscles. These events occur
almost simultaneously, which is in contrast to the slower
motility changes that occur more distally in the esophagus, as
will be discussed later. First, the larynx and soft palate move
upwards, closing off the airway and nasopharynx, respectively.
Next, contraction of several muscles in the anterior portion of
the pharynx causes forward displacement of the larynx and
pharynx as well as helping to open the upper esophageal
sphincter. Sphincter opening also depends on relaxation of the
encircling cricopharyngeal muscle. This is accomplished by a
suppression of impulses normally occurring to this region,
coordinated by the swallowing center via the nucleus ambig-
uus. Longitudinal contractions of the pharynx also bring the
upper esophageal sphincter close to the base of the tongue,
whereupon a pressure gradient developed by the tongue and
pharyngeal muscles serves to force the bolus through the
sphincter. Finally, the posterior wall of the pharynx contracts
in a transverse fashion to clear the area of any remaining food
residues. These transverse contractions are propagated aborally
(i.e., away from the mouth) and can be considered the harbin-
ger of the peristaltic wave that later will carry the bolus through
the esophagus and down into the stomach. The sequence of
events involved in normal swallowing is shown diagrammati-
cally in Figure 54–2.
PERISTALSIS
Once the bolus has moved through the upper esophageal
sphincter into the esophageal lumen, it is moved along the
length of the tube via peristalsis (Figure 54–3). The sequenc-
ing and thus the direction of this propulsive process appears to
be hardwired, with contraction of more distal segments occur-
ring at longer latencies following the swallow than in those
close to the pharynx. The striated muscle region contracts
within 1–2 seconds after the swallow, the middle third of the
esophagus within 3–5 seconds, and the lower third within
5–8 seconds. This means that the ability of the body to transfer
food from the mouth to stomach is largely independent of
body orientation—one can swallow food while hanging upside
down. Nevertheless, gravity influences transit rate, particu-
larly for liquids. The peristaltic wave requires up to 10 seconds,
on average, to sweep solid esophageal contents along its length.
This relatively slow transfer should be contrasted with the
rapid events of swallowing itself.
Peristalsis in the esophagus is stimulated by its distension.
Mechanoreceptors on sensory afferents transmit impulses to
the dorsal vagal complex, which in turn activates somatic and
vagal efferents that terminate either directly on the striated
muscle in the upper third of the esophagus or onto nerves of
the enteric nervous system, respectively. The latter activate
enteric nerves capable of releasing ACh (to induce contrac-
tion) above the location of bolus-induced distension, or nitric
oxide (to induce relaxation) below the bolus (Figure 54–4).
The net effect of the sequential contractions and relaxations is
to move the bolus aborally. The primary wave of peristalsis
along the length of the esophagus may also be followed by a
546 SECTION VIII GI Physiology

Hard palate Soft palate Pharynx

Food

Tongue
Epiglottis

Glottis Upper
esophageal
Trachea sphincter
Esophagus
(a) (b) (c) (d)

FIGURE 54–2 Movement of food through the pharynx and upper esophagus during swallowing. a) The tongue pushes the food
bolus to the back of the mouth. b) The soft palate elevates to prevent food from entering the nasal passages. c) The epiglottis covers the glottis
to prevent food from entering the trachea, and the upper esophageal sphincter relaxes. d) Food descends into the esophagus. (Reproduced with
permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

secondary wave restricted to the smooth muscle portion into the lower esophagus. The response is triggered by disten-
(Figure 54–5). Secondary peristalsis may clear a bolus that sion, and involves both local reflexes within the enteric ner-
was not wholly expelled from the esophagus during the pri- vous system and vagovagal reflexes (Figure 54–6). Studies
mary wave, or remove any gastric contents that reflux back suggest that the presence of acid alone within the distal esoph-
agus, in the absence of significant distension, may also be suf-
ficient to generate a secondary peristaltic response.
Swallow The esophagus also transmits information about its contents
50 mm Hg back to more proximal segments. Thus, the presence of water
Pharynx 0 or, more potently, acid in the esophagus can be shown to
increase the pressure of the upper esophageal sphincter. This
Upper esophageal 50 mm Hg
response depends, at least in part, on vagovagal signaling. On
sphincter 0

50 mm Hg
Striated muscle 0
esophagus Dorsal vagal complex

50 mm Hg
0 Vagal efferents

Vagal afferent
Smooth muscle Myenteric nerves
esophagus 50 mm Hg
NO
0
ACh

Lower esophageal 50 mm Hg
sphincter 0
5 sec Bolus

FIGURE 54–3 Primary peristalsis triggered by swallowing in
the esophagus. Note that the pressure wave that moves down the
esophagus is coordinated with opening of the lower esophageal
sphincter. (Adapted with permission from Biancani P. et al: Esophageal motor function.
In: Textbook of Gastroenterology, 4th ed. Yamada T, Alpers DH, Kaplowitz N, Laine L,
Owyang C, Powell DW (editors). Philadelphia: Lippincott Williams and Wilkins, 2003.)
Orad contraction
Caudad
distension
FIGURE 54–4 Control of peristalsis by vagovagal reflexes in
the lower esophagus. ACh, acetylcholine; NO, nitric oxide.
(Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York:
Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
 CHAPTER 54 Intestinal Motility 547

Balloon LES RELAXATION

inflated
50 mm Hg The final component of esophageal motility is relaxation of the
Pharynx 0 LES, allowing the bolus to move into the stomach. Under rest-
ing conditions, the LES is tonically contracted. There is evi-
Upper esophageal 50 mm Hg
0
dence to suggest that this tonic contraction is accounted for by
sphincter
a mechanism referred to as myogenic—that is, the contractile
50 mm Hg state of the muscle is independent of neural input, and increases
Striated muscle 0 intrinsically as it is stretched. Moreover, the tone of the sphinc-
esophagus ter can also be increased by neurohumoral agents released in
50 mm Hg concert with ingestion of a meal, including ACh and gastrin.
0 The basal tone of the sphincter is critical to protect the lower
portion of the esophagus from the corrosive effect of the gas-
Smooth muscle 50 mm Hg
tric contents. When a food bolus is swallowed, relaxation of
esophagus 0
the LES is closely coordinated with the preceding motility
50 mm Hg events, such that it occurs just as the peristaltic wave reaches
0 the end of the esophagus (Figures 54–3 and 54–5). The careful
integration of peristalsis and sphincter relaxation is brought
Lower esophageal 50 mm Hg about by the combined activity of the vagus nerve and enteric
sphincter 0 nervous system, and is mediated by the release of nitric oxide
5 sec
from inhibitory nerves whose cell bodies lie in the myenteric
FIGURE 54–5 Secondary peristalsis triggered by distention plexus. Vasoactive intestinal polypeptide (VIP) within these
in the smooth muscle portion of the esophagus. Contraction nerves may also contribute to LES relaxation. In general, the
orad to the bolus is followed by a descending pressure wave that is contractile state of the LES at any given moment can be consid-
coordinated with lower esophageal sphincter opening. (Adapted ered to reflect a summation of both positive and negative
with permission from Biancani P. et al: Esophageal motor function. In: Textbook inputs. Even in healthy individuals, the LES relaxes transiently
of Gastroenterology, 4th ed. Yamada T, Alpers DH, Kaplowitz N, Laine L, Owyang C, from time to time independent of either swallowing or second-
Powell DW (editors). Philadelphia: Lippincott Williams and Wilkins, 2003.) ary peristalsis. Such relaxations may be required to facilitate
belching of swallowed air. However, in individuals with reflux
the other hand, if air is present in the esophagus, it induces disease, these transient relaxations occur more frequently and
opening of the upper esophageal sphincter, which is critical to allow reflux of the gastric contents into the distal esophagus.
belching, or the retrograde movement of air that is swallowed
along with food.
BASIC PRINCIPLES
Interneurons
OF GASTRIC MOTILITY
Sensory ROLE AND SIGNIFICANCE
neuron
As we have learned from previous chapters, the stomach is a
Myenteric plexus segment of the gastrointestinal tract in which important
Excitatory aspects of digestion and secretory function are initiated. How-
motor neuron ever, in addition to these functions, which are largely depen-
ACh NO/VIP dent on gastric secretion, the stomach also plays critical roles
Contraction Relaxation that depend on its motility properties.
of circular of circular First, the stomach can be considered as a homogenizer,
muscle muscle mechanically breaking down ingested food into an emulsion of
Distension
ORAD
low pH
CAUDAD
small particles with a vastly increased total surface area, thereby
amplifying the effects of digestion. Second, the stomach matches
FIGURE 54–6 Control of peristalsis by the enteric nervous food delivery to the digestive and absorptive capacity of more
system. Peristalsis can be triggered when a sensory nerve detects
distension or luminal acidity. Interneurons convey the signal to
distal segments of the gut. Under normal circumstances,
excitatory and inhibitory nerves above and below the site of the stomach allows the delivery of approximately 200 kcal/h into
stimulation, respectively. ACh, acetylcholine; NO, nitric oxide; VIP, the small intestine. To accomplish its reservoir function, the
vasoactive intestinal polypeptide. (Reproduced with permission from stomach exhibits remarkable pressure/volume characteristics,
Barrett P. KE: Gastrointestinal Physiology. New York: Lange Medical Books/ which accommodate the volume of the meal without allowing
McGraw-Hill, Medical Pub. Division, 2006.) significant reflux of the gastric contents back into the esophagus,
548 SECTION VIII GI Physiology
or forcing them prematurely into the duodenum. Distention of
the stomach also delivers important information to downstream
segments of the gastrointestinal tract, as well as contributing to
the signaling of satiety. Finally, the stomach possesses distinct
motility functions during the fasted state. The migrating motor
complex (MMC), a “housekeeping” motility pattern, sweeps
undigested materials or ingested foreign objects along the length
of the entire gastrointestinal tract, beginning at the stomach.
FUNCTIONAL ANATOMY OF
THE GASTRIC MUSCULATURE
The stomach is a highly distensible muscular sac with the larg-
est caliber of any intestinal segment. It can be divided into two
functional regions for considerations of motility (Figure 54–7).
The proximal stomach, consisting of the cardia, fundus, and
proximal portion of the body (corpus) of the stomach, serves
primarily as a reservoir and to move gastric contents to the
distal stomach. Tonic contractions of the proximal stomach
are additionally important in gastric emptying. The distal
stomach, on the other hand, consisting of the distal portion of
the body and the antrum, serves predominantly to grind and
pulverize the meal. Finally, the pylorus acts as a sphincter that
controls the amount and size of food particles that can exit the
stomach in the fed state. Conversely, full relaxation of the
pylorus is critical during the housekeeping MMC.
MUSCLE LAYERS
As elsewhere in the gastrointestinal tract, the muscle layers of
the stomach consist of a circular layer of smooth muscle
Lower esophageal sphincter
Fundus
Reservoir
(Tonic contractions)
Body Pacemaker
region
Antrum
Antral pump
Pylorus (Phasic contractions)
FIGURE 54–7 Regions of the stomach involved in motility
responses, and location of the gastric pacemaker. (Reproduced with
permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical
Books/McGraw-Hill, Medical Pub. Division, 2006.)
arranged circumferentially, and closer to the lumen,
and a longitudinal layer that is oriented along the length of the
organ. However, because the stomach is shaped as a sac rather
than a simple tube, these different muscle layers may assume
greater or lesser importance in the different functional regions
of the stomach, likely also important for specific motility pat-
terns. Thus, circular muscle is prominent throughout the
stomach, although it is notable that it is largely electrically iso-
lated from the circular muscle in the small intestine because of
the presence of a connective tissue septum at the level of the
pylorus. On the other hand, longitudinal muscle is more
prominent in the distal stomach, and these muscle fibers are
mostly continuous with those of the duodenum. There is also
a small region of obliquely oriented muscle fibers in the lesser
curvature of the stomach that is continuous with the gastroe-
sophageal junction, and restricted to the cardia. Finally, the
pylorus represents a specialized region of circular muscle at
the point where the caliber of the gastric lumen is sharply
reduced prior to entry into the duodenum; it serves as a
mechanical barrier to food exit that is also enhanced by a
folded, redundant mucosa.
The smooth muscle cells of the different functional regions
of the stomach also display distinctive contractile properties.
Most important for our discussion is the distinction between
phasic and tonic contractions. Some smooth muscles con-
tract and then relax in a matter of seconds, known as phasic
contractions, which are prominent in the distal stomach. Tonic
contractions, on the other hand, are sustained contractions
that are prominent in the proximal stomach, and may persist
for many minutes. Each type of contraction is important in
mediating the specific motility properties that are needed for
the function of each region of the stomach.
INNERVATION
The stomach is richly endowed with both intrinsic and extrin-
sic neural inputs. The major extrinsic pathways are parasym-
pathetic and contained within the vagus nerve. Most vagal
efferents that terminate in the stomach are stimulatory, cho-
linergic nerves although a few nerves with high thresholds for
activation are inhibitory, releasing VIP and nitric oxide as
their major neurotransmitters. Mechanosensitive and chemo-
sensitive vagal afferents are also critical for the control of
motility functions. These activate sites in the nucleus tractus
solitarius of the dorsal motor nucleus in the brain. In a more
limited fashion, sympathetic innervation arrives at the stom-
ach by way of the splanchnic nerve, and these nerves release
noepinephrine as a postganglionic inhibitory neurotransmit-
ter at the level of enteric ganglia. The physiological role of
sympathetic innervation to the stomach is relatively unclear,
but presumed to be minor compared with vagal influences.
On the other hand, sympathetic influences may contribute to
a decrease in gastric motility during times of threat.
Intrinsic innervation via the enteric nervous system is also
critically important to the full expression of gastric motility
 CHAPTER 54 Intestinal Motility 549

responses. Indeed, many of the stereotypical motility responses whereas the duodenum has a BER of 12 cpm. This presumably
of the stomach are largely, if not wholly, independent of central reflects the presence of dominant and separate pacemakers in
input. Myenteric neurons of the stomach also provide for each distinct segment, which then relay electrical information
coordination of gastric motility functions with those of the throughout the segment that they control via the remaining
more distal segments of the gut, particularly during fasting network of interstitial cells of Cajal.
periods. These nerves also communicate with the pacemaker
cells of the intestine, known as interstitial cells of Cajal,
located within the circular muscle layers of the stomach and RECEPTIVE RELAXATION
proximal gut. This communication establishes the maximal
The ability of the stomach to relax as its volume increases is
rate at which contractions of the tissue can occur if an addi-
essential to its reservoir function. The process—receptive
tional excitatory signal is also received, which is known as the
relaxation—results in a drop in gastric pressure immediately
basal electrical rhythm (BER).
after eating that persists until all solids have been emptied
from the stomach. The process involves vagal input coincident
with food intake, vagovagal reflexes, and intrinsic reflexes
FEATURES OF GASTRIC MOTILITY mediated wholly within the wall of the stomach (Figure 54–9).
Vagovagal and intrinsic reflexes are triggered by the activation
BASAL ELECTRICAL RHYTHM of mechanosensitive nerve endings within the stomach wall.
In turn, ACh released by vagal pathways acts presynaptically
The BER refers to waves of rhythmic depolarization of intesti-
to release additional neurotransmitters that actively relax the
nal smooth muscle cells, which originate at a specific point
gastric smooth muscle layers, particularly in the proximal part
and then are propagated along the length of the gastrointesti-
of the stomach. Both VIP and nitric oxide have been impli-
nal tract. The pacemaker potentials originating in this region
cated in this response.
determine the contractile parameters of the stomach as a
Gastric tone may also be affected by feedback signals com-
whole—namely, the maximal frequency of contractions, their
ing from more distal segments of the gastrointestinal tract.
propagation velocity, and the direction in which they propa-
For example, distension of the duodenum or colon, or an
gate. For the stomach, the waves appear to begin at a point in
increase of fat or protein in the duodenum or ileum, results
the body along the greater curvature of the stomach, and then
in a decrease in the tone of the gastric fundus. In this way,
sweep across the stomach toward the pylorus (Figure 54–7). It
gastric emptying is retarded until the duodenum is able to
should also be emphasized that the BER represents only the
process additional nutrients. The response involves reflexes
maximal rate of contraction of the stomach or indeed of any
of the enteric nervous system, as well as CCK by binding to
other segment of the gastrointestinal tract. The waves of depo-
CCK-A receptors expressed on vagal sensory afferents.
larization that occur in response to the pacemaker activity of
Gastric distension, conversely, signals forward to more distal
the network of interstitial cells of Cajal are not of sufficient
segments to ready them for the arrival of the meal. Probably
magnitude to initiate action potentials in the smooth muscle.
the best known of these reflexes is the gastrocolic reflex,
Rather, it is only when the release of stimulatory neurotrans-
which may induce the need to defecate shortly after ingesting
mitters from enteric nerve endings is superimposed on these
a meal.
waves of depolarization that an action potential may occur,
leading in turn to contraction of the smooth muscle
(Figure 54–8). Various patterns of motility can thus be accom- MIXING AND GRINDING
plished depending on whether the stomach is filled with a
meal, or is in the fasted state. The primary motility pattern of the distal portion of the
The BER differs in the various intestinal segments. For exam- stomach during the fed state consists of rapid phasic contrac-
ple, in the stomach the BER is approximately 3 cycles/min (cpm), tions that occur circumferentially, and which can even

Stimulated
0 Resting BER
Membrane
potential
(mV)
FIGURE 54–8 Basal electrical rhythm
established by the gastric pacemaker. Note that
−70 waves of depolarization initiated by the pacemaker
20 s
are insufficient to trigger contractions unless these
5 are superimposed with a contractile stimulus.
Tension (Modified with permission from Barrett KE: Gastrointestinal
(g) Physiology. New York: Lange Medical Books/McGraw-Hill, Medical
0 Pub. Division, 2006.)
550 SECTION VIII GI Physiology
Vago-vagal
reflex
VIP NO
NO VIP
Relaxation
ACh
h
tc
re
St
Stretch
Fat
Protein
CCK
FIGURE 54–9 Intrinsic and vagovagal reflexes involved in
receptive relaxation of the stomach. The figure indicates that
signals triggered by nutrients in the duodenal lumen, or duodenal
distension, also result in relaxation of the gastric fundus. ACh,
acetylcholine; NO, nitric oxide; VIP, vasoactive intestinal polypeptide;
CCK, cholecystokinin; DVC, dorsal vagal complex. (Reproduced with
permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical
Books/McGraw-Hill, Medical Pub. Division, 2006.)
FIGURE 54–10 Gastric motility patterns
contributing to mixing, grinding, and sieving of
gastric contents. 1) A circumferential contraction, A,
sweeps toward the pylorus resulting in anterograde
and retrograde propulsion of material. 2) As
contraction A subsides, a second contraction, B, mixes
contents further. 3) Contraction B is sufficient to cause
transient and partial opening of the pylorus, allowing
particles smaller than 1 mm to exit the stomach.
Pylorus
Larger particles are propelled back into the stomach
to be further dispersed by contraction C. 4) Further
cycles of contraction against a closed pylorus
continue mixing and grinding until all of the meal is
emptied from the stomach. (Reproduced with permission
from Barrett KE: Gastrointestinal Physiology. New York: Lange
Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
occlude the lumen (Figure 54–10). The contractions proceed
DVC
from the gastric pacemaker region and move toward the
pylorus in a peristaltic pattern. As these waves of contraction
begin, they force the gastric contents toward the outlet of the
stomach. However, as the velocity of the peristaltic wave
increases, it overtakes all but the smallest particles in the gas-
tric lumen, and thus the majority of the meal is forced back-
wards (retropulsion), mixing the gastric contents with the
gastric juice and mechanically reducing the size of the food
particles.
GASTRIC EMPTYING AND
THE ROLE OF THE PYLORUS
When the stomach is filled with a meal, the pylorus remains
closed for prolonged periods with only intermittent openings
that allow small food particles (less than 1–2 mm) to enter the
duodenum. The pylorus is regulated by both inhibitory and
excitatory vagal pathways as well as ascending and descend-
ing intrinsic reflexes, and its function is clearly regulated
independently of contractions of the gut segments on either
side. Nitric oxide has been identified as a key mediator of
pyloric relaxation, arising from both vagal and intrinsic path-
ways, whereas opioids released from vagal efferents and CCK
have been implicated in contractions. The presence of nutri-
ents, hypertonicity, or acid in the duodenum also causes the
pylorus to close, with ACh and 5-hydroxytryptamine identi-
fied as mediators.
Emptying of the stomach involves both tonic contractions
of the proximal region and phasic distal contractions. Extrin-
sic innervation, working together with the enteric nervous
system, is vital for normal emptying, with 5-hydroxytryptamine
1 2
Pylorus Gastric
Pylorus contents
Gastric
contents
Contraction B
Contraction A
Contraction A
3 4
Pylorus
Contraction C Contraction D
Contraction B
Contraction C

being identified as a key mediator. 5HT1 receptors have been
implicated in delaying gastric emptying while 5HT3 receptors
increase it. CCK also delays gastric emptying. The rate of gas-
tric emptying also depends on both the physical state of the
contents and their chemical characteristics. Inert liquids empty
most rapidly. If the liquid contains nutrients, a rapid initial
phase is followed by slowed exit, apparently reflecting feed-
back from the small intestine. The rate of emptying also
depends on the caloric density and osmolarity of the contents.
Emptying of solids from the stomach is slower yet, with a half-
time of approximately 1–2 hours. Moreover, emptying of sol-
ids from the stomach does not begin immediately, but occurs
only after a lag phase of up to 1 hour during which retropul-
sion and mixing take place.
GASTRIC MOTILITY DURING FASTING
In the period in between meals, the stomach, in common
with more distal segments of the gastrointestinal tract,
undergoes the stereotypical pattern of motility known as the
MMC. In the absence of feeding, cycles of motility lasting
approximately 100 minutes, and consisting of three phases,
begin in the stomach and are propagated aborally
(Figure 54–11). Phase I is characterized by quiescence. Dur-
ing phase II, contractile activity increases, but with irregular
contractions that fail to propel luminal contents. Finally,
phase III involves a 5–10-minute period of intense, luminally
occlusive contractions that sweep from the body of the stom-
ach to the pylorus, and from there move into the duodenum.
During this time, the pylorus opens fully in normal subjects,
allowing any indigestible residues to be cleared. This house-
keeping function is important for intestinal health, since in
its absence, large quantities of indigestible materials called
bezoars may accumulate and even obstruct the lumen, par-
ticularly in the stomach.
Plasma motilin concentration, pg/ml
800
Feeding
600
400
200
0 complex as assessed in a dog, followed by
Gut motor pattern
Time intervals, 1 hr
CHAPTER 54 Intestinal Motility 551
Some aspects of neurohumoral control of the MMC are
understood. For example, the onset of phase III activity is
independent of either parasympathetic or sympathetic input,
but rather is correlated with levels of plasma motilin
(Figure 54–11). However, the trigger for cyclical release of this
hormone from the duodenal mucosa is not known, other
than the fact that release is suppressed by feeding. Neverthe-
less, it enhances propulsive motility via both direct and
indirect actions, the latter involving the release of ACh,
5-hydroxytryptamine, and nitric oxide. Moreover, while phase
III can occur in the absence of vagal input, impulses from the
vagus can amplify the response. Similarly, phase II of the MMC
is abolished by vagotomy. The MMC is also reduced during
sleep, and slowed by stress.
VOMITING
Vomiting primarily results in evacuation of the gastric con-
tents, and reflects the coordinated interaction of neural,
humoral, and muscular phenomena. Vomiting may be
prompted by both central and peripheral triggers
(Figure 54–12), but pivotally requires the involvement of cen-
tral brain regions to coordinate the responses required. A
chemoreceptor trigger zone, located in the area postrema of
the medulla, receives input from cortical, oral, vestibular, and
peripheral afferents. In addition, the blood/brain barrier in
this region is relatively leaky. This means that the chemorecep-
tor trigger zone can sample chemical constituents of both the
blood and cerebrospinal fluid. Various stimuli can lead to both
nausea (the sensation that vomiting is imminent) and actual
vomiting, such as endocrine changes in pregnancy, noxious
odors, visual stimuli, somatic pain, or unpleasant tastes.
Peripheral afferents can also trigger a vomiting response, such
as when irritants are present in the gastric lumen, or if the
intestine is obstructed. Some vagal afferents originating in the
FIGURE 54–11 The migrating motor
the motility pattern in the fed state. Each
Gastric antrum
antral phase III complex is accompanied by
Upper jejunum an increase in plasma motilin, whereas motilin
Mid-intestine release is suppressed after feeding. (Adapted from
Itoh Z, et al. Changes in plasma motilin concentration and
gastrointestinal contractile activity in conscious dogs.
Am J Dig Dis. 1978;23(10):929–935.)
552 SECTION VIII GI Physiology

Programmed Pain
Pharyngeal vomiting Sights
stimulation response Anticipation

Glossopharyngeal Higher
nerve centers

Nucleus Brain stem

tractus solitarius vomiting center

Vagus nerve Area postrema Cerebellum

chemoreceptor
trigger zone

Labyrinth
Gastric
mucosa
Drugs
FIGURE 54–12 Neural pathways eg, opiates, chemotherapy
leading to the initiation of vomiting in Hormones Motion
response to various stimuli. (Reproduced with eg, pregnancy Vertigo
permission from Barrett KE, Barman SM, Boitano S, Ipecac
Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. Cytotoxic drugs
McGraw-Hill Medical, 2009.)
Irritants

stomach, and presumably linked to chemoreceptors, project to
the area postrema.
A second brain region, the nucleus tractus solitarius, also
contributes to the emetic cascade, particularly following vagal
activation (Figure 54–12). This region receives inputs from the
area postrema, abdominal vagus, and labyrinths, and in turn
coordinates the motor responses required, which are a stereo-
typical program of somatic muscle actions. First, the thoracic,
diaphragmatic, and abdominal muscles contract concurrently
against a closed glottis, resulting in the phenomenon of retch-
ing. The high positive intra-abdominal pressure also forces the
gastric contents into the esophagus. The brain then coordi-
nates the synchronous contraction of inspiratory and expira-
tory muscles, resulting in a reversal of the thoracic pressure
gradient. This high positive thoracic pressure acts in turn to
drive expulsion of the vomitus. Simultaneously, respiration is
suppressed, and movement of laryngeal and pharyngeal struc-
tures prevents aspiration and, usually, passage of vomitus into
the nasal cavity.
Intestinal motility is also regulated during vomiting. The
BER is suspended and replaced by bursts of electrical activity
that propagate orally. These result in a motility pattern referred
to as a retrograde giant contraction, or the retroperistaltic
contractile complex, that moves the gastric contents up and out
of the esophagus. Despite the autonomy of the enteric nervous
system in producing normal patterns of gastric and esophageal
motility, the retrograde propulsion seen during emesis is
entirely dependent on input from extrinsic nerves, coordinated
by the brain centers that also regulate the functions of somatic
muscles that support vomiting, as described earlier.
BASIC PRINCIPLES OF
INTESTINAL MOTILITY
ROLE AND SIGNIFICANCE
IN THE SMALL INTESTINE
The primary role of the small intestine is to digest the vari-
ous components of the meal and to absorb the resulting
nutrients into the bloodstream or lymphatic system. The
motility patterns observed in the small intestine are pro-
foundly altered by eating, with the duration of such changes
depending on the caloric load. During the fed state, the motil-
ity patterns in the small intestine are not designed primar-
ily to propel the intestinal contents aborally, but rather to
mix them with digestive secretions and prolong their expo-
sure to the absorptive epithelium. The speed with which the
contents are propelled also varies along the length of the
small intestine. Movement is fastest in the duodenum and
jejunum, providing for rapid mixing and propulsion of the
contents both orally and aborally. Motility then slows in the
ileum, providing additional time for the absorption of slowly

permeable nutrients, and particularly, lipids. Then, once the
meal is digested and absorbed, the small intestine converts to
the MMC to expel undigested residues through the small
intestine and into the colon.
ROLE AND SIGNIFICANCE IN THE COLON
The functions of the colon are quite distinct from those of the
small intestine, serving primarily to extract and reclaim water
from the intestinal contents, and process the feces for elimina-
tion. As a result, even in the fasted state, the motility functions
of the colon are considerably more biased toward mixing the
contents and retaining them for prolonged periods, and the
colon does not participate in the MMC. On the other hand,
periodically, large propulsive contractions sweep through the
colon, transferring its contents to the rectum and ultimately
promoting the urge to defecate.
FUNCTIONAL ANATOMY
MUSCLE LAYERS
The layer of circular muscle found closest to the mucosa, over-
laid by a longitudinal muscle layer, produces the stereotypical
motility patterns of the small intestine. A thin layer of muscle
sandwiched between the mucosa and submucosa, the muscu-
laris mucosa, also confers specific motility functions on
mucosal structures, such as the villi.
The functions of the circular and longitudinal muscle lay-
ers are closely integrated by electrical coupling through gap
Sigmoid colon
Rectosigmoid junction
Rectum
Rectal valves
Muscle layers
making up internal Internal anal sphincter
and external
anal sphincters
External anal sphincter
Anal canal
CHAPTER 54 Intestinal Motility 553
junctions, and by the activity of interstitial cells of Cajal.
These latter pacemaker cells undergo rhythmic cycles of
depolarization, and dictate the BER, or slow waves, that ulti-
mately control the rate and locations of phasic contractions of
the smooth muscle.
The large intestine also contains both circular and longitu-
dinal muscle layers that regulate its motility, but the ana-
tomic arrangement of these differs somewhat from that seen
in the small intestine. In the ascending, transverse, and
descending colon, the circular muscle layer is overlaid by
three long nonoverlapping bands of longitudinal muscle ori-
ented at 120° to each other, known as the taenia coli. Electri-
cal coupling between the circular muscle and taenia coli is
less effective than that between the corresponding muscle
layers in the small intestine, which likely contributes to less
effective propulsive motility in the colon. The circular mus-
cle layer is also contracted intermittently to divide the colon
into functional segments known as haustra. Note that the
haustral segments are not permanent structures, however,
and thus they can be smoothed out to permit propulsion of
the colonic contents.
In the sigmoid colon and rectum, the intestine becomes
completely enveloped by longitudinal muscle that is impor-
tant to the specialized functions of this region, which include
serving as a reservoir and participating in defecation. The
lumen of the rectum is also partially occluded by transverse
folds, again formed by muscular contraction, which act as
shelves to retard the passage of fecal material (Figure 54–13).
Finally, the most distal portion of the gastrointestinal tract,
the anal canal, is a specialized region that contains both
smooth and striated muscles in its walls.
FIGURE 54–13 Anatomy of the rectum and
anal canal. (Reproduced with permission from Barrett KE:
Gastrointestinal Physiology. New York: Lange Medical Books/
McGraw-Hill, Medical Pub. Division, 2006.)
554 SECTION VIII GI Physiology
ENTERIC NERVOUS SYSTEM
The primary determinant of motility function in both the
small and large intestines derives from the activity of intrinsic
neural circuits. The number of intrinsic nerves vastly exceeds
that of extrinsic inputs, and the role of the latter is normally
felt to be restricted largely to modulating motility patterns
established by the “little brain” of the enteric nervous system.
Enteric nerves are responsible for both contraction and relax-
ation. The major stimulatory neurotransmitters include ACh,
neurokinin A, and substance P, whereas the inhibitory nerves
express VIP and also produce nitric oxide on activation.
There is also an abundant supply of sensory afferents that
respond to the physicochemical characteristics of the luminal
contents.
Modulatory influences of extrinsic nerves derive from a
variety of sources depending on the intestinal segment in
question. The vagus (parasympathetic) and splanchnic
(sympathetic) nerves innervate the small intestine, ileoce-
cal valve, and proximal colon. The pelvic nerves, on the
other hand, are the conduits of extrinsic input to the
remainder of the colon and the internal anal sphincter.
Finally, the pudendal nerves provide input from the sacral
region of the spinal cord to the external anal sphincter and
the muscle layers of the pelvic floor. In fact, unlike the other
gastrointestinal regions discussed earlier, voluntary input
to these latter structures is vital to their function. The abil-
ity to contract the external anal sphincter and pelvic floor
muscles, a behavior learned during toilet training, allows
the deferral of defecation until a time when it is socially
convenient.
SPHINCTERS
The passage of contents along the length of the small intestine
and colon is also regulated by sphincters. The ileocecal valve,
or junction, reflects activity of the circular muscle layer. The
primary function of the ileocecal valve is to limit reflux of
colonic contents into the ileum. The elimination of waste
matter from the colon is under the control of the internal and
external anal sphincters. The internal anal sphincter consists
of a thickened band of gastrointestinal circular muscle
(Figure 54–13). This sphincter supplies approximately
70–80% of the tone of the anal canal at rest, and its regulation
is entirely autonomous. If the rectum is suddenly distended,
the sphincter relaxes and then contributes only 40% of anal
tone, with the remainder supplied by the external anal
sphincter (which is composed of striated muscle). At the
same time, the external anal sphincter pressure is increased.
This rectoanal inhibitory reflex, initiated by rectal disten-
sion, thus allows for efficient defecation while preventing
accidental leakage. After a short period of time, however, the
internal anal sphincter accommodates to the new rectal vol-
ume and regains its tone, unless defecation can conveniently
be completed.
FEATURES OF
INTESTINAL MOTILITY
FED VERSUS FASTED
PATTERNS OF MOTILITY
For the small intestine, there is a marked distinction between
motility observed in the postprandial versus fasting periods;
however, colonic motility has far less temporal association
with the ingestion of a meal. These differences are mirrored by
the times taken for luminal contents to transit these two
intestinal segments. In the small intestine, substances move
from the mouth to the ileocecal valve in a little under 2 hours in
healthy adults, on average, with transit occurring most rapidly
proximally. Transit is slowed in proportion to the number of
calories presented to the intestine. In the colon, on the other
hand, transit from the cecum to the rectum may take 1–2 days
on average, with considerable interindividual variability.
During fasting, the small intestine exhibits the MMC. When
the meal has emptied from the small intestine, the MMC
resumes with its characteristic three phases (Figure 54–14). As
in the stomach, the purpose of the MMC, and of phase III in
particular, appears to be to sweep the intestine clear of any
remaining residues of the meal. The MMC may additionally
play a role in limiting reflux of colonic contents into the ileum
since it does not propagate into the colon in humans.
After a meal is ingested, motility events in the small intes-
tine become more frequent. The fed pattern of motility rests
on the BER, generated by the intestinal pacemaker and propa-
gated to surrounding smooth muscle cells. As in the stomach,
however, the basal rhythm supplies only the nodes at which
contractions can occur at any given moment, because the
rhythmic changes in membrane potential that are induced in
D1
D2
J1
J2
J3
30 min
FIGURE 54–14 Migrating motor complexes in the duodenum
and jejunum as recorded from a fasting human subject by
manometry. D1, D2, J1, J2, and J3 indicate recording points along the
length of the duodenum and jejunum. Note that the intense
contractions occurring rhythmically during phase III propagate
aborally. (Reproduced with permission from Soffer EE et al: Prolonged ambulatory
duodeno-jejunal manometry in humans: normal values and gender effect. Am J
Gastroenterol 1998;93:1318–1323. Copyright American College of Gastroenterology.)

the muscle cells are insufficient to cause contraction. Rather, it
is only when the effects of neurotransmitters are superimposed
on this rhythm that action potentials can take place. The result
is a series of intermittent phasic contractions occurring along
the length of the small intestine, peaking 10–20 minutes after
eating. ACh from the enteric nervous system is a critical medi-
ator of such effects, with any role for hormonal mediators
much less clear.
MIXING AND SEGMENTATION
During the fed state, the primary motility events serve to mix
the contents, and to propel them slowly, if at all. An isolated
contraction in the absence of others either proximal or distal
to it will have the effect of mixing the contents of the lumen in
the immediate vicinity of the contraction (Figure 54–15).
Another common pattern is referred to as segmentation. Seg-
menting contractions serve to move intestinal contents back
and forth within a short segment of bowel. The complex pat-
terns of motility in the small intestine after a meal are the
result of the almost autonomous effects of the enteric neural
circuitry, and presumably reflect a stereotypical “programmed”
response to a given set of physiological conditions.
PERISTALSIS
Peristalsis produces aboral propulsion in both the small intes-
tine and colon. It is a motility response that occurs in response
to deformation of the mucosa, either via the mechanical effects
Isolated contraction
Segmentation
Peristalsis
Contraction
Relaxation
FIGURE 54–15 Patterns of intestinal mixing and propulsion.
An isolated contraction moves contents both orally and aborally.
Segmentation mixes contents over a short length of intestine, as
indicated by the time sequence from left to right. In the diagram on
the left, the vertical arrows indicate the points at which the next set
of contractions is initiated. Finally, peristalsis, which involves both a
contraction and a relaxation, propels the luminal contents aborally.
(Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H:
Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
CHAPTER 54 Intestinal Motility 555
of passage of the food bolus along the wall of the gut or sec-
ondary to intestinal distension. Rapid stretch of the intestine is
most effective in triggering peristalsis.
As in the esophagus, where peristalsis is important in
moving the bolus from mouth to stomach, intestinal peri-
stalsis involves the influences of both an ascending contrac-
tion and a descending relaxation (Figure 54–15). Activation
of stretch and possibly other mechanoreceptors in the
mucosa secondarily induce the release of 5-HT and calci-
tonin gene–related peptide. On the proximal side of the
bolus, the circular muscle shortens and the longitudinal
muscle relaxes, pushing the bolus forward. These responses
have been attributed to the action of ACh and substance P
from enteric nerve endings. On the distal side, the bolus is
received by a segment of intestine of increased caliber,
brought about by shortening of the longitudinal muscle and
relaxation of the circular muscle. These responses relate to
the activity of VIP and nitric oxide.
COLONIC MOTILITY
The motility patterns of the colon are primarily concerned
with mixing the contents and retaining them for a sufficient
period to allow optimal salvage of the fluid utilized during the
digestive process. The colon has the capacity to reabsorb even
unusually large quantities of fluid, provided adequate contact
time with the mucosa occurs. However, periodically the colon
also engages in a propulsive motility pattern that essentially
moves the majority of the colonic contents into the rectum. In
turn, this induces the need to defecate, which will be dealt
with later.
During mixing, the colon shuttles contents back and forth
between its haustra, and progressively propels contents from
one haustra to the next in a motility pattern referred to as seg-
mental propulsion. These patterns are accomplished by two
types of contraction that have been characterized in the colon,
short- and long-duration contractions. Short-duration con-
tractions arise in the circular muscle, and are stationary pres-
sure waves lasting approximately 8 seconds on average, which
effect local mixing. Long-duration contractions, on the other
hand, last for 20–60 seconds and may be stationary or may
propagate for a short distance, and are attributed to contrac-
tion of the longitudinal muscles of the taenia coli. Propagating
contractions account for segmental propulsion.
High-amplitude propagating contractions are distinct
from the motility patterns just described. They propagate
exclusively aborally, and provide for mass movement of the
feces over long distances. While they precede the urge to def-
ecate, they in fact occur about 10 times per day, and are associ-
ated with rising in the morning and with eating. These
contractions originate in the cecum and sweep throughout the
colon to the rectum, also resulting in relaxation of the internal
anal sphincter. The propagation of these contractions is likely
mediated by both cholinergic and neurokinin-dependent
pathways.
556 SECTION VIII GI Physiology
DEFECATION
Defecation is the process of elimination of solid wastes from
the gastrointestinal tract, and it involves several structures in
and around the rectum and anus. Filling of the rectum causes
relaxation of the internal anal sphincter via the release of VIP
and nitric oxide from intrinsic nerves in the rectoanal inhibi-
tory reflex, but this response is offset by a simultaneous action
to increase the tone of the external anal sphincter. Overall, this
reflex can permit efficient defecation while preventing leak-
age. The portion of rectal contents that enters the anal canal is
also identified as being gaseous, solid, or liquid, thereby initi-
ating appropriate activity of the external anal sphincter to
retain each of these, or to permit voluntary expulsion.
When defecation is desired, on the other hand, adopting a
sitting or squatting position changes the relative orientation of
the intestine and surrounding muscular structures to straighten
the pathway for fecal exit. This is also assisted by relaxation
of the puborectalis muscle, which results in a less acute rec-
toanal angle. Rectal contraction then produces the propulsive
force to move the feces out of the body. Evacuation is enhanced
by simultaneous contraction of the rectus abdominus, dia-
phragm, and other levator ani muscles, which increases
intra-abdominal pressure. All of these events occur whether
solid (in health) or liquid (in disease) feces are expelled,
although less force is obviously needed to evacuate liquid feces.
On the other hand, the voluntary expulsion of flatus involves
the contractile functions listed, but the puborectalis muscle
does not relax and there is no change in the rectoanal angle.
This allows the flatus gas to be forced past the acutely angled
anorectum without the simultaneous loss of feces.
CLINICAL CORRELATION
A 90-year-old, bedridden male resident in a nursing
home is given his daily oral medications (pills). He later
regurgitates a bedtime snack and complains of a feeling
that the pill “did not go all the way down,” so is taken to
the emergency room. On physical examination, he is
found to be somewhat underweight, agitated, and clearly
distressed. He is also coughing and retching. The aide
that accompanied him reports that this situation has
occurred previously. A gastroenterologist is called and
performs an upper endoscopy, whereupon the pill can
be seen lodged in the mid-esophagus. It is removed via
the esophagus and the patient’s symptoms slowly subside.
The gastroenterologist advises the nursing home aide
that the patient should be given only semisolid food in
future, and that any needed pills should be crushed and
mixed with apple sauce to administer them to the patient.
Despite these measures, the patient’s problems worsen,
and he is eventually admitted to the hospital suffering
from pneumonia.
Difficulty in swallowing is referred to as dysphagia, and
can result from abnormalities in any of the components of
the swallowing reflex or the anatomic structures involved.
For example, abnormalities of the tongue can result in dys-
phagia because the bolus cannot be propelled backward
toward the pharynx with sufficient force. In general, dys-
phagia can be considered as arising from either the orophar-
ynx and striated muscle region of the esophagus or the
smooth muscle portion of the esophagus, corresponding to
the different innervation and mechanisms of sensation and
control in these two areas. Likewise, dysphagia can result
from either structural or functional causes. Dysphagia is a
common medical problem that is especially frequent in the
elderly, and associated with much distress, as well as the risk
of aspiration, choking, and malnutrition. It is estimated that
up to 13% of hospitalized patients and as many as 60% of
nursing home residents have feeding problems, most of
which are the result of oropharyngeal dysphagia. All
patients with dysphagia will experience problems with solid
food, and may have varying degrees of difficulty swallowing
liquids as well, depending on the severity of the underlying
cause. Structural causes of dysphagia extend to diverticula,
or outpouchings of the pharyngeal or esophageal wall in
which food can become trapped, or to various forms of
obstruction. The latter include mucosal or muscular rings
that circumferentially occlude a portion of the esophageal
lumen. These can occur in response to long-standing tissue
injury secondary to gastroesophageal reflux disease
(GERD); the inflammation eventually leads to scarring and
fibrosis that may occlude the lumen. Esophageal tumors
can also impede passage of esophageal contents. Functional
causes of dysphagia relate to either neurological control of
the oropharyngeal phase of swallowing, peristalsis, and
esophageal sphincter relaxation or defects in the muscle
layers themselves. Treatment of dysphagia depends on the
underlying cause. When there are structural abnormalities,
surgery to repair diverticula, cut overly tight muscles, or
remove an obstructing tumor can often bring some relief.
Mechanical dilation of a stricture (abnormal narrowing) is
also attempted, with varying degrees of success. In the case
of functional disorders, on the other hand, effective therapy
usually depends on whether treatment is available for the
underlying disorder, and surgery is much less helpful.
CHAPTER SUMMARY
■ Regulation of swallowing involves somatic neurotransmission
in the upper third of the esophagus, composed of striated
muscle, and autonomic regulation via the vagus and enteric
nervous system in the lower two thirds, composed of smooth
muscle. Swallowing is initiated voluntarily, but thereafter
reflects a complex integration of regulatory influences
coordinated by the swallowing center in the brain.
■ Two sphincters, normally closed, regulate the movement of the
bolus into and out of the esophagus. The upper esophageal
 CHAPTER 54 Intestinal Motility 557

sphincter is opened in concert with pharyngeal motility. The 2. A 50-year-old man who is markedly overweight comes to his
LES opens to allow the bolus to enter the stomach, coordinated primary care physician complaining that he suffers nightly from
with esophageal motility. a burning sensation in his chest after retiring, which is made
■ The stomach serves to receive the meal from the esophagus, worse if he has had a snack close to bedtime. Which of the
and it displays motility functions that both initiate the process following would be the most appropriate treatment for this
of digestion and control the delivery of nutrients to more distal patient if his symptoms are not resolved by weight loss and
segments. eliminating nighttime meals?
■ Receptive relaxation of the proximal stomach allows the A) cholinergic agonist
stomach to function as a reservoir and ensures that the B) smooth muscle relaxant
pressure within the stomach changes little as its volume C) nitric oxide donor
expands to receive the meal. D) nicotinic agonist
■ The distal stomach uses phasic contractions to grind the E) proton pump inhibitor
meal, moving only the smallest particles to the pylorus. 3. In an experiment, a balloon is inserted into the stomach of a
■ Emptying of the stomach involves tonic contractions of the human volunteer and gradually inflated while intraluminal
proximal portions, and depends on both the physical and pressures are monitored. Although the volume of the balloon
chemical characteristics of the meal. Liquids empty most increases considerably, pressures remain relatively constant.
rapidly; solids empty only after a lag phase. Nutrients and the This remarkable pressure–volume relationship is thought to
osmolarity of the meal feed back to retard gastric emptying involve release of which of the following patterns of
once they reach the small intestine via both neural and neurotransmitters?
humoral mechanisms.
Vasoactive Intestinal
■ Phase III of the MMC results in large contractions that
Acetylcholine Polypeptide Nitric Oxide
propagate aborally, while the pylorus relaxes maximally,
allowing the exit of even large particles. This phase of the A) Yes Yes Yes
MMC is related to release of the GI hormone motilin.
B) Yes Yes No
■ Motility patterns in the small and large intestines serve not
only to propel intestinal contents, but also to mix them with C) No Yes Yes
enzymes and other digestive juices, and to retain them in a D) No Yes No
given segment long enough for optimal absorption to occur.
E) Yes No Yes
■ The colon serves predominantly salvage and reservoir
functions, with slow transit of contents along its length and
marked dehydration of luminal contents. 4. A mother brings her 2-year-old child to the emergency room,
■ Movement of colonic contents out of the body is controlled by distressed because he has swallowed a quarter while the family
the internal and external anal sphincters, under involuntary was eating dinner at a restaurant. The physician reassures her
and voluntary control, respectively. that the quarter, which can be plainly seen in the stomach by
fluoroscopy, will eventually pass in the stool. What physiological
■ Periodically, large propulsive contractions sweep through the
condition or response will be required to permit exit of the
colon and precede the urge to defecate.
quarter from the stomach?
A) receptive relaxation
B) fasting
STUDY QUESTIONS C) eating another meal
1. In a study of the control of esophageal motility, a scientist instills D) mixing and grinding by the stomach
a small amount of dilute hydrochloric acid into the upper third of E) relaxation of the LES
the esophagus of a human volunteer, using an endoscope. This
treatment is most likely to produce which of the following
responses?
A) peristalsis
B) retroperistalsis
C) esophageal spasm
D) relaxation of the upper esophageal sphincter
E) no response
558 SECTION VIII GI Physiology

5. Four medical students studying for their physiology final develop 6. Which of the following substances is not involved in mediating
headaches and take either regular or enteric-coated aspirin with the fed pattern of intestinal motility?
either milk or water (enteric-coated pills will not dissolve until A) ACh
the pH is neutral). Assuming headache relief is proportional to B) VIP
blood aspirin concentrations, place the following conditions in C) 5-hydroxytryptamine (serotonin)
order of headache relief (from fastest to slowest): D) nitric oxide
1. regular aspirin with water; E) motilin
2. enteric-coated aspirin with water;
3. regular aspirin with milk;
4. enteric-coated aspirin with milk.
A) 1 > 2 > 3 > 4
B) 4 > 3 > 2 > 1
C) 1 > 3 > 2 > 4
D) 2 > 4 > 1 > 3
E) 2 > 4 > 3 > 1

Functional Anatomy
of the Liver and Biliary
System
Kim E. Barrett
O B J E C T I V E S
■ Understand the role of the liver in whole body homeostasis and the structural
features that subserve its functions.
■ Understand the functions of bile secretion and the anatomy of the biliary
system.
■ Describe the unusual circulatory features of the liver and the relationship
of blood flow to bile flow.
■ Identify the parenchymal and nonparenchymal cell types of the liver, their
anatomic relationships, and their respective functions.
OVERVIEW OF THE LIVER AND
BILIARY SYSTEMS AND THEIR
FUNCTIONS
The liver is the largest organ in the body, and conducts a myr-
iad of vital metabolic and excretory functions. In addition, by
virtue of its circulatory relationship to the absorptive surface
of the gastrointestinal tract, the liver is the initial site where
most ingested nutrients, and other substances entering via
the gastrointestinal tract, are processed by the body. Thus, the
liver is a gatekeeper that can process useful substances while
detoxifying orally absorbed substances that are potentially
harmful.
METABOLISM AND DETOXIFICATION
The liver contributes in a pivotal way to the biochemical status
of the body as a whole. It is beyond the scope of this text to
provide a comprehensive analysis of all of the metabolic func-
tions of the liver. Instead, we will focus our discussion on
broad categories of metabolic functions of the liver that are
relevant to the function of the gastrointestinal system, or are of
particular importance to whole body homeostasis.
First, the liver performs four specific functions in carbohy-
drate metabolism: glycogen storage, conversion of galactose and
fructose to glucose, gluconeogenesis, and the formation of
Ch55_559-564.indd 559
55
C H A P T E R
many important biochemical compounds from the intermedi-
ate products of carbohydrate metabolism. Many of the sub-
strates for these reactions derive from the products of
carbohydrate digestion and absorption that travel directly to the
liver from the gut, as will be described in more detail in Chapter
58. As a consequence, the liver plays a major role in maintaining
blood glucose concentrations within normal limits, particularly
in the postprandial period (see Chapter 69). The liver removes
excess glucose from the blood and returns it as needed, in a pro-
cess referred to as the glucose buffer function of the liver. The
liver also contributes in a major way to fat metabolism. While
many aspects of lipid biochemistry are common to all cells of
the body, others are concentrated in the liver. Specifically, the
liver supports an especially high rate of oxidation of fatty acids
to supply energy for other body functions. Likewise, the liver
converts amino acids and two-carbon fragments derived from
carbohydrates to fats that can then be transported to adipose
tissue for storage. Finally, the liver synthesizes most of the lipo-
proteins required by the body, as well as large quantities of cho-
lesterol and phospholipids. The liver also serves to detoxify the
blood of substances that originate from the gut or elsewhere in
the body. It is highly active in removing particulates from the
portal blood, such as small numbers of colonic bacteria that
cross the wall of the intestine under normal circumstances. The
majority of this “blood cleansing” is provided for by specialized
cells related to blood macrophages, known as Kupffer cells.
These are highly effective phagocytes that are strategically
located to be exposed to the majority of the blood flow
559
11/26/10 10:29:27 AM
560 SECTION VIII GI Physiology

originating from the gut. Other detoxification functions of the
liver are biochemical in nature. Hepatocytes express large num-
bers of cytochrome P450 and other enzymes that can convert
xenobiotics (foreign chemicals) to inactive, less lipophilic
metabolites that can subsequently be excreted into the bile and
thereby eliminated from the body. In addition to the metabo-
lism of xenobiotics, the liver is responsible for the metabolism
and excretion of a wide variety of hormones and other endoge-
nous regulators that circulate in the bloodstream. In particular,
the liver is responsible for metabolism of the steroid hormones.
PROTEIN METABOLISM
AND SYNTHESIS
The liver is also critical for protein metabolism, and the body
cannot dispense with the liver’s capacity to contribute to pro-
tein processing for more than a few days. The liver contributes
the following important aspects of protein metabolism: deam-
ination of amino acids, formation of urea as a means to dis-
pose of blood ammonia, formation of plasma proteins, and
interconversion of various amino acids, as well as conversion
of amino acids to other intermediates important in the body.
Likewise, the liver can synthesize all of the nonessential amino
acids that need not be supplied in the diet in their native form
(as will be discussed in more detail in Chapter 58).
The liver also synthesizes proteins that are critical to the cir-
culatory system. With the exception of the immunoglobulins
produced by cells of the immune system, the liver provides
most of the plasma proteins. Likewise, the liver is also the major
may increase to almost 90% in the period immediately after a
meal. A schematic diagram of the splanchnic circulation is pro-
vided in Figure 55–1. At a microscopic level, blood perfuses the
liver via a series of sinusoids, which are low-resistance cavities
that receive blood supply both from branches of the portal vein
and from the hepatic artery. At rest, many of these sinusoids
are collapsed, whereas as portal blood flow to the liver increases
coincident with ingestion and absorption of a meal, sinusoids
are gradually recruited to allow the perfusion of the liver with
a much greater volume per unit time but only a minimal
increase in pressure. The liver also has a distinctive morpho-
logic organization that underpins its functions. This organiza-
tion is based on the so-called hepatic triad of branches of the
portal vein, the hepatic artery, and the bile ducts. Blood flows
into a branch of the portal vein in the center of portal areas,
which are linked by anastomosing cords of cuboidal hepato-
cytes to a central venule that in turn drains into the hepatic
vein. Branches of the hepatic artery likewise run close to the
bile ducts, and likely play an important role in supplying energy
Heart
Vena
cava Hepatic veins
1300 mL/min
500 mL/min
t er y * Liver
ar
ic
t
pa
He

700 mL/min
site of synthesis of proteins that contribute to blood clotting.
Celiac artery
Spleen
EXCRETION OF LIPID-SOLUBLE

Portal vein
WASTE PRODUCTS Stomach

Pancreas
The liver handles excretion of lipophilic molecules that do not
700 mL/min
enter the renal filtrate, and excretes them in the bile. In turn,
Aorta

Small
the biliary system is designed to convey these substances out intestine
Superior
of the liver and into the intestinal lumen, where they undergo mesenteric artery
little, if any, reabsorption and thus can be eliminated from the Colon
body in the feces. 400 mL/min

ENGINEERING CONSIDERATIONS
Inferior
BLOOD SUPPLY mesenteric artery

Hepatic Macrocirculation Rest of

and Microcirculation
The liver is unusual in that it receives the vast majority of its
blood supply in the form of venous blood, especially in the
postprandial period. Even at rest, blood flow to the liver via the
portal vein is at a rate of 1,300 mL/min, compared with only
500 mL/min supplied by the hepatic artery. Moreover, the
proportion of blood flow supplied to the liver by the portal vein
body
*Branches of the hepatic artery also supply the stomach,
pancreas and small intestine
FIGURE 55–1 Schematic of the splanchnic circulation under
fasting conditions. Note that even during fasting, the liver receives
the majority of its blood supply via the portal vein. (Reproduced with
permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of
Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
 CHAPTER 55 Functional Anatomy of the Liver and Biliary System
Hepatic
Portal vein
Central vein artery
Bile ducts
Sinusoids
Hepatic artery
Portal vein Bile duct
FIGURE 55–2 Arrangement of blood vessels, bile ducts,
and hepatocytes to form the liver lobule. Branches of the portal
vein and hepatic artery run parallel to bile ducts in the so-called
portal triads. Blood percolates through sinusoids arranged between
the hepatocytes, to be collected eventually in the central vein.
(Reproduced with permission from Ross MH, Reith EJ: Histology. A Text and Atlas.
New York: Harper and Row, 1985.)
and nutrients to the bile duct epithelial cells to support their
transport functions. A diagram showing the interrelationships
of the various cell types that make up the liver is shown in
Figure 55–2.
Enterohepatic Circulation
The circulatory features of the liver are also notable for the fact
that some substances circulate continuously between the liver
and intestine, in the enterohepatic circulation. This involves
passage of solutes through three different environments—the
portal vein and the sinusoids into which it empties, the biliary
system, and the intestinal lumen (Figure 55–3). Most notably,
this occurs for bile acids that are utilized during intestinal
lipid digestion and absorption. The physiological significance
of this circuit is that it permits the secretion rate to greatly
exceed the synthesis or input rate.
HEPATIC PARENCHYMA
AND SINUSOIDS
The most prevalent cell type in the liver is the hepatocyte
(80% of total cells, approximately 100 billion in an adult human
liver), whereas the nonparenchymal cell types include the stel-
late cells, sinusoidal endothelial cells, and previously men-
tioned Kupffer cells. In this section, we will review how their
properties contribute to the physiological functions of the liver.
561
Liver
Gallbladder
Duodenum
Bile duct
Portal vein
Terminal ileum
FIGURE 55–3 Schematic of the enterohepatic circulation of
conjugated bile acids. Bile acids secreted by hepatocytes enter the
bile and flow through the biliary system to the duodenum.
Conjugated bile acids are selectively reabsorbed in the terminal
ileum, and flow through the portal vein back to the liver to be
reabsorbed by hepatocytes and resecreted. (Reproduced with permission
from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/
McGraw-Hill, Medical Pub. Division, 2006.)
Hepatocytes
Hepatocytes are the metabolic “factories” of the liver, and are
responsible for most of its characteristic functions. They are
highly specialized polarized epithelial cells. Their apical mem-
branes are in the form of grooves between adjacent cells,
known as canaliculi (Figure 55–4). The canaliculi form a
SINUSOIDAL LUMEN
Stellate
cell
Tight junction
Bile canaliculus
Hepatocyte
Endothelium
Kupffer cell
SINUSOIDAL LUMEN
Space of
Disse
FIGURE 55–4 Interrelationships of the major cell types
making up the liver. Hepatocytes are arranged in plates joined by
tight junctions, and their apical membranes make up the bile
canaliculi. They are segregated from the blood-filled sinusoids by
fenestrated endothelial cells without a basement membrane, and by a
loose connective tissue layer known as the space of Disse. Kupffer cells
reside in the sinusoidal lumen, whereas stellate cells are found in the
space of Disse. (Reproduced with permission from Barrett KE: Gastrointestinal
Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
562 SECTION VIII GI Physiology
continuous network that drains eventually into the bile
ductules. On the opposing pole of the hepatocyte, the basolat-
eral membrane faces the bloodstream in the form of the
hepatic sinusoids. The apical and basolateral membranes of
hepatocytes are separated by tight junctions that define the
canaliculi. These junctions are relatively permeable, however,
permitting the passage of glucose and other small solutes.
Kupffer Cells
Kupffer cells arise from the macrophage lineage, and line the
sinusoidal epithelium on the bloodstream side (Figure 55–4).
They are presumed to play a major role in host defense. Their
location is such that they are exposed to virtually all of the
portal blood flow. Kupffer cells also express cell-surface recep-
tors for altered proteins, such as Fc immunoglobulin receptors
that can be used to internalize foreign proteins or microorgan-
isms that have been coated with host antibodies.
Sinusoidal Endothelium
The endothelial cells that line the hepatic sinusoids have two
characteristic properties that distinguish them from endothe-
lial cells in other organs of the body. First, they are perforated
by large intracellular pores known as fenestrae, which are
100–200 nm in diameter. These are designed to permit the
passage of even quite large macromolecules out of the blood,
including albumin with bound ligands. Second, sinusoidal
endothelial cells in the healthy liver do not have a basement
membrane. In total, therefore, the sinusoidal endothelium
presents virtually no barrier to the efflux of albumin and other
similarly sized molecules from the vascular space.
Space of Disse
The space of Disse (pronounced Diss-eh) is a layer of loose
connective tissue that lies between the sinusoidal endothelium
and the basolateral membrane of hepatocytes. It is notably
highly permeable to the bidirectional exchange of solutes
between the sinusoidal blood flow and hepatocytes.
Hepatic Stellate Cells
Hepatic stellate cells, previously also referred to as Ito cells,
are star-shaped cells that reside in the space of Disse. They
play an important role in the normal liver by storing a variety
of lipids. In addition, these cells are contractile, and may be
involved in the regulation of sinusoidal diameter. Stellate cells
also play a critical role in liver injury by producing extracellu-
lar matrix materials, such as collagen. This collagen is depos-
ited in the space of Disse and impairs hepatic function.
BILIARY TRACT AND GALLBLADDER
The third functional division of the liver is concerned with the
production and transport of bile out of the liver and into the
gastrointestinal lumen. The functional anatomy of the biliary
From liver
Right and left hepatic
ducts from liver
Cystic duct
Common hepatic duct
Common bile duct
Gallbladder
Pancreatic duct
Sphincter of Oddi
Duodenum
FIGURE 55–5 Functional anatomy of the biliary system.
(Modified with permission from Barrett KE: Gastrointestinal Physiology. New York:
Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
system is depicted in Figure 55–5. Bile drains from the liver via
the right and left hepatic ducts that join to form the common
hepatic duct. A cystic duct diverts bile for storage into the gall-
bladder. The anastomosis of the common hepatic duct and the
cystic duct forms the common bile duct, which transfers bile to
the sphincter of Oddi. At a functional level, the biliary system
can be divided into four components. First, the canaliculi, which
are composed of the adjacent apical membranes of hepatocyte
couplets, form the initial biliary secretion. This secretion is then
modified as it flows along the biliary ductules, which are anal-
ogous to pancreatic ducts. The ductules are made up of colum-
nar epithelial cells (cholangiocytes), and both absorb and
secrete various substances into and out of the bile. The ductules
are perfused by a capillary network arising from the hepatic
artery, rather than from the sinusoids. The majority of this peri-
ductular capillary plexus drains into the sinusoids. Flow in the
periductular capillary plexus is in the opposite direction to bile
flow. The larger bile ductules dilute and alkalinize the bile, again
analogous to the function of the pancreatic ducts.
The bile ducts serve simply as conduits for the bile without
modifying its composition significantly, other than by adding
mucus. Mucus secretion presumably serves to protect the
ductular epithelium from potentially injurious surfactant
effects of the bile itself. Finally, bile is stored in the gallbladder
between meals, which is a blind sac lined by highly absorptive
epithelial cells linked by well-developed tight junctions. The
gallbladder serves not only to store bile, but also to concen-
trate it. However, the gallbladder is not essential to life and can
be removed without compromising nutrition.
CLINICAL CORRELATION
A 70-year-old veteran is seen in the primary care clinic of the
VA hospital. He complains that his girth has increased pro-
gressively over a period of several months, despite attempts
 CHAPTER 55 Functional Anatomy of the Liver and Biliary System 563

to lose weight. His ankles are also noted to be edematous. His CHAPTER SUMMARY
history is notable for service in Korea, where he reports that ■ Functions of the liver and biliary system include glucose
he was diagnosed with acute “liver disease” that subsequently storage and release, protein synthesis, detoxification of
resolved. A needle is inserted into his peritoneal cavity and xenobiotics and ammonia, metabolism of endogenous
several liters of tan-colored fluid drain out. A blood test hormones, initial handling of substances absorbed from
reveals evidence of past exposure to the hepatitis C virus. He the intestine, and excretion of lipophilic molecules and
heavy metals in the bile.
is placed on interferon therapy, and told to return to the GI
■ Functions of the liver are facilitated by its unique circulatory
clinic in 6 weeks for follow-up, but 4 weeks later he presents
features. Blood arrives at the liver via two routes: the portal
at the emergency room vomiting bright red blood. An emer-
vein, which drains blood from the intestine, and the hepatic
gency endoscopic examination reveals a ruptured blood ves- artery.
sel bleeding into his esophagus. Hemostasis is obtained by
■ Blood percolates through the liver via a low-resistance system
placing a band around the bleeding vessel. of sinusoids that maximize exposure of hepatocytes to the
Portal hypertension refers to conditions where the resis- blood’s contents.
tance to blood flow through the liver is increased, which ■ The functions of the liver are also subserved by specific cell
can have several causes and results in a variety of problems. types that assume specific geometric relationships. Hepatocytes
As we have already discussed, the liver has a very low- conduct the majority of the metabolic functions of the liver and
resistance vasculature in health, and pressures increase little produce the initial biliary secretion.
as flow increases since additional sinusoids can be recruited. ■ Kupffer cells line the sinusoids and cleanse the blood of
However, in several liver diseases, inflammatory responses particulates, such as bacteria.
trigger hepatic stellate cells to increase collagen production, ■ The endothelial cells of the liver have large fenestrations that
reducing permeability across the sinusoidal endothelium allow small proteins and other molecules to leave the circula-
and space of Disse and impairing liver function due to the tion, but retain blood cells and intact chylomicrons.
associated fibrosis. The hardening of the liver impedes flow ■ Hepatic stellate cells are contractile and likely regulate
through the sinusoids. Some of the sinusoids and liver sinusoidal caliber. In disease, they play an important role
parenchyma may also be destroyed and replaced by fibrous in generating fibrosis.
tissue, further impairing liver function. The most obvious ■ Liver failure due to damage to the liver cells or to the biliary
clinical consequence of portal hypertension is a condition system, or blockade of biliary drainage, results in a host of
known as ascites. Because the hepatic sinusoids and space systemic problems.
of Disse are very permeable and allow albumin to pass,
large quantities of lymph are produced by the liver even in
health, and are collected by a series of lymph ducts that STUDY QUESTIONS
eventually return the fluid to the blood via the thoracic
1. In a patient with end-stage liver disease, which of the
duct. However, when portal hypertension develops, plasma following combinations of findings would be expected
transudation increases and overwhelms the hepatic lym- in the plasma?
phatics, which may themselves be compromised by liver
fibrosis. The resulting fluid, which contains almost as much Albumin Glucose Ammonia
albumin as the plasma, weeps from the surface of the liver
and accumulates in the peritoneal cavity. In advanced liver A) Increased Increased Increased
disease, many liters of fluid may be found. Another conse- B) Decreased Decreased Decreased
quence of portal hypertension is the development of col- C) Increased Decreased Increased
lateral blood vessels to surrounding structures. These form
in an attempt to bypass the blockage to portal flow posed by D) Decreased Increased Decreased
the hardened liver, and reconnect to the systemic circula- E) Decreased Decreased Increased
tion. If the collateral vessels link to the esophagus, they are
referred to as esophageal varices and are vulnerable to ero- 2. A 60-year-old man comes to his physician complaining of a
sion and rupture, particularly if their internal pressure is progressive increase in girth over several months, despite
high. Rupture of such varices represents a major medical attempts to diet. He is suffering from jaundice (yellowing of the
emergency due to the challenges involved in reestablishing skin and sclera) and also complains of nausea and malaise. When
hemostasis. Ruptured varices are also at high risk for a large needle is inserted into his abdomen, several liters of tan
rebleeding. Variceal pressures can be reduced by construct- fluid drain out. An increase in which of the following does not
account for this accumulation of fluid?
ing a surgical shunt between the portal vein and the sys-
temic circulation, although doing so diverts portal blood A) portal pressure
B) hepatic collagen
from any remaining functional liver parenchyma, and thus
C) plasma albumin
increases complications associated with the loss of the D) stellate cell activity
detoxifying functions of hepatocytes. E) plasma transudation
564 SECTION VIII GI Physiology

3. The liver is responsible for removing the small numbers of 5. What structure in the liver permits protein-bound metabolic
bacteria that enter the portal circulation from the intestines. products to access the basolateral membranes of hepatocytes?
Which cell type fulfills this function? A) canaliculi
A) sinusoidal epithelial cells B) sinusoidal fenestrae
B) cholangiocytes C) Kupffer cells
C) hepatocytes D) bile ducts
D) Kupffer cells E) tight junctions
E) stellate cells
4. A gallstone lodged in which of the following sites will result in
increased bile acid flux through the hepatocytes making up only
the left side of the liver?
A) cystic duct
B) common hepatic duct
C) right hepatic duct
D) left hepatic duct
E) common bile duct
 56
C H A P T E R

Bile Formation,
Secretion, and Storage
Kim E. Barrett

O B J E C T I V E S

■ Understand the physiologic functions of bile as a route for excretion and in

aiding in the digestion and absorption of dietary lipids.
■ Understand how bile acids are formed from cholesterol, how they are
modified during gut passage, and their role in driving bile secretion.
■ Describe the major biliary lipids and how they are transported into the
canaliculus.
■ Describe how the composition of bile is modified as the bile moves through
the biliary ductules.
■ Understand the role of the gallbladder in concentrating bile and coordinating
its secretion with ingestion of a meal, and how contraction of the gallbladder
is regulated.
■ Explain why the gallbladder is vulnerable to the formation of cholesterol
gallstones.

BASIC PRINCIPLES OF BILIARY BILE ACID METABOLISM

EXCRETION AND SECRETION
ROLE AND SIGNIFICANCE
The liver fulfills its excretory function by producing bile, a
lipid-rich solution designed to promote the elimination of
hydrophobic solutes. Bile consists of a micellar solution in
which bile acids, cholesterol metabolites produced by hepato-
cytes, form mixed micelles with phosphatidylcholine. These
mixed micelles solubilize molecules that would otherwise have
minimal aqueous solubility, such as cholesterol itself and a
variety of xenobiotics. Bile also plays an important role in
the digestion and absorption of dietary lipids. While bile acids
are not essential for the uptake of most fatty acids, which have
appreciable aqueous solubility, they do markedly increase
the efficiency of this process. On the other hand, insoluble
dietary lipids, such as saturated long-chain fatty acids and
fat-soluble vitamins, are almost entirely dependent on micel-
lar solubilization for absorption.
Bile secretion in the liver is driven by the active, ATP-dependent
efflux of conjugated bile acids out of the hepatocyte into the
canaliculus. In this section, we will consider how bile acids
are synthesized, and subsequent modifications to their struc-
ture that promote their role as biological detergents.
FORMATION OF BILE ACIDS
FROM CHOLESTEROL
Bile acids are amphipathic end products of cholesterol
metabolism. The term amphipathic refers to the fact that bile
acids have both a hydrophobic and a hydrophilic face, and
form micelles. Synthesis of bile acids from cholesterol occurs
in the hepatocyte. Changes to both the steroid nucleus of
cholesterol and its alkyl side chain are required to convert the
highly insoluble cholesterol to the water-soluble bile acid
product. The initial, and rate-limiting, step in bile acid
formation is the hydroxylation of cholesterol at the 7 position of

565

Ch56_565-574.indd 565 11/26/10 10:27:38 AM

566 SECTION VIII GI Physiology

the steroid nucleus via the enzyme cholesterol 7α-hydroxylase
(Figure 56–1). Note that cholesterol already contains a hydroxyl
group at the 3 position, and this is retained in all of the bile
acids. However, the 3-hydroxyl group in cholesterol is in the
β-orientation, and this is converted to the α-position by a pro-
cess known as epimerization. After these initial reactions,
downstream pathways diverge to yield the two primary bile
acids of humans, chenodeoxycholic acid and cholic acid.
Note that all of the hydroxyl groups in the mature bile acids are
in the form of α-epimers, and are thus oriented to the same
face of the molecule. Cholesterol is a flat molecule, insoluble,
and a major membrane constituent. In contrast, bile acids are
kinked molecules that are highly water soluble when ionized.
Bile acid synthesis in healthy humans is at a rate of approxi-
mately 200–400 mg per day. Synthesis is subject to feedback
inhibition at the level of the 7α-hydroxylase enzyme.
PRIMARY AND SECONDARY
BILE ACIDS
When the primary bile acids enter the distal small intestine or
the colon, they can be acted on by bacterial enzymes to yield
secondary bile acids. The most important conversion is dehy-
droxylation of the 7 position of the steroid nucleus, to yield
lithocholic acid from chenodeoxycholic acid, and deoxy-
cholic acid from cholic acid. Trace amounts of a third second-
ary bile acid, ursodeoxycholic acid (so called because it is a
prominent bile acid in bears), are also generated in humans by
epimerization of the 7α-hydroxyl group. Although only very
little ursodeoxycholic acid is formed in humans, it is impor-
tant to know about this compound because it is used therapeu-
tically. The secondary bile acids are less water soluble than the
primary bile acids. Lithocholic acid, in particular, is cytotoxic
if present at high concentrations, and physiologic mechanisms
have developed to limit its toxicity.
BILE ACID CONJUGATION
Both primary and secondary bile acids are further modified in
the hepatocyte by conjugating them to the amino group of
either glycine or taurine in a stable amide linkage (Figure 56–2).
It is these conjugated bile acids that are the substrates for
active transport across the canalicular membrane. Conjuga-
tion also renders the bile acids more water soluble, and alters
other physicochemical properties.
In addition to bacterial conversion of primary to secondary
bile acids, bacteria can deconjugate both primary and second-
ary bile acids, making them more lipophilic. Unconjugated bile

Cholesterol
OH

7α−hydroxylase

OH

12α−hydroxylase

HO OH HO OH

C27 dehydroxylase C27 dehydroxylase

Primary bile acids

OH
COOH COOH

Chenodoxycholic Cholic acid

HO OH acid
HO OH

Bacteria Bacteria Bacteria

FIGURE 56–1 Structures of primary and
Secondary bile acids

secondary bile acids and their precursors. OH

Primary bile acids are synthesized in the liver, COOH COOH
COOH
whereas secondary bile acids are produced in
the colon by bacterial enzymes. (Modified with
permission from Barrett KE: Gastrointestinal Physiology. HO HO OH
New York: Lange Medical Books/McGraw-Hill, Medical Pub. HO
Division, 2006.) Lithocholic acid Ursodeoxycholic acid Deoxycholic acid

C OH Unconjugated bile
acid
O pKa = 5.0
C O N CH2 C O−
O H O Simple micelle
Glycine conjugate
pKa = 3.9
C O N (CH2)2
O H
Taurine conjugate
pKa < 1
FIGURE 56–2 Conjugation of bile acids with either glycine
or taurine reduces their pKa. (Modified with permission from Barrett KE:
Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical
Pub. Division, 2006.)
acids can be passively absorbed across the wall of the intestine.
They then travel through the portal vein back to the liver, where
they are reconjugated in the hepatocyte. Thus, all bile acids
secreted by the hepatocyte are in their conjugated forms.
Special handling applies to the potentially toxic bile acid,
lithocholic acid. In addition to conjugation with glycine or
taurine, lithocholic acid can be sulfated, particularly if present
in abnormally high concentrations. This increases the hydro-
philicity of the molecule and reduces its cytotoxic effects. The
sulfated conjugates of lithocholic acid also cannot be absorbed
by the intestine, which results in their elimination from the
pool of bile acids that circulate enterohepatically.
PHYSICOCHEMICAL PROPERTIES
OF BILE ACIDS
The amphipathic character of bile acids is vital to the
physiologic function of these molecules. Above a certain
concentration called the critical micellar concentration
(CMC), bile acid molecules are spontaneously self-associated
into structures known as micelles, in which the hydrophobic
faces are masked from the surrounding aqueous environment
(Figure 56–3). However, simple micelles composed of bile
acids alone do not exist in bile or intestinal content. In bile,
bile acids form mixed micelles with phosphatidylcholine. In
turn, these mixed micelles can serve as the “solvent” for hydro-
phobic waste products.
Conjugated bile acids are present in both bile and intestinal
contents as anions because they have a lower pKa than the
CHAPTER 56 Bile Formation, Secretion, and Storage 567
Charged side chain
OH group
Bile acid monomers
S O−
O
Mixed micelle
Phosphatidylcholine
Cholesterol
FIGURE 56–3 Physical forms adopted by bile acids in
solution. Micelles are shown in cross-section, and are actually
thought to be cylindrical in shape. Mixed micelles of bile acids
present in hepatic bile also incorporate cholesterol and
phosphatidylcholine. (Adapted with permission from Barrett KE:
Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill,
Medical Pub. Division, 2006.)
unconjugated forms. Due to this charge, conjugated bile acids
are incapable of crossing cell membranes by passive means,
needing instead an active transport mechanism for their secre-
tion or uptake (Figure 56–4). This allows enterohepatic circu-
lation of bile acids to be coordinated with the period when
they are needed to help digest the meal.
BILE COMPOSITION
CANALICULAR BILE
The secretion of bile begins when bile acids are actively
secreted across the canalicular membrane. Because the bile
acids are osmotically active, canalicular bile is transiently
hyperosmotic. However, the canalicular tight junctions are
relatively permeable, and so water is drawn into the canalicu-
lus to balance this, along with plasma cations to maintain elec-
trical neutrality. Other secondary solutes also enter bile
passively from the plasma, including glutathione, glucose,
amino acids, and urea.
568 SECTION VIII GI Physiology

Hepatocyte phatidylcholine from their normal position in the inner leaflet

of the canalicular membrane, and specifically ejects them into
the canalicular lumen as vesicles. These vesicles then fuse with
secreted bile acids to form mixed micelles. Cholesterol is also
secreted into the bile, particularly in humans, at a ratio of
Tight junction
approximately 0.3 to the amount of phosphatidylcholine (or
one tenth of the amount of bile acids). Such secretion appears
to be mediated by a heterodimer of the transporters ABC5 and
ABC8. Canalicular bile, in health, also contains conjugated
Canaliculus bilirubin, which gives bile its characteristic brown color, and a
Active secretion variety of other organic anions and cations that arise from the
• Bile acids biotransformation of xenobiotics and endogenous hormones.
• Phosphatidylcholine
The membrane transporters that allow these various molecules
• Conjugated bilirubin
to enter the bile are listed in Table 56–1.
• Xenobiotics

Passive permeation
• Water
• Glucose
• Calcium
• Glutathione
• Amino acids
• Urea
FIGURE 56–4 Pathways for solute entry into bile by either
active secretion or passive permeation through the tight
junctions linking adjacent hepatocytes. (Reproduced with permission
from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/
McGraw-Hill, Medical Pub. Division, 2006.)
The composition of canalicular bile is also modified by the
active secretion of additional factors from the hepatocytes.
Phosphatidylcholine, a component of the hepatocyte mem-
brane, enters the bile and forms mixed micelles with the bile
acids. The ratio of phosphatidylcholine to bile acids is approxi-
mately 0.3. Although phosphatidylcholine is only one of the
phospholipids present in the hepatocyte plasma membrane, it
is selectively secreted into bile. This is mediated by multidrug
resistance protein 3 (MDR3), which “flips” molecules of phos-
DUCTULAR BILE
As the bile moves out of the canaliculi, it is transferred to the
smallest bile ductules via structures known as the canals of
Hering. The bile ductules are lined by cholangiocytes, which
are columnar epithelial cells specialized to modify bile
composition. The tight junctions linking the cholangiocytes
are much less permeable than those linking hepatocytes. They
are freely permeable to water, but are only selectively permeable
to electrolytes and impermeable to larger solutes. Because of
their permeability to water, bile rapidly becomes isotonic. The
ductules also serve to scavenge solutes that were filtered into
the bile at the leaky canaliculus. In particular, glucose is actively
reabsorbed. Likewise, glutathione is hydrolyzed to its constitu-
ent amino acids by the apically fixed enzyme, gamma-glutamyl
transpeptidase (GGT). The function of the bile ductules is
also coordinated with ingestion of a meal. In particular, the
cholangiocytes secrete bicarbonate in response to secretin, via
a process involving the coupled activity of the CFTR chloride
channel and chloride/bicarbonate exchange at the apical
membrane. Sodium ions follow paracellularly to maintain
electrical neutrality, in turn drawing additional water into the
bile and increasing its volume and flow. Thus, bile becomes
slightly alkaline. Finally, the ductules secrete IgA molecules
into the bile that contribute to host defense.

TABLE 56–1 Hepatocyte transporters.

Name Location Substrate/Function

Sodium taurocholate cotransporting polypeptide (NTCP) Basolateral membrane Uptake of conjugated bile acids from blood

Organic anion transporting protein (OATP) Basolateral membrane Uptake of bile acids and xenobiotics from blood

Bile salt export pump (BSEP) Canalicular membrane Secretion of conjugated bile acids into bile

Multidrug resistance protein 3 (MDR3) Canalicular membrane “Flippase” that adds phosphatidylcholine to bile

Multidrug resistance protein 1 (MDR1) Canalicular membrane Secretion of hydrophobic cationic drugs into bile

ABC5/ABC8 Canalicular membrane Secretion of cholesterol into bile

Multiple organic anion transport protein (cMOAT, MRP2) Canalicular membrane Secretion of sulfated lithocholic acid and
conjugated bilirubin into bile

HEPATIC BILE
Hepatic bile emerges from the liver in the common hepatic
duct, prior to further modification by gallbladder storage. The
large bile ducts are thought to have little ability to modify bile
composition, other than by adding mucus. Hepatic bile is iso-
osmotic with plasma, slightly alkaline, and contains appreciable
quantities of IgA but essentially no glucose or amino acids.
ENTEROHEPATIC CIRCULATION
OF BILE ACIDS
Unlike the digestive enzymes arising from the pancreas, which
contribute to nutrient digestion catalytically, bile acids contrib-
ute to lipid digestion and absorption by mass action. This means
that considerable quantities of bile acids are needed to solubilize
the quantities of products of fat digestion that are derived from
a typical diet on a daily basis. The liver synthesizes 200–400 mg
of bile acids per day. However, the concentration of bile acids in
the small intestinal lumen during digestion is much higher than
would be predicted, because bile acid secretion with a meal is
about 2,000–3,000 mg/h. This is achieved by recycling the
majority of the bile acids secreted during a meal, such that a
large pool (about 2,000 mg) of these molecules is constantly
cycling between the intestine and liver (Figure 56–5).
INTESTINAL UPTAKE MECHANISMS
Bile acids secreted into the gut lumen are initially in conju-
gated form. Because these bile acids are ionized, they cannot
Hepatic synthesis
Sphincter of Oddi
Spillover from
liver into
systemic Gallbladder
circulation Small intestine
Active
ileal
uptake
Large intestine
Return
to liver Spillover into colon
Passive uptake
of deconjugated
bile acids from colon
Fecal loss ( = hepatic synthesis)
FIGURE 56–5 Quantitative aspects of the circulation of bile
acids. The majority of the bile acid pool circulates between the small
intestine and liver. A minority of the bile acid pool is in the systemic
circulation (due to incomplete hepatocyte uptake from portal blood)
or spills over into the colon and is lost to the stool. Fecal loss is
equivalent to hepatic synthesis of bile acids at steady state. (Adapted
with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange
Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
CHAPTER 56 Bile Formation, Secretion, and Storage 569
cross the wall of the intestine passively. Rather, there is a
specific, sodium-coupled transporter known as the apical
sodium-dependent bile salt transporter (asbt) that
recognizes bile acid conjugates and reabsorbs them. The
expression of asbt in the intestine is limited to epithelial cells
in the terminal ileum. Thus, conjugated bile acids remain
with the meal in the lumen until the nutrients are absorbed,
whereupon they are reclaimed from the lumen and enter the
portal circulation via a second bile acid transporter, OST, to
be returned to the liver. Only a minor portion of the bile
acid pool spills over into the colon in health. Moreover,
conjugated bile acids that enter the colon are deconjugated
by the resident bacteria. Deconjugated bile acids are largely
nonionized and can be absorbed passively. The amount of
bile acids found in the feces balances daily synthesis at
steady state (Figure 56–5).
HEPATOCYTE TRANSPORT
MECHANISMS
Bile acids return to the liver bound to albumin, leave the por-
tal circulation in the sinusoids, and then are specifically and
efficiently taken up across the basolateral membrane of the
hepatocytes via a variety of specific transporters (Table 56–1).
Probably the best characterized is the sodium taurocholate
cotransporting polypeptide (NTCP), a sodium-coupled
transporter for the taurine conjugate of cholic acid that shares
homology with asbt. Other bile acids are apparently trans-
ported by members of the organic anion transporting
polypeptide (OATP) family, which are sodium-independent.
Unconjugated bile acids are reconjugated with either tau-
rine or glycine, and overall the recycled bile acids are handled
in much the same way as bile acids that have been newly
synthesized, being actively transported into the bile canaliculus
via the bile salt export pump (BSEP). The only exception
applies to secretion of the sulfated forms of conjugated
lithocholic acid, which enter the bile via the multiple organic
anion transporter (MOAT), also referred to as MRP2.
REGULATION OF BILE ACID SYNTHESIS
AND TRANSPORT
The enterohepatic cycling of bile acids also controls the rate
at which they are synthesized and transported. Bile acids exert
feedback inhibition on cholesterol 7α-hydroxylase, such that
when return of bile acids from the intestine is high, the
synthesis of new primary bile acids is reduced. Conversely,
interruption of the enterohepatic circulation of bile acids for
any reason will relieve this feedback inhibition, increasing the
rate at which cholesterol is converted to bile acids. Normal
rates of bile acid synthesis can increase 10–20-fold under these
conditions. This increased synthetic rate may or may not be
sufficient to maintain the size of the circulating bile acid pool,
depending on fecal losses.
570 SECTION VIII GI Physiology
Dietary
cholesterol 0.2 g/day
Hepatic and
Body Bile
extrahepatic
cholesterol acid
synthesis
pools pools
0.8−1 g/day
Intact cholesterol Cholesterol
0.8 g/day excreted as
bile acids
0.2−0.4 g/day
Fecal excretion = Input
FIGURE 56–6 Relationship of bile acid pools to whole body
cholesterol homeostasis in health. The combined fecal excretion of
cholesterol and bile acids is equivalent to input of cholesterol from
the diet plus endogenous synthesis of cholesterol. (Modified with
permission from the Undergraduate Teaching Project of the American
Gastroenterological Association, Unit 11. Copyright 2002.)
Bile acid synthesis should also be considered in the context
of whole body cholesterol metabolism (Figure 56–6). The cho-
lesterol pools reflect hepatic and extrahepatic synthesis (as
well as a small component derived from absorption of dietary
cholesterol). At steady state, cholesterol input must be bal-
anced by elimination. Cholesterol is lost from the body in two
forms by being secreted intact into the bile or after conversion
to bile acids. In either case, the sole excretory pathway is via
the bile as no cholesterol or bile acids are excreted in urine in
healthy individuals. Because it is possible to increase bile acid
synthesis by interrupting the enterohepatic circulation, this
represents a pharmaceutical approach to enhance cholesterol
elimination.
BASIC PRINCIPLES OF
GALLBLADDER FUNCTION
ROLE AND SIGNIFICANCE
The gallbladder serves to store and concentrate bile coming
from the liver in the period between meals. Gallbladder func-
tion therefore permits coordination of the secretion of a bolus
of concentrated bile with the entry of dietary lipids into the
small intestine. The gallbladder is not essential to normal
digestion and absorption of a meal. In the absence of a func-
tioning gallbladder, the bile acid pool continues to cycle
through the enterohepatic circulation, and the majority of the
bile acid pool is stored in the small intestine.
FUNCTIONAL ANATOMY
OF THE GALLBLADDER
The gallbladder is a muscular sac with a capacity of approximately
50 mL in adult humans. It is linked to the biliary system via the
cystic duct, a bidirectional conduit for bile flow. During periods
of fasting, bile secreted by the liver is diverted into the gallbladder.
On the other hand, when the gallbladder receives neurohumoral
cues that fats are present in the small intestine, it contracts and
bile flows out of the gallbladder and into the intestine.
EPITHELIUM
The gallbladder has two functional layers. The inner of these,
facing the bile, is a columnar epithelium that participates
actively in bile concentration. The tight junctions that link
adjacent epithelial cells are among the best developed any-
where in the body, making the epithelium highly resistant to
the passive flux of solutes. This “tight” epithelium prevents the
passive loss of bile acid molecules and thus is essential to the
ability of the gallbladder to concentrate the bile.
MUSCULATURE
The epithelial layers are underlaid by smooth muscle that can
alter the caliber of the gallbladder lumen. The muscle cells
l Dorsal
ga vagal
Va rents complex
e
eff
ACh Vagal
ACh and CCK
cause smooth Gall-
afferent
muscle contraction bladder NO
VIP
CCK Sphincter
of Oddi Duodenum
Nutrients
Via CCK
bloodstream
CCK
FIGURE 56–7 Neurohumoral control of gallbladder
contraction and biliary secretion. Nutrients in the duodenum
lead to the release of cholecystokinin (CCK), which acts through
both endocrine and neurocrine routes to activate gallbladder
contraction and relax the sphincter of Oddi, resulting in the
secretion of a bolus of concentrated bile into the duodenal lumen.
Secondary neurotransmitters released by the enteric nervous
system in response to a vagovagal reflex include the excitatory
neurotransmitter acetylcholine (ACh) and the inhibitory transmitters
vasoactive intestinal polypeptide (VIP) and nitric oxide (NO).
(Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks
H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

receive cholinergic input from the vagus nerve. They also
express receptors for CCK. CCK additionally activates nerves
that innervate the gallbladder (Figure 56–7).
GALLBLADDER STORAGE OF BILE
EFFECTS ON COMPOSITION
Hepatic bile is isotonic with plasma, with sodium as its
major cation and chloride as its major anion. After gallblad-
der storage, water is removed from the lumen and the con-
centration of bile acids is increased by approximately 10-fold,
whereas chloride and bicarbonate concentrations decrease.
On the other hand, the concentrations of all cations in the
bile increase, although to a lesser degree than those of the
bile acids, indicating that cations are also subject to net
absorption by the gallbladder epithelium. A comparison of
the compositions of hepatic and gallbladder bile is shown as
Figure 56–8.
Despite the dramatic increase in the sum of anions and
cations during gallbladder storage of bile, bile remains iso-
tonic. How is this possible? The answer lies in the fact that the
majority of the bile acid molecules are physically in the form of
mixed micelles that also contain cholesterol and phosphatidyl-
choline. Once the CMC is reached, the monomeric concentra-
tion of bile acids does not change. Any additional bile acid
molecules are immediately incorporated into existing micelles.
Each particle in a solution contributes the same amount of
osmotic force, be it a molecule, ion, or micelle. This allows the
osmolality of bile to remain constant despite its concentration.
Bile also changes from being slightly alkaline (a result of bicar-
bonate secretion in the ductules) to slightly acidic.
Hepatic bile
Gallbladder bile
300
Na+
250
Concentration (mM)
200
Bile acid anions
150
Cl−
100
HCO3−
50
0 1 2 3 4 5
Storage time (h)
FIGURE 56–8 Changes in bile composition during
gallbladder storage. (Reproduced with permission from Barrett KE:
Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical
Pub. Division, 2006.)
CHAPTER 56 Bile Formation, Secretion, and Storage 571
The solubility of cholesterol in bile depends on its concen-
tration relative to that of bile acids and phosphatidylcholine.
As bile is concentrated, bile acids cannot leave the gallblad-
der since they are too large to pass through the tight junc-
tions linking adjacent epithelial cells, and they are also not
actively transported by the gallbladder epithelium. Accord-
ingly, the proportion of bile acids to cholesterol plus phos-
phatidylcholine does not change, or even increases slightly,
because the gallbladder can absorb cholesterol. As a result,
bile becomes slightly less saturated in cholesterol as it is
stored. Gallstone disease is nevertheless quite prevalent in
humans because we secrete relatively high concentrations of
cholesterol in hepatic bile.
MECHANISM FOR BILE
CONCENTRATION
Bile is concentrated in the gallbladder via the active transport
of ions across the tight gallbladder epithelium (Figure 56–9).
Sodium in the bile is exchanged for protons via members of
the NHE family of exchangers that we encountered in the gas-
trointestinal tract. Protons that are secreted into the stored bile
react with bicarbonate ions, yielding CO2 and water. The CO2
diffuses out of the gallbladder lumen passively, and water can
be reabsorbed. In addition to sodium absorption, moreover,
chloride is also actively absorbed by the gallbladder epithe-
lium. Finally, water leaves across the gallbladder epithelium to
follow the osmotic effect of absorbed sodium chloride.
MOTOR FUNCTIONS OF
THE GALLBLADDER AND
BILIARY SYSTEM
GALLBLADDER CONTRACTION
Postprandial gallbladder contraction coincides with gastric
emptying. The entry of the meal into the duodenum triggers
the release of a series of neurohumoral messengers that
increase gallbladder tone (Figure 56–7). Cholecystokinin
(CCK) released from cells lining the duodenal lumen travels
through the bloodstream, and binds directly to CCK-A recep-
tors on gallbladder smooth muscle cells. In addition, CCK
activates vagal afferents in the wall of the duodenum, and
these in turn initiate a vagovagal reflex that releases ACh at
gallbladder synapses, further increasing contractile activity.
6
SPHINCTER OF ODDI FUNCTION
Even if the gallbladder contracts fully, this does not allow
for bile secretion into the duodenum if pressure at the sphinc-
ter of Oddi remains high. Therefore, relaxation of the sphinc-
ter is normally coordinated with gallbladder contraction. The
572 SECTION VIII GI Physiology
FIGURE 56–9 Mechanism of bile concentration
by gallbladder epithelial cells. Sodium is reabsorbed
via a sodium/hydrogen exchanger on the apical
membrane (NHE), in exchange for protons generated
intracellularly by carbonic anhydrase (CA).The pathway
for chloride absorption is less well characterized, but
may involve the cystic fibrosis transmembrane
conductance regulator (CFTR) chloride channel and/or
a chloride/bicarbonate exchanger (not shown).
Gallbladder epithelial tight junctions have extremely
low permeability, and resist the passage of bile acid
anions (BA−) out of the lumen. (Reproduced with permission
from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical
Books/McGraw-Hill, Medical Pub. Division, 2006.)
reduction in sphincter of Oddi tone is primarily brought about
by CCK. CCK activates predominantly a neural mechanism to
initiate this physiologic response, transmitted through the
enteric nervous system. The final mediators acting at the level
of the sphincter smooth muscle are VIP and nitric oxide,
released from sphincter of Oddi nerve ganglia.
CLINICAL CORRELATION
A 43-year-old woman who is a mother of three comes to
her primary care physician complaining of sharp, colicky
abdominal pain, usually when she enjoys a pepperoni
pizza or other large, fatty meals. Recently, she has had
pain with any meal. Her physical examination is unre-
markable other than a finding that she is overweight.
Nevertheless, having ruled out any cardiac disease, her
physician refers her for an imaging study of her gallblad-
der. This reveals several stones. The patient undergoes a
laparoscopic removal of her gallbladder (cholecystec-
tomy) and her symptoms subside, other than the fact that
she still cannot tolerate pepperoni pizza or fatty meals
without some discomfort and bloating.
The formation of stones in the gallbladder is a common
disease that has afflicted humans for millennia. More than
20 million Americans have gallstones. Gallstone-related
symptoms and complications are among the most com-
mon gastroenterologic disorders requiring hospitaliza-
tion, at great cost to the health care system. Gallstones are
of two types, related to the deposition of either cholesterol
(cholesterol stones) or bilirubin (pigment stones). Choles-
LUMEN BLOODSTREAM
CO2 + H2O
Na+ CA 3Na+
NHE
H+ H+ + HCO3− 2K+
H+ + HCO3−
H2O + CO2
CFTR? ?
Cl− Cl−
?
Reabsorbed
BA−
terol stones account for the majority of gallstones in most
Western countries.
Human bile is unusually rich in cholesterol. In choles-
terol gallstone disease, the balance between the normal
ratios of cholesterol to the other biliary lipids is disrupted,
either due to cholesterol hypersecretion, relative hyposecre-
tion of bile acids or phospholipids, or some combination of
these. Obesity, the use of oral contraceptives, estrogen, old
age, sudden weight loss, and genetic factors may lead to
cholesterol hypersecretion. Conversely, a diminished bile
acid pool can occur if the enterohepatic circulation is inter-
rupted. In either case, patients are at risk for supersatura-
tion of cholesterol and thus for the development of
gallstones. Supersaturation is not necessarily sufficient for
stone formation, however, since nucleation must also
occur. Some patients may be genetically predisposed to
secrete proteins that can act as nucleating agents, whereas
other proteins in bile may retard nucleation. Two thirds
of patients with gallstones will have no associated symp-
toms. Others present with episodic pain in the epigastric
region. In most patients, the pain is biliary colic, thought to
reflect a tonic spasm resulting from transient obstruction
of the cystic duct by a stone, and sometimes precipitated by
eating a large meal. Biliary colic, while severe, usually sub-
sides within a few hours, which serves to distinguish it from
acute cholecystitis, where obstruction of the cystic duct
leads to inflammation of the gallbladder. In some patients,
acute inflammation may progress to chronic cholecystitis,
resulting in a thickened and fibrotic gallbladder. The defin-
itive treatment for symptomatic gallstone disease is chole-
cystectomy, which is usually simple, safe, and curative,
particularly with the advent of laparoscopic approaches.
 CHAPTER 56 Bile Formation, Secretion, and Storage 573

CHAPTER SUMMARY 2. The composition of bile is modified as it flows through the biliary
ductules. Which of the following is expected to increase in
■ Bile is secreted by the liver as a vehicle to excrete lipid-soluble concentration during this transit?
waste products of metabolism as well as xenobiotics, and it also
A) glucose
aids in fat digestion and absorption.
B) bile acid monomers
■ The major solutes driving the primary secretion of bile are the C) alanine
bile acids, which are amphipathic molecules synthesized from D) glutathione
cholesterol in the hepatocyte. E) IgA
■ Bile acids are actively secreted into the bile canaliculus in 3. A scientist studying the enterohepatic circulation measures the
conjugated forms by an energy-dependent transporter. portal concentration of conjugated bile acids in rats treated with
■ Bile also contains cholesterol and phosphatidylcholine, which various drugs. An inhibitor of which of the following ion
are actively transported into the primary secretion, as well as transport proteins would be expected to reduce the uptake of
solutes filtered from the plasma, such as calcium and glucose. sodium taurocholate from the small intestinal lumen?
■ Bile acids recycle several times daily from the intestine to the A) Na+,K+-ATPase
liver in the enterohepatic circulation; in their conjugated forms, B) CFTR
they are actively reabsorbed in the terminal ileum, thereby C) ENaC
generating a recycling pool of bile acids. D) NKCC1
■ The gallbladder serves to store bile between meals and to E) chloride/bicarbonate exchanger
coordinate the release of a concentrated bolus of bile with the 4. Compared with hepatic bile, bile that has been stored in the
presence of the meal in the duodenum. gallbladder for several hours would be expected to display which
■ Gallbladder storage of bile results in changes in its composi- of the following changes in concentration?
tion, such that bile acids become the dominant anions.
■ Bile remains isotonic during this process as bile acid monomers Cholesterol Base Equivalents Calcium
are rapidly incorporated into mixed micelles.
A) Increased Increased Increased
■ Concentration of bile results from active transport processes
taking place in the lining epithelial cells. B) Decreased Decreased Decreased

C) Increased Decreased Increased

D) Decreased Increased Decreased

STUDY QUESTIONS
E) Decreased Decreased Increased
1. A patient with Crohn’s disease undergoes surgical resection of
her diseased terminal ileum. After recovering from the surgery, F) Increased Increased Decreased
she is noted to have moderate steatorrhea. What level of bile acid
synthesis by the patient’s hepatocytes would be expected 5. Sphincter of Oddi relaxation is normally coordinated with
compared with a normal individual? gallbladder contraction to allow bile outflow into the duodenum.
A) 10-fold higher Which of the following mediators circulates through the
B) 10% higher bloodstream to mediate this coordination when the meal is
C) unchanged in the duodenum?
D) 10% less A) gastrin
E) 10-fold less B) motilin
C) acetylcholine
D) cholecystokinin
E) nitric oxide
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 57
C H A P T E R

Handling of Bilirubin and

Ammonia by the Liver
Kim E. Barrett

O B J E C T I V E S

■ Understand the origins of bilirubin in the plasma, the need to excrete this
substance, and how it is transported through the body.
■ Describe the pathway of bilirubin handling, and further metabolic
modifications that occur.
■ Define the contributors to the level of ammonia in the circulation, and
explain why a mechanism for disposal of this metabolite is needed.
■ Describe the metabolic steps involved in the conversion of ammonia to urea
in the hepatocyte.
■ Understand the routes for eventual disposal of urea.

BASIC PRINCIPLES OF PATHWAYS OF BILIRUBIN

BILIRUBIN METABOLISM
Bilirubin is a metabolite of heme, a compound that serves to
coordinate iron in various proteins. Very recently, bilirubin has
been shown to possess important functions as an antioxidant,
but it also serves simply as a means to excrete unwanted heme,
derived from various heme-containing proteins such as hemo-
globin, myoglobin, and various P450 enzymes. Bilirubin and its
metabolites are also notable for the fact that they provide color
to the bile and stool, as well as, to a lesser extent, the urine.
ROLE AND SIGNIFICANCE
It is important for the body to be able to excrete bilirubin as it is
potentially toxic. Excessive levels of bilirubin in the bloodstream
can lead to accumulation of bilirubin in the brain due to its abil-
ity to cross the blood–brain barrier, a condition known as ker-
nicterus (meaning “stained nuclei”). The development of this
condition impairs brain function and can be fatal if untreated.
Bilirubin is also notable for its yellow coloration. Accumulation
of this substance in the blood is the basis for jaundice, or a yellow
discoloration of the skin and eyes, which is a common symptom
of liver diseases. Thus, measurement of bilirubin in the plasma
can be a useful marker of such conditions.
SYNTHESIS AND METABOLISM
Bilirubin derives from two main sources. The majority (80%)
of the bilirubin formed in the body comes from the heme
released from senescent red blood cells. The remainder origi-
nates from various heme-containing proteins found in other
tissues, notably the liver and muscles.
CELLULAR HEME METABOLISM
Bilirubin is produced by a two-stage reaction that occurs in
cells of the reticuloendothelial system, including phagocytes,
the Kupffer cells of the liver, and cells in the spleen and bone
marrow. Heme is taken up into these cells and acted on by
heme oxygenase, liberating the chelated iron from the heme
structure and releasing an equimolar amount of carbon mon-
oxide, which is eliminated via the lungs. The reaction yields a
green pigment known as biliverdin (Figure 57–1). Biliverdin
is then acted on by the enzyme biliverdin reductase, produc-
ing the yellow bilirubin.
Bilirubin is almost insoluble in aqueous solutions at neutral
pH. Thus, after its release into the plasma, it is taken up by
albumin and transported throughout the body. The binding
affinity of unconjugated bilirubin for albumin is extremely

575

Ch57_575-582.indd 575 11/26/10 10:30:16 AM

576 SECTION VIII GI Physiology

COO− COO− Once inside the hepatocyte, bilirubin requires special han-
dling to maintain its solubility and traffic it appropriately.
Thus, it is believed to bind to a variety of intracellular pro-
CH3
teins, including fatty acid–binding proteins that direct the
H3C molecule to the microsomal compartment for conjugation.
N N These proteins are likely also responsible for vectorial trans-
Heme
Fe port of the conjugated bilirubin to the canalicular membrane
N N for transport into the bile.
H2 C CH3 Following its conjugation, bilirubin exits the hepatocyte
into the bile via a membrane transport protein known as
CH3 CH2 MRP2. While this transporter has a relatively broad specific-
ity, transporting additional metabolic products as well as
some drug conjugates, it appears that its main physiological
NADPH + O2 substrate is conjugated bilirubin. Insights into the role and
Heme oxygenase significance of this transporter have been gained from a
CO + Fe3+ + NADP+ genetic disorder known as Dubin–Johnson syndrome, where
mutations in the MRP2 gene lead to the absence of the trans-
porter. However, even in health, transport of either unconju-
M V M P P M M V
gated or conjugated bilirubin through the hepatocyte cytosol
Biliverdin is not entirely efficient, and some escapes back into the plasma
where it binds once more to albumin and can be transported
O N N N N O around the body. On the other hand, only conjugated biliru-
H H H
bin is able to enter the bile via MRP2. It is primarily present in
the aqueous fraction of the bile and is not believed to associ-
NADPH ate to any significant extent with the mixed micelles formed
Biliverdin
reductase
by the biliary lipids. Conjugated bilirubin is also neither fur-
NADP+ ther metabolized nor absorbed during its passage along the
biliary tree.
M V M P P M M V

Bilirubin
O N N N N O
H H H H
H H
FIGURE 57–1 Conversion of heme to bilirubin is a two-step
reaction catalyzed by heme oxygenase and biliverdin reductase.
M, methyl; P, proprionate; V, vinyl. (Modified with permission from Barrett KE:
Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical
Pub. Division, 2006.)
high; there is usually very little free unconjugated bilirubin in
the plasma. When the bilirubin-laden albumin reaches the
liver, the high permeability of the hepatic microcirculation, as
discussed in Chapter 55, allows the complex to enter the space
of Disse such that it encounters the basolateral aspect of hepa-
tocytes. At this site, bilirubin is taken up by a specific transport
mechanism to enter the hepatocyte. However, this process is
relatively inefficient, with the first-pass clearance of bilirubin
being only about 20%.
HEPATIC TRANSPORT MECHANISMS
The transporter responsible for uptake of the bilirubin into
the hepatocyte is thought to be a member of the organic anion
transporting polypeptide (OATP) family (Figure 57–2).
HEPATOCYTE CONJUGATION
The hepatocyte plays an important role in bilirubin handling
by conjugating the molecule to glucuronic acid. This reaction
is catalyzed by UDP glucuronyl transferase (UGT), and
results in the sequential esterification of two glucuronide moi-
eties to the propionic acid side chains of bilirubin (Figure 57–2).
Under normal conditions, most molecules of bilirubin are
modified with two glucuronide groups, forming bilirubin
diglucuronide. Conjugation has several important effects on
the physicochemical properties of bilirubin. First, it markedly
increases its water solubility, allowing it to be transported in
the bile without a protein carrier. Second, as a result of this
increase in hydrophilicity, and increased molecular size, con-
jugated bilirubin cannot be passively reabsorbed from the
intestinal lumen. There are also no specific transporters for
the uptake of conjugated bilirubin in the intestine. Thus, con-
jugation serves to promote the elimination of this metabolic
waste product. Finally, conjugation modestly decreases the
affinity of bilirubin for albumin. Normal levels of total serum
bilirubin are approximately 1–1.5 mg/dL in human adults,
consisting of approximately 90% unconjugated and 10% con-
jugated bilirubin. The relative proportions of conjugated and
unconjugated bilirubin in disease states provide important
clues about the level of any dysfunction in the bilirubin export
pathway.
 CHAPTER 57 Handling of Bilirubin and Ammonia by the Liver 577

Alb B BILIRUBIN HOMEOSTASIS

Reflux to plasma
BACTERIAL METABOLISM
Alb + B
OATP Space of Diss
e In the small intestine, there appears to be little deconjugation
or additional metabolism of bilirubin in the healthy gut.
However, when conjugated bilirubin enters the colon, it can
B
be rapidly deconjugated by the enteric flora, releasing it for
UDP glucuronyl UDP-G further metabolism by anaerobic bacteria (Figure 57–3). Bili-
transferase UDP rubin is extensively metabolized in this site, producing mol-
BG ecules known as urobilinogens and stercobilinogens. These
BG Canaliculus
BG2
MRP2 BG2 are further metabolized to urobilins and stercobilins, which
give color to the stool. Urobilinogen, which is able to cross
the colonic epithelium passively, also enters the enterohepatic
circulation. In turn, it can be conjugated by the hepatocyte
and secreted into bile.
Hepatocyte

FIGURE 57–2 Handling of bilirubin by hepatocytes. Albumin

(Alb)-bound bilirubin (B) enters the space of Disse, and bilirubin is
selectively transported into the hepatocyte, where it is either
monoconjugated or diconjugated with glucuronic acid (G).The
conjugates are secreted into bile via the multidrug resistance protein
2 (MRP2). Some unconjugated and conjugated bilirubin may also
reflux into the plasma. OATP, organic anion transporting polypeptide.
(Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H:
Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
URINARY ELIMINATION
Even under conditions of hyperbilirubinemia, little, if any,
unconjugated bilirubin is able to enter the urine because of
its tight binding to albumin. Urobilinogen, on the other
hand, has appreciable aqueous solubility, and a small frac-
tion (typically less than 5% of the urobilinogen pool) is lost
to the urine on a daily basis, and is thought to contribute to
the color of urine.

Bilirubin UroB

Liver
Systemic UroBG2
circulation BG2

Enterohepatic
ne circulation
intesti
UroB Small

Urine B
(1−3%) Bacteria

UroB

Colon

Fecal urobilins and stercobilins

(97−99%)
FIGURE 57–3 Cycling of bilirubin and its products through the liver, intestines, portal and systemic circulations, and kidneys.
B, bilirubin; UroB, urobilinogen; G, glucuronide. Most UroB reabsorbed from the colon is taken up by the liver, but a small portion (indicated by
the dashed arrow) spills over into the systemic circulation, from where it can be excreted by the kidneys. (Adapted with permission from Barrett KE:
Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
578 SECTION VIII GI Physiology

Jaundice

Bilirubin No bilirubin
in urine in urine

Genetic Hepatobiliary Overproduction Impaired

defects in disease conjugation
FIGURE 57–4 Differential diagnosis of excretion
jaundice depending on whether bilirubin is or is
not present in the urine. (Reproduced with permission
from Barrett KE: Gastrointestinal Physiology. New York: Lange Extrahepatic Intrahepatic Impaired
Medical Books/McGraw-Hill, Medical Pub. Division, 2006.) cholestasis cholestasis hepatic uptake

HYPERBILIRUBINEMIA AMMONIA FORMATION

Hyperbilirubinemia simply refers to excessive levels of biliru- AND DISPOSITION
bin in the blood. This can be detected during clinical examina-
Ammonia in the circulation originates in a number of differ-
tion by the yellowish coloration it imparts to the skin (jaundice),
ent sites. A diagram showing the major contributors to ammo-
and is an important marker of several disease states, some of
nia levels is shown in Figure 57–5. Note that the liver is
which center on the liver. It is important to distinguish whether
efficient in taking up ammonia from the portal blood in
the plasma contains increased levels of conjugated bilirubin,
health, leaving only approximately 15% to spill over into the
unconjugated bilirubin, or both, in order to define the mecha-
systemic circulation.
nism of disease. This can be assessed directly, but clues can
also be provided by the presence of bilirubin in the urine,
which imparts a brown coloration. Because of its less avid INTESTINAL PRODUCTION
binding to albumin, an increase in urinary bilirubin reflects
almost exclusively the conjugated molecule. In general, because The major contributor to plasma ammonia is the intestine,
conjugated bilirubin can be excreted in the urine, increases in supplying about 50% of the plasma load. Intestinal ammonia
its plasma levels represent a less serious state than those asso- is derived via two major mechanisms. First, ammonia is
ciated with severe unconjugated hyperbilirubinemia. An algo-
rithm for the differential diagnosis of hyperbilirubinemia that
takes account of these factors is presented in Figure 57–4.

BASIC PRINCIPLES OF
AMMONIA METABOLISM
Ammonia (NH3) is a small metabolite that results predominantly
from protein degradation. It is highly membrane permeable and
readily crosses epithelial barriers in its nonionized form. Renal
Intestinal
production
production
40%
(mostly colonic)
ROLE AND SIGNIFICANCE 50%

Ammonia is important clinically because it is highly toxic to

the nervous system. Because ammonia is being formed con-
stantly from the deamination of amino acids, it is important
that mechanisms exist to provide for its timely and efficient Red
disposal. The liver is critical for ammonia catabolism because blood Muscle
cells 5%
it is the only tissue in which all elements of the urea cycle, also
5%
known as the Krebs–Henseleit cycle, are expressed, providing
for the conversion of ammonia to urea. Ammonia is also con- FIGURE 57–5 Sources of ammonia production. (Reproduced
sumed in the synthesis of nonessential amino acids, and in with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange
various facets of intermediary metabolism. Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
 CHAPTER 57 Handling of Bilirubin and Ammonia by the Liver 579

Net reaction
Hepatocyte 2NH3 + CO2 = Urea + H2O

NH3 O NH3+

ATP H2N C NH (CH2)3 CH COO−

P
HCO3− ADP O O
Citrulline
Aspartate
1
+
NH4 H2N C O P O− 2
1
Carbamoyl AMP
Mitochondrion O−
phosphate
COO− NH2+ NH3+
OOC CH2 CH NH C NH (CH2)3 CH COO−
Arginine succinate
3
Ornithine NH3+ Fumarate
+
−
H3N (CH2)2 CH COO
NH2+ NH3+
H2N C NH (CH2)3 CH COO−
Arginine
Urea cycle
4 H 2O

O
Cytosol
H2N C NH2
Urea
To circulation
1 Carbamoyl synthetase 2 Arginosuccinate synthetase 3 Arginine succinate lyase 4 Arginase
FIGURE 57–6 Whole body ammonia homeostasis in health. The majority of ammonia produced by the body is excreted by the kidneys in
the form of urea. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

liberated from urea in the intestinal lumen by enzymes UREA CYCLE

known as ureases. Ureases are not expressed by mammalian
cells, but are products of many bacteria, and convert urea to
ammonia and carbon dioxide. Second, after proteins are
digested by either host or bacterial proteases, further break-
down of amino acids generates free ammonia. Ammonia in
its nonionized form crosses the intestinal epithelium freely,
and enters the portal circulation to travel to the liver; how-
ever, depending on the pH of the colonic contents, a portion
of the ammonia will be protonated to ammonium ion.
Because the colonic pH is usually slightly acidic, the ammo-
nium is thereby trapped in the lumen and can be eliminated
in the stool.
EXTRAINTESTINAL PRODUCTION
The second largest contributor to plasma ammonia levels is
the kidney. You will recall from renal physiology that ammo-
nia transport by tubular epithelial cells is an important part
of the response to whole body acid–base imbalances (see
Chapter 47). Ammonia is also produced in the liver during
the deamination of amino acids. Minor additional compo-
nents of plasma ammonia derive from adenylic acid metabo-
lism in muscle cells, as well as glutamine released from
senescent red blood cells.
The most important site for ammonia catabolism is the liver,
where the elements of the urea cycle are expressed in hepato-
cytes. A depiction of the urea cycle is provided in Figure 57–6.
Ammonia is converted in the mitochondria to carbamoyl
phosphate, which in turn reacts with ornithine to generate cit-
rulline. Citrulline, in turn, reacts in the cytosol with aspar-
tate, produced by the deamination of glutarate, to yield
sequentially arginine succinate, and then arginine itself. The
enzyme arginase then dehydrates arginine to yield urea and
ornithine, the latter of which returns to the mitochondria and
can reenter the cycle to generate additional urea. The net reac-
tion is the combination of two molecules of ammonia with one
of carbon dioxide, yielding urea and water.
UREA DISPOSITION
A “mass balance” for the disposition of ammonia and urea is
presented in Figure 57–7. As a small molecule, urea can cross
cell membranes readily. Likewise, it is filtered at the glomeru-
lus and enters the urine. While urea can be passively reab-
sorbed across the renal tubule as the urine is concentrated, its
permeability is less than that of water such that only approxi-
mately half of the filtered load can be reabsorbed. Because of
580 SECTION VIII GI Physiology

Systemic
circulation ening of the liver alters several aspects of structure and func-
a l c ir c u l a ti o
tion. Indeed, alcohol abuse is one of the most important
15% P o rt n causes of chronic liver disease, and cirrhosis (irreversible
85% deposition of excess collagen in the liver) accounts for the
majority of all medical deaths among alcoholics. Most
NH3 ingested ethanol is metabolized rapidly in the liver. Products
of ethanol metabolism, most notably acetaldehyde, impair
n Urea several aspects of hepatocyte metabolic function, as well as
latio
cu producing oxidative stress and forming protein adducts that
cir
may trigger adverse immune reactions that lead to cell death.
c
mi
Syste

In its initial stages, alcoholic liver disease involves the accu-

25% Urea
75%
Proteins
+ portal triads with central veins, and small, regenerative nod-
Amino
acids
Urinary
excretion
as urea Fecal excretion
as ammonium ion
FIGURE 57–7 The urea cycle, which converts ammonia to
urea, takes place in the mitochondria and cytosol of hepatocytes.
(Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H:
Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
this, the kidney serves as the site where the majority of the
urea produced by the liver is excreted. However, some circu-
lating urea may also passively back diffuse into the gut, where
it is acted on by bacterial ureases to again yield ammonia and
water. Some of the ammonia generated is excreted in the form
of ammonium ion; the remainder is again reabsorbed to be
handled by the liver once more.
CLINICAL CORRELATION
A 55-year-old homeless man is brought to the emergency
room by the police because he has been found unrespon-
sive in the street. His friends state that he has been drinking
heavily. On physical examination, he is found to show signs
of malnutrition, and his skin and the sclera of his eyes have
a yellowish coloration. His abdomen is markedly distended,
and palpation shows that his liver is enlarged. Over the next
hour, he regains consciousness, but still shows signs of sig-
nificant confusion, and cannot supply his name, or identify
the day of the week or the current President. A counselor
comes to see him to discuss the likely adverse outcomes of
continued alcohol ingestion, and he is referred to a shelter
and a treatment program.
Chronic ingestion of excessive quantities of alcohol can
have insidious effects on hepatic function, as fibrotic hard-
mulation of fat in the liver. Ultimately, hepatic stellate cells
NH3 H
+ are activated to produce collagen, and this occurs chroni-
cally if ingestion of excessive amounts of alcohol continues.
In a subset of patients, hepatitis and fibrosis will progress to
NH4+ cirrhosis, characterized by fibrous bands connecting the
ules. Patients with alcoholic liver disease that has progressed
at least to hepatitis and fibrosis present with a spectrum of
symptoms of chronic liver failure, including jaundice, nau-
sea, and malaise. Male patients may have hypogonadism
and feminization, ascribable to both the direct toxic effects
of ethanol on testicular Leydig cells and effects on estrogen
production and reduced estrogen breakdown. In severe
cases, there can be a collection of fluid in the abdominal
cavity known as ascites that may become infected (see
Chapter 55), hepatic encephalopathy, renal failure, and
eventually death. The primary treatment is to secure absti-
nence from alcohol, although some liver changes may be
irreversible even after drinking has stopped.
When ammonia degradation is reduced, it can accumu-
late in the plasma to levels that become toxic to the central
nervous system. Remember that ammonia, as a small, neu-
tral molecule, is relatively permeable across cell membranes
and can easily traverse the blood–brain barrier. Patients
will experience a gradual decline in mental status with con-
fusion and dementia, followed eventually by coma if the
condition is untreated. The increase in plasma ammonia in
liver disease occurs by two mechanisms. First, if hepatocyte
function is compromised, there is less capacity to degrade
ammonia coming from the intestine and extraintestinal
sites. Second, if blood flow through the liver is impaired by
cirrhosis and portal hypertension has set in (see also Chap-
ter 55), collateral blood vessels may form that shunt the
portal blood flow around the liver, bypassing the residual
capacity of the liver to degrade ammonia. It is likely that
both mechanisms contribute to the rise in plasma ammo-
nia in the setting of long-standing liver disease.
Because the intestine supplies the largest load of ammo-
nia to the circulation, treatments for hepatic encephalo–
pathy focus primarily on reducing the delivery of ammonia
into the portal circulation. A common technique is to give
a sugar, lactulose, which cannot be degraded by mamma-
lian digestive enzymes but is broken down by bacteria in
 CHAPTER 57 Handling of Bilirubin and Ammonia by the Liver 581

2. A 2-year-old boy is brought to the pediatrician because his

the colon to form short-chain fatty acids. In turn, the pH of mother has noted a persistent, dark brown coloration of his
the colonic lumen is decreased, and more of the ammonia urine. He is otherwise healthy, and his mother notes that a
being formed in that site is protonated and “trapped” as cousin displayed similar symptoms. Tests reveal conjugated
ammonium ion to be lost to the stool. Similarly, patients hyperbilirubinemia. Bile produced by this child would be
can be given a nonabsorbable antibiotic such as neomycin expected to display which of the following changes in
that reduces the level of bacterial colonization in the intes- composition compared with that of a normal child?
tine, thereby reducing ammonia production. Finally,
patients with liver disease are often advised to follow a low- Bilirubin Urobilinogen Bile Acids
protein diet, again in an effort to reduce ammonia produc- A) Decreased Decreased Decreased
tion in the intestine. Ultimately, however, the only lasting
B) Increased Increased Increased
treatment for hepatic encephalopathy is a liver transplant,
and mental symptoms often are reversible if they have not C) Decreased Increased Decreased
been too long-standing. Nevertheless, transplantation D) Increased Decreased Increased
remains controversial in alcoholic patients.
E) Decreased Decreased Unchanged

F) Increased Increased Unchanged

CHAPTER SUMMARY 3. In health, ammonia formed in the colon is partially excreted in

■ Bilirubin is a highly insoluble antioxidant produced by the the stool. Which of the following allows for this excretion?
metabolism of heme. It is derived mostly from senescent red A) limited diffusion of ammonia across colonocytes
blood cells and circulates with albumin. B) short-chain fatty acid production
■ Bilirubin is taken up into hepatocytes, conjugated with C) active secretion of ammonia by colonocytes
glucuronide, and transported across the bile canaliculus by D) absorption of ammonium ions
MRP2. Conjugation increases the solubility of bilirubin and E) uptake by bacteria
prevents its reuptake from the intestinal lumen. 4. A 70-year-old man with long-standing alcoholic liver disease is
■ Only conjugated bilirubin is transported into the bile, but both noted to have progressively worsening confusion and
conjugated and unconjugated bilirubin may regurgitate from disorientation. Loss of the function of which cell type accounts
the hepatocyte into the plasma. for his altered mental state?
■ Bilirubin is deconjugated and further metabolized by colonic A) Kupffer cells
bacteria; some of the products may circulate enterohepatically— B) hepatocytes
notably urobilinogen, which also enters the urine. C) colonocytes
■ Hyperbilirubinemia can arise from an increase in the plasma D) vascular endothelial cells
levels of conjugated bilirubin, unconjugated bilirubin, or both, E) stellate cells
and often reflects liver disease. 5. A patient with severe portal hypertension is noted to have
■ Ammonia in plasma is derived from protein degradation and bulging veins that protrude into his esophagus (esophageal
deamination of amino acids, as well as from metabolism of varices) on endoscopic examination. He is treated surgically by
urea by bacterial ureases. The intestine supplies the majority of the placement of a shunt connecting the portal vein to the vena
plasma ammonia. cava. Which of the following will pertain after the surgery
compared with before?
■ Excessive amounts of ammonia in the circulation are toxic to
the central nervous system, so circulating levels are carefully
regulated in health. Risk of Encephalopathy Risk of Variceal Bleeding
■ The liver is the site of ammonia catabolism via the Krebs– A) Increased Decreased
Henseleit, or urea, cycle. The urea produced is mostly excreted
B) Decreased Decreased
by the kidneys.
C) Unchanged Decreased

D) Increased Increased
STUDY QUESTIONS E) Decreased Increased
1. A newborn infant is noted to be suffering from mild jaundice,
F) Unchanged Increased
but no bilirubin is found in the urine. The child’s symptoms are
most likely attributable to a developmental delay in the
expression or establishment of which of the following?
A) colonic bacterial colonization
B) MDR2
C) UGT
D) heme oxygenase
E) biliverdin reductase
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 58
C H A P T E R

Digestion and Absorption

of Carbohydrates, Proteins,
and Water-soluble Vitamins
Kim E. Barrett

O B J E C T I V E S

■ Understand the barriers to assimilation of water-soluble macromolecules

into the body.
■ Describe dietary sources of carbohydrates, and the pathways involved in the
digestion and absorption of carbohydrate polymers, dietary disaccharides,
and monosaccharides.
■ Compare and contrast protein assimilation with that of carbohydrates.
■ Identify essential amino acids, and understand why they must be provided
in the diet.
■ Describe pathways involved in the digestion and absorption of proteins,
peptides, and amino acids.
■ Understand how protein assimilation is regulated.
■ Define how key water-soluble vitamins are taken up into the body.

BASIC PRINCIPLES OF TABLE 58–1 Nutritionally important carbohydrates.

CARBOHYDRATE AND Starch
Amylose
PROTEIN ASSIMILATION Amylopectin

ROLE AND SIGNIFICANCE Disaccharides

Sucrose
Lactose
Carbohydrates and proteins are water-soluble macromolecules
Monosaccharides
of nutritional significance. Together with lipids, discussed in
Glucose
the next chapter, they represent the major sources of calories Galactose
in the diet, and each supplies specific building blocks for mol- Fructose
ecules needed for the physiologic function of the body as a Dietary fiber
whole. Dietary carbohydrates are the major exogenous source
of glucose, which is utilized by cells as an energy source. Nutri-
tionally significant carbohydrates include both large polymers While the body can synthesize glucose de novo from a variety
and disaccharides (Table 58–1). Proteins supply amino acids, of substrates, some amino acids (essential amino acids) can-
which are resynthesized into new proteins needed by the body. not be synthesized by the body.

583

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584 SECTION VIII GI Physiology
BARRIERS TO THE ASSIMILATION OF
WATER-SOLUBLE MACROMOLECULES
Due to their hydrophilicity, proteins and carbohydrates are “at
home” in the aqueous environment of the intestinal lumen.
However, neither they nor the water-soluble end products of
their digestion can readily traverse the membranes of the epi-
thelial cells that line the small intestine. Moreover, intact
dietary polymers are too large to be transported into cells.
Thus, an ordered series of chemical reactions breaks down
both proteins and carbohydrate polymers to their component
monomers or short oligomers. Digestion of both carbohy-
drates and proteins takes place in two sites. First, enzymes
secreted into the intestinal lumen begin the digestive process.
Second, membrane-bound hydrolases localized to the
microvillous membrane (“brush border”) of the epithelial
cells lining the villus tips in the small intestine mediate the
next stage of digestion. The epithelium is only capable of trans-
porting monosaccharides, so even dietary disaccharides must
be digested at the brush border before they can be absorbed.
For proteins, on the other hand, the epithelium expresses
transporters that can take up short peptides, as well as those
specific for monomeric amino acids. Thus, peptides taken up
into the enterocytes undergo a third stage of digestion in the
cytosol, mediated by intracellular hydrolases.
CARBOHYDRATE ASSIMILATION
SOURCES OF
CARBOHYDRATE IN THE DIET
Carbohydrates represent a major component of most human
diets, and assume particular importance in specific popula-
tions (Table 58-1). There are three main forms of carbohydrate
that have nutritional significance—starch, sucrose, and lac-
tose. Starch is the name given to a complex mixture of dietary
polymers of glucose derived from plant sources, such as cere-
als and starchy vegetables. There are two different types of glu-
cose polymers in starch, which is significant because they
require different enzymes to digest them fully. About 25% of
starch consists of amylose, which is composed of simple,
straight-chain polymers of glucose (Figure 58–1A). The
remainder of the nutritional portion of starch consists of amy-
lopectin, which is composed of complex, branched polymers
of glucose (Figure 58–1A).
Sources of starch also supply other carbohydrate polymers,
as well as noncarbohydrate polymers, that collectively are
known as dietary fiber. Fiber is characterized by the fact that
constituent polymers cannot be degraded by mammalian
digestive enzymes. It is critical for intestinal health because,
being indigestible in the small intestine, it remains in the
lumen and provides bulk to the stool, retaining fluid and aid-
ing passage of the fecal material through the colon. Fiber has
additional nutritional significance in that, although it is not
subject to digestion by mammalian enzymes, it can be broken
down by hydrolases expressed by certain colonic bacteria.
These reactions generate short-chain fatty acids, which are
important energy sources for colonocytes.
LUMINAL DIGESTION
OF CARBOHYDRATE
Salivary Digestion
Digestion of carbohydrates begins in the mouth. Saliva con-
tains a 56-kd amylase enzyme that is closely related to the
55-kd amylase that is secreted into the pancreatic juice. As its
name implies, salivary amylase is capable of digesting amy-
lose, the straight-chain component of starch. Salivary amylase
is not essential for the normal digestion of carbohydrates,
since all of the enzymes in the pancreatic juice are present in
considerable excess of requirements. However, the salivary
enzyme likely does assume an important role in infants, where
there is a developmental delay in the production of pancreatic
enzymes, and as a backup in patients with pancreatic insuffi-
ciency, such as in those with cystic fibrosis.
Salivary amylase is quite sensitive to acidic pH. However, its
activity can be protected if its substrate occupies the active site
of the enzyme. Thus, while starch is present in the gastric
lumen, it is likely that its digestion mediated by salivary amy-
lase can continue, until the task is assumed by pancreatic amy-
lase. The latter is also sensitive to acid, but acts in an
environment where gastric juices have been neutralized by
duodenal, pancreatic, and biliary bicarbonate secretion.
The synthesis and secretion of salivary amylase in the serous
cells of the salivary glands are regulated by neurohumoral sig-
nals coincident with ingestion of a meal. Interestingly, in com-
mon with the pancreatic isoform, the synthesis of salivary
amylase is upregulated by carbohydrate ingestion. Thus, the
substrate controls the availability of the means of its digestion.
Intestinal Digestion
In health, the majority of starch digestion likely involves the
55-kd amylase that is secreted as an active enzyme into the
pancreatic juice by pancreatic acinar cells (see Chapter 51).
Both the pancreatic and salivary enzymes act rapidly to cleave
starch into a mixture of products, depending on whether amy-
lose or amylopectin is the substrate. The amylase enzymes tar-
get internal α-1,4 bonds of both molecules, but the terminal
bonds, as well as the α-1,6 bonds that provide for the branched-
chain structure of amylopectin, are resistant (Figure 58–1A).
This means that while the action of amylase is rapid, none of
the products it generates can immediately be absorbed by the
enterocytes, since the epithelium can only transport monosac-
charides. By the time the meal reaches the proximal small
intestine, therefore, digestion of starch will generate a mixture
of maltose (a dimer of glucose), maltotriose (a trimer of glu-
cose), and α-limit dextrins, which are the simplest structures
that can be derived from the branch points in amylopectin.
 CHAPTER 58 Digestion and Absorption of Carbohydrates, Proteins, and Water-soluble Vitamins 585

A B
Glucose Maltose
α1,4 bond 1
Maltotriose
Amylose
Glucoamylase
Sucrase
Isomaltase

Amylase

α1,6 bond 2
Amylopectin
α-limit dextrin

Glucoamylase

Maltose

Maltotriose +
Glucose oligomers
Isomaltase

+
α-limit dextrin Glucoamylase
Sucrase
Isomaltase

FIGURE 58–1 A) Structure of amylose and amylopectin, which are polymers of glucose (indicated by circles). These molecules are
partially digested by the enzyme amylase, yielding the products shown at the bottom of the figure. B) Brush border hydrolases responsible for
the sequential digestion of the products of luminal starch digestion. Glucose monomers are indicated by circles. Panel 1 depicts the digestion of
linear oligomers of glucose; panel 2 shows the final steps in digestion of α-limit dextrins. (Reproduced with permission from Barrett KE, Barman SM, Boitano
S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

Both maltose and maltotriose are resistant to amylase as they
contain only terminal, and no internal, α-1,4 bonds.
BRUSH BORDER DIGESTION
OF OLIGOSACCHARIDES
AND DISACCHARIDES
The products of luminal starch digestion, as well as dietary
disaccharides, then are acted on by specific hydrolases present
on the enterocyte brush border. Brush border digestion is an
essential component of the pathways leading to assimilation of
all dietary carbohydrates, with the exception of glucose. Brush
border hydrolysis of carbohydrates, as well as other dietary
components, likely increases the efficiency of carbohydrate
absorption because the monosaccharides generated are pro-
duced in close proximity to the transporters that are then
required for their uptake. Likewise, this may also sequester
digested monosaccharides from the limited numbers of small
intestinal bacteria.
Brush border hydrolysis is catalyzed by a series of enzymes
that are synthesized in the enterocytes as they differentiate
along the crypt–villus axis, with highest expression in the
villus tips as well as in the proximal part of the small intestine.
The enzymes are trafficked specifically to the apical mem-
brane of the cells in these sites and anchored in the membrane
by a single transmembrane segment. Brush border hydrolases
are also heavily glycosylated. This may protect them, to some
degree, from proteolysis. The enzymatic activities involved in
brush border hydrolysis include sucrase, isomaltase, glu-
coamylase, and lactase. Sucrase and isomaltase activities are
actually encoded in a single polypeptide chain with two dis-
tinct active sites, and thus the complete protein is referred to
as sucrase-isomaltase. Overall, the brush border hydrolases
cooperate to facilitate the complete digestion of dietary car-
bohydrates and the products derived from their luminal
digestion.
Glucose Oligomers and α-Limit Dextrins
The final digestion of these products of amylose and amylo-
pectin digestion involves the concerted action of several brush
border enzymes (Figure 58–1B). Glucoamylase, sucrase, and
isomaltase activities are all capable of digesting the bonds
586 SECTION VIII GI Physiology
1
Sucrase
Isomaltase
Brush border
membrane
Glucose
Fructose
2
Lactase
FIGURE 58–2 Brush border digestion
and assimilation of the disaccharides sucrose
(panel 1) and lactose (panel 2). SGLT-1,
sodium-glucose cotransporter-1. (Reproduced with
permission from Barrett KE, Barman SM, Boitano S, Brooks
H: Ganong’s Review of Medical Physiology, 23rd ed.
McGraw-Hill Medical, 2009.)
contained in linear, short-chain (2–9 sugar units) oligomers of
glucose, which include maltose and maltotriose. However,
isomaltase is critical for the full digestion of starch, since it is
unique among the listed activities in being able to cleave not
only the α-1,4 bonds of linear glucose oligomers, but also the
α-1,6 bonds of the α-limit dextrins. Glucose uptake is then
mediated by SGLT-1, the sodium/glucose cotransporter.
This cotransporter takes advantage of the low intracellular
sodium concentration established by the basolateral Na,K-
ATPase to accumulate glucose in the cytosol against a concen-
tration gradient (i.e., uphill transport).
Sucrose
Sucrose (table sugar) is a prominent carbohydrate in many
Western diets and requires no luminal digestion because it is a
simple disaccharide consisting of glucose and fructose. Rather,
it is specifically digested at the level of the brush border by the
enzyme sucrase, yielding the respective monosaccharides
(Figure 58–2). Expression of sucrase-isomaltase is usually in
excess of the requirements for this enzyme, at least in Western
populations that emphasize sucrose in the diet. This means
that the rate-limiting step for sucrose assimilation is not
its hydrolysis, but rather the uptake of the released products
Sucrose
Na+
SGLT-1 GLUT5
Cytosol
Lactose
Na+
SGLT-1
Cytosol
Glucose
Galactose
across the apical membrane of the enterocyte. This is particu-
larly the case for fructose, which enters the cytosol not via the
SGLT-1 transporter, but rather via a sodium-independent,
facilitated diffusion pathway (GLUT5).
Lactose
Lactose is an important nutrient in those who consume large
quantities of milk, such as infants. It is a disaccharide that con-
sists of glucose and galactose and is broken down at the brush
border by lactase, an enzyme that contains two identical active
sites within a single polypeptide chain. The products of this
hydrolysis reaction are, in turn, both substrates for SGLT-1
and thus can be accumulated against a concentration gradient
(Figure 58–2).
Lactose assimilation is limited in two important ways. First,
there is a developmental decline in lactase expression, meaning
that levels of this enzyme in adulthood may be inadequate to
hydrolyze all of the substrate presented to them. Thus, lactose
hydrolysis, rather than transport of the products of this reac-
tion, is usually rate limiting for assimilation. Second, the activity
of lactase is inhibited by glucose, in a process known as “end-
product inhibition.” If glucose levels increase in the vicinity of
the enzyme, breakdown of lactose will further be inhibited.
 CHAPTER 58 Digestion and Absorption of Carbohydrates, Proteins, and Water-soluble Vitamins
MONOSACCHARIDE UPTAKE
PATHWAYS
The final steps in carbohydrate assimilation involve specific
membrane transport pathways that permit uptake of these
hydrophilic molecules across the enterocyte apical membrane,
as well as mediating their transfer out of the enterocyte across
the basolateral membrane and thence into the portal circula-
tion. We have already discussed two of these transporters,
SGLT-1 and GLUT5. SGLT-1 is synthesized by villus entero-
cytes but not by those in the crypts, likely as a result of tran-
scriptional regulatory mechanisms that parallel those involved
in establishing brush border hydrolase expression. It exists in
the membrane as a homotetramer, which appears to be impor-
tant for its function. The protein mediates the ordered transfer
of both sodium and glucose across the membrane. Sodium
binds first to an extracellular site on the transporter, followed
by glucose, which triggers a conformational change in the pro-
tein. This transfers these substrates to the cytoplasmic face of
the membrane, where first glucose, and then sodium, can dis-
sociate into the cytosol. Transporters of the GLUT family also
play important roles in carbohydrate assimilation. The portion
of absorbed glucose that is not needed for immediate energy
needs of the enterocyte exits the cell across the basolateral
membrane via a facilitated diffusion pathway (GLUT2). GLUT2
is sodium-independent, and thus the movement of glucose
through this transporter will depend only on the relative con-
centrations of the sugar inside and outside the cell. It is also
expressed in many other cell types throughout the body, where
it participates in glucose uptake. A related molecule, GLUT5,
provides for the brush border uptake of the fructose that is gen-
erated from the hydrolysis of sucrose (Figure 58–2). GLUT5 is
also present in the basolateral membrane and thus can mediate
transfer of fructose to the bloodstream, although there is evi-
dence that fructose is additionally a substrate for GLUT2.
REGULATION OF CARBOHYDRATE
ASSIMILATION
Developmental
In humans, the machinery for brush border digestion and
absorption of carbohydrates is all in place before birth. How-
ever, the capacity for luminal digestion of carbohydrates is regu-
lated in the postnatal period. Expression of pancreatic amylase
is low in infants below the age of 1 and is gradually induced as
starch is added to the diet. Conversely, lactase levels in the brush
border decline after weaning. However, both of these responses
likely do not reflect strict developmental regulation, but rather
are appropriate adaptive responses to the appearance or disap-
pearance of the relevant substrates in the normal diet.
Dietary
The various components of the systems involved in carbohy-
drate assimilation are regulated by the diet in both the short
587
and long terms. Acutely, brush border hydrolases on the sur-
face of enterocytes are degraded at the end of the meal, when
dietary protein is no longer available to compete for the activ-
ity of pancreatic proteases. These enzymes are then resynthe-
sized by the enterocyte to ready the epithelium to handle
carbohydrates in the next meal. This cycle of degradation and
resynthesis is not specific for the enzymes involved in carbo-
hydrate digestion, but occurs for the entire complement of
brush border proteins needed for nutrient assimilation. On
the other hand, and on a longer time scale, if carbohydrates are
specifically withheld from the diet, there is a gradual decline in
the expression of the hydrolases and transporters that are
involved in the assimilation of this class of nutrients, and likely
also in the expression of amylase. All of these components are,
in turn, upregulated if carbohydrate is then returned to the
diet. These long-term changes are specific for the nutrient
withdrawn from the diet. There are also hormonal influences
on the expression of brush border hydrolases and transporters
that match the capacity for carbohydrate assimilation with the
body’s needs. Insulin, in particular, appears to suppress the
levels of these molecules, meaning that glucose assimilation
can be enhanced in the setting of type I diabetes mellitus.
PROTEIN ASSIMILATION
COMPARISON WITH CARBOHYDRATE
ASSIMILATION
The digestion and absorption of proteins and carbohydrates
shares many similar features, since both are water-soluble
macromolecules, including a role for both luminal and brush
border digestion and the presence of specific transporters in
the apical membranes of enterocytes that take up the products
of these digestion reactions. However, there are also important
differences. First, the 20 naturally occurring amino acids,
compared with the 3 nutritionally significant monosaccha-
rides, mean that proteins represent a significantly more diverse
set of substrates and require a broader spectrum of peptidases
and transporters to mediate their digestion and uptake. Sec-
ond, the intestine is capable of transporting not only single
amino acids, but also short oligomers, encompassing dipep-
tides, tripeptides, and perhaps even tetrapeptides. In fact,
some amino acids are absorbed much more efficiently in the
form of peptides than as the single molecules. Finally, the exis-
tence of peptide transport in the intestine implies that these
molecules must eventually be digested to their component
amino acids in order for them to be useful to other body tis-
sues. This final stage of protein digestion takes place in the
cytosol of the enterocyte.
Essential Amino Acids
Another important concept when considering protein assimi-
lation is that of the essential amino acid. While the body (prin-
cipally the liver) is able to convert one amino acid to another,
588 SECTION VIII GI Physiology
Neutral
FIGURE 58–3 Naturally occurring amino acids
organized on the basis of their physicochemical
properties. Residues that are boxed are essential
amino acids that must be obtained from dietary
Aliphatic
sources by humans. (Reproduced with permission from Gly, Ala
Barrett KE: Gastrointestinal Physiology. New York: Lange Medical
Val , Leu , Ile
Books/McGraw-Hill, Medical Pub. Division, 2006.)
nine of the naturally occurring amino acids cannot be synthe-
sized de novo, and therefore must be obtained from the diet
and absorbed either as the amino acid itself or in peptide form
(Figure 58–3). Proteins derived from animal sources contain
all of the essential amino acids. However, proteins from vege-
table sources are “incomplete,” meaning that they lack one or
more of the essential amino acids.
LUMINAL PROTEOLYSIS
Gastric
Digestion of dietary proteins begins in the stomach—there are
no nutritionally significant proteolytic enzymes found in the
saliva. As we learned in Chapter 50, on the other hand, the
chief cells of the gastric glands synthesize and store pepsino-
gens, inactive precursors of pepsins, which are a group of
related proteolytic enzymes especially suited to action in the
stomach. At low pH, there is autocatalytic cleavage of an
N-terminal peptide from pepsinogen that yields the active
form. Pepsins preferentially cleave dietary proteins at neutral
amino acids, with a preference for large aliphatic or aromatic
side chains. They are also sensitive to the pH of their environ-
ment, and are inactivated above a pH of 4.5. This means that
gastric pepsins are quickly inactivated once they enter the
small intestine, which may be important to prevent digestion
of the epithelium.
Because of the relatively limited specificity of pepsins, gas-
tric proteolysis results in incomplete digestion with only a few
free amino acids; the products are mostly large, nonabsorbable
peptides. And in common with other aspects of the gastroin-
testinal system that are either redundant or present in excess,
gastric proteolysis does not appear to be essential for normal
levels of protein assimilation.
Intestinal
The bulk of proteolysis occurs in the small intestinal lumen.
This is a highly ordered process mediated by two families of
pancreatic proteases, the secretion of which we discussed in
Chapter 51. Endopeptidases cleave proteins and peptides at
internal amide bonds. Ectopeptidases cleave at the terminal
amino acid. All of the ectopeptidases secreted by the pancreas
are carboxypeptidases—that is to say, they cleave off the
Amino acids
Basic Acidic
Arg
Lys , His
Glu, Gln
Asp, Asn
Aromatic Hydroxyl Sulfur Imino
Tyr Ser Cys Pro
Phe , Try Thr Met Hydroxypro
amino acid located at the C-terminus. Despite their various
specificities, however, all of the pancreatic peptidases have one
important feature in common. They are all stored in the pan-
creatic acinar cells as inactive precursors, which apparently is
important to prevent autodigestion of the pancreas.
How then are these inactive enzymes converted to their
active forms only when they are in small intestinal lumen? The
answer lies in yet another proteolytic enzyme—enterokinase—
expressed on the apical membrane of small intestinal epithe-
lial cells. When the pancreatic juice is secreted into the
intestine, it comes into contact with enterokinase, which
cleaves an N-terminal hexapeptide from trypsinogen, yield-
ing active trypsin. Trypsin, in turn, can then activate addi-
tional trypsin molecules as well as all of the other inactive
pancreatic peptidases only once they are in the intestinal
lumen (Figure 58–4).
The pathways of luminal proteolysis are shown in diagram-
matic form in Figure 58–5. Large peptides derived from gastric
proteolysis are sequentially cleaved by the endopeptidases
(trypsin, chymotrypsin, and elastase). These reactions yield
shorter peptides with either neutral or basic amino acids at
their C-termini, which can be acted on in turn by carboxypep-
tidase A or carboxypeptidase B, respectively. Thus, the prod-
ucts of proteolysis in the intestinal lumen consist of free basic
and neutral amino acids as well as short peptides that cannot
be cleaved further due to the lack of an appropriate amino acid
at their C-terminus. Approximately 60–70% of dietary protein
is in the form of small oligopeptides following luminal hydro-
lysis; the remainder is in the form of amino acids.
BRUSH BORDER HYDROLYSIS
Like carbohydrate assimilation, the degradation of proteins in
the lumen is incomplete and they also undergo a process of
brush border hydrolysis. However, because of the diversity of
possible substrates, there is the requirement for a much larger
number of brush border hydrolases. These membrane-bound
enzymes comprise both endopeptidases and ectopeptidases,
and are expressed by villus, but not crypt, enterocytes. The
activity of these enzymes yields free amino acids in the vicinity
of the enterocyte apical membrane, although some peptides
remain relatively resistant to hydrolysis, and are taken up in
their unhydrolyzed form.
 CHAPTER 58 Digestion and Absorption of Carbohydrates, Proteins, and Water-soluble Vitamins 589

Pancreatic juice

Enterokinase

Trypsinogen
Trypsin

Trypsinogen Trypsin

Chymotrypsinogen Chymotrypsin FIGURE 58–4 Mechanism to avoid

activation of pancreatic proteases until they
Proelastase Elastase are in the duodenal lumen. Trypsinogen is
cleaved by the enzyme enterokinase, which is
Procarboxypeptidase A Carboxy- expressed on the apical membrane of
peptidase A duodenal epithelial cells (depicted as the pair
of scissors).The trypsin that is thereby liberated
Procarboxypeptidase B Carboxy-
peptidase B can activate all of the other pancreatic
proteases. (Reproduced with permission from Barrett
KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of
Lumen Epithelium Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

UPTAKE MECHANISMS FOR substrate specificity, accommodating peptides of various sizes

OLIGOPEPTIDES AND AMINO ACIDS
Peptide Transporters
Perhaps the most fascinating aspect of protein assimilation is its
dependence, in part, on a remarkable peptide transporter desig-
nated as peptide transporter 1 (PEPT1) (Figure 58–6). This
protein is expressed on the apical membrane of enterocytes, and
mediates the proton-coupled uptake of a broad variety of short
peptides. What makes PEPT1 so intriguing is its extremely broad
and charges. Moreover, the stoichiometry of proton coupling can
change, depending on the net charge of the peptide being trans-
ported. On the other hand, transport is strictly stereospecific—
transport of peptides comprised of d-amino acids is negligible.
The activity of this transporter is nutritionally significant,
because it mediates the uptake of peptides resistant to brush bor-
der hydrolysis and thus increases the efficiency of protein assim-
ilation from the gut. Indeed, certain amino acids are much more
effectively absorbed in peptide form than when presented as
individual molecules, especially glycine and proline.

Ser
Carboxypeptidase A
Chymotrypsin Peptide with
Elastase C-terminal
neutral AA

Large Arg
peptides Ser
Short peptides
free neutral and
basic AA’s
FIGURE 58–5 Luminal digestion of
Trypsin
peptides resulting from partial proteolysis
Carboxypeptidase B
in the stomach. Individual amino acid
Arg residues are shown as squares. (Reproduced with
Peptide with permission from Barrett KE, Barman SM, Boitano S,
C-terminal Brooks H: Ganong’s Review of Medical Physiology, 23rd
basic AA ed. McGraw-Hill Medical, 2009.)
590 SECTION VIII GI Physiology
Na+ 3Na+
NHE
H+ 2K+
Cytosolic
digestion
H+
PEPT1
Basolateral
amino acid
Di-, tripeptides transporters
FIGURE 58–6 Disposition of short peptides in intestinal
epithelial cells. Peptides are absorbed together with a proton
supplied by an apical sodium/hydrogen exchanger (NHE) by the
peptide transporter 1 (PEPT1). Absorbed peptides are digested by
cytosolic proteases, and any amino acids that are surplus to the needs
of the epithelial cell are transported into the bloodstream by a series
of basolateral transport proteins. (Reproduced with permission from Barrett
KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed.
McGraw-Hill Medical, 2009.)
Amino Acid Transporters
Despite the significance of peptide uptake in the intestine,
many amino acids are absorbed predominantly in molecular
form. The physiology of amino acid transport in the intestine
was at one time a complex topic, given the diversity of trans-
porters that had been defined only functionally as well as some
overlapping specificities. Moreover, some, but not all, amino
acid transporters are sodium-dependent, analogous to SGLT-1
that we considered earlier for glucose uptake as well as the
sodium-dependent bile acid transporter that recovers these
molecules in the distal ileum. Others, analogous to PEPT1,
may transport specific amino acids in concert with one or
more protons. Finally, some amino acid transporters clearly
have properties that classify them as facilitated diffusion path-
ways or even channels.
More recently, some clarity has been brought to this field by
molecular cloning of a large number of amino acid transport
proteins from the gut, and their organization into families. We
now know that there are multiple transport systems for neu-
tral, cationic, and anionic amino acids, with each system being
distinct but exhibiting overlapping specificity. However, it is
beyond the scope of an introductory course in physiology to
discuss all of these transporters in detail.
CYTOSOLIC PROTEOLYSIS
Peptides absorbed into the enterocyte cytosol are further
degraded before passing into the portal circulation. A portion
of the released amino acids, as well as those taken up in molec-
ular form, may also be utilized locally for the enterocyte’s own
needs for protein synthesis. Peptide breakdown is mediated by
a series of cytosolic peptidases that act to cleave N-terminal
amino acids from these molecules, such as amino dipeptidases
and amino tripeptidases. A cytosolic propeptidase, which
hydrolyzes absorbed proteins that contain proline, has also
been identified. Recall that peptides containing proline (and
glycine) are relatively resistant to luminal or brush border
hydrolysis.
REGULATION OF PROTEIN
ASSIMILATION
Many of the factors that regulate carbohydrate assimilation
have analogous effects on protein assimilation. For example,
brush border hydrolases, peptide transporters, and amino acid
transporters can be degraded by proteolytic enzymes; these
molecules are then resynthesized by the enterocyte to partici-
pate in the digestion and absorption of the next meal. Simi-
larly, the membrane proteins involved in protein assimilation
are expressed in gradients along the proximal to distal and
crypt to villus axes.
WATER-SOLUBLE VITAMIN
ASSIMILATION
Vitamins are molecules that cannot be synthesized by the
body, but which are essential to normal metabolism. Many act
as cofactors for specific biochemical reactions, or play other
critical roles in the body. Like essential amino acids, most vita-
mins must be obtained from dietary sources. We will consider
here the uptake of two key water-soluble vitamins, since this
process is analogous to the assimilation of the end products of
carbohydrate and protein digestion. Lipid-soluble vitamins
will be discussed in the next chapter.
VITAMIN C
Vitamin C (ascorbic acid) acts as an antioxidant in the
body as well as participates in a number of hydroxylation
reactions. It is obtained from a variety of dietary sources,
including citrus fruits and several vegetables. Having a pKa
of 4.2, it is ionized at the pH of the small intestinal lumen
and thus its passive diffusion across the epithelium is negli-
gible. Thus, specific transport mechanisms exist to ensure
its assimilation.
Uptake of vitamin C is predominantly localized to the ileum.
Ascorbic acid is transported across enterocyte apical mem-
branes via a family of sodium-coupled cotransporters (SVCT1
and SVCT2), and uptake is controlled by intracellular signals.
Vitamin C uptake is also regulated by its own levels in the
body. Thus, supplementation with this vitamin, either orally
or via injection, leads to a decrease in intestinal capacity for its
transport. This finding implies that, unlike nutrient uptake,
the intestine displays a capacity to allow for “vitamin homeo-
stasis,” maintaining whole body levels of vitamins at a rela-
tively stable level.
 CHAPTER 58 Digestion and Absorption of Carbohydrates, Proteins, and Water-soluble Vitamins 591

VITAMIN B12 (COBALAMIN)
Another water-soluble vitamin of note is vitamin B12, which is
utilized by all cells in its coenzyme form in various metabolic
reactions. Unlike vitamin C, whose uptake occurs via a simple,
sodium-coupled mechanism, the uptake of cobalamin is more
complex, and requires the participation of a specific binding
factor secreted by parietal cells, known as intrinsic factor.
Intrinsic factor secretion is triggered in the stomach by the
same neurohumoral cues that result in gastric acid secretion.
Intrinsic factor then binds to dietary cobalamin and later pro-
vides for the uptake of this vitamin. In an analogous fashion,
cobalamin in the circulation is bound to a separate protein,
plasma transcobalamin II (TC II). Specific receptors exist to
mediate the endocytosis of cobalamin bound to each of these
carrier proteins.
Here, of course, we are chiefly concerned with the processes
mediating cobalamin uptake from the intestinal lumen (Fig-
ure 58–7). In the gastric lumen, cobalamin is released from
Food-bound
Cbl
dietary proteins and binds initially to the R-binding protein
(also known as haptocorrin), forming a complex that is stable
at the acidic pH at this site. R-binding protein derives pre-
dominantly from the salivary glands. Intrinsic factor cannot
bind to cobalamin at low pH. Rather, it follows the cobala-
min–R-binding protein complex into the duodenum, where
the R-binding protein is degraded by pancreatic proteases and
the cobalamin is transferred to intrinsic factor at the increased
pH that is brought about as gastric secretions are neutralized.
The N-terminus of intrinsic factor also contains a binding
sequence recognized by an apical receptor for this molecule
that is expressed by enterocytes, known as the intrinsic
factor-cobalamin receptor (IFCR). IFCR is highly expressed
in the terminal ileum. When the complex of intrinsic factor
and cobalamin binds to IFCR, the receptor plus the bound
ligand is internalized, and these are then directed to a vesicu-
lar pathway for sorting and trafficking. Intrinsic factor is
degraded, and the released cobalamin is then bound to TC II,
synthesized by the enterocyte. In turn, this new complex is
trafficked to the basolateral membrane, and released into the
circulation in this form. Cobalamin bound to TC II can in
turn be taken up via the specific receptor for this complex that
is ubiquitously expressed throughout the body.

Cbl bound
Acid pH CLINICAL CORRELATION
Biliary
Cbl Cbl free An 18-year-old, Asian American college freshman is living
R away from home for the first time. Having been brought up
in a household that emphasized a traditional Chinese diet,
R-Cbl and having been forbidden by his parents from indulging
+ Parietal
cells
in snacks and junk food, he is particularly excited by the
IF
secrete IF broad range of dishes to choose from in the cafeteria. He
becomes particularly enamored of cheese pizza and choco-
late ice cream. However, 2 weeks after the start of term, he
R∗ comes to the student health center complaining of frequent
Proteolytic Pancreatic proteases diarrhea, gas, and bloating. A physical exam reveals that he
degradation
of R protein is otherwise healthy and well nourished, and the patient
Cbl
denies any fever or bloody stools. Based on his history and
Cbl released
after R protein +IF IF-Cbl symptoms, a diagnosis of lactose intolerance is made.
degradation A deficiency in the ability to assimilate dietary lactose is
IF-Cbl complex forms a common disorder, particularly in specific ethnic groups
IF-Cbl
such as African-Americans and Asians who have not tradi-
tionally emphasized milk as a component of the adult diet.
lleal enterocyte
with receptor for Lactose intolerance arises secondary to the normal devel-
Enterocyte
IF-Cbl complex opmental decline in lactase-phlorizin hydrolase levels that
occurs after weaning, which occurs to a greater extent in
FIGURE 58–7 Sequential steps in the gastrointestinal some people than in others. In susceptible individuals,
absorption of vitamin B12 (cobalamin, Cbl). In the stomach, Cbl
ingestion of lactose in dairy products overwhelms the
binds salivary R protein and intrinsic factor (IF) secreted by parietal
cells. Proteolytic degradation of the R protein in the intestinal lumen capacity of the brush border lactase-phlorizin hydrolase to
yields a complex of only Cbl and IF, which then binds to a specific digest this disaccharide, leaving the undigested material in
receptor located in the apical membrane of epithelial cells lining the the small intestinal lumen from where it passes to the colon.
terminal ileum. (Reproduced with permission from Halsted CH, Lonnerdal BL: In the colon, commensal bacteria are highly active in
Vitamin and mineral absorption. In: Textbook of Gastroenterology, 4th ed. Yamada T, degrading lactose as an energy source, leading to symptoms
Alpers DH, Kaplowitz N, Laine L, Owyang C, Powell DW (editors). Philadelphia: of abdominal pain and bloating from the hydrogen and
Lippincott Williams and Wilkins, 2003.)
592 SECTION VIII GI Physiology

2. An infant with diarrhea is given a glucose and electrolyte solution

CO2 gases that are produced. The delayed production of orally. What membrane protein accounts for the ability of this
hydrogen (or labeled CO2) in the breath following lactose solution to provide rapid hydration?
ingestion can accordingly be used as a test for the presence A) sucrase-isomaltase
of lactose intolerance. B) SGLT-1
Patients with lactose intolerance who wish to consume C) CFTR
dairy products can do so without major discomfort if they D) chloride–bicarbonate exchanger
also take oral supplements of a lactase enzyme derived from E) lactase-phlorizin hydrolase
bacteria. This supplemental lactase is resistant to degrada- 3. Glucose–galactose malabsorption is a rare disorder caused by
tion by gastric acid, and thus is available in the small intes- mutations in SGLT-1. Infants with this disorder develop severe
tinal lumen to cleave dietary lactose into its component osmotic diarrhea if they consume certain carbohydrates. Of the
monosaccharides, which can then be absorbed by the small following, which would not be expected to cause symptoms in
intestine. these patients?
A) sucrose
B) glucose
C) amylopectin
CHAPTER SUMMARY D) lactose
E) fructose
■ Carbohydrates and proteins are water-soluble polymers that are
4. A child is brought to the pediatrician because of severe failure to
important sources of nutrition.
thrive, diarrhea, and edema of the extremities. Blood tests reveal
■ The end products of digestion are hydrophilic, and thus that he has low plasma protein concentration (hypoproteinemia).
specific transporters are needed to translocate them across the Duodenal aspirates are obtained at endoscopy after intravenous
plasma membrane of enterocytes. administration of cholecystokinin, and are found to be incapable
■ Both carbohydrates and proteins, with the exception of glucose of protein hydrolysis at neutral pH unless a small amount of
monomers, must be digested to allow for their uptake across trypsin is added. The patient is likely suffering from a congenital
the intestinal epithelium. lack of which of the following?
■ Only monosaccharides can be absorbed by the intestine, A) pepsinogen
whereas the intestine can assimilate short peptides in addition B) PEPT1
to free amino acids. C) trypsinogen
■ Digestion of both carbohydrates and proteins occurs in an D) carboxypeptidases
ordered series of distinct stages. E) enterokinase
■ Both luminal and brush border hydrolysis are important; the 5. A 75-year-old woman comes to her physician complaining of
latter may increase efficiency. progressively worsening fatigue and numbness in her fingers.
■ Absorbed peptides also undergo cytosolic digestion in the A blood test reveals that she is anemic, despite adequate iron
enterocyte. intake. Her symptoms resolve following a series of vitamin
injections. Her symptoms are consistent with an age-related
■ Water-soluble vitamins also undergo selective transport across
decline in synthesis of which of the following proteins?
the intestinal epithelium.
A) haptocorrin
B) intrinsic factor
C) transcobalamin
STUDY QUESTIONS D) SVCT1
1. Digestive enzymes can be secreted by the pancreas in active or E) PEPT1
inactive forms. Enzymes capable of digesting which of the
following nutrients are only secreted as inactive precursors?
A) starch
B) nucleic acids
C) proteins
D) triglyceride
E) cholesterol esters

Lipid Assimilation
Kim E. Barrett
O B J E C T I V E S
■ Understand the special barriers to absorption of lipids supplied in the diet.
■ Describe the phases of lipid digestion.
■ Describe events at the level of the intestinal epithelium that govern uptake
of different classes of lipids.
■ Understand how the products of lipolysis cross the brush border.
■ Delineate pathways for lipid processing in the enterocyte.
■ Describe how chylomicrons are formed and their eventual disposition.
GENERAL PRINCIPLES
OF LIPID ASSIMILATION
ROLE AND SIGNIFICANCE
Lipids are organic substances that are hydrophobic, and thus
are more soluble in organic solvents (or cell membranes) than
in aqueous solutions. They form an important part of most
human diets. First, they are denser in calories than either pro-
teins or carbohydrates, increasing the nutritional content of a
given meal. Second, the fat-soluble vitamins are lipids. Third,
many of the compounds that account for the flavor and aroma
of foods are volatile hydrophobic molecules, meaning that
lipids serve as an important vehicle to render food palatable.
BARRIERS TO ASSIMILATION
OF HYDROPHOBIC MOLECULES
The products of lipid digestion (lipolysis) are, in large part,
readily able to cross cell membranes to allow for absorption into
the body. However, lipids are not “at home” in the aqueous
milieu of the intestinal contents. Likewise, they must interact
with lipolytic enzymes that are themselves soluble proteins.
Finally, the products of lipolysis must arrive at the brush border
at a sufficient rate to allow for uptake before being propelled
along and out of the gut. Systems therefore exist to maintain
lipids in suspension in the gut contents with a sufficiently
Ch59_593-600.indd 593
59
C H A P T E R
dispersed surface area to allow for lipolysis at the oil/water inter-
face. Additional phase transitions allow for efficient trafficking
of lipids to the enterocyte surface, where they can be absorbed.
DIETARY AND ENDOGENOUS SOURCES
OF LIPIDS IN INTESTINAL CONTENT
Lipids represent a major source of calories in most Western
diets, with an average of 120–150 g consumed daily by a typi-
cal adult. On a daily basis, the intestine is also presented with
40–50 g of endogenous lipids arising from the biliary system.
Despite their hydrophobicity, the process of lipid assimilation
has evolved to be highly efficient, with significant reserve
capacity also present. The ready availability of lipid-rich foods
in developed countries is an important contributor to the bur-
geoning problem of obesity.
Lipids in the diet as well as in endogenous pools are com-
posed of several distinct molecular classes. The majority of
lipid in the diet is in the form of long-chain triglycerides (i.e.,
fatty acids with at least 12 carbon atoms each, esterified to glyc-
erol). Phospholipids, which are components of cell mem-
branes, are also significant contributors. Other, more minor
sources of dietary lipids include plant sterols (whose absorp-
tion may be inefficient) and cholesterol, another membrane
constituent that is present in the diets of all except vegans.
However, even vegans will encounter cholesterol in the intesti-
nal contents because it is secreted into the bile, along with the
593
11/26/10 10:27:50 AM
594 SECTION VIII GI Physiology

other biliary lipid, phosphatidylcholine. In fact, the endoge- 1

Gastric lipase
nous secretion of cholesterol of 1–2 g per day usually exceeds
dietary intake of 200–500 mg that is typical of most individuals. H2O
While fat-soluble vitamins are only present in trace amounts, O
their absorption is critical for a variety of body processes. The CH2 O C
fat-soluble vitamins are A, D, E, and K. Vitamin A (retinoic
O
acid) is an important regulator of gene transcription. The active
metabolite of vitamin D (calciferol) regulates calcium and CH O C
phosphate absorption by the intestine, and homeostasis of these O
ions throughout the body (see Chapters 48 and 64). Vitamin E
CH2 O C
(tocopherol) is a vital antioxidant. Finally, vitamin K is utilized
by the liver to catalyze the posttranslational modification of Fatty acid plus
several blood clotting factors. The fat-soluble vitamins, as a diglyceride
group, have negligible aqueous solubility. 2 Pancreatic lipase
H2O

INTRALUMINAL DIGESTION O

CH2 O C
Like in the assimilation of protein and carbohydrate, the initial
O
stages of lipid assimilation take place in the intestinal lumen.
Luminal events include dispersion of the lipid, which is liquid CH O C
at body temperature, into an emulsion, thereby maximizing O
the area of the oil/water interface at which lipolysis occurs.
CH2 O C
Luminal events also include lipolysis, mediated by a series of
Fatty acids plus
pancreatic and other enzymes, and uptake of the products of monoglyceride
lipolysis into micelles that can then transfer these molecules H2O
to the epithelial surface. Indeed, there is an ordered series of Pancreatic lipase
phase transitions that facilitate lipid assimilation. Oil droplets
are converted to lamellar, vesicular, and liquid crystalline FIGURE 59–1 Positional specificity of gastric (1) and
pancreatic (2) lipases. Both enzymes can digest triglycerides
product phases, and finally to micelles that contain the
but the products differ. (Modified with permission from Barrett KE:
products of lipolysis together with bile acids. Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill,
Medical Pub. Division, 2006.)

GASTRIC DIGESTION
Digestion of the lipid components of the diet begins in the
stomach. Gastric peristalsis and mixing patterns provide a
shearing action that disperses triglyceride and phospholipids
into a fine emulsion. The oil droplets can then be acted upon
by gastric lipase, which binds to the surface of the oil droplets
where it can act on triglyceride molecules to generate free fatty
acids and diglycerides. However, at the low pH of the gastric
lumen, the fatty acids become protonated and move into the
center of oil droplets. Thus, overall, gastric lipolysis is incom-
plete, and fails to generate products that are free to diffuse to
the mucosal surface. In general, 10–30% of overall lipolysis
takes place in the stomach in a healthy adult, and gastric
digestion of lipids is not essential to their normal uptake. Gas-
tric lipase, the enzyme that initiates digestion in the lumen
of the stomach, is specialized for activity in the unique condi-
tions that pertain in this segment of the gastrointestinal tract.
Most notably, the enzyme displays a pH optimum consistent
with that of the gastric contents—4.0–5.5. The enzyme is also
relatively resistant to the action of pepsin. Further, gastric
lipase is independent of the presence of any specific cofactors,
but is inhibited by bile acids in the duodenum. Finally, gastric
lipase acts preferentially to hydrolyze the fatty acid linked to
the first position of triglyceride (Figure 59–1) and is subject to
end-product inhibition such that gastric lipolysis is largely
incomplete because the triglyceride molecule is not fully bro-
ken down to its component parts.
INTESTINAL DIGESTION
As the pH increases in the small intestine, the fatty acids that
were liberated by gastric lipase become ionized and orient
themselves to the outside of the oil droplets. This surrounds
the droplet with a layer of ionized fatty acids that stabilizes the
fat emulsion. Because even long-chain fatty acids have some
solubility in water, some will dissociate from the droplet and
traverse the lumen to the intestinal epithelium. Fatty acids are
potent stimuli of cholecystokinin (CCK) release. CCK has a
number of actions that are pertinent to lipid digestion and
absorption. First, it causes an increase in secretion of pancre-
atic enzymes. Second, it relaxes the sphincter of Oddi, allow-
ing outflow of the pancreatic juice into the intestinal lumen,
and finally, it contracts the gallbladder, providing a bolus of
concentrated bile that contains the bile acids needed eventu-
ally to dissolve the products of lipolysis in mixed micelles.
 CHAPTER 59 Lipid Assimilation 595

Enzymes and Other Factors 3

Involved in Digestion
Pancreatic acinar cells secrete a number of proteins that are C
L
important in fat digestion (Table 59–1). The first of these is
3
pancreatic lipase. This enzyme is functionally related to gastric

Fatty acids released

2 Bile acids
lipase, but it displays a number of important differences. First, Bile acids added
it has a different positional specificity, acting on both the 1 and L
2
3 positions of the glycerol molecule to liberate esterified fatty
acids (Figure 59–1). Thus, the products of pancreatic lipase are
fatty acids and monoglycerides. Second, it displays a pH opti- 1 Colipase added 1
mum in the neutral range. However, both gastric and pancre-
atic lipases share the property of being inhibited by bile acids. Fat L
This is not a major issue in the stomach, which is proximal to droplet
the entry of bile. How to solve this conundrum, on the other
hand, for pancreatic lipase? The answer lies in the presence of Time
a second product of pancreatic acinar cells, colipase. Colipase FIGURE 59–2 Role of colipase in promoting lipase activity in
is synthesized as an inactive precursor (procolipase) that is the intestinal lumen. Lipase (L) can absorb to the surface of fat
secreted in approximately equimolar amounts with lipase, and droplets (1), but is displaced by the binding of amphipathic bile acids
is activated by proteolytic cleavage in the intestinal lumen. that arrange themselves around the exterior of the oil droplet (2).
Colipase is capable of binding to both bile acids and lipase, Colipase (C) can bind to both bile acids and lipase, again bringing
which stabilizes the presence of lipase on the surface of oil lipase in proximity to its substrates in the oil droplet (3). (Modified with
permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical
droplets. The significance of this interaction is shown in
Books/McGraw-Hill, Medical Pub. Division, 2006.)
Figure 59–2. If lipase alone is present, it adsorbs to the surface
of the oil droplets and generates free fatty acids. With addition
of bile acids, however, these array themselves on the surface of
including those of pancreatic duct cells, this delayed activation
the oil droplets and displace lipase, halting its enzymatic activ-
of the enzyme is important in the prevention of autodigestion of
ity. However, if colipase is also present, it can anchor lipase to
the pancreas. Phospholipase A2 breaks down dietary phospho-
the oil droplet, and thus lipolytic action is restored.
lipids by cleaving the fatty acid located in the 2 position of glyc-
Additional pancreatic exocrine products also contribute to
erol, as well as degrading (and thereby reclaiming) the
lipid digestion. Phospholipase A2 is also stored in pancreatic
phosphatidylcholine that is present in biliary secretions. The
acinar cells as an inactive proform that is activated by prote-
activity of this enzyme is dependent on luminal calcium. A final
olytic cleavage once it reaches the intestinal lumen. Because
lipolytic enzyme in the pancreatic juice is cholesterol esterase,
phospholipids are the major constituent of cell membranes,
also referred to as nonspecific esterase. This enzyme is capable
of degrading not only esters of cholesterol derived from dietary
sources, but also the esters of vitamins A, D, and E. Likewise,
TABLE 59–1 Mediators of intestinal lipolysis.
the broad specificity of this enzyme renders it capable of com-
Protein Source Activity Comments plete digestion of triglycerides, since it is capable of hydrolyzing
the 2-position fatty acid that is left untouched by both the gas-
Pancreatic Pancreatic Hydrolyzes 1 Inhibited by
tric and pancreatic lipases. Cholesterol esterase acts in the
lipase acinar cells and 3 positions bile acids
of triglyceride lumen as a tetramer, and, interestingly, the formation of this
complex depends on the presence of bile acids, distinguishing
Colipase Proform secreted Cofactor for Binds to lipase
by pancreatic lipase and to bile
this enzyme from both acid (i.e., gastric) and pancreatic lipases.
acinar cells acids It is also important to note that an enzyme closely related to
cholesterol esterase, known as breast milk lipase, is produced
Secretory Proform secreted Hydrolyzes fatty Requires
phospholipase by pancreatic acid in 2 position calcium for in the mammary gland of lactating females. This enzyme may
A2 acinar cells of phospholipids activity “predigest” the lipid components of breast milk, increasing the
Cholesterol Pancreatic Broad substrate Requires bile
efficiency of their uptake in the neonatal period. Breast milk
esterase acinar cells specificity— acids for lipase shares the broad specificity of cholesterol esterase.
cholesterol and activity
vitamin esters; 1,
2, and 3 positions Phase Transitions Involved
of triglyceride in Product Solubilization
Breast milk Mammary Related to Important Not only must dietary and endogenous lipids be digested by
lipase gland cholesterol in neonates
esterase
enzymes to allow for their assimilation into the body, but they
must also be trafficked across the intestinal lumen. This is
596 SECTION VIII GI Physiology
accomplished in the first instance by “phase transitions” that
move the products of lipolysis from the oil droplets where they
are generated to the epithelial surface.
The phases involved in lipid absorption can actually be visu-
alized by mixing an emulsion of fat with lipase, colipase, and
bile acids on a microscope slide. The products of lipolysis that
are released from the surface of the oil droplet form a lamellar
phase similar to the lipid bilayer that surrounds cells. Vesicles
bud off from this lamellar phase, which can be observed under
the microscope as a liquid crystalline phase that is clearly dis-
tinct from the oil droplets. Eventually, micelles are formed, or
a true solution of lipids in water. The phase transitions in the
small intestine are directed to a single end—to transfer the
products of lipolysis ultimately to the absorptive epithelium.
ROLE OF BILE ACIDS/MICELLES
As the gallbladder contracts, the meal encounters a bolus of
concentrated bile. The bile acids have an important role in
solubilizing the end products of lipolysis and promoting their
transfer to the absorptive epithelium. As the ratio of bile acids
to lipolytic products increases, the relatively insoluble lipids
are incorporated into mixed micelles. The formation of these
structures is dependent on the physicochemical properties of
bile acids. Likewise, micelle formation depends on the concen-
tration of bile acids in the lumen, since these structures cannot
form unless bile acid concentrations exceed the “critical micel-
lar concentration” (CMC). Lipolytic products that are cap-
tured in micelles are truly in solution, compared with the
emulsion of oil droplets that has been their physical form hith-
erto. The micelles that form in small intestinal content are piv-
otally dependent on the amphipathic nature of bile acids, with
both a hydrophilic and a hydrophobic face. The structure of
the mixed micelles in the intestine is analogous to that of the
biliary mixed micelles we discussed in Chapter 56 (Figure
56–3). The bile acids assemble such that their hydrophilic faces
are opposed to the aqueous environment. At the same time,
the hydrophobic faces of the bile acid molecules can sequester
the products of lipolysis such that their solubility is measurably
increased. The resulting mixed micelles carry fatty acids and
other lipolytic products through the aqueous lumen, markedly
increasing their rate of diffusion. Indeed, the rate-limiting step
for lipid assimilation is the ability to present lipid molecules at
a sufficient concentration at the brush border to provide for
uptake. While bile acids increase the efficiency of uptake of the
products of lipolysis, the majority of such products are not
dependent on micellar solubilization for their assimilation into
the body. Fatty acids and monoglycerides have measurable
aqueous solubility and can diffuse in molecular form to
the brush border, where they can then be absorbed. This raises
the concept of the “anatomic reserve” of the small intestine.
The normal surface area of the small intestine, and its length,
is sufficient to provide for molecular uptake of fatty acids and
monoglycerides even if micelles are absent, although transport
rates are slower. On the other hand, some dietary lipids have
such limited aqueous solubility that they are essentially inca-
pable of absorption unless dissolved in micelles. This is the
case for cholesterol, fat-soluble vitamins, and plant sterols.
EPITHELIAL EVENTS IN
LIPID ASSIMILATION
BRUSH BORDER EVENTS
Mechanisms of Absorption
of Lipolytic Products
In theory, the products of lipolysis have sufficient hydrophobic-
ity that they should be able to passively “flip” across the
enterocyte apical membrane by simply partitioning into the
lipid bilayer. Such a mechanism may indeed contribute to the
intestinal uptake of the various products of the mixed micelle,
with the exception of conjugated bile acids, which are exclu-
sively absorbed via an active transport mechanism localized
to the terminal ileum. However, there are likely also to be car-
rier-mediated mechanisms that assist in transporting the prod-
ucts of lipid digestion across the microvillous membrane.
Uptake of plant sterols from the diet is inefficient. At least
part of the reason for this was revealed by studying the disease
known as sitosterolemia, in which patients accumulate
abnormally high levels of plant sterols in the plasma. This dis-
ease is caused by mutations in two transporters, ABCG5 and
ABCG8. Together, these proteins normally come together to
form an efflux pump that transports any plant sterols that are
taken up into the enterocyte back out into the intestinal lumen
(Figure 59–3). The transporter so formed also can export cho-
lesterol, albeit with less efficiency, explaining why the absorp-
tion of either dietary or biliary cholesterol is incomplete.
Enterocytes also express at least one specific pathway for choles-
terol uptake, known as the Niemann–Pick C1-like 1 (NPC1L1)
gene product (Figure 59–3).
In summary, uptake of the products of lipolysis appears to
involve a combination of passive transfer across the brush bor-
der membrane, as well as facilitated diffusion for some lipids
that is mediated by specific protein carriers. Intestinal absorp-
tion of at least some lipids is additionally compromised by
pumps that can efflux lipid substrates from the enterocyte
cytosol, limiting their ability to enter the body.
Special Considerations for
Medium-chain Fatty Acids
Fatty acid chain length, likely via effects on aqueous solubility,
also appears to have an important influence on the molecular
mechanisms that govern uptake of these molecules. Impor-
tantly, medium-chain fatty acids, with 6–12 carbon atoms,
have increased water solubility, and this means that they have
measurable absorption via the paracellular route. Medium-
chain fatty acids therefore appear to bypass the intracellular
processing events that are encountered by the long-chain fatty

Cholesterol
LUMEN
NPC1L1
ABC G5
ABC G8
ATP
ADP
Utilized Chylomicron
by enterocyte assembly
Exocytosis
FIGURE 59–3 Intestinal handling of cholesterol. Cholesterol
in the intestinal lumen is taken up via the NPC1L1 transporter.
Absorbed cholesterol can be effluxed back out of the cell via the
ABCG5/ABCG8 efflux pump at the expense of ATP hydrolysis, can be
retained for use in the enterocyte, or can be packaged with other
absorbed lipids into chylomicrons, which leave the epithelial cell via
exocytosis. (Modified with permission from Barrett KE: Gastrointestinal Physiology.
New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)
acids that predominantly enter the enterocyte cytosol, dis-
cussed in greater detail later. As a result, such fatty acids also
follow a different route out of the gut, being exported chiefly
via the portal circulation rather than the lymphatic route used
by other lipids.
INTRACELLULAR PROCESSING
Role of Fatty Acid Binding Proteins
The small intestinal epithelium expresses a family of low-molec-
ular-weight binding proteins that are capable of binding fatty
acids and other dietary lipids. The best studied of these are the
ileal-fatty acid binding protein (I-FABP) and the liver-type
(hepatic) FABP. These and related proteins participate in the
directed trafficking of absorbed lipids to the smooth endoplas-
mic reticulum, which is the site of intracellular lipid processing.
Chylomicron Formation
Unlike the products of protein and carbohydrate digestion,
which are exported to the body in their digested forms, the
products of lipid digestion are reassembled in the enterocyte
CHAPTER 59 Lipid Assimilation 597
prior to export to the systemic circulation. Long-chain fatty
acids and monoglycerides are reesterified into triglyceride in
the smooth endoplasmic reticulum; phospholipids, choles-
terol, and fat-soluble vitamins are also selectively trafficked
and reesterified. Approximately 75% of absorbed fatty acids is
reassembled into triglyceride; the remainder is retained within
the enterocyte for local needs.
The various reassembled lipids are then coated with proteins
known as apoproteins for export from the enterocyte
(Figure 59–4). Apoproteins are synthesized in the rough endo-
plasmic reticulum, and undergo glycosylation in the Golgi appa-
ratus where they also encounter the reesterified lipids taken up
from the intestinal lumen. The particles that are formed via this
process are referred to as chylomicrons, and have a core of trig-
lyceride surrounded by phospholipids, cholesterol esters, and the
apoproteins. The chylomicron is the structure used to transport
dietary lipids to other locations in the body. Approximately
80–90% (w/w) of the chylomicron is composed of triglyceride,
with 8–9% phospholipids and trace amounts of cholesterol, fat-
soluble vitamins, and protein. The resulting structure is exported
across the basolateral membrane by exocytosis.
LYMPHATIC UPTAKE
OF ABSORBED LIPID
The physical form of lipid exported from the enterocyte deter-
mines the subsequent route this nutrient can take to leave the
gut. Chylomicrons range in size from 750 to 5,000 Å in diam-
eter. They are therefore too large to cross the intercellular
junctions linking capillary endothelial cells. This means that
the only way for them to leave the intestine is via the lymphatics,
which have leakier junctions. However, eventually these chy-
lomicrons will enter the systemic circulation via the thoracic
Smooth ER FA/MG Synthesis of TG and
TG
phospholipids
Synthesis of
apolipoproteins
Rough ER Apolipoprotein
glycosylation
Exocytosis
Golgi
Chylomicrons
FIGURE 59–4 Secretion of chylomicrons by intestinal
epithelial cells. Absorbed fatty acids (FA) and monoglycerides (MG)
are reesterified to form triglyceride (TG) in the smooth endoplasmic
reticulum. Apolipoproteins are synthesized in the rough endoplasmic
reticulum and glycosylated, and then coated around lipid cores and
secreted from the basolateral pole of the enterocyte via a mechanism
of exocytosis. (Reproduced with permission from Barrett KE, Barman SM, Boitano S,
Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)
598 SECTION VIII GI Physiology
duct. The lipid-bearing chylomicrons serve to carry lipids to
various body tissues. They are too large to exit the bloodstream
across the fenestrae of hepatic endothelial cells, and thus are
retained in the plasma, although components may leave the
chylomicron as needed at this and other body sites. Eventually,
the chylomicrons are reduced to remnants that are small
enough to pass into the space of Disse, and can finally have
their remaining components recycled by hepatic metabolism.
ABSORPTION OF
FAT-SOLUBLE VITAMINS
Despite their importance, relatively little is understood about
the specific molecular basis of the absorption and handling of
fat-soluble vitamins by intestinal epithelial cells. It is known
that such vitamins are reesterified in the enterocyte, and incor-
porated into the developing chylomicron. Presumably this is
the form in which they are trafficked to sites of need. Traffick-
ing of fat-soluble vitamins to the brush border membrane is
essentially entirely dependent on micelles. A failure to form
micelles in the intestinal lumen will almost inevitably be fol-
lowed by deficiencies in fat-soluble vitamins in the body as a
whole, which may manifest clinically as rickets and osteomal-
acia (see Chapter 64), night blindness (see Chapter 15), or an
inability to effectively clot the blood, among others. Many
fat-soluble vitamins are now available in more water-soluble
forms that can be used to treat such problems, such as prior to
elective surgery.
CLINICAL CORRELATION
A 30-year-old woman suffering from inflammation of the
ileum (Crohn’s disease) undergoes a surgical resection of
a long segment of her small bowel, including the terminal
ileum. The remaining proximal segment of small bowel is
connected directly to the ileocecal valve. After recovering
from her surgery and resuming oral feeding, she notes
that diarrheal symptoms have returned, and fears a recur-
rence of her bowel inflammation. However, in contrast to
the bloody diarrhea with cramping that she experienced
previously, now her stools are large, bulky, and foul-
smelling, but with no blood. She also experiences some
abdominal bloating. Examination of a fecal smear under
the microscope reveals prominent lipid droplets.
Short bowel syndrome is defined as being present in a
patient who no longer has sufficient mucosal area for the
adequate uptake of nutrients via the enteric route, and
thus such patients may require parenteral nutritional sup-
port (i.e., via the intravenous route). Even if sufficient
bowel remains for absorption of the majority of nutrients,
if the segment of missing bowel includes the terminal
ileum, the situation will be complicated further by a
decrease in the bile acid pool, in the absence of an anatomic
reserve that might otherwise compensate for this. Short
bowel syndrome is usually the consequence of surgery—
either to remove segments of necrotic bowel in a pediatric
condition known as necrotizing enterocolitis, which may
have an infectious pathogenesis in some cases, or in patients
who have undergone resections for extensive Crohn’s dis-
ease. Eventually, small bowel transplantation may offer
hope that such patients will be able to dispense with paren-
teral nutrition, although problems with conserving bowel
in a viable state prior to transplantation, as well as the usual
problems of rejection, have not yet fully been resolved.
Likewise, some exciting experimental treatments that
employ growth factors to increase mucosal mass may hold
promise, but concerns that these therapies might predis-
pose to intestinal malignancies must be resolved. This is
particularly the case in inflammatory bowel disease, where
the risk of intestinal malignancy is already increased.
CHAPTER SUMMARY
■ Lipids are important constituents of most diets, make food
more palatable, and are energy-dense.
■ Lipid digestion and absorption involves a complex series of
events designed to emulsify, digest, and solubilize these
hydrophobic dietary constituents.
■ Biliary excretion of cholesterol may substantially exceed dietary
intake.
■ Micelles increase the efficiency of absorption of the products of
triglyceride digestion, but they are not required for this process
in healthy individuals.
■ Absorption of fat-soluble vitamins and cholesterol is entirely
dependent on micellar solubilization.
■ Absorbed lipids are esterified and repackaged in the enterocyte
into a structure known as a chylomicron, which then traffics
absorbed lipids around the body, initially bypassing the portal
circulation.
■ Chylomicrons consist predominantly of resynthesized
triglyceride, but apoproteins are essential components.
■ Lipid digestion is a highly efficient process and significant
excess capacity exists in the system.
STUDY QUESTIONS
1. A patient with obstructive jaundice who is scheduled for
gallbladder surgery is found to have an increased prothrombin
time, which indicates an increase in blood clotting time. This
laboratory finding is most likely due to malabsorption of which
of the following vitamins?
A) A
B) B12
C) D
D) E
E) K
 CHAPTER 59 Lipid Assimilation 599

2. A patient is treated for hypercholesterolemia with 4. A patient with a long-standing history of mild cystic fibrosis
cholestyramine, a resin that binds bile acid molecules. notices that his stools are becoming bulky and oily. Laboratory
Absorption of which of the following is likely to be abnormal tests confirm steatorrhea. Which of the following is not involved
in this patient? in the apparently decreased fat assimilation in this patient?
A) long-chain triglyceride A) lipase inactivation
B) medium-chain triglyceride B) decreased pancreatic lipase output
C) starch C) reduced pancreatic bicarbonate secretion
D) vitamin D D) loss of the anatomic reserve
E) vitamin C E) decreased colipase synthesis
3. A mouse was constructed in which the expression of NPC1L1 5. An otherwise healthy child is found to have mild, intermittent
was knocked out by genetic targeting. Assimilation of which of steatorrhea but no evidence of malabsorption of fat-soluble
the following substances from the diet would be expected to be vitamins. There are also no defects in protein or carbohydrate
abnormal in this animal? assimilation. His brother was similarly affected. Lack of which
A) triglyceride of the following is most consistent with the clinical picture?
B) vitamin D A) bile acid micelles
C) vitamin E B) cholesterol esterase
D) cholesterol C) L-FABP
E) phospholipids D) gastric lipase
E) pancreatic lipase
This page intentionally left blank
 SECTION IX ENDOCRINE AND
METABOLIC PHYSIOLOGY
General Principles of
Endocrine Physiology
Patricia E. Molina
O B J E C T I V E S
■ Contrast the terms endocrine, paracrine, and autocrine.
■ Define the terms hormone, target cell, and receptor.
■ Understand the major differences in cellular mechanisms of action of
peptides, steroid, and thyroid hormones.
■ Understand the role of hormone-binding proteins.
■ Understand the feedback control mechanisms of hormone secretion.
■ Explain the effects of secretion, degradation, and excretion on plasma
hormone concentrations.
THE ENDOCRINE SYSTEM:
PHYSIOLOGIC FUNCTIONS
AND COMPONENTS
Some of the key functions of the endocrine system include:
• regulation of sodium and water balance and control of blood
volume and pressure;
• regulation of calcium and phosphate balance to preserve ex-
tracellular fluid concentrations required for cell membrane
integrity and intracellular signaling;
• regulation of energy balance and control of fuel mobilization,
utilization, and storage to ensure that cellular metabolic
demands are met;
• coordination of the responses to stress;
• regulation of reproduction, development, growth, and se-
nescence.
The endocrine system is an integrated network of multiple
organs derived from different embryologic origins that release
Ch60_601-612.indd 601
60
C H A P T E R
hormones ranging from small peptides to glycoproteins, which
exert their effects in either neighboring or distant target cells.
This endocrine network of organs and mediators does not
work in isolation, and is closely integrated with the central and
peripheral nervous systems as well as with the immune sys-
tems, leading to currently used terminology such as “neuroen-
docrine” or “neuroendocrine–immune” systems for describing
their interactions. Three basic components make up the core
of the endocrine system:
• Endocrine glands: The classic endocrine glands are duct-
less and secrete their chemical products (hormones) into
the interstitial space from where they reach the circulation.
Unlike the cardiovascular, renal, and digestive systems, the
endocrine glands are not anatomically connected and are
scattered throughout the body (Figure 60–1). Communica-
tion among the different organs is ensured through the
release of hormones or neurotransmitters.
• Hormones— Hormones are chemical products, released
in very small amounts from the cell, that exert a biologic
action on a target cell. Hormones can be released from
601
11/26/10 10:31:12 AM
602 SECTION IX Endocrine and Metabolic Physiology

Hypothalamus
Releasing hormones:
GHRH, CRH, Pituitary gland
TRH, GnRH Growth hormone,
Inhibitory hormones: Prolactin
Somatostatin, ACTH, MSH
Dopamine TSH, FSH, & LH
Projecting to Posterior Pituitary:
Antidiuretic Hormone
Oxytocin
Parathyroid glands
Parathyroid hormone
Thyroid gland
T3, T4, & calcitonin
FIGURE 60–1 The classic endocrine system.
Endocrine organs are located throughout the body,
and their function is controlled by hormones delivered Adrenal glands
Cortisol
through the circulation or produced locally or by direct Aldosterone
neuroendocrine stimulation. Integration of hormone Adrenal androgens Pancreas
production from endocrine organs is under regulation Epinephrine Insulin
by the hypothalamus. Many other tissues are now Norepinephrine Glucagon
known to produce hormones and can thus be Somatostatin
considered part of the endocrine system. Examples
include adipose tissue (e.g., leptin), the gastrointestinal
tract (e.g., ghrelin), skeletal muscle (myokines), the
kidneys (erythropoietin), and the heart (e.g., atrial Ovaries
natriuretic peptide). GHRH, growth hormone–releasing Estrogens
Progesterone
hormone; CRH, corticotropin-releasing hormone; TRH,
thyrotropin-releasing hormone; GnRH, gonadotropin-
releasing hormone; ACTH, adrenocorticotropic
hormone; MSH, melanocyte-stimulating hormone; TSH, Testes
thyroid-stimulating hormone; FSH, follicle-stimulating Testosterone
hormone; LH, luteinizing hormone; T3, triiodothyronine;
T4, thyroxine. (Modified with permission from Molina PE:
Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

the endocrine glands (i.e., insulin, cortisol); the brain (i.e.,
corticotropin-releasing hormone, oxytocin, and antidiuretic
hormone); and other organs such as the heart (atrial natriuretic
peptide), liver (insulin-like growth factor-I), and adipose tis-
sue (leptin).
• Target organ: The target organ contains cells that express
hormone-specific receptors and that respond to hormone
binding by a demonstrable biologic response.
HORMONE CHEMISTRY AND
MECHANISMS OF ACTION
Based on their chemical structure, hormones can be classified
into proteins (or peptides), steroids, and amino acid derivatives
(amines). Hormone structure, to a great extent, dictates the loca-
tion of the hormone receptor, with amines and peptide hormones
binding to receptors in the cell surface and steroid hormones
able to cross plasma membranes and bind to intracellular recep-
tors. An exception to this generalization is thyroid hormone, an
amino acid–derived hormone that is transported into the cell in
order to bind to its nuclear receptor. Hormone structure influ-
ences the half-life of the hormone as well, with peptides having
shorter half-lives than steroid hormones.
PROTEIN OR PEPTIDE HORMONES
Protein or peptide hormones constitute the majority of hor-
mones. Most are synthesized as preprohormones and
undergo posttranslational processing. They are stored in
secretory granules before being released by exocytosis
(Figure 60–2). Examples of peptide hormones include insu-
lin, glucagon, and adrenocorticotropic hormone (ACTH).
Some hormones in this category, such as the gonadotropic
hormone, luteinizing hormone (LH), and follicle-stimulating
hormone (FSH), together with thyroid-stimulating hormone
(TSH) and human chorionic gonadotropin (hCG), contain
carbohydrate moieties, leading to their designation as glyco-
proteins.
STEROID HORMONES
Steroid hormones are derived from cholesterol and are syn-
thesized in the adrenal cortex, gonads, and placenta. They are
lipid soluble, require binding proteins to circulate in plasma,
and cross the plasma membrane to bind to intracellular
cytosolic or nuclear receptors. Vitamin D and its metabolites
are also steroid hormones.
 CHAPTER 60 General Principles of Endocrine Physiology 603

Endocrine cell

Granular endoplasmic
reticulum Synthesis

Preprohormone

Nucleus Prohormone

Packaging

Golgi Prohormone
apparatus
Hormone

Storage
Secretory Hormone
vesicles

Plasma
membrane
Secretion
Hormone
(and any
Cytosol "pro" fragments)

Interstitium
Ca2+
FIGURE 60–2 Peptide hormone synthesis. Peptide hormones are synthesized as preprohormones in the ribosomes and processed
to prohormones in the endoplasmic reticulum (ER). In the Golgi apparatus, the hormone or prohormone is packaged in secretory vesicles,
the contents of which are released from the cell in response to an influx of Ca2+. The increase in cytoplasmic Ca2+ is required for docking of the
secretory vesicles in the plasma membrane and for exocytosis of the vesicular contents. The hormone and the products of the posttranslational
processing that occurs inside the secretory vesicles are released into the extracellular space. Examples of peptide hormones are ACTH, insulin,
growth hormone, and glucagon. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

AMINO ACID–DERIVED HORMONES
Amino acid–derived hormones are synthesized from the
amino acid tyrosine and include the catecholamines norepi-
nephrine, epinephrine, and dopamine, as well as the thyroid
hormones, derived from the combination of two iodinated
tyrosine amino acid residues.
HORMONE EFFECTS
The biologic effect of a hormone can be classified in many ways
(Figure 60–3). The effect is endocrine when a hormone is
released into the circulation and then travels in the blood to pro-
duce a biologic effect on distant target cells. The effect is para-
crine when a hormone released from one cell produces a biologic
effect on a neighboring cell, which is frequently a cell in the same
organ or tissue. The effect is autocrine when a hormone pro-
duces a biologic effect on the same cell that released it, and intra-
crine when the hormone has an intracellular effect without first
being released into the extracellular space.
HORMONE TRANSPORT
Hormones released into the circulation can circulate either
freely or bound to carrier proteins, also known as binding
proteins. The binding proteins serve as a reservoir for the
hormone and prolong the hormone’s half-life, the time during
which the concentration of a hormone decreases to 50% of its
initial concentration. The free or unbound hormone is the
active form of the hormone, which binds to the specific
hormone receptor. Hormone binding to its carrier protein
serves to regulate the activity of the hormone by determining
how much hormone is free to exert a biologic action. Most
carrier proteins are globulins and are synthesized in the liver.
604 SECTION IX Endocrine and Metabolic Physiology

Interstitial space

Endocrine cell

Hormone

Circulatory Paracrine signaling

system

Hormone-specific
receptor

Endocrine signaling Autocrine

signaling

Intracrine
signaling

FIGURE 60–3 Mechanisms of hormone action. Depending on where hormones exert their effects, they can be classified into endocrine,
paracrine, autocrine, or intracrine mediators. Hormones that enter the bloodstream and bind to hormone receptors in target cells in distant organs
mediate endocrine effects. Hormones that bind to cells near the cell that released them mediate paracrine effects. Hormones that produce their
physiologic effects by binding to receptors on the same cell that produced them mediate autocrine or intracrine effects. (Modified with permission from
Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

As a result, alterations in hepatic function may result in abnor-
malities in binding protein levels and may indirectly affect
total hormone levels. The majority of amines, peptides, and
protein (hydrophilic) hormones circulate in their free form.
Steroid and thyroid (lipophilic) hormones circulate bound to
specific transport proteins.
The interaction between a given hormone and its carrier
protein is in a dynamic equilibrium and allows adjustments
that prevent clinical manifestations of hormone deficiency or
excess. Secretion of the hormone is adjusted rapidly following
changes in the levels of carrier proteins. For example, plasma
levels of cortisol-binding protein increase during pregnancy.
The increase in circulating levels of cortisol-binding protein
leads to an increased binding capacity for cortisol (a steroid
hormone produced in the adrenal glands), resulting in a
decrease in free cortisol levels. This decrease in free cortisol
stimulates the hypothalamic release of CRH, which stimulates
ACTH release from the anterior pituitary and consequently
cortisol synthesis and release from the adrenal glands. This
feedback mechanism restores free cortisol levels and prevents
manifestation of cortisol deficiency.
The half-life of a hormone is inversely related to its rate of
removal from the circulation. Once hormones are released
into the circulation, they can bind to their specific receptor in
a target organ, they can undergo metabolic transformation by
the liver, or they can undergo urinary excretion. In the liver,
hormones can be inactivated through Phase I (hydroxylation
or oxidation) and/or Phase II (glucuronidation, sulfation, or
reduction with glutathione) reactions, and then excreted by
the liver through the bile or by the kidney. In some instances,
the liver can actually modify a hormone precursor, as is the
case for vitamin D synthesis. Hormones can be degraded at
their target cell through internalization of the hormone–
receptor complex followed by lysosomal degradation of the
hormone. Only a very small fraction of total hormone produc-
tion is excreted intact in the urine and feces.
 CHAPTER 60 General Principles of Endocrine Physiology 605

HORMONE CELLULAR EFFECTS
The biologic response to hormones is elicited through binding
to hormone-specific receptors at the target organ. Hormones
circulate in very low concentrations (10−7 to 10−12 M), so the
receptor must have high affinity and specificity for the hor-
mone to produce a biologic response.
Affinity is determined by the rates of association and
dissociation for the hormone–receptor complex under equi-
librium conditions. It is a reflection of how tight the hor-
mone–receptor interaction is. Specificity is the ability of a
hormone receptor to discriminate between hormones with
related structures.
The binding of hormones to their receptors is saturable,
with a finite number of hormone receptors to which a hor-
mone can bind. Abnormal endocrine function is the result of
either excess or deficiency in hormone action. This can result
from abnormal production of a given hormone (either in
excess or in insufficient amounts) or from decreased receptor
number or function. Hormone–receptor agonists and antag-
onists are widely used clinically to restore endocrine function
in patients with hormone deficiency or excess.
HORMONE RECEPTORS AND
SIGNAL TRANSDUCTION
Hormones produce their biologic effects by binding to specific
hormone receptors in target cells, and the type of receptor to
which they bind is largely determined by the hormone’s chem-
ical structure. Hormone receptors are classified depending on
their cellular localization, as cell membrane (Figures 60–4
and 60–5) or intracellular receptors (Figure 60–6).
CELL MEMBRANE RECEPTORS
These receptor proteins are located within the phospholipid
bilayer of the cell membrane of target cells (Figures 60–4 and
60–5). Functionally, cell membrane receptors can be divided

Amino acid derived: Peptide and protein:

Epinephrine, norepinephrine Glucagon, Angiotensin, GnRH, SS,
GHRH, FSH, LH, TSH, ACTH
N

E1 E2 E3

α γ γ
β β Ion channels,
GDP PI3Kγ, PLC-β, Biological responses
I1 I2 I3
adenylate cyclases Proliferation, differentiation,
C development, cell survival,
angiogenesis, hypertrophy,
cancer
G-protein−independent
effector molecules

αi αq αs α12

GTP GTP GTP GTP Gene expression

Adenylate PLC-β Adenylate RhoGEFs regulation
P
cyclase DAG cyclase Rho
cAMP Ca++ cAMP P
PKC

Transcription
Nucleus
factors

FIGURE 60–4 G protein–coupled receptors. Peptide and protein hormones bind to cell surface receptors coupled to G proteins. Binding
of the hormone to the receptor produces a conformational change that allows the receptor to interact with the G proteins. This results in the
exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) and activation of the G protein. The second-messenger systems
that are activated vary depending on the specific receptor, the α-subunit of the G protein associated with the receptor, and the ligand it binds.
Examples of hormones that bind to G protein–coupled receptors are shown. DAG, diacylglycerol; PLC, phospholipase C; cAMP, cyclic adenosine
monophosphate; RhoGEFs, Rho guanine nucleotide exchange factors; PI3K, phosphatidyl-3-kinase; PKC, protein kinase C; GnRH, gonadotropin-
releasing hormone; SS, somatostatin; GHRH, growth hormone–releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone;
TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropin hormone. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York:
McGraw-Hill Medical, 2010.)
606 SECTION IX Endocrine and Metabolic Physiology

N N
N N Growth
factor

Plasma Plasma
membrane membrane

Tyrosine Non-
kinase receptor Cytosol
domain tyrosine
kinase
C C

ATP Kinase
PO4
ADP JAK kinase
Docking
protein
Docking Protein +ATP Protein-PO4 + ADP
protein

Recruitment & Protein activation

activation of proteins
FIGURE 60–5 Receptor kinase and receptor-linked kinase receptors. Receptor kinases are receptors that have intrinsic tyrosine or
serine kinase activity that is activated by binding of the hormone to the amino terminal of the cell membrane receptor. The activated kinase
recruits and phosphorylates downstream proteins producing a cellular response. An example of hormones that utilize this receptor pathway
is insulin. Receptor-linked tyrosine kinase receptors do not have intrinsic activity in their intracellular domain. They are closely associated with
kinases that are activated with binding of the hormone. Examples of hormones using this mechanism are growth hormone and prolactin.
ATP, adenosine triphosphate; ADP, adenosine diphosphate; JAK, janus kinase. (Modified with permission from Cooper GM: The Cell: A Molecular Approach,
4th ed. Sinauer, 2007.)

Extracellular Cytoplasm Nucleus

fluid

Steroid Activated
Steroid enters target
cell by diffusion receptor dimer

Gene
transcription

Steroid DNA
receptor Steroid response
element

Nuclear
Plasma envelope
membrane

FIGURE 60–6 Intracellular receptors. The general scheme for the mechanism of action of steroid receptors. The ligand (steroid) diffuses
into the cell and binds to the cytosolic receptor. Once binding occurs, the receptors dimerize (pair up) and are translocated to the nucleus where
they bind to a steroid response element on the DNA. This activates gene transcription to mRNA, and ultimately, through increased mRNA
translation to specific proteins, results in a cellular response. Some intracellular receptors, rather than being in the cytosol in the unbound state,
reside in the nucleus (e.g. thyroid hormone receptors), but their ultimate mechanisms of activation of gene transcription and translation are
similar. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)
 CHAPTER 60 General Principles of Endocrine Physiology
into ligand-gated ion channels and receptors that regulate
activity of intracellular proteins.
Ligand-gated Ion Channels
These receptors are functionally coupled to ion channels. Hor-
mone binding to this receptor produces a conformational
change that opens ion channels on the cell membrane, pro-
ducing ion fluxes in the target cell. The cellular effects occur
within seconds of hormone binding.
Receptors that Regulate Activity
of Intracellular Proteins
These receptors are transmembrane proteins that transmit sig-
nals to intracellular targets when activated. Ligand binding to
the receptor on the cell surface and activation of the associated
protein initiate a signaling cascade of events that activates
intracellular proteins and enzymes and that can include effects
on gene transcription and expression. The main types of cell
membrane hormone receptors in this category are the G pro-
tein–coupled receptors (Figure 60–4) and the receptor protein
tyrosine kinases (Figure 60–5). An additional type of receptor,
the receptor-linked kinase receptor, activates intracellular
kinase activity following binding of the hormone to the plasma
membrane receptor. This type of receptor is used in producing
the physiologic effects of growth hormone (Figure 60–5).
G protein–coupled receptors
G protein–coupled receptors are transmembrane proteins cou-
pled to heterotrimeric guanine-binding proteins (G proteins)
consisting of three subunits: α, β, and γ. Hormone binding to
the G protein–coupled receptor produces a conformational
change that induces interaction of the receptor with the regula-
tory G protein, stimulating the release of guanosine diphos-
phate (GDP) in exchange for guanosine triphosphate (GTP),
resulting in activation of the G protein (Figure 60–4). The acti-
vated G protein (bound to GTP) dissociates from the receptor
followed by dissociation of the α from the βγ subunits. The
subunits activate intracellular targets, which can be either an
ion channel or an enzyme. Hormones that use this type of
receptor include TSH, antidiuretic hormone or arginine vaso-
pressin, and catecholamines.
On the basis of the Gα subunit, G proteins can be classified
into four families associated with different effector proteins.
The signaling pathways of three of these have been extensively
studied. The Gαs activates adenylate cyclase, Gαi inhibits
adenylate cyclase, and Gαq activates phospholipase C; the
second-messenger pathways used by Gα12 have not been com-
pletely elucidated.
The interaction of Gαs with adenylate cyclase and its activa-
tion result in increased conversion of adenosine triphosphate
to cyclic 3′,5′-adenosine monophosphate (cAMP), with the
opposite response elicited by binding to Gαi-coupled receptors.
The increase in intracellular cAMP activates protein kinase A,
which in turn phosphorylates effector proteins, responsible for
607
producing cellular responses. The action of cAMP is termi-
nated by the breakdown of cAMP by the enzyme phosphodi-
esterase. In addition, the cascade of protein activation can also
be controlled by phosphatases, which dephosphorylate pro-
teins. Phosphorylation of proteins does not necessarily result
in activation of an enzyme. In some cases, phosphorylation of
a given protein results in inhibition of its activity.
Gαq activation of phospholipase C results in the hydrolysis
of phosphatidylinositol bisphosphate and the production of
diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG
activates protein kinase C, which phosphorylates effector pro-
teins. IP3 binds to calcium channels in the endoplasmic reticu-
lum, leading to an increase of Ca2+ influx into the cytosol. Ca2+
can also act as a second messenger by binding to cytosolic pro-
teins such as calmodulin. Binding of Ca2+ to calmodulin
results in the activation of kinases, leading to a cascade of
phosphorylation of effector proteins and cellular responses.
Receptor protein tyrosine kinases
Receptor protein tyrosine kinases are usually single trans-
membrane proteins that have intrinsic enzymatic activity that
is activated by hormone binding. This results in phosphoryla-
tion of tyrosine residues on the catalytic domain of the recep-
tor itself, increasing its kinase activity. Phosphorylation outside
the catalytic domain creates specific binding or docking sites
for additional proteins that are recruited and activated, initiat-
ing a downstream signaling cascade.
Hormone binding to cell surface receptors results in rapid
activation of cytosolic proteins and cellular responses. Through
protein phosphorylation, hormone binding to cell surface
receptors can also alter the transcription of specific genes
through the phosphorylation of transcription factors. An
example of this mechanism of action is the phosphorylation of
the transcription factor cAMP response element-binding
protein (CREB) by protein kinase A in response to receptor
binding and adenylate cyclase activation. This same transcrip-
tion factor (CREB) can be phosphorylated by calcium–calm-
odulin following hormone binding to receptor tyrosine kinase
and activation of phospholipase C. Therefore, hormone bind-
ing to cell surface receptors can elicit immediate responses
when the receptor is coupled to an ion channel or through the
rapid phosphorylation of preformed cytosolic proteins, and it
can also activate gene transcription through phosphorylation
of transcription factors.
INTRACELLULAR RECEPTORS
Receptors in this category belong to the steroid receptor
superfamily (Figure 60–6). These receptors are transcription
factors that have binding sites for the hormone (ligand) and
for DNA and function as ligand (hormone)-regulated tran-
scription factors. Hormone–receptor complex formation and
binding to DNA result in either activation or repression of
gene transcription. Binding to intracellular hormone recep-
tors requires that the hormone be hydrophobic and cross the
608 SECTION IX Endocrine and Metabolic Physiology
plasma membrane. Steroid hormones and the active steroid
derivative of vitamin D fulfill this requirement (Figure 60–6).
Thyroid hormones must be actively transported into the cell.
The distribution of the unbound intracellular hormone
receptor can be cytosolic or nuclear. Hormone–receptor com-
plex formation with cytosolic receptors produces a conforma-
tional change that allows the hormone–receptor complex to
enter the nucleus and bind to specific DNA sequences to regu-
late gene transcription. Once in the nucleus, the receptors
regulate transcription by binding, generally as dimers, to hor-
mone response elements normally located in regulatory
regions of target genes. In all cases, hormone binding leads to
a nearly complete nuclear localization of the hormone–
receptor complex. Unbound intracellular receptors may be
located in the nucleus, as in the case of thyroid hormone recep-
tors. The unoccupied thyroid receptor represses transcription
of genes. Binding of thyroid hormone to the receptor activates
gene transcription.
HORMONE–RECEPTOR REGULATION
Hormones can influence responsiveness of the target cell by
modulating receptor function. Target cells are able to detect
changes in hormone signal over a very wide range of stimulus
intensities. This requires the ability to undergo a reversible
process of adaptation or desensitization, whereby a pro-
longed exposure to a hormone decreases the response to that
level of hormone. This allows cells to respond to changes in
the concentration of a hormone (rather than to the absolute
concentration of the hormone) over a very wide range of hor-
mone concentrations. Several mechanisms can be involved in
desensitization to a hormone. Hormone binding to cell-
surface receptors, for example, may induce their endocytosis
and temporary sequestration in endosomes. Such hormone-
induced receptor endocytosis can lead to the destruction of
the receptors in lysosomes, a process that leads to receptor
downregulation. In other cases, desensitization results from
a rapid inactivation of the receptors, for example, as a result of
a receptor phosphorylation. Desensitization can also be
caused by a change in a protein involved in signal transduc-
tion following hormone binding to the receptor or by the pro-
duction of an inhibitor that blocks the transduction process.
In addition, one hormone can downregulate or decrease the
expression of receptors for another hormone and reduce that
hormone’s effectiveness. Hormone receptors can also undergo
upregulation.
Upregulation of receptors involves an increase in the num-
ber of receptors for the particular hormone and frequently
occurs when the prevailing levels of the hormone have been
low for some time. The result is an increased responsiveness to
the physiologic effects of the hormone at the target tissue
when the levels of the hormone are restored or when an ago-
nist to the receptor is administered. A hormone can also
upregulate the receptors for another hormone, increasing the
effectiveness of that hormone at its target tissue. An example
of this type of interaction is the upregulation of cardiac myo-
cyte adrenergic receptors following sustained elevations in
thyroid hormone levels.
CONTROL OF HORMONE RELEASE
The secretion of hormones involves synthesis or production of
the hormone and its release from the cell. In general, the dis-
cussion of regulation of hormone release in this section refers
to both synthesis and secretion; specific aspects pertaining to
the differential control of synthesis and release of specific hor-
mones will be discussed in the respective chapters when they
are considered of relevance.
Plasma levels of hormones oscillate throughout the day,
showing peaks and troughs that are hormone specific
(Figure 60–7). This variable pattern of hormone release is
determined by the interaction and integration of multiple con-
trol mechanisms, which include hormonal, neural, nutritional,
and environmental factors that regulate the constitutive (basal)
and stimulated (peak levels) secretion of hormones. The peri-
odic and pulsatile release of hormones is critical in maintain-
ing normal endocrine function and in exerting physiologic
effects at the target organ. The hypothalamus plays an impor-
tant role in control of hormone pulsatility. Although the
mechanisms that determine the pulsatility and periodicity of
hormone release are not completely understood for all the dif-
ferent hormones, three general mechanisms can be identified
as common regulators of hormone release.
NEURAL CONTROL
Control and integration by the central nervous system is a key
component of hormonal regulation and is mediated by direct
neurotransmitter control of endocrine hormone release
(Figure 60–8). Neural control plays an important role in the
regulation of peripheral endocrine hormone release. Endo-
crine organs such as the pancreas receive sympathetic and
parasympathetic input, which contributes to the regulation of
insulin and glucagon release.
HORMONAL CONTROL
Hormone release from an endocrine organ is frequently con-
trolled by another hormone. When the outcome is stimulation
of hormone release, the hormone that exerts that effect is
referred to as a tropic hormone, as is the case for most of the
hormones produced and released from the anterior pituitary.
One example of this type of hormone release control is the
regulation of glucocorticoid release by ACTH. Hormones can
also suppress another hormone’s release. An example of this is
the inhibition of growth hormone release by somatostatin
from the hypothalamus.
Hormonal inhibition of hormone release plays an important
role in the process of negative feedback regulation of hormone
release, described below and in Figure 60–9. In addition, hor-
 CHAPTER 60 General Principles of Endocrine Physiology 609

Cortisol
600

500

Cortisol (nmoI/L)
400

300

200

100

0
09 11 13 15 17 19 21 23 01 03 05 07 09
Clock time

Growth Hormone
30
Sleep

25
Plasma growth hormone

20
(mIU/L)

15

10

0
09 11 13 15 17 19 21 23 01 03 05 07 09
Clock time
FIGURE 60–7 Patterns of hormone release. Plasma hormone concentrations fluctuate throughout the day. Therefore, plasma hormone
measurements do not always reflect the function of a given endocrine system. Both cortisol and growth hormone show considerable variations
in blood levels throughout the day. These levels can also be affected by sleep deprivation, light, stress, and disease, and are dependent on their
secretion rate, rates of metabolism and excretion, metabolic clearance rate, circadian pattern, fluctuating environmental stimuli, and internal
endogenous oscillators. Biologic influences include illness, night work, sleep patterns, changes in longitude, and prolonged bed rest. (Modified
with permission from Molina PE: Endocrine Physiology, 2nd ed. New York: McGraw-Hill Medical, 2007.)

mones can stimulate the release of a second hormone in what
is known as a feedforward mechanism.
NUTRIENT OR ION REGULATION
Plasma levels of nutrients or ions can also regulate hormone
release (Figure 60–9). In all cases, the particular hormone reg-
ulates the concentration of the nutrient or ion in plasma either
directly or indirectly. Examples of nutrient and ion regulation
of hormone release include the control of insulin release by
plasma glucose levels and the control of parathyroid hormone
release by plasma calcium and phosphate levels.
Release of one hormone can be influenced by more than one
of these mechanisms. For example, insulin release is regulated
by nutrients (plasma levels of glucose and amino acids), neural
(sympathetic and parasympathetic stimulation), and hormonal
(somatostatin) mechanisms. The ultimate function of these con-
trol mechanisms is to allow the neuroendocrine system to adapt
to a changing environment, integrate signals, and maintain
homeostasis. The responsiveness of target cells to hormonal
action leading to regulation of hormone release constitutes a
610 SECTION IX Endocrine and Metabolic Physiology
Postganglionic
SNS or PSNS
FIGURE 60–8 Neural control of hormone
release. Endocrine function is under
tight regulation by the nervous system, hence the
term “neuroendocrine.” Hormone release by
endocrine cells can be modulated by
postganglionic neurons from the sympathetic
nervous system (SNS) or parasympathetic
nervous system (PSNS) using acetylcholine
(ACh) or norepinephrine (NE) as
neurotransmitters, or by preganglionic neurons Endocrine
using acetylcholine as a neurotransmitter. cell
Therefore, pharmacologic agents that interact
with the production or release of
neurotransmitters affect endocrine function.
(Modified with permission from Molina PE: Endocrine
Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.) Hormone release
feedback control mechanism. A dampening or inhibition of the
initial stimulus is called negative feedback. Stimulation or
enhancement of the original stimulus is called positive feedback
(Figure 60–9). Negative feedback is the most common control
mechanism regulating hormone release. The integrity of the sys-
tem ensures that adaptive changes in hormone levels do not lead
to pathologic conditions. Furthermore, the control mechanism
plays an important role in short- and long-term adaptations to
changes in the environment. Three levels of feedback can be
identified: long loop, short loop, and ultrashort loop.
ASSESSMENT OF
ENDOCRINE FUNCTION
In general, disorders of the endocrine system result from
alterations in hormone secretion or target cell responsiveness to
hormone action. Alterations in target cell response can be due
to increased or decreased biologic responsiveness to a particular
hormone (Figure 60–10). The initial approach to assessment of
endocrine function is measurement of plasma hormone levels.
Preganglionic
Neuron Neuron
ACh
Neuron
ACh or NE ACh
Adrenomedullary
cell
Hormone release
INTERPRETATION OF
HORMONE MEASUREMENTS
Because of the variability in circulating hormone levels result-
ing from pulsatile release, circadian rhythms, sleep/wake
cycle, and nutritional status, interpretation of isolated plasma
hormone measurements should always be done with caution
and with understanding of the integral components of the
hormone axis in question.
Some general aspects that should be considered when inter-
preting hormone measurements are as follows:
• Hormone levels should be evaluated with their appropriate
regulatory factors (e.g., insulin with glucose, calcium with
parathyroid hormone, thyroid hormone with TSH, etc.).
• Simultaneous increase of pairs (increase in both the hor-
mone and the substrate that it regulates, such as increased
plasma glucose and insulin levels) can indicate a hormone
resistant state.
• Urinary excretion of hormone or hormone metabolites over
24 hours may be a better estimate of hormone secretion
 CHAPTER 60 General Principles of Endocrine Physiology 611

a. Negative feedback A. Decreased hormone responsiveness

150
TSH Maximal response

Hormone effect (%)

Effect produced by
saturating dose
100
of hormone
Anterior Thyroid
pituitary gland
50

Thyroid 0
hormone Log [hormone]

b. Positive feedback
B. Decreased hormone sensitivity
LH 150

Hormone effect (%)

100
Hypothalamus
Ovary
Pituitary Sensitivity
50 Hormone concentration
required to elicit half-
maximal response
Estradiol 0
Log [hormone]
c. Product regulation
FIGURE 60–10 Receptor function. A. Hormone
PTH responsiveness. Decreased responsiveness to hormone effects can
be due to a decreased number of hormone receptors, a decreased
concentration of enzyme activated by the hormone, an increased
Parathyroid concentration of noncompetitive inhibitor, or a decreased number of
Bone
gland target cells. When responsiveness is decreased, then no matter how
high the hormone concentration is, a maximal response will not be
achieved. B. Hormone sensitivity. A decrease in hormone sensitivity
requires higher hormone concentrations to produce 50% of the
Ca++
maximal response. Decreased sensitivity can be due to decreased
FIGURE 60–9 Mechanisms regulating hormone release hormone–receptor affinity, decreased hormone–receptor number,
a. Negative feedback regulation. In some cases, the endocrine gland is increased rate of hormone degradation, and increased levels of
itself a target organ for another hormone. In this case, endocrine cells antagonistic or competitive hormones. (Modified with permission from
Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)
from organ 1 produce a hormone that stimulates the target organ to
produce another hormone (hormone 2). Hormone 2 decreases the
production and release of the hormone that stimulated its release, also
known as a tropic hormone. An example is the regulation of anterior
pituitary release of thyroid-stimulating hormone (TSH) by thyroid TABLE 60–1 Interpretation of hormone levels.
hormones produced by the thyroid gland. b. Positive feedback
regulation, occurs when the release of a hormone stimulates a second Pituitary Target Hormone Level
hormone that then stimulates the first hormone, resulting in a vicious Hormone
cycle. An example is the stimulation of LH release by estradiol during Level Low Normal High
the middle of the menstrual cycle. c. Product control of hormone High Primary failure Autonomous
release. The production and release of a hormone can be regulated by of target secretion of
the circulating levels of the substrate that it controls. An example is the endocrine pituitary
regulation of parathyroid hormone release from the parathyroid glands organ hormone or
by the prevailing serum levels of Ca2+. (Modified with permission from Molina resistance to
target hormone
PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)
action

Normal Normal range

than one-time plasma-level measurement. However, these Low Pituitary failure Autonomous
measures rely on adequate renal function. secretion by
• Target hormone excess should be evaluated with the target
endocrine
appropriate tropic hormone. organ
The possible interpretations of altered hormone and regula- Reproduced with permission from Kibble J and Halsey CR: The Big Picture, Medical
tory factor pairs are summarized in Table 60–1. Physiology. New York: McGraw-Hill, 2009
612 SECTION IX Endocrine and Metabolic Physiology
CHAPTER SUMMARY
■ Hormones are classified into protein, amino acid derived, and
steroid based on their chemistry.
■ Binding proteins regulate hormone availability and physiologic
function.
■ Physiologic effects of hormones require binding to specific
receptors in target organs.
■ Hormone release is under neural, hormonal, and product
regulation.
■ Hormones can control their own release through feedback
regulation.
■ Interpretation of hormone levels requires consideration of
hormone pairs or of the nutrient or factor controlled by the
hormone.
STUDY QUESTIONS
1. Which of the following statements concerning a particular
hormone is correct?
A) It will bind to cell membrane receptors in all cell types.
B) It is lipid soluble and has an intracellular receptor.
C) It circulates bound to a protein, and this shortens its
half-life.
D) It is a small peptide; therefore, its receptor localization will
be in the nucleus.
2. Which of the following would be expected to alter hormone levels?
A) changes in mineral and nutrient plasma levels
B) pituitary tumor
C) transatlantic flight
D) training for the Olympics
E) all of the above
3. Which of the following statements concerning hormonal
regulation is correct?
A) A hormone does not inhibit its own release.
B) The substrate a hormone regulates does not affect that
hormone’s release.
C) Negative feedback regulation occurs only at the level of the
anterior pituitary.
D) Feedback inhibition may be exerted by nutrients and
hormones.
4. The structure of a newly discovered hormone shows that it is a
large peptide with a glycosylated subunit. The hormone is
likely to
A) bind to DNA and affect gene transcription
B) bind to adenylate cyclase and stimulate protein kinase C
C) bind to a cell membrane receptor
D) be secreted intact in the urine
 61
C H A P T E R

The Hypothalamus and

Posterior Pituitary Gland
Patricia E. Molina

O B J E C T I V E S

■ Describe the physiologic and anatomic relationships between the

hypothalamus and the anterior and the posterior pituitary.
■ Understand the integration of hypothalamic and pituitary function, and identify
the two different pathways used for hypothalamic–pituitary interactions.
■ Identify the appropriate hypothalamic releasing and inhibitory factors
controlling the secretion of each of the anterior pituitary hormones.
■ Differentiate between the routes of transport of hypothalamic neuropeptides
to the posterior and anterior pituitary.
■ Identify the mechanisms that control the release of oxytocin and antidiuretic
hormone (ADH; arginine vasopressin [AVP]).
■ Understand the physiologic target organ responses and the cellular
mechanisms of oxytocin and ADH action.

The hypothalamus is the region of the brain involved in coordi-
nating the physiologic responses of different organs that together
maintain homeostasis. It does this by integrating signals from the
environment, other brain regions, and visceral afferents, and then
stimulating the appropriate neuroendocrine responses. In doing
so, the hypothalamus influences many aspects of daily function,
including food intake, energy expenditure, body weight, fluid
intake and balance, blood pressure, thirst, body temperature, and
the sleep cycle. Most of these hypothalamic responses are medi-
ated through hypothalamic control of pituitary function
(Figure 61–1). This control is achieved by the following two
mechanisms: (1) release of hypothalamic neuropeptides synthe-
sized in hypothalamic neurons and transported through the
hypothalamohypophysial tract to the posterior pituitary gland
and (2) neuroendocrine control of the anterior pituitary through
the release of peptides that mediate anterior pituitary gland
hormone release (hypophysiotropic hormones) (Figure 61–2).
FUNCTIONAL ANATOMY
The hypothalamus is the part of the diencephalon located
below the thalamus and between the lamina terminalis and
the mamillary bodies forming the walls and the floor of the
third ventricle. At the floor of the third ventricle, the two
halves of the hypothalamus are rejoined to form a bridgelike
region known as the median eminence (Figure 61–1). The
median eminence is important because this is where axon ter-
minals of hypothalamic neurons release neuropeptides
involved in the control of anterior pituitary function. In addi-
tion, the median eminence is traversed by the axons of hypo-
thalamic neurons ending in the posterior pituitary. The median
eminence funnels down to form the infundibular portion of
the neurohypophysis or posterior pituitary.
HYPOTHALAMIC NUCLEI
In the hypothalamus, the neuronal bodies are clustered in
nuclei with projections reaching other brain regions as well as
ending in other hypothalamic nuclei. This intricate system of
neuronal connections allows continuous communication
between the hypothalamic neurons and other brain regions.
Some of the neurons that make up the hypothalamic nuclei
are neurohormonal in nature. Neurohormonal refers to the
ability of these neurons to synthesize neuropeptides that func-
tion as hormones and to release these neuropeptides from axon
terminals in response to neuronal depolarization. Two types of

613

Ch61_613-622.indd 613 11/26/10 10:36:07 AM

614 SECTION IX Endocrine and Metabolic Physiology

Small diame
ter ne
u rons
TRH GnRH
Hypothalamus CRH
GHRH
Somatostatin
Dopamine

Hypothalamus
Optic PVN Preprooxyphysin
chiasm Mamillary
SON Prepropressophysin
body
Superior hypophyseal
artery Optic
chiasm Mamillary
body
Posterior
pituitary
Anterior
pituitary
Oxytocin

Anterior ADH
pituitary
Posterior pituitary
ACTH TSH
GH FSH LH Inferior hypophysial
Prolactin artery

FIGURE 61–1 Anatomic and functional relationship between the hypothalamus and the pituitary. The hypothalamus is
anatomically and functionally linked with the anterior and posterior pituitary. They are closely related because of the portal system of blood
supply. The superior, medial, and inferior hypophyseal arteries provide arterial blood supply to the median eminence and the pituitary.
Magnocellular neurons of the supraoptic and paraventricular nuclei have long axons that terminate in the posterior pituitary. Antidiuretic
hormone (ADH, also known as arginine vasopressin) and oxytocin are synthesized in magnocellular neurons as precursors (preprohormones),
post-translationally processed, and released from the posterior pituitary into the blood. The axons of parvocellular neurons terminate in
the median eminence where they release their neuropeptides. The long portal veins drain the median eminence, transporting the peptides
from the primary capillary plexus to the secondary plexus that provides blood supply to the anterior pituitary. TRH, thyrotropin-releasing
hormone; CRH, corticotropin-releasing hormone; GnRH, gonadotropin-releasing hormone, GHRH, growth-hormone releasing hormone; PVN,
paraventricular nucleus; SON, supraoptic nucleus; ADH, antidiuretic hormone; ACTH, adrenocorticotropin; TSH, thyroid-stimulating hormone;
GH, growth hormone; FSH, follicle stimulating hormone; LH, luteinizing hormone. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture,
Medical Physiology. New York: McGraw-Hill, 2009.)

FIGURE 61–2 Magnocellular neurons are larger in size Magnocellular neuron Parvocellular neuron
and produce large quantities of neurohormones. Located
predominantly in the paraventricular and supraoptic nuclei of
the hypothalamus, their unmyelinated axons form the
hypothalamohypophyseal tract that traverses the median Axonal transport
eminence ending in the posterior pituitary. They synthesize the
neurohormones oxytocin (OT), and antidiuretic hormone (ADH),
and neurophysin (NP), that are transported in neurosecretory Median eminence
Axonal transport CRH, TRH, GnRH, GHRH, SST, DA
vesicles down the hypothalamohypophyseal tract and stored
in varicosities at the nerve terminals in the posterior pituitary. Long portal veins
Parvocellular neurons are small in size and have projections
that terminate in the median eminence, brainstem, and spinal
Anterior pituitary
cord. They release small amounts of releasing or inhibiting
neurohormones (hypophysiotropic hormones - CRH, TRH, Posterior pituitary
GnRH, GHRH, SST, DA) that control anterior pituitary function OT, ADH, NP
(discussed in the next chapter). These are transported in the ACTH, TSH, LH/FSH, GH, Prl
long portal veins to the anterior pituitary where they stimulate
the release of pituitary hormones (ACTH, TSH, LH/FSH, GH, Prl)
into the systemic circulation. (Modified with permission from Molina PE:
Systemic circulation Systemic circulation
Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)
 CHAPTER 61 The Hypothalamus and Posterior Pituitary Gland
neurons are important in mediating the endocrine functions
of the hypothalamus: the magnocellular and the parvocellu-
lar neurons (Figure 61–2). The magnocellular neurons are
predominantly located in the paraventricular and supraoptic
nuclei of the hypothalamus and produce large quantities of the
neurohormones oxytocin and antidiuretic hormone (ADH)
also known as arginine vasopressin (AVP). The unmyelinated
axons of these neurons form the hypothalamohypophysial
tract, the bridgelike structure that traverses the median emi-
nence and ends in the posterior pituitary. Oxytocin and ADH
are released from the posterior pituitary in response to an
action potential. Parvocellular neurons have projections that
terminate in the median eminence, brainstem, and spinal cord.
These neurons release small amounts of releasing or inhibiting
neurohormones (hypophysiotropic hormones) that control
anterior pituitary function.
HYPOTHALAMIC NEUROPEPTIDES
Two general types of neurons constitute the endocrine hypo-
thalamus: the magnocellular neurons, with axons terminating
in the posterior pituitary, and the parvocellular neurons, with
axons terminating in the median eminence. Hypophysiotropic
peptides released near the median eminence are transported
down the infundibular stalk to the anterior pituitary, where
they bind to specific cell membrane receptors in cells of the
anterior pituitary, activating intracellular second-messenger
cascades that result in the release of anterior pituitary hor-
mones into the systemic circulation (Table 61–1). Peptides
released from the anterior pituitary (adrenocorticotropic
hormone [ACTH], prolactin, growth hormone [GH],
luteinizing hormone [LH], follicle-stimulating hormone
[FSH], and thyroid-stimulating hormone [TSH]) and the
axons of magnocellular neurons terminating in the posterior
pituitary (oxytocin and ADH) are transported in the venous
blood draining the pituitary that enters the intercavernous
sinus and the internal jugular veins to reach the systemic
circulation.
TABLE 61–1 Key aspects of hypophysiotropic hormones.
Hypophysiotropic Hormone Predominant Hypothalamic Nuclei
Thyrotropin-releasing hormone Paraventricular nuclei
Gonadotropin-releasing hormone Anterior and medial hypothalamus;
preoptic septal areas
Corticotropin-releasing hormone Medial parvocellular portion of
paraventricular nucleus
Growth hormone–releasing hormone Arcuate nucleus, close to median
eminence
Somatostatin or growth hormone– Anterior paraventricular area
inhibiting hormone
Dopamine Arcuate nucleus
The six recognized hypophysiotropic factors and the predominant locations of their cells of origin are listed in the left columns. The right columns list the anterior pituitary
hormone that each hypophysiotropic factor regulates and the cell that releases the specific hormones.
615
REGULATION OF HORMONE RELEASE
Because the hypothalamus receives and integrates afferent
signals from multiple brain regions, it does not function in
isolation from the rest of the central nervous system. Some
of these afferent signals convey sensory information about
the individual’s environment such as light, heat, cold, and
noise. Among the environmental factors, light plays an
important role in generating the circadian rhythm of hor-
mone secretion. This endogenous rhythm is generated
through the interaction between the retina, the hypotha-
lamic suprachiasmatic nucleus, and the pineal gland
through the release of melatonin. Melatonin is a hormone
synthesized and secreted by the pineal gland at night that
conveys information concerning the daily cycle of light and
darkness to body physiology and participates in the organi-
zation of circadian rhythms. Its rhythm of secretion is
entrained to the light/dark cycle. Other signals perceived by
the hypothalamus are visceral afferents that provide infor-
mation to the central nervous system from peripheral organs
such as the intestines, the heart, the liver, and the stomach.
The neuronal signals are transmitted by various neurotrans-
mitters released from the afferent fibers, including gluta-
mate, norepinephrine, epinephrine, serotonin, acetylcholine,
histamine, γ-aminobutyric acid, and dopamine. In addi-
tion, circulating hormones produced by endocrine organs
and substrates such as glucose can regulate hypothalamic
neuronal function. Together, these neurotransmitters, sub-
strates, and hormones influence hypothalamic hormone
release. Therefore, hypothalamic hormone release is under
environmental, neural, and hormonal regulation. The ability
of the hypothalamus to integrate these signals makes it a
center of command for regulating endocrine function and
maintaining homeostasis.
Hormones can signal the hypothalamus to either inhibit or
stimulate hypophysiotropic hormone release. This control
mechanism of negative (or positive) feedback regulation
consists of the ability of a hormone to regulate its own cascade
Anterior Pituitary Hormone Controlled Target Cell
Thyroid-stimulating hormone and prolactin Thyrotroph
Luteinizing hormone and follicle-stimulating Gonadotroph
hormone
Adrenocorticotropic hormone Corticotroph
Growth hormone Somatotroph
Growth hormone Somatotroph
Prolactin Lactotroph
616 SECTION IX Endocrine and Metabolic Physiology

of release (see Figure 60–9). For example, cortisol produced
from the adrenal gland can inhibit the release of CRH, thus
inhibiting the production of proopiomelanocortin and ACTH
and consequently decreasing adrenal gland synthesis of corti-
sol. This loop of hormonal control and regulation of its own
synthesis is critical in maintaining homeostasis and prevent-
ing disease. A shorter loop of negative feedback inhibition
also exists, which depends on the inhibition of hypophysio-
tropic neuropeptide release by the pituitary hormone that it
stimulates. In this case, an example would be the ability of
ACTH to inhibit CRH release by the hypothalamus. Some
neuropeptides also possess an ultrashort feedback loop, in
which the hypophysiotropic neuropeptide itself is able to
modulate its own release. As an example, oxytocin stimulates
its own release, creating a positive feedback regulation of neu-
ropeptide release.
This continuous regulation of hormonal release is dynamic;
it is continuously adapting to changes in the environment and
in the internal milieu of the individual. Throughout a given
day, the hypothalamus integrates a multitude of signals to
ensure that the rhythms of hormone release are kept in pace
with the needs of the organism. Disruption of these factors can
alter the patterns of hormone release.
HORMONES OF THE
POSTERIOR PITUITARY
The neuropeptides produced by the magnocellular neurons,
and consequently released from the posterior pituitary, are
oxytocin and ADH. Oxytocin and ADH are closely related
peptides consisting of nine amino acids with ring structures.
They are synthesized as large precursor molecules in the
magnocellular neurons and packaged into neurosecretory
vesicles (Figure 61–3). Within the neurosecretory vesicles, the
precursor hormone undergoes additional posttranslational
processing during axonal transport, producing the biologi-
cally active peptides ADH and oxytocin as well as small pep-
tide products of hormone processing called neurophysins.
Following neuronal depolarization, neuropeptides released
enter the systemic circulation through venous drainage of the
posterior pituitary into the intercavernous sinus and internal

Nucleus
Cell body Pre-prohormone synthesis
in ER followed by packaging
into secretory granules
in GA occurs in the cell
body of magnocellular neurons.

Axon

Neurosecretory vesicles are transported

down the hypothalamo-hypophysial
tract. Hormone processing occurs
FIGURE 61–3 Synthesis and processing of during this stage yielding hormone
oxytocin and antidiuretic hormone. Oxytocin and and neurophysins.
antidiuretic hormone are synthesized in the endoplasmic
reticulum (ER) of hypothalamic magnocellular neurons
as preprohormones. In the Golgi apparatus (GA) they are
packaged in secretory granules and are transported
down the hypothalamohypophyseal tract. During their Contents of neurosecretory vesicles
are released from nerve terminals in Mitochondria
transport the precursor hormones are processed, yielding
the posterior pituitary. Exocytosis is
the final hormone and the respective neurophysins. The triggered by Ca2+ influx through
contents of the neurosecretory vesicles are released by Synaptic vesicle
voltage-gated channels opened
exocytosis from the axon terminals in the posterior during neuronal depolarization.
pituitary. Exocytosis is triggered by the influx of Ca2+
through voltage-gated channels that are opened during
the neuronal depolarization. The rise in Ca2+ produces
the docking of the secretory vesicles on the axonal plasma
membrane and the release of the neuropeptides into the
interstitial space. (Modified with permission from Molina PE:
Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)
 CHAPTER 61 The Hypothalamus and Posterior Pituitary Gland
jugular vein. In the systemic circulation, oxytocin and ADH
circulate unbound. They are rapidly cleared from the circula-
tion by the kidney and, to a lesser extent, by the liver and brain.
Their half-life is short and is estimated to range between 1 and
5 minutes.
OXYTOCIN
The neuropeptide oxytocin is released in response to sensory
stimulation during breastfeeding (lactation) and childbirth
(parturition) (Figure 61–4).
Physiologic Effects of Oxytocin
The two main target organs for oxytocin’s physiologic effects
are the lactating breast and the uterus during pregnancy
(Figure 61–4). The physiologic effects of oxytocin are achieved
by binding to cell membrane Gq/11 protein–coupled oxytocin
receptors expressed in the uterus, mammary glands, and
brain. In the lactating breast, oxytocin stimulates milk ejection
by producing contraction of the myoepithelial cells that line
the alveoli and ducts in the mammary gland. In the pregnant
uterus, oxytocin produces rhythmic contractions to help
induce labor and to promote regression of the uterus following
delivery. Oxytocin analogs are used clinically during labor and
delivery to promote uterine contractions and during the
postpartum period to help decrease bleeding and return the
uterus to its normal size (uterine involution) (Table 61–2).
PVN & SON
Fear, pain,
noise, fever
Posterior Stretch of cervix
pituitary end of pregnancy
Oxytocin release
Sucking of
lactating breast
Contraction of
myoepithelial cells
Uterine
contraction
617
The physiologic effects of oxytocin in the pregnant uterus
are augmented by a dramatic increase in sensitivity to the hor-
mone during the onset of labor, due to an increased density
(upregulation) of oxytocin receptors in the uterine muscle,
increased gap junction formation between smooth muscle
cells, and by increased synthesis of prostaglandins.
Control of Oxytocin Release
The principal stimulus for oxytocin release is mechanical
stimulation of the uterine cervix by the fetus near the end of
gestation and by the forceful contractions of the uterus during
the fetal expulsion reflex. In addition, oxytocin release is also
triggered by stimulation of tactile receptors in the nipples of
the lactating breast during suckling (Figure 61–4).
The role of oxytocin in males is not clear, although recent
studies have suggested that it may participate in ejaculation.
ANTIDIURETIC HORMONE
ADH, also known as arginine vasopressin (AVP), is the other
neuropeptide produced by magnocellular neurons of the
hypothalamus and released from the posterior pituitary. The
principal effect of ADH is to increase water reabsorption by
enhancing permeability to water in the distal convoluted
tubules and the medullary collecting ducts in the kidney (see
Chapter 45). The result is the production of smaller volumes
of concentrated urine. In addition, ADH increases vascular
resistance. This function of ADH may be important during
FIGURE 61–4 Physiologic effects and regulation of
oxytocin release. The release of oxytocin is stimulated by
the distention of the cervix at term of pregnancy and by
the contraction of the uterus during parturition. The signals
are transmitted to the paraventricular nuclei (PVN) and
supraoptic nuclei (SON) of the hypothalamus, where they
provide a positive feedback regulation of oxytocin release.
The increased number of oxytocin receptors, the increased
number of gap junctions between smooth muscle cells,
and the increased synthesis of prostaglandins enhance the
responsiveness of the uterine muscle. Oxytocin release
causes an increase in uterine contractility, aiding in the
delivery of the baby, and involution of the uterus after
parturition. Suckling of the nipple of the lactating breast
also stimulates oxytocin release. The afferent sensory
signals elicit a rise in oxytocin release into the circulation.
Oxytocin produces contraction of the myoepithelial cells
lining the breast ducts, resulting in milk ejection. (Modified
with permission from Molina PE: Endocrine Physiology, 3rd ed. New York:
McGraw-Hill Medical, 2010.)
618 SECTION IX Endocrine and Metabolic Physiology

TABLE 61–2 Key aspects of posterior pituitary hormones.

Oxytocin Antidiuretic Hormone

Receptor Gq/11 protein–coupled G protein–coupled (V1R, Gq/11, V2R, Gs)

Second messenger Phospholipase C ↑ [Ca2+]i (V1R) Phospholipase C ↑ [Ca2+]i

(V2R) Adenylate cyclase cAMP

Target organ or cells Uterus V2R: kidney collecting ducts

Mammary myoepithelial cells V1R: smooth muscle cells

Physiologic effects Uterine contraction Increased H2O permeability

Milk ejection Vasoconstriction

cAMP, cyclic adenosine monophosphate.

periods of severe lack of responsiveness to other vasoconstric-
tors, as may occur during severe blood loss (hemorrhagic
shock) or systemic infection (sepsis).
Physiologic Effects of ADH
The cellular effects of ADH are mediated by binding
to G protein–coupled membrane receptors. Three ADH
receptors have been characterized thus far, which differ in
terms of where they are expressed as well as in the specific
G proteins to which they are coupled and, thus, in the
second-messenger systems that they activate. The main
effects of ADH are mediated through the V2R receptor.
The main target site of ADH is the collecting duct in the
kidney. Water permeability of the collecting duct can be
dramatically increased (within a few minutes) through the
production of cyclic adenosine monophosphate (cAMP)
following ADH binding to V2 receptors in the basolat-
eral membrane of the principal cells in the collecting duct
(Figure 61–5).
The increase in cAMP activates protein kinase A and subse-
quently the phosphorylation of an aquaporin (AQP2) leading

Interstitial space

ADH
H2O H2O
V2R Adenylate cyclase
AQP3
AQP4
Basolateral
α
membrane βγ α α

FIGURE 61–5 Cellular mechanism of ATP cAMP

ADH water conservation. The principal

function of antidiuretic hormone (ADH) is to
increase water reabsorption and to conserve PKA
water. ADH binds to the V2 G protein–coupled
receptor (V2R) in the principal cells of the
Principal cell
distal tubule. This triggers the activation of
distal tubule
adenylate cyclase and the formation of
AQP2
cAMP, leading to activation of protein kinase AQP2
A (PKA). PKA phosphorylates the water
channel aquaporin 2 (AQP2), leading to the Cytosolic
insertion of AQP2 into the luminal cell H2O pool of
AQP2 AQP2
membrane. The insertion of water channels Apical
AQP2
into the membrane increases the permeability membrane
to water. Water reabsorbed through these
water channels leaves the cell through
aquaporins 3 (AQP3) and 4 (AQP4), which are
constitutively expressed in the basolateral
H2O
membrane of the principal cells. (Modified with
permission from Molina PE: Endocrine Physiology, 3rd ed.
New York: McGraw-Hill Medical, 2010.) Lumen-collecting duct
 CHAPTER 61 The Hypothalamus and Posterior Pituitary Gland 619

TABLE 61–3 Key features of aquaporins.

Aquaporin Features

AQP1 Constitutively expressed in apical and basolateral membranes of epithelial cells of proximal tubules and descending limb of
Henle’s loop. Involved in 90% of water reabsorption

AQP2 Exclusively expressed in the collecting ducts. The only aquaporin directly regulated by ADH. Binding to the V2 ADH (AVP) receptor
stimulates insertion into the luminal membrane

AQP3, AQP4 Constitutively expressed in the basolateral membranes of epithelial cells in the collecting ducts. Enhance water reabsorption
following AQP2 insertion into the luminal membrane
AQP, aquaporin; ADH, antidiuretic hormone; AVP, arginine vasopressin.

to its movement from cytoplasmic pools and its insertion in
the luminal (apical) epithelial cell membrane of the collecting
duct cells. The result is an increase in the number of functional
water channels in the luminal membrane, making it more per-
meable to water. AQP2, one of the several members of the
aquaporin family, is exclusively expressed in the collecting
ducts of the kidney (Table 61–3). It is the only aquaporin that
is directly regulated by ADH via the V2 ADH receptor. AQP3
and AQP4 are constitutively expressed in the basolateral mem-
branes of the collecting ducts and contribute to the enhanced
water reabsorption following AQP2 insertion into the luminal
membrane. Water that enters the epithelial cell through AQP2
on the apical membrane leaves the cell through AQP3 and
AQP4, located in the basolateral membranes of these cells,
eventually entering the vasculature. ADH also binds the V1
receptor, found in the vascular smooth muscle, producing
contraction and increasing peripheral vascular resistance. The
hormone is known as vasopressin because of these vasocon-
strictor effects.
Control of ADH Release
ADH is released into the circulation following either an
increase in plasma osmolality or a decrease in blood volume
(Figure 61–6). Under physiologic conditions, the most impor-
tant stimulus for ADH release is the “effective” plasma osmo-
lality detected by special osmoreceptor neurons located in the
hypothalamus and in three structures associated with the lam-
ina terminalis: the subfornical organ, the median preoptic
nucleus, and the organum vasculosum lamina terminalis.
The sensitivity of this system is quite high. That is, very small
changes in plasma osmolality (as little as 1% change) above the
osmotic threshold of 280–284 mOsm/kg water produce
significant increases in ADH release.

Fluid loss
Hemorrhage, vomiting, diarrhea

10
MABP
Plasma ADH (pg/ml)

8
10% blood loss
FIGURE 61–6 Integration of signals
6
Baroreceptor stretch and firing that trigger ADH release. Release of ADH is
4 stimulated by an increase in plasma osmolality
9th and 10th cranial
and a decrease in blood volume. Small changes
2
Thirst nerve afferents in plasma osmolality above a threshold of
0 280–284 mOsm/kg produce an increase in
270 280 290 300 310 ADH release before the stimulation of thirst.
Plasma osmolarity (mOsm/kg)
A decrease in blood volume sensitizes the
Plasma osmolarity system and increases the responsiveness to
small changes in plasma osmolality. Blood
loss and a decrease in mean arterial blood
Shrinkage of Sympathetic
tone pressure (MABP) greater than 10% signal
osmoreceptors
the hypothalamus to increase the release
of ADH. The afferent signals are transmitted
by the 9th and 10th cranial nerves. These
ADH release
Restore fluid signals increase sympathetic tone, therefore
balance decreasing magnocellular neuron inhibition
and stimulating ADH release. (Modified with
Magnocellular permission from Molina PE: Endocrine Physiology, 3rd ed.
H2O reabsorption
neuron inhibition New York: McGraw-Hill Medical, 2010.)
620 SECTION IX Endocrine and Metabolic Physiology
ADH secretion is also stimulated by a decrease in blood
pressure of greater than 10%. Factors that reduce cardiac out-
put, such as a decrease in blood volume greater than 8%,
orthostatic hypotension, and positive pressure breathing, are
all stimuli for ADH release. ADH secretion is far more sensitive
to small changes in plasma osmolality than to changes in blood
volume. The volume-induced sensitization of ADH release
results in a more accentuated ADH response to changes in
plasma osmolality. ADH is barely detectable below a certain
plasma osmolality (287 mOsm/kg) threshold. Above this
threshold, the plasma AVP concentration rises steeply in direct
proportion to plasma osmolality.
Disorders of ADH Production
Either excess or deficiency of ADH can result in clinical dis-
ease. The concentrations of ADH may be altered in various
chronic pathophysiologic conditions, including congestive
heart failure, liver cirrhosis, and nephrotic syndrome. A
decrease in ADH release or action results in diabetes insipi-
dus, a clinical syndrome in which the ability to form concen-
trated urine is reduced.
Diabetes insipidus Diabetes insipidus is characterized by
the excretion of abnormally large volumes (up to 30 mL/kg of
body weight per day for adult subjects) of dilute (<250 mmol/kg)
urine and excessive thirst. Three basic defects have been identi-
fied in the etiology (only the first two pertain to alterations re-
lated to components of the ADH system itself):
• Decreased ADH release: Neurogenic (central or hypotha-
lamic) diabetes insipidus is due to a decrease in ADH release
from the posterior pituitary, resulting from diseases affect-
ing the hypothalamic-neurohypophysial axis. Three causes
can be identified: traumatic, inflammatory or infectious,
and cancer related.
• Decreased renal responsiveness to ADH: Renal (nephro-
genic) diabetes insipidus results from renal insensitivity to
the antidiuretic effect of ADH. ADH production and release
are not affected, but responsiveness at the distal tubule is
impaired. Nephrogenic diabetes insipidus can be inherited
or acquired and is characterized by an inability to concen-
trate urine despite normal or elevated plasma concentra-
tions of ADH. About 90% of inherited cases are males with
the X-linked recessive form of the disease who have muta-
tions in the ADH type 2 receptor gene. A small number of
cases of inherited nephrogenic diabetes insipidus are due to
mutations in the AQP2 water channel gene. Acquired neph-
rogenic diabetes insipidus can result from lithium treat-
ment, hypokalemia, and postobstructive polyuria.
• Excess water intake: Finally, the third possible cause of dia-
betes insipidus is excess water intake. This cause does not
involve dysfunction of the ADH system.
Syndrome of inappropriate ADH secretion An increase
or excess in the release of ADH, also known as the syndrome of
inappropriate ADH secretion, may be the result of tumor pro-
duction of ADH. The tumor can be located in the brain, but ma-
lignancies of other organs such as the lung have also been shown
to produce high levels of ADH. The excess production of ADH
results in the production of very small volumes of concentrated
urine. Retention of water may lead to decreased plasma sodium
(hyponatremia). Management of this condition entails fluid re-
striction and in some cases the use of saline solutions to restore
adequate plasma sodium levels.
CLINICAL CORRELATION
A head trauma patient on his third day in the surgical
intensive care unit is reported to have an excessive urine
output of 20 L in the past 24 hours. Laboratory findings
show hypernatremia (high serum Na) and hypotonic
urine. Withholding drinking water did not decrease urine
output or increase urine osmolarity. Urine osmolarity
increased in response to exogenous antidiuretic hormone
(vasopressin) administration. He is diagnosed as having
posttraumatic diabetes insipidus.
Neurogenic diabetes insipidus is the result of decreased
release of ADH characterized by polyuria (increased
urine output) and hypernatremia. This can be the result
of destruction of neurons that produce and release ADH
resulting from inflammation, neoplasia, vascular abnor-
malities, or traumatic injury. Patients are treated with
desmopressin, a synthetic analog of ADH, which binds
to V2 receptors, increasing water reabsorption in the
kidney, decreasing urine output, and restoring serum
osmolarity.
CHAPTER SUMMARY
■ The parvocellular neurons of the hypothalamus produce
neuropeptides that are released at the median eminence and
are transported to the anterior pituitary, where they regulate
the release of anterior pituitary hormones.
■ The hypothalamus integrates information from various brain
regions, the environment, and peripheral organs and mediates
systemic responses that help maintain homeostasis.
■ The magnocellular neurons of the hypothalamus produce
oxytocin and ADH, hormones that are released from the
posterior pituitary into the systemic circulation.
■ Prohormone posttranslational modification and processing of
oxytocin and ADH occur inside the secretory granules during
axonal transport.
■ ADH binds to the V2 receptor and increases water reabsorption
by stimulating the insertion of aquaporin 2 into the apical
(luminal) membrane of tubular collecting duct epithelial cells.
■ The release of ADH is more sensitive to small changes in
plasma osmolality than to small changes in blood volume.
■ Deficiency of ADH results in the production of large quantities
of dilute urine.
 CHAPTER 61 The Hypothalamus and Posterior Pituitary Gland 621

STUDY QUESTIONS 4. Oxytocin

A) is released from the anterior pituitary during parturition
1. The renal effects of ADH (AVP) are mediated by B) is synthesized in the posterior pituitary and released during
A) binding to V2 G protein–coupled receptor, protein parturition
phosphorylation, and insertion of aquaporin 2 into luminal C) is produced in the magnocellular neurons of the
cell membrane in collecting duct hypothalamus and released from the posterior pituitary
B) binding to nuclear receptors, protein phosphorylation, and during parturition
insertion of aquaporin 2 into basolateral membrane of D) is produced in the magnocellular neurons of the
collecting duct hypothalamus and released from the anterior pituitary
C) binding to V1 G protein–coupled receptor, protein during parturition
phosphorylation, and insertion of aquaporin 1 into luminal 5. Uterine muscle responsiveness to oxytocin
cell membrane of collecting duct
A) is not altered throughout pregnancy
D) binding to nuclear receptors, protein phosphorylation, and
B) is prevented by high prostaglandin levels during pregnancy
insertion of aquaporin 2 into luminal cell membrane of
C) is decreased by lower gap junction formation during the
collecting duct
third trimester
2. On a hot summer day after profuse sweating, the release of D) is enhanced by increased oxytocin receptor density
ADH occurs
A) when plasma osmolality is 270 mOsm/kg
B) immediately following stimulation of thirst
C) only after more than a 10% decrease in blood volume
D) before stimulation of thirst
3. Which of the following can be manifestations of the syndrome of
inappropriate ADH secretion?
A) hypernatremia with high urine osmolality
B) hyponatremia with high urine osmolality
C) hypophosphatemia with low urine osmolality
D) hyponatremia with low urine osmolality
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 62
C H A P T E R

Anterior Pituitary Gland

Patricia E. Molina

O B J E C T I V E S

■ Identify the three families of anterior pituitary hormones and their main
structural differences.
■ Understand the mechanisms that regulate anterior pituitary hormone
production and describe the actions of tropic hormones on target organs.
■ Diagram the short- and long-loop negative feedback control of anterior
pituitary hormone secretion.
■ Predict the changes in secretory rates of hypothalamic anterior pituitary and
target gland hormones caused by oversecretion or undersecretion of any of
these hormones or receptor deficit for any of these hormones.
■ Explain the importance of pulsatile and diurnal hormone secretion.

The anterior pituitary plays a central role in the regulation of
endocrine function through the production and release of
tropic hormones (Figure 62–1). The function of the anterior
pituitary, and thereby the production of tropic hormones, is
under hypothalamic regulation by the hypophysiotropic neu-
ropeptides released in the median eminence, summarized in
Table 62–1. The tropic hormones produced by the anterior
pituitary bind to specific receptors at their target organs to
produce a physiologic response, most frequently involving the
release of a hormone (Figure 62–2). The hormones produced
by the target organs affect anterior pituitary function as well as
the release of hypophysiotropic neuropeptides, maintaining
an integrated feedback control system of endocrine function.
FUNCTIONAL ANATOMY
The pituitary, or hypophysis, consists of an anterior and a
posterior lobe that differ from one another in their embryo-
logic origin, mode of development, and structure. The ante-
rior lobe, also known as the adenohypophysis, is the remnant
of Rathke’s pouch; it is a highly vascularized structure consist-
ing of epithelial cells derived from the ectodermal lining of the
roof of the mouth. The pituitary cells that line the capillaries
produce the tropic (also known as trophic) hormones: adre-
nocorticotropic hormone (ACTH), thyroid-stimulating
hormone (TSH), growth hormone (GH), prolactin, and the
gonadotropins [luteinizing hormone (LH) and follicle-
stimulating hormone (FSH)] (Figure 62–1). All of these hor-
mones are released into the systemic circulation.
HYPOTHALAMIC CONTROL
OF ANTERIOR PITUITARY
HORMONE RELEASE
The production of pituitary tropic hormones is under direct
regulation by the hypothalamic neurohormones released from
neuronal terminals in the median eminence.
The responsiveness of the anterior pituitary to the inhibitory
or stimulatory effects of hypophysiotropic neurohormones can
be modified by several factors, including hormone levels, nega-
tive feedback inhibition, and circadian rhythms The release of
anterior pituitary hormones is cyclic in nature, and this cyclic
pattern of hormone release is governed by the nervous system.
Most daily (circadian) rhythms are driven by an internal bio-
logic clock located in the hypothalamic suprachiasmatic
nucleus; this clock is synchronized by external signals such as
light and dark periods. Both sleep and circadian effects interact
to produce the overall rhythmic pattern of pituitary hormone
release and the associated responses. Some of the 24-hour

623

Ch62_623-632.indd 623 11/26/10 4:43:25 PM

624 SECTION IX Endocrine and Metabolic Physiology

Artery
Artery
Anterior pituitary
Posterior pituitary
gland
gland

GH
TSH ACTH

Thyroid hormone Cortisol,

aldosterone, &
androgens

H2O & Na
balance
FIGURE 62–1 Anterior pituitary hormones, target Growth &
Inflammation Insulin-like
organs, and physiologic effects. Thyroid-stimulating differentiation
& metabolism growth factor
Energy balance
hormone (TSH) stimulates the thyroid gland to produce
and release thyroid hormones that regulate growth, LH &
differentiation, and energy balance. Luteinizing hormone FSH Growth & differentiation
(LH) and follicle-stimulating hormone (FSH) stimulate
gonadal production of sex steroids, which mediate Prl
reproductive function and behavior. Adrenocorticotropic
hormone (ACTH) stimulates the adrenal glands to produce
steroid hormones, which regulate water and sodium
balance, inflammation, and metabolism. Prolactin (Prl)
stimulates breast development and milk production.
Growth hormone (GH) exerts direct effects on tissue
growth and differentiation and indirect effects through Estrogen, progesterone,
the stimulation of insulin-like growth factor I production, & testosterone
which mediates some of the growth and differentiation
effects of GH. (Modified with permission from Molina PE: Endocrine Reproductive Breast development
Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.) function & behavior Milk production

hormonal rhythms depend on the circadian clock (i.e., ACTH,
cortisol, and melatonin) and some are sleep related (i.e., prolac-
tin, GH, and TSH). For example, GH secretion is influenced by
the first slow-wave sleep episode at the beginning of the night.
Pulses of prolactin and GH are positively linked to increases in
delta-wave activity, present during the deepest phases of sleep
and occurring primarily during the first third of the night. Pulses
of TSH and cortisol are related to superficial phases of sleep.
Although the regulation of the patterns of hormone release
is not well understood, it is clear that the respective patterns
of anterior pituitary hormone release play a crucial role in
achieving their physiologic effects and, thus, in maintaining
homeostasis. The importance of this regulation has become
evident because constant or continuous exogenous hormone
administration produces effects that differ from the hor-
mone’s natural physiologic effects. These observations have
highlighted the importance of trying to simulate as much as
possible the endogenous cyclic patterns of hormone release
when giving hormone replacement therapy to a patient.
HORMONES OF THE
ANTERIOR PITUITARY
The hormones of the anterior pituitary can be classified into
three families: the glycoproteins, those derived from proopi-
omelanocortin (POMC), and those belonging to the GH and
prolactin family.
 CHAPTER 62 Anterior Pituitary Gland 625

TABLE 62–1 Anterior pituitary cell type, regulatory GLYCOPROTEINS

hypothalamic factor, and hormone product.
Glycoprotein hormones are among the largest hormones
Anterior Hypothalamic Pituitary Hormone
Pituitary Cells Factor Produced
known to date. They include TSH, FSH, LH, and human chor-
ionic gonadotropin produced by the placenta. These hor-
Lactotrophs Dopamine (−) Prolactin mones are heterodimeric glycoproteins consisting of a
Corticotrophs CRH (+) POMC: ACTH, β-LPH, common α-subunit and a unique β-subunit, which confers the
α-MSH, β-endorphin biologic specificity of each hormone.
Thyrotrophs TRH (+) Thyroid-stimulating
hormone
Thyroid-stimulating Hormone
Gonadotrophs GnRH (+) LH and FSH TSH is a glycoprotein synthesized and secreted from thyrotro-
Somatotrophs GHRH (+) and SST (−) Growth hormone phs of the anterior pituitary gland. Thyrotrophs consti-
(+), stimulatory factor; (−), inhibitory factor; CRH, corticotropin-releasing tute approximately 5% of all adenohypophysial cells. They
hormone; POMC, proopiomelanocortin; ACTH, adrenocorticotropic hormone; synthesize and release TSH in response to stimulation by
LPH, lipotropin; MSH, melanocyte-stimulating hormone; TRH, thyrotropin-
releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing thyrotropinreleasing hormone (TRH), which is synthesized
hormone; FSH, follicle-stimulating hormone; GHRH, growth hormone– in the hypothalamus and released from nerve terminals in
releasing hormone; SST, somatostatin.
the median eminence. TSH binds to a Gs protein–coupled

Hypothalamic Peptides
TRH GnRH CRH Somatostatin GHRH Dopamine

Median eminence

G protein−coupled receptors in anterior pituitary

Thyrotroph Gonadotroph Corticotroph Somatotroph Lactotroph

PLC PLC AC AC AC AC, K+ , Ca2+

TSH LH & FSH ACTH GH Prl

G protein−coupled receptors Class 1 cytokine receptor

AC AC AC Kinase activity Kinase activity

Target organ physiologic response

FIGURE 62–2 Cellular signaling pathways involved in hypothalamo-pituitary hormone-mediated effects. All hypothalamic
releasing and inhibiting factors mediate their effects predominantly via G protein–coupled receptors. Anterior pituitary hormones bind
to either G protein–coupled receptors (thyroid-stimulating hormone [TSH], luteinizing hormone [LH], follicle-stimulating hormone [FSH],
adrenocorticotropic hormone [ACTH]) or class 1 cytokine receptors (growth hormone [GH] and prolactin [Prl]). Most of the cellular responses
elicited by anterior pituitary hormones that bind to G protein–coupled receptors are mediated by modulation of adenylate cyclase activity.
The cellular responses evoked by anterior pituitary binding to class 1 cytokine receptors are mediated through protein kinase activation.
TRH, thyrotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; CRH, corticotropin-releasing hormone; GHRH, GH-releasing
hormone; PLC, phospholipase C activity; AC, adenylate cyclase activity. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York:
McGraw-Hill Medical, 2010.)
626 SECTION IX Endocrine and Metabolic Physiology
receptor in the thyroid gland, and stimulates all the events
involved in thyroid hormone synthesis and release. In addi-
tion, it acts as a growth factor for the thyroid gland. The release
of TSH from the anterior pituitary gland is under negative
feedback inhibition by thyroid hormones.
Gonadotropins (FSH and LH)
The gonadotropic hormones LH and FSH are synthesized and
secreted by gonadotrophs of the anterior pituitary in response
to stimulation by gonadotropin-releasing hormone (GnRH).
Gonadotrophs constitute about 5–10% of the pituitary cells.
Most of the gonadotrophs (60%) produce both LH and FSH.
The remainder of the gonadotroph population produces LH
(18%) or FSH (22%) exclusively. GnRH is synthesized and
secreted by the hypothalamus in a pulsatile manner.
FSH and LH exert their physiologic effects on multiple cells
of the reproductive system by binding to Gαs protein–coupled
receptors and activation of adenylate cyclase. Among the target
cells for gonadotropins are ovarian granulosa cells, theca
interna cells, testicular Sertoli cells, and Leydig cells. The
physiologic responses produced by the gonadotropins include
stimulation of sex hormone synthesis (steroidogenesis), sper-
matogenesis, folliculogenesis, and ovulation. Therefore, their
central role is the control of reproductive function in both
males and females. GnRH controls the synthesis and secretion
of both FSH and LH by the pituitary gonadotroph cell. Gonad-
otropin synthesis and release, as well as differential expression,
is under both positive and negative feedback control by
gonadal steroids and gonadal peptides. Gonadal hormones
can decrease gonadotropin release both by decreasing the fre-
quency and amplitude of pulses of GnRH release from the
hypothalamus and by affecting the ability of GnRH to stimu-
late gonadotropin secretion from the pituitary itself.
PROOPIOMELANOCORTIN-
DERIVED HORMONES
Proopiomelanocortin (POMC) is a precursor prohormone
produced by the corticotrophs of the anterior pituitary.
Corticotrophs account for 10% of the secretory cells of the
anterior pituitary. The production and secretion of POMC-
derived hormones from the anterior pituitary are regulated
predominantly by corticotropin-releasing hormone (CRH)
produced in the paraventricular nucleus of the hypothalamus
and released in the median eminence. CRH binds to Gs pro-
tein–coupled CRH receptors.
POMC is posttranslationally cleaved to ACTH; β-endorphin,
an endogenous opioid peptide; and α-, β-, and γ-melanocyte-
stimulating hormones (MSH) (Figure 62–3). The biologic
effects of POMC-derived peptides are largely mediated
through melanocortin receptors (MCRs), of which five have
been described. MC1R, MC2R, and MC5R have defined roles
in the skin, adrenal steroid hormone production, and thermo-
regulation, respectively. MC4R is expressed in the brain and
has been implicated in feeding behavior and appetite regula-
tion. The role of MC3R is not well defined.
Adrenocorticotropic Hormone
The main hormone of interest produced by the cleavage of
POMC is ACTH. The release of ACTH is stimulated by psy-
chological and physical stressors such as infection, hypoglyce-
mia, surgery, and trauma and is considered critical in mediating
the adaptive response of the individual to stress. ACTH is
released in pulses, with the highest concentrations occurring
in the morning and the lowest concentrations around mid-
night. ACTH released into the systemic circulation binds to a
Gαs protein–coupled receptor at the adrenal cortex and stimu-
lates the production and release of glucocorticoids (cortisol)
and, to a lesser extent, mineralocorticoids (aldosterone). The
release of cortisol follows the same diurnal rhythm as that of
ACTH. The feedback inhibition of ACTH and of CRH release
by cortisol is mediated by glucocorticoid receptor binding in
the hypothalamus and in the anterior pituitary.
Melanocyte-stimulating Hormone
α-MSH is produced by the proteolytic cleavage of POMC,
mainly in the pars intermedia of the pituitary gland
(Figure 62–3). Only small amounts of α-MSH are produced in
the human pituitary under normal conditions. Melanocortin
peptides exert their effects through MC1R found in melano-
cytes, which are key components of the skin’s pigmentary sys-
tem, endothelial cells, monocytes, and keratinocytes.
β-Endorphin
β-Endorphin, the most abundant endogenous opioid peptide,
is another product of POMC processing in the pituitary
(Figure 62–3). The physiologic effects of this opioid peptide
are mediated by binding to opiate receptors, expressed in mul-
tiple cell types in the brain as well as in peripheral tissues. The
physiologic actions of endorphins are not well understood, but
may include analgesia, behavioral effects, and neuromodula-
tory functions.
GROWTH HORMONE &
PROLACTIN FAMILY
Growth Hormone
GH is a 191–amino acid peptide hormone, with a molecular
weight of approximately 22 kd and structural similarity to pro-
lactin and chorionic somatomammotropin (human placen-
tal lactogen), a placental-derived hormone. GH is released
from the somatotrophs, an abundant (50%) cell type in the
anterior pituitary. It is released in pulsatile bursts, with the
majority of secretion occurring nocturnally in association
with slow-wave sleep (see Figure 60–7). The basis of the pulsa-
tile release of GH and the function of this pattern are not fully
 CHAPTER 62 Anterior Pituitary Gland 627

Pro-opiomelanocortin

Signal peptide

NH2 COOH

β-LPH

N-terminal
ACTH

γ-LPH β-end

ACTH
receptor β-MSH

γ-MSH α-MSH CLIP

Opiate
Melanocortin receptor
receptor
FIGURE 62–3 Proopiomelanocortin (POMC) processing. Corticotropin-releasing hormone stimulates the production, release, and
processing of POMC, a preprohormone synthesized in the anterior pituitary. POMC is posttranslationally cleaved to adrenocorticotropic hormone
(ACTH); β-endorphin, an endogenous opioid peptide; and α-, β-, and γ-melanocyte-stimulating hormones (MSH). The cellular effects of these
peptides are mediated via melanocortin (ACTH and MSH) or opiate (β-end) receptors. LPH, β-lipotropin; CLIP, corticotropin-like intermediate lobe
peptide. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

understood; however, nutritional, metabolic, and age-related
sex steroid mechanisms, adrenal glucocorticoids, thyroid
hormones, and renal and hepatic functions are all thought
to contribute to the pulsatile release of GH and appear to
be essential in achieving optimal biologic potency of the
hormone.
Regulation of GH release
The two principal hypothalamic regulators of GH (soma-
totropin) release from the anterior pituitary are growth
hormone-releasing hormone (GHRH) and somatostatin
(SST), which exert stimulatory and inhibitory influences,
respectively, on the somatotrophs (Figure 62–4). GH release is
also inhibited by insulin-like growth factor-I (IGF-I), the
hormone produced in the periphery, particularly in the liver,
in response to GH receptor stimulation, in a classic negative
feedback mechanism of hormone control. More recently,
ghrelin has been identified as an additional GH secretagogue.
Ghrelin is a peptide released predominantly from stomach.
The overall contribution of ghrelin to regulation of GH release
in humans is still not fully elucidated.
Other regulators
In addition to regulation by GHRH and SST, GH is regulated
by other hypothalamic peptides and neurotransmitters, which
act by regulation of GHRH and SST release, as summarized in
Table 62–2. Catecholamines, dopamine, and excitatory amino
acids increase GHRH and decrease SST release, resulting in an
increase in GH release. Hormones such as cortisol, estrogen,
androgens, and thyroid hormone can also affect somatotroph
responsiveness to GHRH and SST and consequently GH
release. Metabolic signals such as glucose and amino acids can
affect GH release. Decreased blood glucose concentrations
(hypoglycemia) stimulate GH secretion in humans. Glucose
and nonesterified fatty acids decrease GH release, whereas
amino acids, particularly arginine, increase GH release.
Consequently, arginine administration is also an effective chal-
lenge to elicit an increase in GH release in the clinical setting.
628 SECTION IX Endocrine and Metabolic Physiology

Sleep
Aging
Hypoglycemia (+) (–) Disease
Stress
Glucose

GHRH (+) (–)

(–) SST (–)

Adipose tissue
Glucose uptake
(–) Lipolysis

(–)
GH

Muscle
Glucose & AA
uptake
Protein
synthesis
Chondrocytes
AA uptake
Protein synthesis
DNA & RNA synthesis
Chondroitin sulfate IGF-I
Collagen
Cell size & number

FIGURE 62–4 Growth hormone release and effects. Growth hormone release from the anterior pituitary is modulated by several factors,
including stress, exercise, nutrition, sleep, and growth hormone itself. The primary controllers of GH release are growth hormone–releasing
hormone (GHRH) that stimulates both the synthesis and secretion of growth hormone and somatostatin (SST) that inhibits growth hormone
release in response to GHRH and to other stimulatory factors such as low blood glucose concentration. Growth hormone secretion is also part of
a negative feedback loop involving IGF-1. High blood levels of IGF-1 lead to decreased secretion of growth hormone not only by directly
suppressing the somatotroph, but also by stimulating release of somatostatin from the hypothalamus. Growth hormone also feeds back to
inhibit GHRH secretion and probably has a direct (autocrine) inhibitory effect on secretion from the somatotroph. Integration of all the factors
that affect growth hormone synthesis and secretion leads to a pulsatile pattern of release. GH effects in peripheral tissues are mediated by GH
binding to its receptor and through the synthesis of insulin-like growth factor 1 (IGF-1) by the liver and at the tissue level. The overall effects of
GH and IGF-I are anabolic. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

GH is released from the anterior pituitary into the systemic Physiologic effects of GH
circulation. The half-life of the hormone averages 6–20 minutes. GH can have direct effects on cellular responses, by binding to
GH is degraded in the lysosomes following binding to its recep- the GH receptor at target tissues, and, indirectly, by stimulat-
tor and internalization of the hormone–receptor complex. ing the production and release of IGF-I, a mediator of several
of growth hormone’s effects at target tissues. IGF-I is a small
peptide (about 7.5 kd) structurally related to proinsulin that
TABLE 62–2 Factors that regulate growth hormone
mediates several of the anabolic and mitogenic effects of GH
release.
in peripheral tissues. The most important physiologic effect of
Stimulation of GH Release Inhibition of GH Release GH is stimulation of postnatal longitudinal growth. GH also
plays a role in regulation of substrate metabolism, adipocyte
GHRH Somatostatin
differentiation; and maintenance and development of the
Dopamine IGF-I immune system.
Catecholamines Glucose

Excitatory amino acids FFA GH receptor

Thyroid hormone
In the peripheral tissues, GH binds to specific cell surface recep-
tors belonging to the class 1 cytokine receptor superfamily (see
GHRH, growth hormone–releasing hormone; IGF-I, insulin-like growth factor-I; FFA,
free fatty acids. Figure 60–5) that includes the receptors for prolactin, erythro-

poietin, leptin, interferons, granulocyte colony–stimulating
factor, and interleukins. GH receptors are present in many
biologic tissues and cell types, including liver, bone, kidney,
adipose tissue, muscle, eye, brain, heart, and cells of the immune
system. The GH molecule exhibits two binding sites for the GH
receptor, resulting in dimerization of the receptor, a step that is
required for biologic activity of the hormone.
GH effects at target organs
• Bone: GH, both directly and indirectly through circulating
and localized production of IGF-I, stimulates longitudinal
growth by increasing the formation of new bone and carti-
lage. The growth effects of GH are not critical during the
gestational period, but begin gradually during the first and
second years of life and peak at the time of puberty. Before
the epiphyses in long bones have fused, GH and IGF-1 stim-
ulate chondrogenesis and widening of the cartilaginous epi-
physial plates, followed by bone matrix deposition. In addi-
tion to its effects on linear growth stimulation, GH plays a
role in regulating the normal physiology of bone formation
in the adult by increasing bone turnover, with increases in
bone formation and, to a lesser extent, bone resorption.
• Adipose tissue: GH stimulates release and oxidation of free
fatty acids, particularly during fasting. These effects are
mediated by a reduction in the activity of lipoprotein lipase,
the enzyme involved in clearing triglyceride-rich chylomi-
crons and very-low-density lipoprotein particles from the
bloodstream. Thus, GH favors the availability of free fatty ac-
ids for adipose tissue storage and skeletal muscle oxidation.
• Skeletal muscle: GH and IGF-I have anabolic actions on
skeletal muscle tissue mediated through stimulation of ami-
no acid uptake and incorporation into protein, cell prolif-
eration, and suppression of protein degradation.
• Liver: GH stimulates hepatic IGF-I production and release.
It stimulates hepatic glucose production.
Overall, GH counteracts the action of insulin on lipid and
glucose metabolism, by decreasing skeletal muscle glucose uti-
lization, increasing lipolysis, and stimulating hepatic glucose
production.
Key aspects of GH physiology can be summarized as follows:
• GH is produced and stored in somatotrophs in the anterior
pituitary.
• The production of GH is pulsatile, mainly nocturnal, and is
controlled mainly by GHRH and SST.
• Circulating levels of GH increase during childhood, peak
during puberty, and decrease with aging.
• GH stimulates lipolysis, amino acid transport into cells, and
protein synthesis.
• GH stimulates the production of IGF-I, which is responsible
for many of the activities attributed to GH.
Insulin-like Growth Factors
Many of the growth and metabolic effects of GH are medi-
ated by the IGFs, or somatomedins. The importance of this
CHAPTER 62 Anterior Pituitary Gland 629
hormone in linear growth is clearly demonstrated by the
severe growth failure in children with congenital IGF-I defi-
ciency. These small peptide hormones are members of a
family of insulin-related peptides including relaxin, insulin,
IGF-I, and IGF-II. The IGFs are synthesized primarily by
the liver and act as a mitogen, stimulating DNA, RNA, and
protein synthesis. IGF-I circulates in blood either free (half-
life is about 15–20 minutes) or bound to one of the several
specific binding proteins that prolong the half-life of the
peptide.
IGF receptor IGF-I and IGF-II bind specifically to two
high-affinity membrane-associated receptors that are ty-
rosine kinases and belong to the same family of receptors as
insulin. The insulin and IGF-I receptors, although similar in
structure and function, play different physiologic roles in
vivo. The insulin receptor is primarily involved in metabolic
functions, whereas the IGF-I receptor mediates growth and
differentiation. The separation of these functions is con-
trolled by several factors, including the tissue distribution of
the respective receptors, the binding with high affinity
of each ligand to its respective receptor, and the binding of
IGF to plasma insulin-like growth factor binding proteins
(IGFBPs).
Prolactin
Prolactin is a polypeptide hormone synthesized and secreted
by lactotrophs in the anterior pituitary gland. The lactotro-
phs account for approximately 15–20% of the cell population
of the anterior pituitary gland, and this increases dramati-
cally in response to elevated estrogen levels, particularly dur-
ing pregnancy. Prolactin levels are higher in females than in
males, and the role of prolactin in male physiology is not
completely understood. Plasma concentrations of prolactin
are highest during sleep and lowest during the waking hours
in humans.
Regulation of prolactin release
Prolactin release is predominantly under tonic inhibition by
dopamine derived from dopaminergic (D2) neurons of the
hypothalamus. D2 inhibition of lactotroph release of prolactin
is mediated by D2 Gαi protein–coupled receptors.
Prolactin release is affected by a large variety of stimuli
provided by the environment, and the internal milieu, the
most important being suckling, increased levels of ovarian
steroid hormones, primarily estrogen. The release of prolac-
tin in response to suckling is a classical neuroendocrine reflex
also referred to as a stimulus-secretion reflex (Figure 62–5).
This surge in prolactin release in response to a suckling stim-
ulus is mediated by a decrease in the amount of dopamine
released at the median eminence, relieving the lactotroph
from tonic inhibition. Estrogen stimulates growth of the lac-
totrophs during pregnancy as well as prolactin gene expres-
sion and release. Several neuropeptides have been identified
as potential prolactin-releasing factors. These include TRH,
630 SECTION IX Endocrine and Metabolic Physiology
Hypothalamus
Dopamine
Dopamine
release Pituitary
Prolactin
Breast differentiation
Duct proliferation and branching
Glandular tissue development
Milk protein synthesis
Lactogenic enzyme synthesis
• Mammary gland development
• Milk production
FIGURE 62–5 Physiologic effects of prolactin. Prolactin plays
an important role in the normal development of mammary tissue and
in milk production. Prolactin release is predominantly under negative
control by hypothalamic dopamine. Suckling stimulates the release of
prolactin. Prolactin inhibits its own release by stimulating dopamine
release from the hypothalamus. (Modified with permission from Molina PE:
Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)
oxytocin (OT), vasoactive intestinal peptide (VIP), and neu-
rotensin (NT).
Prolactin regulates its own secretion through a short-loop
feedback mechanism by binding to prolactin receptors located
in neuroendocrine D2 neurons; this binding leads to increased
hypothalamic dopamine synthesis (Figure 62–5). When the
concentration of dopamine in the hypothalamo-hypophysial
portal blood increases, the release of prolactin from the lac-
totrophs is suppressed.
Physiologic effects of prolactin The physiologic effects
of prolactin are mediated by the prolactin receptor found in the
mammary gland and the ovary. The main physiologic effects of
prolactin are stimulation of growth and development of the
mammary gland, synthesis of milk, and maintenance of milk se-
cretion (Figure 62–5). Prolactin stimulates glucose and amino
acid uptake and synthesis of the milk proteins β-casein and
α-lactalbumin, the milk sugar lactose, and milk fats by the mam-
mary epithelial cells. During pregnancy, prolactin prepares the
breast for lactation. The production of milk is prevented during
pregnancy by the high progesterone levels. Additional effects of
prolactin include inhibition of GnRH release, progesterone bio-
synthesis, and luteal cell hypertrophy during pregnancy. Prolac-
tin also modulates reproductive and parental behavior.
DISEASES OF THE
ANTERIOR PITUITARY
Alterations in function of the anterior pituitary can be due to
excess or deficient production of pituitary hormones or to
altered responsiveness to hormone effects at the target organ.
HORMONE-PRODUCING
PITUITARY ADENOMAS
The most common cause of excess production of pituitary
hormones is a hormone-producing pituitary adenoma, a usu-
ally benign neoplasm. Prolactinomas are the most common
(40–45%) pituitary tumors, followed by somatotroph (20%),
corticotroph (10–12%), gonadotroph (15%), and very rarely
thyrotroph adenomas. Small pituitary adenomas can cause
manifestations of excess tropic hormone production, whereas
larger tumors can produce neurologic symptoms by mass
effect in the sellar area. Patients with a prolactinoma present
with elevated levels of prolactin (hyperprolactinemia), milk
secretion (galactorrhea), and reproductive dysfunction. In
males, prolactinomas may cause infertility by producing
hypogonadism. In most cases, dopamine agonists are extremely
effective in lowering serum prolactin levels, restoring gonadal
function, decreasing tumor size, and improving visual fields
decreased because of tumor compression of the optic chiasm.
GH-secreting adenomas can be associated with acromegaly or
bone and soft tissue overgrowth in adults, and with gigantism
in children. ACTH-releasing adenomas are associated with
excess cortisol production or Cushing syndrome; patients
present with central obesity, proximal myopathy, hyperten-
sion, mood changes, dorsocervical fat pads, and hyperglyce-
mia, among other clinical signs and symptoms. Gonadotroph
pituitary adenomas are frequently inefficient in hormone pro-
duction. Thyrotropin-secreting tumors are exceedingly rare
and are frequently large when diagnosed.
HYPOPITUITARISM
Hypopituitarism, or deficiency of anterior pituitary hor-
mones, can be congenital or acquired. Pituitary insufficiency
can result from trauma, such as that associated with surgery,
penetrating injury, or automobile accidents, particularly
involving head trauma. Severe blood loss and decreased
blood flow (ischemia) of the pituitary can also lead to pitu-
itary insufficiency. Ischemic damage to the pituitary gland or
hypothalamic-pituitary stalk during the peripartum period
leads to Sheehan syndrome, manifested as hypothyroidism,
adrenal insufficiency, hypogonadism (failure to resume nor-
mal menses), and GH deficiency.
GH deficiency and retarded growth may result from impaired
release of GH from the pituitary gland because of diseases of the
hypothalamus or pituitary gland or genetic predisposition.

Alternatively, mutations in the gene for the GH receptor can
cause insensitivity to GH and growth retardation with low serum
IGF-I concentrations. GH insensitivity syndrome is also known
as Laron syndrome and is characterized by failure to generate
IGF-I and IGFBP-3. The typical manifestation is short stature or
dwarfism, which can be prevented by IGF-I treatment.
EVALUATION OF ANTERIOR
PITUITARY FUNCTION
Measurements of anterior pituitary hormone concentrations
and of the respective target gland hormone levels are used to
assess the functional status of the system. For example, paired
measures of TSH and thyroid hormone, FSH and estradiol,
and ACTH and cortisol are used to evaluate the integrity of the
respective systems. In addition, stimulation and inhibition
tests can be used to assess the functional status of the pituitary
gland. These tests are based on the normal physiologic feed-
back mechanisms that control tropic hormone release. For
example, administration of the amino acid arginine can be
used to elicit an increase in GH release in patients with sus-
pected GH deficiency. In contrast, suppression tests can be
used to diagnose Cushing syndrome, a clinical state resulting
from prolonged, inappropriate exposure to excessive endoge-
nous secretion of cortisol.
CLINICAL CORRELATION
CASE A
A mother of two school-age children still in her reproduc-
tive years consults her physician because she has had no
menstrual periods for the past 6 months. A pregnancy test
is negative, and she is not taking any medications. She also
complains of problems with her peripheral (temporal)
vision, and has also noted milky discharge from her nip-
ples. An magnetic resonance image (MRI) scan of the
brain reveals a pituitary mass. On physical examination,
she is afebrile and has a normal blood pressure. Laboratory
values are within normal ranges for serum glucose, Na+
and K+. Increased levels of prolactin are measured, with
normal levels of all other pituitary hormones. She is diag-
nosed as having a prolactinoma.
Prolactinomas account for 50% of functioning pitu-
itary tumors and are more frequent in females than in
males. Tumor size is correlated with prolactin levels.
Women present with amenorrhea (lack of menses),
galactorrhea (milk discharge from nipples), and infertil-
ity. Large tumors extending caudal to the pituitary are
associated with visual defects due to compression of the
optic chiasm. In males, presentation is impotence, loss of
libido, and infertility as well as headaches and alterations
in visual field. Initial treatment consists of administra-
CHAPTER 62 Anterior Pituitary Gland 631
tion of dopamine agonists to reduce prolactin production.
Tumors that do not shrink in size with medical treatment
may require focused radiation therapy and/or surgical
removal.
CASE B
A middle-aged male patient consults his family physician
because he has noticed that his hat and wedding ring are
tight and his shoe size has increased one size during the
past couple of years. He complains of joint aches and pains.
He also states that he has noticed his voice getting deeper
and his facial features being thicker and coarser when com-
pared to his pictures of 10 years ago. Laboratory values
show increased growth hormone and IGF-I levels and
increased fasting plasma glucose. An intravenous infusion
of glucose fails to decrease growth hormone levels. Brain
MRI reveals a tumor localized to the pituitary. The patient
is diagnosed with acromegaly resulting from a growth hor-
mone–producing tumor.
Acromegaly occurs as a result of growth hormone pro-
duction in middle-aged adults. The symptoms of acromeg-
aly develop slowly over many years, resulting in a frequent
delay in diagnosis after the estimated onset of symptoms.
The clinical manifestations result from soft tissue growth in
response to growth hormone stimulation. This is evident in
thickening of facial features, hands, and feet but is also
associated with organomegaly (enlargement of internal
organs). Because of growth hormone’s anti-insulin actions
in adipose tissue, patients present with increased fasting
plasma glucose levels or impaired glucose tolerance. Diag-
nosis is made by measurement of growth hormone release
during the 2-hour period following a 75-g oral glucose load
(similar to that used for the glucose tolerance test), as well
as by measurement of peripheral IGF-I levels. Treatment
consists of administration of long-acting somatostatin ana-
logs such as octreotide and surgical removal of the tumor
in cases that do not respond to medical treatment. There
are also GH receptor antagonists currently available that
can be used to treat the symptoms of GH excess.
CHAPTER SUMMARY
■ Anterior pituitary function is under regulation by the hypo-
thalamus.
■ Anterior pituitary hormone release is under feedback regula-
tion by peripheral hormone levels.
■ Pulsatile release of hypothalamic, pituitary, and target organ
hormones plays an important role in endocrine function.
■ Growth hormone exerts direct and indirect (IGF-I) effects on
linear growth and metabolism.
■ With the exception of dopamine inhibition of prolactin and
SST inhibition of GH, adenohypophysial hormones are under
stimulatory hypothalamic control.
632 SECTION IX Endocrine and Metabolic Physiology

STUDY QUESTIONS 3. A patient has been taking pharmacologic doses of a steroidal

anti-inflammatory drug for a prolonged period for his asthma
1. A female patient presents with milky discharge from both flare-ups. Which of the following is likely to occur to
nipples and menstrual irregularity. The patient has no history of hypothalamic CRH release and plasma cortisol?
headache or visual abnormalities. A pregnancy test is negative, A) low CRH and high cortisol
and her mammogram and breast exam are normal. She has a list of B) high CRH and high cortisol
medications that her psychiatrist has recently prescribed. Which C) low CRH and low cortisol
of the following could be responsible for the milky discharge? D) high CRH and low cortisol
A) levodopa 4. Growth hormone excess in an adult male can present with
B) dopamine antagonist
A) longitudinal growth of the extremities
C) D2 agonist
B) thickening of cartilaginous tissue
D) serotoninergic agonist
C) hypoglycemia
2. Damage to the axons passing through the pituitary stalk during D) low IGFBP-3
an automobile accident could be expected to result in any of the
following with the exception of
A) decreased prolactin release
B) decreased TSH release
C) decreased LH and FSH release
D) decreased GH release
 63
C H A P T E R

Thyroid Gland
Patricia E. Molina

O B J E C T I V E S

■ Identify the steps and control factors of thyroid hormone biosynthesis,

storage, and release.
■ Describe the distribution of iodine and the metabolic pathway involved in
thyroid hormone synthesis.
■ Explain the importance of thyroid hormone binding in blood for free and
total thyroid hormone levels.
■ Understand the significance of the conversion of tetraiodothyronine (T4) to
triiodothyronine (T3) and reverse T3 (rT3) in extrathyroidal tissues.
■ Understand how thyroid hormones produce their cellular effects.
■ Describe their effects on development and metabolism.
■ Understand the causes and consequences of excess and deficiency of thyroid
hormones.

Thyroid hormones play important roles in maintaining energy
homeostasis and regulating energy expenditure. Their physio-
logic effects, mediated at multiple target organs, are primarily to
stimulate cell metabolism and activity. The vital roles of these
hormones, particularly in development, differentiation, and mat-
uration, are underscored by the severe intellectual and develop-
mental delay observed in infants with deficient thyroid hormone
function during gestation. Thyroid hormones are derived from
the amino acid tyrosine and are produced by the thyroid gland in
response to stimulation by thyroid-stimulating hormone (TSH)
produced by the anterior pituitary. TSH, in turn, is regulated by
negative feedback by thyroid hormone and by the hypophysio-
tropic peptide thyrotropin-releasing hormone (TRH).
FUNCTIONAL ANATOMY
The thyroid gland is a highly vascular, ductless gland
located in the anterior neck in front of the trachea. The cel-
lular composition of the thyroid gland is diverse, including
the following:
• follicular (epithelial) cells, involved in thyroid hormone
synthesis;
• endothelial cells lining the capillaries that provide the blood
supply to the follicles;
• parafollicular or C cells, involved in the production of
calcitonin, a hormone with a minor role in calcium ho-
meostasis (discussed in Chapter 64);
• fibroblasts, lymphocytes, and adipocytes.
THYROID FOLLICLE
The main function of the thyroid gland is the synthesis and
storage of thyroid hormone. The functional unit of the thy-
roid gland is the thyroid follicle, a spherical structure con-
sisting of a layer of thyroid epithelial cells arranged around
a large central cavity filled with colloid. Colloid makes up
about 30% of the thyroid gland mass and contains a protein
called thyroglobulin. Thyroglobulin plays a central role in
the synthesis and storage of thyroid hormone. The parafol-
licular cells are in the spaces between follicles. Most para-
follicular cells synthesize and secrete the hormone
calcitonin, and therefore they are frequently referred to as
C cells.

633

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634 SECTION IX Endocrine and Metabolic Physiology
REGULATION OF BIOSYNTHESIS,
STORAGE, AND SECRETION OF
THYROID HORMONES
HYPOTHALAMIC REGULATION
OF TSH RELEASE
Thyroid hormone synthesis and release is under negative feed-
back regulation by the hypothalamic–pituitary–thyroid axis
(Figure 63–1). TRH is a tripeptide synthesized in the hypo-
thalamus, released from nerve terminals in the median emi-
nence, and transported to the anterior pituitary where it
stimulates release of TSH into the systemic circulation. The
release of TSH is inhibited by the thyroid hormones tri-
iodothyronine (T3) and tetraiodothyronine (T4, thyroxine).
TSH is transported in the bloodstream to the thyroid gland,
where it binds to the TSH receptor located on the thyroid folli-
cular epithelial cells. The TSH receptor is an important antigenic
site involved in thyroid autoimmune disease. Autoantibodies to
the receptor may act as agonists mimicking the actions of TSH
in Graves’ disease.
Somatostatin
Glucocorticoids
FIGURE 63–1 The hypothalamic–pituitary–thyroid axis.
Thyrotropin-releasing hormone (TRH) is synthesized in parvocellular
neurons of the paraventricular nucleus of the hypothalamus and
released from nerve terminals in the median eminence, from where
it is transported via the portal capillary plexus to the anterior
pituitary. TRH binds to a G protein–coupled receptor in the anterior
pituitary, leading to an increase in intracellular Ca2+ concentration,
which in turn results in stimulation of exocytosis and release of
thyroid-stimulating hormone (TSH) into the systemic circulation.
TSH stimulates the thyroid gland to increase the synthesis and
secretion of tetraiodothyronine (T4) and triiodothyronine (T3) into
the circulation. T4 and T3 inhibit the secretion of thyrotropin (TSH)
both directly and indirectly by inhibiting the secretion of TRH.
Additional factors that inhibit TSH release are glucocorticoids,
somatostatin, and dopamine. (Modified with permission from Molina PE:
Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)
TSH receptor activation results in stimulation of all of the
steps involved in thyroid hormone synthesis, including iodine
uptake and organification, production and release of thyroid
hormones from the gland, and promotion of thyroid growth.
The biologic effects of TSH include stimulation of activity and
production of the Na+/I− symporter, thyroglobulin, thyroid
peroxidase, and T4 and T3. Both growth and function of the
thyroid are stimulated by TSH stimulation. Therefore, contin-
ued stimulation of the TSH receptor causes hyperthyroidism
and thyroid hyperplasia.
THYROID HORMONE SYNTHESIS
Thyroglobulin is a glycoprotein synthesized in the thyroid
follicular epithelial cells and secreted into the follicular lumen,
where it is stored in the colloid. It undergoes major posttrans-
lational modification during the production of thyroid hor-
mones consisting of iodination of multiple tyrosine residues,
followed by coupling of some of the iodotyrosine residues to
form T3 and T4. A small amount of noniodinated thyroglobulin
is also secreted into the circulation, and it can be increased in
diseases such as thyroiditis and Graves’ disease.
Hypothalamus
TRH
(-)
Dopamine (-)
Pituitary
(-)
TSH
T4
T3
Thyroid
 CHAPTER 63 Thyroid Gland 635

The iodide required for thyroid hormone synthesis is read-
ily absorbed from dietary sources, primarily from iodized salt,
but also from seafood and plants grown in soil that is rich in
iodine. Iodide is removed from the blood primarily by the thy-
roid and the kidneys.
REGULATION OF IODINE METABOLISM
IN THE THYROID FOLLICULAR CELL
Iodide is concentrated in thyroid epithelial cells by a sodium–
iodide (Na+/I−) symporter (Figure 63–2). This ability of the
thyroid gland to accumulate iodine allows therapeutic admin-
istration of radioactive iodine for the treatment of Graves’ dis-
ease and toxic nodules, and to ablate thyroid tissue in the
treatment of thyroid cancer.
The iodination of thyroglobulin residues is a process that
occurs at the apical membrane of the thyroid follicular cell.
Thus, once inside the cell, iodide must leave the follicular cell
through apical efflux via a chloride–iodide transporting
protein (iodide channel). The uptake, concentration, and
efflux of iodide are all functions of TSH-stimulated transepi-
thelial transport of iodide.
The transport of iodine through the Na+/I− symporter can
be substituted by other substances including perchlorate and
pertechnetate. Radiolabeled pertechnetate (Tc99m-pertechne-
tate) can be used for imaging of the thyroid gland that reflects
the ability of specific regions of the thyroid to take up the iso-

Follicle lumen
(colloid)
Apical
membrane

Follicular
Thyroid cell
gland

Iodide

2Na+/I –
symporter
I–
Na+

3Na+/2K+
ATPase
FIGURE 63–2 Mechanism of iodide concentration
Na +

by the thyroid gland. Iodide is transported into the cytosol

K+

of the follicular cell by active transport against a chemical

and electrical gradient. The energy is derived from the
Basolateral
K + ATP

electrochemical gradient of sodium. Two sodium ions are

membrane
transported inside the thyroid follicular cell with each iodide
P
Na +

AD

molecule. Sodium moves down its concentration gradient,

which is maintained by the Na+/K+-ATPase that constantly
pumps sodium out of the cytoplasm of the thyroid follicular
Low epithelial cell, maintaining the low intracytoplasmic
intracellular concentration of sodium. Iodide must reach the colloid space,
Na where it is used for organification of thyroglobulin. This process
is achieved by efflux through the iodide channel. One of the
early effects of TSH binding to its receptor is the opening of
these channels, which facilitate the leakage of iodide into the
extracellular space. This transcellular transport of iodide relies
on the functional and morphologic polarization of the thyroid
Iodide channel follicular epithelial cell. ATP, adenosine triphosphate. (Modified
Apical
with permission from Molina PE: Endocrine Physiology, 3rd ed. New York:
membrane
McGraw-Hill Medical, 2010.)
Colloid
636 SECTION IX Endocrine and Metabolic Physiology

1 BLOOD 90% T4 10% T3 roglobulin yields monoiodinated tyrosine (MIT) and diiodi-
Iodide Na+ I– 5 nated tyrosine (DIT) residues that are enzymatically coupled
trapping to form T3) or T4 by the enzyme thyroid peroxidase. Because
Hormone
secretion not all of the iodinated tyrosine residues undergo coupling,
2 T3 thyroglobulin stored in the follicular lumen contains MIT and
T4
Tg synthesis DIT residues as well as formed T3 and T4.
and secretion
Iodine metabolism within the thyroid can also be regulated
independently of TSH, particularly when plasma iodide levels
are increased via an autoregulatory phenomenon known as
I– I– MIT
the Wolff–Chaikoff effect. This effect lasts for a few days and
pool pool DIT is followed by the so-called “escape” phenomenon, at which
MIT point the organification of intrathyroidal iodine resumes and
Tg DIT
T3 T4 the normal synthesis of T4 and T3 returns.

Tg
REGULATION OF THYROID
HORMONE RELEASE
I–
Tg TSH stimulates release of thyroid hormones from the thyroid
4 gland. This process involves endocytosis of vesicles containing
Colloid uptake thyroglobulin from the apical surface of the follicular cell, lys-
Tg by endocytosis
I– I° osomal fusion of the vesicles, and proteolytic cleavage of thy-
iodine Thyroid iodine
peroxidase 3 MIT roglobulin. As a result, the products of proteolytic cleavage
Iodination include the thyroid hormones T4 and T3, which are released
+ conjugation Tg DIT
T3 T4
into the circulation, and the iodinated tyrosine residues (MIT
and DIT) that are deiodinated intracellularly. With normal
THYROID COLLOID
iodine intake, greater amounts of T4 than T3 are released
FIGURE 63–3 Overview of thyroid hormone synthesis in the (plasma concentrations of T4 are 40-fold higher than those of
thyroid follicular epithelial cell. Thyroid hormone synthesis T3). Most of the T4 released is converted to T3 (the more active
involves concentration of iodide by the Na+/I− symporter (1) and form of the hormone) in peripheral tissues by the removal of
transport of iodide through the epithelial cell and into the
iodine from carbon 5 on the outer ring of T4. Key features of
extracellular compartment of the follicular cells, where it is oxidized
thyroid regulation and function are listed in Table 63–1.
to iodine by thyroid peroxidase (3) and is then used in the iodination
of thyroglobulin (Tg) synthesized within the cell and released into the
colloid (2). Iodine organification is an extracellular process that
takes place inside the thyroid follicles at the apical membrane
surface facing the follicular lumen. Iodine is bound to either carbon
TABLE 63–1 Key features of thyroid regulation
3 or carbon 5 of the tyrosyl residues of thyroglobulin to form and function.
monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT). An MIT
Key Features
and a DIT, or two DITs are conjugated to form triiodothyronine (T3)
and tetraiodothyronine (T4), respectively. Secretion of the hormone TSH Binds to Gαs protein–coupled receptor
involves endocytosis of colloid containing thyroglobulin (4), followed on thyroid follicular cells. Main second-
by degradation of thyroglobulin and release of T4 and T3 (5). Some of messenger system is cAMP. Stimulates
the T4 produced is deiodinated in the thyroid follicle to T3, which is all steps involved in thyroid hormone
then released into the bloodstream. In addition, intracellular synthesis: iodine uptake and
organification, production and release
deiodination provides a mechanism for recycling iodide to participate
of thyroid hormone, and promotion of
in the synthesis of new thyroid hormone at the apical cell surface. A thyroid growth
small fraction of thyroglobulin is released from the follicular epithelial
cell into the circulation. (Reproduced with permission from Kibble J, Halsey CR: Thyroid gland Can store 2–3-month supply of thyroid
hormones in the thyroglobulin pool
The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)
(colloid). Produces more T4 than T3

Thyroid hormone Synthesis and release are under negative

tope and therefore to function normally. In the follicular
lumen, tyrosine residues of thyroglobulin are iodinated by
iodine (Io; formed by oxidation of I− by thyroid peroxidase)
(Figure 63–3). This reaction requires hydrogen peroxide.
Iodine bonds to carbon 3 or carbon 5 of the tyrosine residues
on thyroglobulin in a process referred to as the organification
of iodine. The iodination of specific tyrosines located on thy-
feedback regulation by the hypothalamic–
pituitary–thyroid axis. T4 is converted to T3
in peripheral tissues. Biologic activity of T3
is greater than that of T4. Binds to nuclear
receptors and modulates gene
transcription
TSH, thyroid-stimulating hormone; cAMP, cyclic adenosine monophosphate; T4,
tetraiodothyronine; T3, triiodothyronine.
 CHAPTER 63 Thyroid Gland 637

TRANSPORT AND TISSUE DELIVERY
OF THYROID HORMONES
Once thyroid hormones are released into the circulation, most of
them circulate bound to plasma proteins (thyroid-binding glob-
ulin [TBG], transthyretin, and albumin). This high percentage
of protein-bound hormone significantly prolongs thyroid hor-
mone half-life. A small fraction of each hormone circulates in the
free form that is bioavailable and can enter the cell to bind to
the thyroid receptor. Of the two thyroid hormones, T4 binds more
tightly to binding proteins than T3 and thus has a lower metabolic
clearance rate and a longer half-life (7 days) than T3 (1 day).
THYROID HORMONE METABOLISM
Thyroid hormone peripheral metabolism is a sequential deio-
dination process catalyzed by tissue deiodinases, leading first
to a more active form of thyroid hormone (T3) and finally to
complete inactivation of the hormone (Figure 63–4). Approxi-
mately 40% of T4 is deiodinated at carbon 5 in the outer ring to
yield the more active T3. In about 33% of T4, iodine is removed
from carbon 5 in the inner ring to yield reverse T3 (rT3). rT3 has
little or no biologic activity. Following conversion of T4 to T3 or
rT3, these are converted to T2, a biologically inactive hormone.
This extrathyroidal progressive deiodination of thyroid hor-
mones catalyzed by deiodinases plays a significant role in thy-
roid hormone metabolism and involves three deiodinases
(type I, II, and II) that differ in their tissue distribution, cata-
lytic profiles, substrate specificities, physiologic functions, and
regulation outlined in Figure 63–4.
BIOLOGIC EFFECTS OF
THYROID HORMONES
Thyroid hormones are essential for normal growth and devel-
opment; they control the rate of metabolism and hence the
function of practically every organ in the body. Thyroid hor-
mone receptors are expressed in most tissues and affect mul-
tiple cellular events. The following are some examples of the
specific effects of thyroid hormone.
Their effects are mediated primarily by the transcriptional
regulation of target genes, and are thus known as genomic

Glucuronidation
(T4G)
Tetraiodothyronine (T4, thyroxine).
NH2
Sulfation HO O CH2 CH COOH
(T4S)

Deiodinase I & II Deiodinase I & III

FIGURE 63–4 Thyroid hormone

Outer ring Inner ring metabolism. Peripheral metabolism of thyroid
deiodination deiodination hormones involves the sequential removal of
(T3) (rT3)
iodine molecules, converting T4 into the more
active T3 and inactivating thyroid hormones
before their excretion. In addition, thyroid
O O hormones can undergo conjugation in the liver,
=

which increases their solubility and facilitates

=

3' 3 CH2 CH C OH HO CH2 CH C OH

HO O O their biliary excretion. The type I iodothyronine
5
NH2 NH2 deiodinase is expressed predominantly in liver,
3,5,3' – Triiodothyronine
kidney, and thyroid. It catalyzes both outer- and
Reverse T3 (rT3)
(T3) inner-ring deiodination of thyroid hormones. It
is the primary site for clearance of plasma rT3
and a major source of circulating T3. Type II
deiodinase is expressed primarily in the human
Deiodinase I & III Deiodinase I & II brain, anterior pituitary, and thyroid. It has only
outer-ring deiodination activity and plays an
important role in the local production of T3 in
tissues that express this enzyme. The type III
deiodinase is located predominantly in human
O
brain, placenta, and fetal tissues. It has only
=

HO O CH2 CH C OH inner-ring activity and catalyzes the inactivation

of T3 more effectively than that of T4, thereby
NH2 regulating intracellular T3 levels. (Modified with
permission from Molina PE: Endocrine Physiology, 3rd ed.
Diiodothyronine (T2) New York: McGraw-Hill Medical, 2010.)
638 SECTION IX Endocrine and Metabolic Physiology
effects. Thyroid hormones enter cells by a carrier-mediated
energy-, temperature-, and Na+-dependent process. The cel-
lular actions of thyroid hormones are mediated by nuclear
receptors. They bind thyroid hormones with high affinity
and specificity, particularly for T3. Thyroid hormone recep-
tors are DNA-binding transcription factors that function
as molecular switches in response to hormone binding. The
hormone receptor can activate or repress gene transcription,
depending on the promoter context and ligand-binding sta-
tus. The cellular events mediated by thyroid hormones are:
• transcription of cell membrane Na+/K+-ATPase, leading to
an increase in oxygen consumption;
• transcription of uncoupling proteins, enhancing fatty acid
oxidation and heat generation without production of ATP;
• protein synthesis and degradation, contributing to growth
and differentiation;
• epinephrine-induced glycogenolysis and gluconeogenesis,
affecting insulin-induced glycogen synthesis and glucose
utilization;
• cholesterol synthesis and low-density lipoprotein receptor
regulation.
ORGAN-SPECIFIC EFFECTS OF
THYROID HORMONE
Bone
Thyroid hormone is important for bone growth and develop-
ment through activation of osteoclast and osteoblast activities.
Deficiency during childhood affects growth. In adults, excess
thyroid hormone levels are associated with increased risk of
osteoporosis.
Cardiovascular System
Thyroid hormone has cardiac inotropic and chronotropic
effects, increases cardiac output and blood volume, and
decreases systemic vascular resistance. These responses are
mediated through thyroid hormone changes in gene transcrip-
tion of several proteins including Ca2+-ATPase, phospholam-
ban, myosin, β-adrenergic receptors, adenylate cyclase,
guanine nucleotide–binding proteins, Na+/Ca2+ exchanger,
Na+/K+-ATPase, and voltage-gated potassium channels. The
effect on β-adrenergic receptor expression accounts for the
sympathomimetic effects of high levels of thyroid hormone.
Fat
Thyroid hormone induces white adipose tissue differentiation,
lipogenic enzymes, and intracellular lipid accumulation; stim-
ulates adipocyte cell proliferation; stimulates uncoupling pro-
teins; and uncouples oxidative phosphorylation. The induction
of catecholamine-mediated lipolysis by thyroid hormones
results from an increased β-adrenoceptor (AR) number and a
decrease in phosphodiesterase (PDE) activity resulting in an
increase in cAMP level and hormone-sensitive lipase (HSL)
activity.
Liver
Thyroid hormone regulates triglyceride and cholesterol
metabolism, as well as lipoprotein homeostasis. It also modu-
lates cell proliferation and mitochondrial respiration.
Pituitary
Thyroid hormone regulates the synthesis of pituitary hormones,
facilitates growth hormone production, and inhibits TSH.
Brain
Thyroid hormone controls expression of genes involved in
myelination, cell differentiation, migration, and signaling. It is
necessary for axonal growth and development.
DISEASES OF THYROID
HORMONE OVERPRODUCTION
AND UNDERSECRETION
The widespread distribution of thyroid hormone receptors
and the multitude of physiologic effects that they exert are
highlighted in cases of abnormal thyroid function (Table 63–2).
Dysfunction can result from three factors: (1) alterations in
the circulating levels of thyroid hormones, (2) altered metabo-
lism of thyroid hormones in the periphery, and (3) resistance
to thyroid hormone actions at the tissue level.
An individual whose thyroid function is normal is said to
be in a euthyroid state. The clinical state resulting from an
alteration in thyroid function is classified as either hypothy-
roidism (low thyroid function) or hyperthyroidism (exces-
sive thyroid function). Autoimmunity plays an important role
in thyroid disease. Abnormal immune responses directed to
thyroid-related proteins result in two opposite pathogenic
processes: thyroid enlargement (hyperplasia) in Graves’
disease and thyroid inflammation and/or destruction in
Hashimoto’s thyroiditis.
The most common presentations of thyroid hormone abnor-
malities are summarized as follows.
HYPOTHYROIDISM
Hypothyroidism is the condition resulting from insufficient
thyroid hormone action. It has an incidence of 2% in adult
women and is less common in men. Two main types are dis-
tinguished, primary and secondary hypothyroidism, although
the former is more common.
Primary Hypothyroidism
When the decrease in thyroid function occurs in utero, the
result is severe intellectual and developmental delay or cretin-
ism, underscoring the vital role that thyroid hormone plays in
development and growth. Hypothyroidism may be associated
with thyroid enlargement, resulting from inflammation as in

TABLE 63–2 Clinical and laboratory manifestations of excess or deficient thyroid hormone function.
Hypothyroidism
Clinical Presentation
In utero:
Cretinism, mental and growth retardation, short limbs
Adult onset:
Tiredness, lethargy, constipation, decreased appetite,
cold intolerance, abnormal menstrual flow, hair loss,
brittle nails, dry coarse skin, hoarse voice
Chronic:
Myxedema, thickened features, periorbital edema,
swelling of hands and feet without indentation,
delayed muscle contraction and relaxation, delayed
tendon reflexes, reduced stroke volume and heart
rate, decreased cardiac output, enlarged heart,
pericardial effusion, pleural and peritoneal fluid
accumulation, slowing of mental function, impaired
memory, slow speech, decreased initiative,
somnolence, hypothermia
T4, thyroxine; T3, triiodothyronine; TSH, thyroid-stimulating hormone.
Hashimoto’s thyroiditis and increases in TSH due to dietary
iodine deficiency.
Secondary Hypothyroidism
Secondary hypothyroidism is characterized by decreased
TSH secretion and subsequently decreased thyroid hormone
release, and is usually due to hypopituitarism (decreased
anterior pituitary function).
HYPERTHYROIDISM
Hyperthyroidism is excessive functional activity of the thyroid
gland, characterized by increased basal metabolism and distur-
bances in the activity of the autonomic nervous system as a result
of excess thyroid hormone production. The incidence is higher in
women than in men. Several conditions can lead to hyperthy-
roidism, but the most common cause in adults is Graves’ disease.
Graves’ Disease
Graves’ disease is an autoimmune condition leading to auton-
omous thyroid hormone secretion resulting from the stimula-
tion of TSH receptor by TSH-like antibodies called
thyroid-stimulating immunoglobulins (TSI). Clinically, about
40–50% of patients with hyperthyroidism present with pro-
truding eyes (exophthalmos or proptosis) as a result of lym-
phocyte and fibroblast infiltration of the extraocular tissues
and muscles, and accumulation of hyaluronate, a glycosamin-
oglycan produced by fibroblasts in the tissues and muscles.
The majority (90%) of patients with thyroid ophthalmopathy
have Graves’ hyperthyroidism.
TSH-secreting Adenomas
Secondary hyperthyroidism is due to increased thyroid hor-
mone release by the thyroid gland in response to increased
TSH levels derived from TSH-secreting pituitary adenomas.
CHAPTER 63 Thyroid Gland 639
Hyperthyroidism
Laboratory Values Clinical Presentation Laboratory Values
Primary: Palpitations, exercise impairment, Primary:
Low free T4; low widened pulse pressure, tachycardia at Low TSH; high T4
or sometimes rest and during exercise, increase in (2-fold) and T3
normal T3; high blood volume, palpable enlarged (3–4-fold). In Graves’
TSH thyroid gland, infiltrative disease, elevated
Secondary: ophthalmopathy, nervousness, anti-TSH receptor
Low T4 and T3, irritability, hyperactivity, emotional antibody titers
normal or instability, tenseness, pounding of the Secondary:
inappropriately heart, heat intolerance, weight loss High TSH, T4, and T3
low TSH despite increased food intake, decreased
or absent menstrual flow, increased
number of bowel movements, warm
moist skin or velvety texture, proximal
muscle weakness, fine hair, fine tremor,
excessive sweating
TSH-secreting adenomas represent a very small fraction
(<1%) of all pituitary adenomas and result in a syndrome of
excess secretion of TSH. The hormonal profile is characterized
by the inability to suppress TSH despite increased levels of free
thyroid hormones (T3 and T4).
ABNORMALITIES IN IODINE
METABOLISM
Iodine is an essential component of thyroid hormone, but both
low and high iodine intake may lead to disease. Several drugs
can interfere with the ability of the thyroid gland to concen-
trate iodide. Perchlorate is a contaminant that can be found in
drinking and groundwater, and occasionally in cow’s milk.
Ingestion of high levels, as with consumption of well water,
can lead to inhibition of iodine transport into the follicular
cells. Methimazole, the active form of carbimazole, inhibits
iodide uptake and organification of iodine. Thiouracil and
propylthiouracil inhibit iodine organification.
Abnormalities in the metabolism or supply of iodine have
particular importance in fetal development. Severe iodine
deficiency of the mother may lead to insufficient thyroid hor-
mone synthesis in both mother and fetus, resulting in develop-
mental brain injury. Iodine deficiency is the leading cause of
preventable mental retardation worldwide, although it is rare
in the USA where table salt is supplemented with iodine. On
the other hand, excess iodine given to the mother (e.g., use of
an antiarrythmic iodine-containing drug called amiodarone
or excess iodine supplementation) may inhibit fetal thyroid
function, leading to hypothyroidism and goiter, or may pre-
cipitate hyperthyroidism (iodine toxicity).
Goiter
Goiter is defined as an overall enlargement of the thyroid
gland. It can be associated with either decreased (iodine
640 SECTION IX Endocrine and Metabolic Physiology
deficiency or Hashimoto’s) or increased (Graves’ disease)
thyroid function. Enlargement of the gland can be the result
of increased TSH receptor stimulation leading to thyroid
hyperplasia or of localized inflammatory and/or autoimmune
processes.
Thyroiditis
Thyroiditis, or inflammation of the thyroid gland, may lead
to abnormalities in thyroid hormone state. This condition
may be acute, subacute, or chronic. Chronic thyroiditis
(Hashimoto’s thyroiditis, chronic lymphocytic thyroiditis,
autoimmune thyroiditis) is an autoimmune disease of the thy-
roid gland characterized by lymphocyte infiltration and circu-
lating autoimmune antibodies. These antibodies inhibit the
Na+/I− symporter, preventing iodide uptake and consequently
thyroid hormone synthesis. Hashimoto’s thyroiditis is the most
common cause of adult hypothyroidism; it is more prevalent
in women than in men, and peaks at the age of 30–50 years.
EVALUATION OF THE
HYPOTHALAMIC–PITUITARY–
THYROID AXIS
TSH AND THYROID HORMONE LEVELS
TSH levels are useful in evaluation of the patient because small
changes in free thyroid hormone levels lead to greater changes
in TSH levels. Serum TSH concentrations are considered the
single most reliable test to screen for all common forms of
hypothyroidism and hyperthyroidism, particularly in the
ambulatory setting. Overt primary hyperthyroidism is accom-
panied by low serum TSH concentrations. Interpretation of
abnormal TSH levels is best done with simultaneous measures
of thyroid hormone levels.
CLINICAL CORRELATION
A premenopausal woman presents with palpitations and a
history of weight loss over the past 6 months. In addition,
she complains of increased irritability and anxiety, inability
to sleep, and heat intolerance. Physical examination reveals
tachycardia (pulse of 120 beats/min), hypertension (a
blood pressure of 139/80 mm Hg), and a diffusely enlarged
nontender thyroid gland. In addition, she has infrequent
blinking and characteristic stare, sweaty hands, and tremor.
Her serum TSH level is low, and the level of free thyroxine
is increased. She is diagnosed with Graves’ disease.
Graves’ disease accounts for 50–80% of cases of
hyperthyroidism, affects approximately 0.5% of the
population, and is more frequent in females than in
males. The excess production of thyroid hormone in
Graves’ disease is the result of circulating IgG antibodies
that bind to the TSH receptor on the thyroid gland, acti-
vating the G protein–coupled receptor. This excess stim-
ulation of the receptor leads to follicular hypertrophy and
hyperplasia, causing thyroid enlargement, as well as
increases in thyroid hormone production. As a result of
excess thyroid hormone production, the release of TSH is
markedly suppressed via negative feedback. Clinical
manifestations are the result of excess thyroid hormone
activity. Treatment for Graves’ disease includes antithy-
roid drugs (inhibitors of thyroid hormone synthesis),
radioiodine ablation of the thyroid tissue, and surgical
removal of the thyroid gland.
CHAPTER SUMMARY
■ The thyroid gland is regulated by the hypothalamic–pituitary–
thyroid axis.
■ Dietary iodine is required for thyroid hormone synthesis.
■ The thyroid gland produces thyroid hormones by a process of
concentration of iodine in the thyroid, iodination of tyrosine
residues of thyroglobulin in the colloid space of the follicle, and
endocytosis of colloid followed by proteolytic release of thyroid
hormones (T4 and T3).
■ Thyroid hormones undergo metabolism in peripheral tissues,
leading to the production of the more active T3 and deactiva-
tion of thyroid hormones.
■ The presence of deiodinases and their substrate specificity play
a central role in thyroid hormone function in target tissues.
■ Thyroid hormone receptors are located intracellularly, bound
to DNA, and alter gene transcription on binding by thyroid
hormone.
■ Thyroid hormone actions are systemic and vital for develop-
ment, growth, and metabolism.
STUDY QUESTIONS
1. Which of the following blood laboratory values would be
compatible with hyperthyroidism due to Graves’ disease?
A) low TSH and T4 levels
B) high TSH but low T4 levels
C) low TSH and high T4 levels
D) high T4 and low T3 levels
2. The following laboratory results are available before physical
examination of a new patient: very low TSH levels, and increased
T4 and T3. Which of the following signs and symptoms would you
expect to find?
A) heart rate of 45 beats/min, diarrhea, and weight gain
B) sweaty hands, 40-g goiter, and constipation
C) heat intolerance, irritability, and weight loss
D) insomnia, delayed muscle relaxation, and diarrhea

3. Blood laboratory values that would be compatible with endemic
goiter due to iodine deficiency include
A) increased TSH, and decreased T4 and T3 levels
B) increased free T4 levels and thyroid-stimulating Ig positive
C) low TSH, T4, and T3 levels
D) normal free T4 and low TSH levels
CHAPTER 63 Thyroid Gland 641
4. A radioactive iodine scan revealed greater concentration of
radioiodine when compared to that of other asymptomatic
individuals. Subsequent laboratory values came back positive for
serum titers of autoantibodies to the TSH receptor. The
pathophysiology of disease in this patient involves
A) increased deiodination of T4 to T3 in the liver
B) decreased thyroid hormone–binding levels
C) increased cAMP formation in the thyroid follicular cell
D) downregulation of the Na+/I– symporter
This page intentionally left blank
 64
C H A P T E R

Parathyroid Gland and

Calcium and Phosphate
Regulation
Patricia E. Molina

O B J E C T I V E S

■ Identify the origin, target organs and cell types, and physiologic effects of
parathyroid hormone.
■ Describe the functions of osteoblasts and osteoclasts in bone remodeling
and the factors that regulate their activities.
■ Describe the regulation of parathyroid hormone secretion, the role of the
calcium-sensing receptor, and the negative feedback relationship between
parathyroid hormone and the biologically active form of vitamin D.
■ Identify the sources, biosynthetic pathway, and physiologic effects of vitamin
D and its active metabolites.
■ Describe the causes and consequences of excess or deficiency of parathyroid
hormone and vitamin D.
■ Describe the regulation of calcitonin release and the cell of origin and target
organs for calcitonin action.
■ Explain the hormonal regulation of plasma calcium concentration through
bone resorption, renal excretion, and intestinal absorption.
■ Explain the hormonal regulation of plasma phosphate concentration through
exchange with bone, renal excretion, and dietary intake and absorption.

The regulation of plasma calcium levels is critical for normal

cell function, neural transmission, membrane stability, bone
structure, blood coagulation, and intracellular signaling. This
regulation relies on the interactions between parathyroid
hormone (PTH) from the parathyroid glands and dietary and
endogenous vitamin D (Figure 64–1). PTH stimulates bone
resorption and the release of calcium (and phosphate) into
the circulation. In the kidney, PTH promotes Ca2+ reabsorp-
tion and inorganic phosphate excretion in the urine. In addi-
tion, PTH stimulates the hydroxylation of 25-hydroxyvitamin
D (25(OH)D) at the 1-position, leading to the formation of
1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of
vitamin D. 1,25(OH)2D exerts its main effects through
increased intestinal absorption of dietary calcium. In addition,
and to a lesser degree, it contributes to renal reabsorption of
filtered calcium and bone resorption. The overall result of the
interactions between PTH and vitamin D is the maintenance
of normal plasma calcium concentrations.
FUNCTIONAL ANATOMY
The parathyroid glands are pea-sized glands located at the top
and bottom posterior borders of the lateral lobes of the thyroid
gland. The chief cells synthesize and secrete the polypeptide
PTH, which plays a major role in bone remodeling, calcium
homeostasis, renal excretion of phosphate, and activation of
vitamin D.
REGULATION OF PTH RELEASE
PTH is synthesized as a prepropeptide that is posttranslation-
ally modified to yield PTH, an 84–amino acid polypeptide.
PTH release is controlled in a tight feedback system by small
changes in plasma calcium levels detected by the parathyroid
calcium-sensing receptor, a G protein–coupled receptor
located on the plasma membrane of the parathyroid chief cells;

643

Ch64_643-654.indd 643 11/30/10 3:30:58 AM

644 SECTION IX Endocrine and Metabolic Physiology

1,25(OH)2D

FIGURE 64–1 Regulation of parathyroid Kidney:

hormone (PTH) release. A decrease in calcium ↑Vitamin D activation
Ca2+ ↑Ca2+ reabsorption
(Ca2+) stimulates the release of PTH from the
↓Pi reabsorption
parathyroid gland. PTH increases the activity of
1α-hydroxylase in the kidney, leading to ↑Ca2+ ↓PTH release
increased production of 1,25(OH)2D. In addition,
PTH increases the reabsorption of calcium and
decreases the reabsorption of inorganic
phosphate (Pi). In bone, PTH stimulates bone ↑PTH release
resorption, increasing the plasma calcium levels.
↑Pi
The increases in 1,25(OH)2D and plasma calcium
levels exert negative feedback inhibition of ↓ Ca2+
PTH release. Increases in plasma phosphate (Pi)
levels stimulate the release of PTH. (Modified with Bone:
permission from Molina PE: Endocrine Physiology, 3rd ed. ↑Bone
Ca2+ resorption
New York: McGraw-Hill Medical, 2010.)

it is also found in kidney tubule cells and thyroid C cells
(Figure 64–2). An acute decrease in circulating calcium levels
(hypocalcemia) triggers PTH release within seconds. In addi-
tion, increases in plasma phosphate levels increase PTH
secretion.
PTH release can be stimulated by a decrease in plasma Mg2+.
The balance of magnesium is closely linked to that of calcium;
magnesium depletion or deficiency is frequently associated
with hypocalcemia. A combined decrease in Mg2+ and calcium
leads to impairment in the individual’s ability to secrete PTH.
Moreover, severe hypomagnesemia impairs not only the
release of PTH from the parathyroid gland in response to
hypocalcemia, but also prevents the responsiveness of bone to
PTH-mediated bone resorption. Table 64–1 lists the factors
that regulate PTH release.
PTH TARGET ORGANS AND
PHYSIOLOGIC EFFECTS
The primary target organs for the physiologic effects of PTH
are kidney and bone. The main physiologic response elicited by
PTH is to increase plasma calcium levels by increasing renal
calcium reabsorption, bone resorption, and intestinal cal-
cium absorption indirectly (via 1,25(OH)2D, the active form

↓ [Ca++]
↑ [Ca++]
Activates 1,25(OH)2D Relaxed
Ca++ sensor Ca++ sensor

FIGURE 64–2 Parathyroid Ca2+-

sensing receptor and regulation of PTH ↓ PTH release ↑ PTH release
release. PTH release is decreased by
increased serum calcium (Ca2+) Nucleus
concentrations and by increased
1,25(OH)2D. PTH is increased by decreased
calcium, decreased magnesium, and ↓ PTH synthesis
increased phosphate levels. Changes in
calcium concentrations are sensed by a
G protein–coupled receptor on the
parathyroid chief cells. (Modified with permission
from Molina PE: Endocrine Physiology, 3rd ed. New York:
McGraw-Hill Medical, 2010.) ↓ Magnesium ↑ Phosphate
 CHAPTER 64 Parathyroid Gland and Calcium and Phosphate Regulation 645

TABLE 64–1. Regulation of parathyroid hormone peptide product of a different gene from that which encodes
release. for PTH, and is expressed in multiple tissues. It binds to the
PTHR1 in bone and kidney, resulting in elevated plasma cal-
PTH Release is Increased by PTH Release is Decreased by cium levels. PTHrP released from cancerous tissue is respon-
sible for the hypercalcemia of malignancy. Therefore, PTHR1
Hypocalcemia Hypercalcemia
not only mediates the physiologic effects of PTH, but also plays
Hyperphosphatemia 1,25(OH)2D an important role in the pathophysiologic effects of PTHrP.
Catecholamines Severe hypomagnesemia
PTH, parathyroid hormone.
CELLULAR EFFECTS OF PTH
In the kidney, PTH directly stimulates calcium reabsorption,
of vitamin D). PTH also increases renal 1α-hydroxylase activ- decreases the reabsorption of phosphate causing an increase in
ity and renal phosphate excretion. The effects of PTH are medi- phosphate excretion, and stimulates the activity of
ated through binding to G protein–coupled PTH receptors. At 1α-hydroxylase, the enzyme responsible for formation of
least three receptors have been identified, but the important 1,25(OH)2D. PTH regulation of calcium reabsorption is medi-
physiologic effects of PTH are mediated by PTHR1. ated in the distal tubules (Figure 64–3). PTH stimulates the
PTHR1 is expressed in bone osteoblasts and kidney, where it insertion and opening of the apical calcium channel, facilitat-
binds PTH and PTH-related protein (PTHrP). PTHrP is a ing calcium reabsorption as discussed in Chapter 48. It

Ca2+
Distal tubule
PTH
+
Ca2+ channel Luminal membrane

Calbindin-D28K

+
1,25(OH)2D

+
ATP ADP 3 Na+

Basolateral membrane
Ca2+/Na+
Ca2+ ATPase exchanger

Ca2+
Ca2+
Interstitial space
FIGURE 64–3 Parathyroid hormone (PTH) increases renal calcium reabsorption. The transcellular reabsorption of calcium (Ca2+) by
the distal tubule is regulated by PTH and 1,25(OH)2D. PTH increases the insertion of calcium channels in the apical membrane and facilitates the
entry of calcium. Inside the cell, calcium binds to calbindin-D28K, a vitamin D–dependent calcium-binding protein that facilitates the cytosolic
diffusion of calcium from the apical influx to the basolateral efflux sites. Calcium transport out of the cell through the basolateral membrane into
the interstitial space is mediated by a Na+/Ca2+ exchanger and a Ca2+-ATPase. 1,25(OH)2D contributes to the enhanced calcium reabsorption by
stimulating the synthesis of calbindin and the activity of Ca2+-ATPase. ATP, adenosine triphosphate. (Modified with permission from Molina PE: Endocrine
Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)
646 SECTION IX Endocrine and Metabolic Physiology

Proximal tubule
Pi 3Na+

PTH
Luminal Type I Type IIa
membrane

Type IIa PTH

+
• Internalization
• Destruction

Type IIa Lysosomes

A–

Basolateral
Type III
membrane

Pi Na+
Pi

Pi

Interstitial space
FIGURE 64–4 Parathyroid hormone (PTH) decreases renal inorganic phosphate (Pi) reabsorption. Renal reabsorption of phosphate
occurs through apical sodium (Na+)/Pi cotransport. Three different Na/Pi cotransporters have been identified: types I, II, and III. Types I and II
cotransporters are located in the apical membrane. Type II cotransporters are expressed in the renal proximal tubule (type IIa) and in the small
intestine (type IIb). Type IIa cotransporters are the major target for PTH regulation and contribute to most (up to 70%) of proximal tubular Pi
reabsorption. PTH acutely stimulates internalization of the type IIa cotransporters, directing them to the lysosomes for destruction, resulting in
a decrease in Pi reabsorption as indicated by the dotted line. Type III cotransporters are most likely located at the basolateral membrane and
play a general “housekeeping” role in ensuring basolateral Pi influx if apical Pi entry is insufficient to satisfy cellular requirements. Basolateral
exit, which is necessary to complete transcellular Pi reabsorption, is not well defined. Several Pi transport pathways have been suggested
including Pi cotransport, anion (A−) exchange, and even an “nonspecific” Pi channel. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed.
New York: McGraw-Hill Medical, 2010.)

decreases the renal (and intestinal) reabsorption of phosphate
by decreasing the expression of the type II Na+/phosphate
cotransporters by stimulating their internalization via coated
vesicles and subsequent lysosomal degradation (Figure 64–4).
In the bone, PTH binds to receptors found in osteoblasts stim-
ulating the activity of several proteins, including osteoclast-
differentiating factor (ODF), also known as receptor activator
of nuclear factor-κβ ligand (RANKL) or osteoprotegerin
ligand (Figure 64–5). In addition, PTH stimulates osteoblast
expression of genes involved in degradation of the extracellu-
lar matrix and bone remodeling (collagenase-3), production of
growth factors (insulin-like growth factor I), and stimulation
and recruitment of osteoclasts (RANKL and interleukin-6).
PTH MOBILIZATION OF BONE CALCIUM
The inorganic phase of bone matrix is composed mainly of
hydroxyapatite, which functions as a reservoir of calcium and
phosphate ions and plays a major role in the homeostasis of
these minerals. Bone remodeling involves the continuous
removal of bone (bone resorption) followed by synthesis of
new bone matrix and subsequent mineralization (bone forma-
tion). Osteoclastic activity induced by PTH is indirectly medi-
ated through osteoblast activation. Osteoclastic bone resorption
involves several steps, including recruitment and differentia-
tion of osteoclast precursors into mononuclear osteoclasts
(preosteoclasts) and fusion of preosteoclasts to form multinu-
cleated functional osteoclasts (Figure 64–6). PTH stimulation
of osteoblast synthesis of ODF (RANKL or osteoprotegerin
ligand) facilitates recruitment and binding of osteoclast precur-
sors expressing the ODF receptor (RANK). This interaction
initiates the differentiation and activation of osteoclasts
(Figures 64–5 and 64–6). Another protein that participates in
this sequence of events is osteoprotegerin, a member of the
TNF receptor superfamily, secreted by osteoblasts. Osteoprote-
gerin acts as a natural antagonist of RANKL, decreasing
RANK–RANKL interaction and, as a result, bone resorption.
Osteoclastic bone resorption involves the attachment of osteo-
clasts to the bone surface, generating an isolated extracellular
 CHAPTER 64 Parathyroid Gland and Calcium and Phosphate Regulation 647

Osteoclast
Osteoprotegerin
precursor

RANKL
+ RANK
PTH

Osteoblast
Mature
Osteoclast
Osteoblast

Ca2+, Pi, alkaline phosphatase

HCO3 –

Osteoclast Cl–
Osteoblast

Cl–

H+

Cl–
H+ Hydroxyapatite
Bone

FIGURE 64–5 PTH-mediated osteoclast differentiation. Upper Panel: PTH binds to PTHR1 in osteoblasts and stimulates the expression
of receptor activator of nuclear factor-κβ ligand (RANKL) expression on the cell surface. RANKL binds to RANK, a cell surface protein on osteoclast
precursors. Binding of RANKL to RANK activates osteoclast gene transcription and the differentiation into a mature osteoclast, characterized by
the ruffled membrane under which bone resorption occurs. Lower Panel: Osteoclasts attach to the bone surface through β-integrins generating
an isolated extracellular microenvironment. Hydrogen ions generated are delivered across the plasma membrane by H+-ATPases at the cell’s
ruffled membrane. The acidification of this microenvironment to ~pH 4 favors the dissolving of hydroxyapatite and provides optimal conditions
for the action of the lysosomal proteases including collagenase and cathepsins. The products of bone degradation (ionized Ca2+, inorganic
phosphate [H2PO4−], and alkaline phosphatases) are endocytosed by the osteoclast and transported to and released at the cell’s antiresorptive
surface. Osteoprotegerin, a soluble protein secreted by osteoblasts that serves as a decoy ligand for RANKL, prevents binding of RANKL to RANK,
thereby inhibiting the process of osteoclastic bone resorption. As a result, there is a decreased differentiation of precursor cells into oscteoclasts
and decreased bone resorption. Production of osteoprotegerin is increased by estrogen and decreased by glucocorticoids and PTH. Cl−, chloride;
HCO3−, bicarbonate; H+, hydrogen ion. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

microenvironment between osteoclasts and the bone surface
that in effect functions as a lysosome in which bone resorption
takes place. The products of bone degradation (including cal-
cium and phosphate), as well as intracellular enzymes such as
alkaline phosphatase, are also released into the circulation.
CALCIUM HOMEOSTASIS
The human body contains approximately 1,100 g of calcium,
99% of which is deposited in bones and teeth. The small
amount found in plasma is divided into three fractions:
ionized calcium (50%), protein-bound calcium (40%), and
calcium complexed to citrate and phosphate forming soluble
complexes (10%). The complexed and ionized calcium frac-
tions (about 60% of total plasma calcium) can cross the plasma
membrane. The majority (80–90%) of protein-bound calcium
is bound to albumin, and this interaction is sensitive to changes
in blood pH. Acidosis leads to a decrease in protein binding of
calcium and an increase in “free” or ionized calcium in the
plasma. Alkalosis results in increased calcium binding and a
decrease in ionized calcium in the plasma. A smaller fraction
(10–20%) of protein-bound calcium is bound to globulins.
Calcium is a key intracellular messenger, a cofactor for vari-
ous enzymes, and has diverse extracellular functions (e.g., in
the clotting of blood, maintenance of skeletal integrity, and
modulation of neuromuscular excitability). Therefore, stable
calcium levels are critical for normal physiologic function. For
example, Na+ channel voltage gating is dependent on the extra-
cellular calcium concentration. Decreased plasma calcium
concentrations (hypocalcemia) reduce the voltage threshold
for the action potential firing, resulting in neuromuscular
hyperexcitability. This can result in muscle cramps or numb-
ness and tingling of fingertips, toes, and the perioral region.
Clinically, neuromuscular irritability can be demonstrated by
mechanical stimulation of the hyperexcitable nerve leading to
tetanic-like muscle contraction by eliciting Chvostek’s sign
(ipsilateral contraction of facial muscles elicited by tapping the
648 SECTION IX Endocrine and Metabolic Physiology

Bone remodeling Growth hormone

Osteoblast Stromal
vessels
Increase in insulin-like
Stroma
growth factor I
Trabeculae

Circulating
osteoblasts

Osteogenic Chondrocytes
cells in bone
marrow
Endochondral
Systemic bone formation
circulation

Periosteum
Osteoblast
Osteoclast

Periosteal appositional
bone formation

Blood vessel

PTH New lining

Local factors
cells
Lining cells
Osteoblasts

Osteoclasts Osteoid

New
osteocytes
Microcrack New bone
Osteocyte
apoptosis
Cement line

Old bone

FIGURE 64–6 Bone remodeling involves bone formation by osteoblasts and bone resorption by osteoclasts. PTH stimulates both
aspects of the process. Growth hormone, acting through insulin-like growth factor, also stimulates bone formation particularly during the linear
growth phase in children. Bone remodeling ensures bone repair and is necessary to maintain calcium homeostasis. (Reproduced with permission from
Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. NEJM. 2007;357:905-916. Copyright Massachusetts Medical Society. All rights reserved.)

skin over the facial nerve) or Trousseau’s sign (carpal spasm
induced by inflation of the blood pressure cuff to 20 mm Hg
above the patient’s systolic blood pressure for 3–5 minutes).
INTERACTION OF BONE, KIDNEY,
AND INTESTINE IN MAINTAINING
CALCIUM HOMEOSTASIS
Plasma concentrations of calcium are mainly regulated by the
actions of PTH and 1,25(OH)2D and three tissues: bone, kid-
ney, and intestine.
Bone
Calcium in bone is distributed in a readily exchangeable
pool and a stable pool. The readily exchangeable pool is
involved in maintaining plasma calcium levels by the daily
exchange of approximately 550 mg of calcium between the
bone and extracellular fluid. The stable calcium pool is
involved in bone remodeling.
Kidney
In the kidney, virtually all filtered calcium is reabsorbed, of
which about 40% is under hormonal regulation by PTH.
 CHAPTER 64 Parathyroid Gland and Calcium and Phosphate Regulation 649

Intestine
The availability of dietary calcium is a critical determinant of cal-
cium homeostasis. Dietary intake of calcium averages 1,000 mg
per day, of which only 30% is absorbed in the intestinal tract.
This percentage of dietary calcium that is absorbed is signifi-
cantly enhanced by 1,25(OH)2D.
HORMONAL REGULATION
OF CALCIUM HOMEOSTASIS
A slight decrease in the calcium level results in an increased
release of PTH. In bone, PTH increases resorption and the
release of calcium and phosphate into the circulation. In the
kidney, PTH promotes calcium reabsorption and phosphate
excretion in urine. In addition, PTH stimulates the formation
of 1,25(OH)2D. 1,25(OH)2D increases intestinal absorption of
dietary calcium and, to a lesser extent, renal reabsorption of
filtered calcium. In bone, 1,25(OH)2D increases bone turnover,
with a resulting increase in the release of calcium into the cir-
culation. The increase in calcium levels decreases PTH release
from the parathyroid gland, decreases activation of 25(OH)D
in the kidney, and stimulates release of calcitonin from the
parafollicular cells of the thyroid gland. At high pharmaco-
logical concentrations, calcitonin can inhibit osteoclast activ-
ity and increase renal calcium excretion. Overall, PTH and
1,25(OH)2D are the critical hormones that work together to
maintain plasma calcium levels within a normal range.
ROLE OF VITAMIN D
IN CALCIUM HOMEOSTASIS
Synthesis and Activation of Vitamin D
Vitamin D is a lipid-soluble vitamin synthesized either from
dietary plant- and animal-derived precursors or through the
action of sunlight on cholesterol-derived precursors found in the
skin (Figure 64–7). Active vitamin D (calcitriol; 1,25(OH)2D)

UV light Liver

Cholecalciferol

Provitamin D 25(OH)Vitamin D
7-dehydrocholesterol Ergocalciferol
in skin (Vitamin D2) in diet Kidney
24α-Hydroxylase
Ca
PTH
1α-Hydroxylase 24, 25 (OH)2 Vitamin D
(Inactive form)

1, 25 (OH)2 Vitamin D
(Active form)

Bone Ca Ca PTH
resorption absorption reabsorption synthesis
Plasma Ca2+ concentrations

FIGURE 64–7 Vitamin D metabolism and physiologic effects at target organs. Provitamin D (7-dehydrocholesterol) in the skin is
converted to cholecalciferol by ultraviolet (UV) light. Cholecalciferol and ergocalciferol (from plants) are transported to the liver, where they
undergo the first step in bioactivation, the hydroxylation at C-25 to 25-hydroxyvitamin D (25(OH)D), the major circulating form of vitamin D.
The second hydroxylation step, at C-1, occurs in the kidney and results in the hormonally active 1,25(OH)2D. This activation step, mediated by
1α-hydroxylase, is under tight regulation by parathyroid hormone (PTH), calcium levels, and 1,25(OH)2D. The activity of 1α-hydroxylase is
stimulated by PTH and inhibited by calcium and 1,25(OH)2D. Decreased activity of 1α-hydroxylase favors C-24 hydroxylation and formation of
the less active 24,25(OH)2D. 1,25(OH)2D increases bone resorption, increases calcium absorption from the intestine (the major effect), increases
renal calcium reabsorption, and decreases the production of PTH by the parathyroid glands. The overall effect of 1,25(OH)2D is to increase plasma
calcium concentrations. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)
650 SECTION IX Endocrine and Metabolic Physiology

is the product of two consecutive hydroxylation steps. The first
hydroxylation of the precursors cholecalciferol (D3, derived
from skin or diet) and ergocalciferol (D2, derived from diet)
takes place in the liver. Cholecalciferol is produced in the skin
by ultraviolet radiation acting on 7-dehydrocholesterol, an inert
precursor. Vitamin D circulates to the liver bound to vitamin
D–binding protein. The precursors are hydroxylated at C-25 to
the prehormone 25(OH)D. 25(OH)D is the major circulating
and storage form of vitamin D, and circulates bound to vitamin
D–binding protein. In the kidney, it is hydroxylated by
1α-hydroxylase resulting in 1,25(OH)2D. This second hydroxy-
lation step is a tightly regulated process enhanced by PTH and
under negative feedback regulation by plasma calcium levels.
An increase in plasma calcium levels inhibits the hydroxylation
at C-1 and favors hydroxylation at C-24, leading to the synthesis
of an inactive metabolite of vitamin D (24,25(OH)2D).
Cellular Effects of Vitamin D
1,25(OH)2D mediates its effects through binding to a steroid
receptor located in the intestines, bone, kidney, and parathy-
roid gland, where it stimulates intestinal calcium absorption,
regulates bone turnover, increases renal calcium reabsorption,
and suppresses the synthesis of PTH (Figure 64–7).
deficiency can result in bone deformities (rickets) when it occurs
in children and decreased bone mass (osteomalacia) in adults.
Vitamin D deficiency is associated with weakness, bowing of the
weight-bearing bones, dental defects, and hypocalcemia.
ROLE OF CALCITONIN
IN CALCIUM HOMEOSTASIS
Calcitonin is a 32–amino acid peptide hormone produced by
the parafollicular or C cells in the thyroid gland in response to
total plasma concentrations greater than 9 mg/dL. The two
target organs for calcitonin’s physiologic effects are bone and
kidney. Calcitonin inhibits bone resorption, and increases uri-
nary calcium excretion. The cellular effects of calcitonin are
mediated through G protein–coupled receptors from the same
receptor family as the PTH, PTHrP receptor superfamily. Cal-
citonin does not appear to be critical for the regulation of cal-
cium homeostasis in humans; in fact, total removal of the
thyroid does not produce major alterations in calcium homeo-
stasis. However, calcitonin has been used therapeutically for
the prevention of bone loss and for the short-term treatment
of hypercalcemia of malignancy.

Abnormal Vitamin D Levels ADDITIONAL REGULATORS OF

Vitamin D belongs to the class of vitamins that are lipid soluble
(i.e., A, D, E, and K), and can be stored in tissues. Extremely
high levels of vitamin D (vitamin D toxicity) may lead to prob-
lems such as calcinosis (calcification of soft tissues), deposi-
tion of calcium and phosphate in the kidney, and increased
plasma calcium levels, resulting in cardiac arrhythmia.
Deficiency of vitamin D is extremely common and can be
the result of inadequate dietary intake or absorption, or lack of
sunlight, resulting in decreased conversion of inactive precursors
to the substrates used in the synthesis of 25(OH)D. Vitamin D
CALCIUM AND BONE METABOLISM
PTH and vitamin D play central roles in the regulation of bone
metabolism. However, additional hormones participate in this
process (Table 64–2). Sex steroids (androgens and estrogens)
decrease bone resorption through increased osteoprotegerin
synthesis, osteoblast proliferation, expression of type I collagen
and alkaline phosphatase, and modulation of the effects of
growth hormone, vitamin D, progesterone, and PTH. Growth
hormone and insulin-like growth factor-I stimulate proliferation

TABLE 64–2 Factors involved in the regulation of calcium and bone metabolism.
Regulator Action

PTH Increases bone resorption and plasma calcium

1,25(OH)2D Increases intestinal calcium absorption, bone resorption, and facilitates renal calcium reabsorption

Calcitonin Decreases bone resorption and plasma calcium

Sex steroids (androgens and estrogens) Increase 1α-hydroxylase activity

Increase osteoprotegerin synthesis
Net decrease in bone loss

Growth hormone and insulin-like growth factor Stimulate bone synthesis and growth

Thyroid hormone Increases bone resorption

Prolactin Increases renal calcium reabsorption and 1α-hydroxylase activity

Glucocorticoids Increase bone resorption, decrease bone synthesis

Inflammatory cytokines Increase bone resorption

PTH, parathyroid hormone.
 CHAPTER 64 Parathyroid Gland and Calcium and Phosphate Regulation
and differentiation of osteoblasts, bone protein synthesis, and
growth, and promote synthesis of type I collagen. Normal thy-
roid function is required for physiologic bone remodeling; yet,
excess thyroid hormone levels result in increased bone resorp-
tion. Glucocorticoids increase bone resorption, decrease bone
synthesis, and inhibit osteoprotegerin synthesis, together lead-
ing to decreased bone mass. The proinflammatory cytokines are
potent stimulators of bone resorption in vitro and in vivo. The
overall interaction of these various factors during health and dis-
ease plays an important role in maintaining bone mass.
REGULATION OF PHOSPHATE
BALANCE
Phosphorus in the form of phosphate accounts for more than
50% of bone mineral mass in the form of calcium phosphate.
It plays numerous vital roles in cell function. Most food prod-
ucts, whether plant or animal, contain relatively abundant
quantities of phosphorus. The skeleton contains 85% of the
body’s phosphorus; the rest is distributed in the ECF and ICF.
Total extracellular phosphorus is found in an ionized form
and a nonionized form (organic and inorganic forms). The
inorganic form may be found ionized or free in the form of
phosphate (50%); complexed with calcium, Mg2+, and Na+
(35%); or bound to protein (15%).
Phosphate homeostasis is maintained by intestinal absorp-
tion, renal excretion, balance of phosphate exchange in and
out of the cells, and hormonal regulation. Most phosphate
absorbed from the diet undergoes urinary excretion. Extracel-
lular phosphate concentration is tightly regulated principally
through urinary excretion. Alterations in extracellular phos-
phate concentrations lead to rapid adjustments in renal phos-
phate excretion and slower and less regulated adjustments in
intestinal absorption. Phosphate excretion by the kidney is
stimulated by PTH (Figure 64–4). 1,25(OH)2D stimulates
phosphate intestinal absorption by stimulating the brush-
border membrane Na+–HPO42− cotransport in the upper small
intestine. Thus, PTH promotes phosphate excretion, whereas
1,25(OH)2D and insulin promote phosphate renal reabsorp-
tion and intestinal absorption. Vitamin D deficiency leads to
increased phosphate renal excretion and decreased intestinal
phosphate and calcium absorption, resulting in a severe loss of
both calcium and phosphate from bone (the major site of both
of these mineral stores) because of enhanced PTH activity,
resulting in loss of bone mineral and osteomalacia. This is in
contrast to osteoporosis induced by calcium deficiency.
HORMONAL REGULATION OF
BONE METABOLISM
Bone remodeling results from the interactions of multiple ele-
ments, including osteoblasts, osteoclasts, hormones, growth
factors, and cytokines, the result being a dynamic maintenance
651
of the bone architecture and systemic preservation of calcium
homeostasis. In early life, a careful balance exists between bone
formation by osteoblasts and bone resorption by osteoclasts.
With aging, the process of coupled bone formation–resorption
(turnover) is affected by the reductions in osteoblast differen-
tiation, activity, and life span, which are further potentiated in
the perimenopausal years by hormone deprivation (estrogen
and dehydroepiandrosterone) and an increase in osteoclast
activity.
Decreased calcium intake below obligatory calcium loss
(through the urine, feces, and skin) mobilizes calcium from the
skeleton to maintain the ionized calcium concentration in the
ECF, resulting in bone destruction. Vitamin D deficiency
decreases the concentration of ionized calcium in the ECF
(from loss of the calcemic action of 1,25(OH)2D on bone),
resulting in stimulation of PTH release (secondary hyperpara-
thyroidism), increased phosphate excretion (hypophos-
phatemia), and failure to mineralize new bone as it is being
formed. Simple calcium deficiency is associated with compen-
satory increases in PTH and calcitriol, which together cause loss
of whole bone, whereas true vitamin D deficiency reduces the
mineral content of the bony tissue itself, leading to abnormal
bone composition. However, these two nutritional deficiencies
cannot be completely separated because calcium malabsorption
is the first manifestation of vitamin D deficiency.
CHILDHOOD–ADULT
Bone mass increases throughout childhood and adolescence.
In girls, the rate of increase in bone mass decreases after
menarche, whereas in boys, gains in bone mass persist up to
17 years of age and are closely linked to pubertal stage and
androgen status. By age 17–23, the majority of peak bone mass
has already been achieved in both sexes. Skeletal growth is
achieved through the interaction between osteoblasts and
osteoclasts, which work cooperatively under the influence of
the mechanical strain placed on bone by skeletal muscle force
such as that exerted during exercise. Decreased mechanical
strain (such as that associated with prolonged bed rest or
immobilization) leads to bone loss, whereas increased mechan-
ical strain (weight-bearing exercise) stimulates osteoblastic
activity and bone formation. Peak bone mass is attained in the
third decade of life and is maintained until the fifth decade,
when age-related bone loss begins in both men and women.
PREGNANCY AND LACTATION
Overall requirements for calcium are significantly increased
during pregnancy and lactation. The uptake and release of cal-
cium from the skeleton are increased during pregnancy, and
the rate of calcium mobilization continues to be increased
during the early months of lactation, returning to prepreg-
nancy rates during or after weaning. Calcium absorption, uri-
nary calcium excretion, and bone resorption are higher during
pregnancy than before conception or after delivery.
652 SECTION IX Endocrine and Metabolic Physiology
TABLE 64–3 Measurements used frequently for the clinical evaluation of abnormalities in parathyroid hormone
function or calcium homeostasis.
Normal Range
Plasma calcium 8.5–10.5 mg/dL
Plasma phosphate 3–4.5 mg/dL
Intact plasma PTH levels 10–65 pg/mL
Alkaline phosphatase 30–120 U/L
Bone-specific alkaline phosphatase 17–48 U/L
Osteocalcin (intact) <1–23 ng/mL
PTH, parathyroid hormone.
MENOPAUSE
The acute loss of bone that accompanies menopause involves
most of the skeleton but particularly affects the trabecular com-
ponent. The associated biochemical changes include increases
in the complexed fraction of plasma calcium (bicarbonate),
increases in plasma alkaline phosphatase and urinary hydroxy-
proline (representing increased bone resorption followed by a
compensatory increase in bone formation), increased obliga-
tory calcium loss in the urine, and a small but significant
decline in calcium absorption (Table 64–3). These changes are
ameliorated by hormone treatment with estrogen or selective
estrogen receptor modulators (SERMs), calcium supplementa-
tion, thiazide diuretic administration (which reduces calcium
excretion), and restriction of salt intake, which reduces obliga-
tory calcium loss. In some cases of osteoporosis, calcium
absorption is low, and high bone resorption can be suppressed
by treatment with vitamin D that in turn leads to improvement
in calcium absorption. The process of bone loss is progressive,
starting at about the age of 50 in men and at menopause in
women. Bone loss is faster in women than in men and affects
some bones more than others; the consequences include
decreased bone mineral density (BMD) and increased risk of
fractures. Estrogen deficiency is a major pathogenic factor in
the bone loss associated with menopause and the subsequent
development of postmenopausal osteoporosis. In males, bone
loss is not associated with a rise in bone resorption markers.
Instead, bone loss in men is linked to an age-related decline in
gonadal function and is due to a decrease in bone formation,
not so much an increase in bone resorption.
Bone Density
Bone density determines the degree of osteoporosis and the
fracture risk. The main determinants of peak bone density are
genetics, calcium intake, and exercise. The most common test
for measuring bone density is dual-energy x-ray absorptiom-
etry (DEXA) scanning. Additional approaches include com-
puted tomography, radiologic techniques (morphometry or
Abnormality
Increased with ↑ PTH, vitamin D intoxication, ↑ bone resorption
Decreased in hyperparathyroidism, vitamin D deficiency; increased in renal
failure, hypoparathyroidism, vitamin D intoxication
Increased in hyperparathyroidism; decreased in hypoparathyroidism
High levels indicate increased osteoblastic activity (bone turnover)
High bone turnover, useful marker of active bone formation
Marker for skeletal bone turnover
densitometry), or bone biopsy. DEXA uses x-rays to measure
bone density and provides two measures of how dense bone is:
the T score and the Z score. The T score compares the person’s
bone density with the average bone density of young healthy
adults of the same sex, a time when bone density is at its peak.
The Z score compares a person’s bone density with that of peo-
ple of the same age, sex, and weight, and is less valuable in
making predictions of risk of fracture or in making decisions
about treatment.
Prevention of Osteoporosis
The principal current approaches include:
• Estrogen replacement therapy: Estrogen decreases bone loss
in postmenopausal women by inhibiting bone resorption, re-
sulting in a 5–10% increase in BMD over 1–3 years. Calcium
supplements enhance the effect of estrogen on BMD.
• Bisphosphonates: Bisphosphonates have a strong affinity
for bone apatite and are potent inhibitors of bone resorption.
These agents reduce the recruitment and activity of osteo-
clasts and increase their apoptosis.
• Calcitonin: Calcitonin reduces bone resorption by direct
inhibition of osteoclast activity. Intranasal calcitonin pro-
duces significant effects on BMD. Calcitonin is less effective
in prevention of cortical bone loss than cancellous bone loss
in postmenopausal women.
• PTH: Intermittent administration of human recombinant
PTH restores bone strength by stimulating new bone forma-
tion at the periosteal (outer) and endosteal (inner) bone sur-
faces, thickening the cortices and existing trabeculae of the
skeleton, and perhaps increasing trabecular numbers and
their connectivity.
• SERMs: SERMs are compounds that exert estrogenic ef-
fects in specific tissues and antiestrogenic effects in oth-
ers. Raloxifene competitively inhibits the action of estro-
gen in the breast and the endometrium and acts as an
estrogen agonist on bone and lipid metabolism. In early
postmenopausal women, raloxifene prevents postmeno-
pausal bone loss at all skeletal sites, reduces markers of
 CHAPTER 64 Parathyroid Gland and Calcium and Phosphate Regulation
bone turnover to premenopausal concentrations, and re-
duces the serum cholesterol concentration and its low-
density lipoprotein fraction without stimulating the
endometrium.
• Vitamin D analogs: Vitamin D analogs induce a small in-
crease in BMD that seems to be limited to the spine.
• Exercise: Physical activity early in life contributes to high
peak bone mass. Walking, weight training, and high-impact
exercises induce a small (1–2%) increase in BMD at some
skeletal sites. These effects disappear if the exercise program
is stopped. Load-bearing exercise is more effective for in-
creasing bone mass than are other types of exercise.
DISEASES OF PTH PRODUCTION
PRIMARY HYPERPARATHYROIDISM
Excess PTH production is often due to parathyroid gland hyper-
plasia, adenoma, or carcinoma. The manifestations include
increased PTH levels, increased plasma calcium levels (hyper-
calcemia), increased urinary calcium excretion (hypercalciu-
ria) with increased formation of kidney stones (urolithiasis),
and decreased plasma phosphate levels due to the large increase
in urinary excretion. The increase in PTH results in increased
bone resorption and further increases in extracellular calcium
concentrations leading to increased filtered load of calcium in
the kidney that exceeds the reabsorptive transport capacity, as
discussed in Chapter 48.
SECONDARY HYPERPARATHYROIDISM
Secondary hyperparathyroidism and hyperplasia of the para-
thyroid glands are complications that occur in patients with
chronic renal failure. In early renal failure, a reduction in
plasma 1,25(OH)2D and moderate decreases in ionized cal-
cium contribute to greater synthesis and secretion of PTH.
As renal disease progresses, parathyroid expression of recep-
tors for vitamin D and calcium is reduced, making the para-
thyroid gland more resistant to both the 1,25(OH)2D and
calcium negative feedback regulation of PTH release. Thus,
for any increase in plasma calcium, the inhibition of PTH
secretion is less efficient. As a result, for any particular plasma
calcium concentration, secretion of PTH is enhanced, result-
ing in a shift in the calcium–PTH set point toward secondary
hyperparathyroidism. Hyperphosphatemia independent of
calcium and 1,25(OH)2D levels further enhances uremia-
induced parathyroid gland hyperplasia and PTH synthesis
and secretion, the latter by posttranscriptional mechanisms.
HYPOPARATHYROIDISM
Hypoparathyroidism, resulting from impaired production of
PTH, can be associated with other endocrine disorders and
neoplasias or may result from surgical removal of the parathy-
653
roid glands. Because of the important role of PTH in the acute
regulation of plasma calcium levels, an early manifestation of
surgical removal of the parathyroid glands is hypocalcemic
tetany. The classic clinical sign is known as the Chvostek’s
sign, which is twitching or contraction of the facial muscles in
response to tapping the facial nerve at a point anterior to the
ear and above the zygomatic bone.
PSEUDOHYPOPARATHYROIDISM
Pseudohypoparathyroidism—PTH resistance—is the result
of a decreased response to PTH because of a congenital defect
in the G protein associated with the PTHR1.
CLINICAL CORRELATION
A postmenopausal patient is referred for asymptomatic
hypercalcemia and history of repeated episodes of uro-
lithiasis (kidney stones). Blood laboratory values reveal
increases in intact PTH, 1,25(OH)2D, and markers of bone
resorption. Neck ultrasound revealed a mass below the
right lobe of the thyroid gland. Surgical removal and patho-
logical examination of the excised gland led to the diagno-
sis of parathyroid adenoma.
Parathyroid adenomas cause the majority (90%) of cases
of primary hyperparathyroidism. Excess PTH release leads
to increased bone resorption, increased hydroxylation of
25(OH)D, and increased intestinal calcium absorption.
Urolithiasis results from increased concentrations of cal-
cium in the glomerular filtrate. Increased bone resorption
leads to increased release of bone proteins that are markers
of bone resorption, such as osteocalcin and bone alkaline
phosphatase. With measurement of total plasma calcium
during routine laboratory testing, hypercalcemia in the
absence of clinical manifestations is now a more frequent
presentation of these adenomas.
CHAPTER SUMMARY
■ PTH release is under negative feedback regulation by calcium
and vitamin D.
■ The main physiologic effects of PTH are mediated by the
PTHR1 expressed in bone and kidney.
■ PTHR1 binds PTH and PTHrP, a peptide responsible for the
pathophysiologic elevation of plasma calcium in some
malignancies.
■ In the kidney, PTH increases renal calcium reabsorption,
increases the activity of 1α-hydroxylase (which mediates the
final activation step in the synthesis of vitamin D), and
decreases phosphate reabsorption.
■ In bone, PTH increases osteoclast-mediated bone resorption
indirectly through stimulation of osteoblast activity.
654 SECTION IX Endocrine and Metabolic Physiology

■ Calcitonin decreases bone resorption and lowers plasma 3. A 73-year-old woman is admitted to the hospital following a bout
calcium levels. of severe vomiting and generalized weakness. Initial laboratory
■ Synthesis of the active form of vitamin D (1,25(OH)2D; calcitriol) values reveal increased plasma calcium levels. The referring
involves hydroxylation in the liver (C-25) and kidney (C-1). physician tells you that she has breast cancer and her bone scan
■ 1,25(OH)2D increases bone resorption, renal calcium reabsorp- indicates metastasis to bone. Which of the following blood
tion, and intestinal calcium absorption. laboratory values would be compatible with this clinical scenario?
■ Plasma calcium levels are tightly regulated through hormone- A) low PTH and phosphate, and high alkaline phosphatase
mediated effects on bone. B) high PTH and phosphate, and low alkaline phosphatase
C) low PTH and phosphate, and low alkaline phosphatase
■ Bone mineral density and mass are under nutritional and
D) low PTH and phosphate, and normal alkaline phosphatase
hormonal control.
4. The most likely cause of hypercalcemia in the patient described
■ Phosphate is regulated principally through effects on renal
in Question 3 is
excretion.
A) increased PTH production
B) increased responsiveness of the PTH receptor 1
C) increased PTHrP production
STUDY QUESTIONS D) increased calcitonin release
1. A 43-year-old male is admitted to the emergency room for severe 5. Hyperventilation usually leads to muscle cramping (tetanic
pain in his left flank, radiating to the groin. The pain is contractions). What is the physiologic concept that explains what
intermittent and initiated after running a marathon on a hot happens in that situation?
summer day. The patient is asked for a urine specimen and blood A) hypercalcemia secondary to PTH-mediated bone resorption
is detected in the urine. He is hydrated and additional diagnostic B) increased dissociation of protein-bound calcium
procedures are done. Laboratory values show an increased C) decreased ionized plasma calcium levels
plasma calcium of 12 mg/dL, and increased plasma intact PTH D) increased renal calcium excretion
values of 130 pg/mL. Which of the following findings would be
predictable in this patient?
A) increased plasma phosphate
B) increased serum alkaline phosphatase
C) increased intestinal calcium loss
D) decreased urinary calcium excretion
2. In the patient described above, the mechanism underlying the
abnormalities observed is
A) increased calcitonin release
B) decreased hepatic 25-hydroxylase activity
C) increased osteoclast apoptosis
D) increased bone resorption
 65
C H A P T E R

Adrenal Gland
Patricia E. Molina

O B J E C T I V E S

■ Identify the functional anatomy and zones of the adrenal glands and the
principal hormones secreted from each zone.
■ Describe and contrast the regulation of synthesis and release of the adrenal
steroid hormones (glucocorticoids, mineralocorticoids, and androgens) and
the consequences of abnormalities in their biosynthetic pathways.
■ Understand the cellular mechanism of action of adrenal cortical hormones
and identify their major physiologic actions, particularly during injury and
stress.
■ Identify the major mineralocorticoids, their biologic actions, and their target
organs or tissues.
■ Describe the regulation of mineralocorticoid secretion and relate this to the
regulation of sodium and potassium excretion.
■ Identify the causes and consequences of overproduction and underproduction
of glucocorticoids, mineralocorticoids, and adrenal androgens.
■ Identify the chemical nature of catecholamines and their biosynthesis and
metabolic fate.
■ Describe the biologic consequences of sympathoadrenal medulla activation
and identify the target organs or tissues for catecholamine effects along with
the receptor types that mediate their actions.
■ Describe and integrate the interactions of adrenal medullary and cortical
hormones in response to stress.
■ Identify diseases caused by oversecretion of adrenal catecholamines.

The adrenal glands contribute significantly to maintaining

homeostasis through their role in the regulation of the adap-
tive response to stress, in the maintenance of body water,
sodium, and potassium balance, and in the control of blood
pressure. The main hormones produced by the human adre-
nal glands belong to two different families based on their
structure; these are the steroid hormones including the glu-
cocorticoids, mineralocorticoids, and androgens; and the
catecholamines norepinephrine and epinephrine.
FUNCTIONAL ANATOMY
AND ZONATION
The adrenal glands are located above the kidneys and consist
of two different components: the outer cortex derived from
mesodermal tissue and the inner medulla derived from a sub-
population of neural crest cells (Figure 65–1). The cortex
makes up the majority of the gland and synthesizes the adrenal

655

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656 SECTION IX Endocrine and Metabolic Physiology

Zona Aldosterone
glomerulosa

Zona
Cortex

fasciculata Cortisol
and
androgens

Zona
reticularis
Medulla

Epinephrine
and
norepinephrine

Cortex

Medulla

FIGURE 65–1 Adrenal glands. The adrenal glands are composed of a cortex and a medulla, each derived from a different embryologic
origin. The cortex is divided into three zones: reticularis, fasciculata, and glomerulosa. The cells that make up the three zones have distinct
enzymatic capacities, leading to a relative specificity in the products of each of the adrenal cortex zones. The adrenal medulla is made of cells
derived from the neural crest; the adrenal cortex is made of cells derived from mesodermal tissue. (Reproduced with permission from Widmaier EP, Raff H,
Strang KT [editors]: Vander’s Human Physiology: The Mechanisms of Body Function, 11th ed. McGraw-Hill, 2007.)

steroid hormones. The medulla synthesizes the catecholamines
epinephrine and norepinephrine.
HORMONES OF THE ADRENAL CORTEX
The adrenal cortex consists of three zones that vary in both
their morphologic and functional features and, thus, the ste-
roid hormones they produce (Figure 65–1):
• The zona glomerulosa is the unique source of the mineral-
ocorticoid aldosterone.
• The zona fasciculata produces the glucocorticoids, cortisol
and corticosterone, and the androgens, DHEA and DHEA
sulfate (DHEAS).
• The zona reticularis (which develops postnatally) produces
glucocorticoids and androgens.
The steroid hormones produced by the adrenal cortex are
classified into three general categories: glucocorticoids,
mineralocorticoids, and androgens. They share an initial
step in their biosynthesis (steroidogenesis), which is the
conversion of cholesterol to pregnenolone (Figure 65–2).
This step involves the release of cholesterol by the enzyme
cholesterol esterase, the transfer of cholesterol from
the outer mitochondrial membrane to the inner mitochon-
drial membrane by steroidogenic acute regulatory
(StAR) protein (the rate-limiting step), and the conversion
of cholesterol to pregnenolone by cytochrome P450 side-
chain cleavage (SCC) enzyme (P450scc; or cholesterol SCC
desmolase).
Defects in the activity of specific enzymes involved in the
pathway leading to production of steroid hormones can result in
disease with various degrees of severity depending on the enzy-
matic step that is compromised. The key enzymes involved in
steroid hormone synthesis and the consequences of their defi-
ciency are described in Table 65–1. The severity of the manifes-
tations ranges from death in utero as in the case of congenital
deficiency of cholesterol SCC enzyme (P450scc) to abnormalities
that become evident in adult life and that are not life threaten-
 CHAPTER 65 Adrenal Gland 657

StAR

Cholesterol

Cholesterol side
chain cleavage
17α-hydroxylase/ 17α-hydroxylase/
17,20 lyase 17,20 lyase
Pregnenolone 17-OH-Pregnenolone DHEA

3β-hydroxysteroid 3β-hydroxysteroid
dehydrogenase dehydrogenase

Progesterone 17-OH-Progesterone Androstenedione

21-hydroxylase 21-hydroxylase
Androgens

DOC 11-Deoxycortisol

Aldosterone
11β-hydroxylase
synthase

Corticosterone Cortisol

Aldosterone
synthase Glucocorticoid

Aldosterone

Mineralocorticoid

FIGURE 65–2 Overview of the zone-specific adrenal steroid hormone synthetic pathway. Steroidogenic acute regulatory (StAR) protein
mediates cholesterol transfer into the mitochondria where cholesterol is converted to pregnenolone by cholesterol side-chain cleavage enzyme.
Pregnenolone is converted to progesterone by 3β-hydroxysteroid dehydrogenase. These two initial steps are shared in the synthetic pathway of
mineralocorticoids, glucocorticoids, and androgens. Activity of 17α-hydroxylase/17,20 lyase expressed in the zona fasciculata and zona reticularis
produces 17-OH-pregnenolone and 17-OH-progesterone necessary to produce androgens and to produce precursors for the glucocorticoid
pathway. Cortisol is produced by the activity of 11β-hydroxylase in the zona fasciculata and zona reticularis. Aldosterone is produced by
processing deoxycorticosterone (DOC) to corticosterone, and then to aldosterone by the enzyme aldosterone synthase unique to the zona
glomerulosa. (Modified with permission from Kronenberg HM, Melmed S, Polonsky KS, Larsen PR. Williams Textbook of Endocrinology. Philadelphia, Saunders Elsevier, 2008).

ing. An enzymatic defect of 21-hydroxylase accounts for 95% of
the genetic abnormalities in adrenal steroid hormone synthesis
(Figure 65–3). The second most frequent abnormality in gluco-
corticoid synthesis is deficiency of the enzyme 11β-hydroxylase.
Deficiencies in these enzymes result in impaired cortisol synthe-
sis, lack of negative feedback inhibition of the release of adreno-
corticotropic hormone (ACTH), high ACTH levels, and greater
stimulation of cholesterol conversion to pregnenolone. Because
of the lack of negative feedback inhibition of ACTH release (due
to insufficient cortisol production) and the resulting high ACTH
levels and greater stimulation of steroidogenesis (resulting from
the higher ACTH-mediated stimulation of the initial steps in
steroid hormone synthesis), the intermediate metabolites (before
the enzymatic step that is deficient) continue to be synthesized,
and their buildup leads to a shunting to the alternate enzymatic
pathways. Thus, more pregnenolone is shunted to the DHEA–
androstenedione pathway and more intermediate metabolites
are converted to androgens, resulting in virilization (presence
of masculine traits). One consequence of 21-hydroxylase defi-
ciency is the loss of sodium as a result of mineralocorticoid
deficiency. In contrast, patients with 11β-hydroxylase deficiency
produce excess 11-deoxycortisol and 11-deoxycorticosterone,
which have active mineralocorticoid activity. Because of the
resulting excess in mineralocorticoid-like activity, patients with
this deficiency retain salt and water and may present with high
blood pressure (hypertension).
Glucocorticoid Synthesis and Release
The release of cortisol is under direct stimulation by ACTH
released from the anterior pituitary. The release of cortisol
follows a circadian rhythm that is exquisitely sensitive to
light, sleep, stress, and disease (see Figure 60–7). Release of
cortisol is greatest during the early waking hours; levels
decline as the afternoon progresses and are lowest at around
midnight.
Cortisol inhibits the biosynthesis and secretion of hypotha-
lamic corticotropin-releasing factor (CRH) and pituitary
658 SECTION IX Endocrine and Metabolic Physiology
TABLE 65–1 Key enzymes involved in steroid hormone synthesis and metabolism.
Enzyme and Relevance Physiologic Function
21-Hydroxylase
Accounts for 95% of genetic Converts progesterone to
abnormalities in adrenal steroid 11-deoxycorticosterone and
hormone synthesis 17α-hydroxyprogesterone to
11-deoxycortisol
11β-Hydroxylase
Second most frequent abnormality in Converts 11-deoxycorticosterone to
adrenal steroid hormone synthesis corticosterone; 11-deoxycortisol to cortisol
11β-Hydroxysteroid dehydrogenase type II
Inhibited by glycyrrhetinic acid, a Converts cortisol into cortisone that has less
compound in authentic licorice affinity for the mineralocorticoid receptor
adrenocorticotropin (ACTH) in a classic example of negative
feedback regulation by hormones. This closely regulated
circuit is referred to as the hypothalamic–pituitary–adrenal
(HPA) axis (Figure 65–4).
Metabolism of Glucocorticoids
Free cortisol accounts for 5–8% of total cortisol in the circula-
tion. Most (>90%) of cortisol circulates in a conjugated form
(e.g., as sulfate or glucuronide derivatives) or bound to pro-
teins (noncovalent, reversible binding). Most of cortisol
released into the blood is bound to glucocorticoid-binding
α2-globulin (transcortin or cortisol-binding globulin
[CBG]), a specific carrier of cortisol. The hepatic synthesis of
transcortin is stimulated by estrogen and decreased by liver
disease (cirrhosis). The liver and kidney are the two major
sites of hormone inactivation and elimination, or catabolism.
Inactive hormones are mainly eliminated as urinary (mostly
conjugated) metabolites. Inactivation of cortisol to cortisone
and to tetrahydrocortisol and tetrahydrocortisone is followed
by conjugation and renal excretion.
Localized tissue metabolism by the isoforms of the enzyme
11β-hydroxysteroid dehydrogenase contributes to modula-
tion of the physiologic effects of glucocorticoids. Corticos-
teroid 11β-hydroxysteroid dehydrogenase type I is a
low-affinity NADPH-dependent reductase that converts cor-
tisone back to its active form cortisol. This enzyme is
expressed in liver, adipose tissue, lung, skeletal muscle, vas-
cular smooth muscle, gonads, and the central nervous sys-
tem. The conversion of cortisol to cortisone, its less active
metabolite, is mediated by the enzyme 11β-hydroxysteroid
dehydrogenase type II. This high-affinity NAD-dependent
dehydrogenase is expressed primarily in the kidney, where
it converts cortisol to the inactive metabolite corti-
sone. This conversion is critical in preventing excess miner-
alocorticoid activity resulting from cortisol binding to the
mineralocorticoid receptor. Increased expression and activ-
ity of 11β-hydroxysteroid dehydrogenase type I amplifies
Consequence of Deficiency
Decreased cortisol and aldosterone. Loss of sodium
because of mineralocorticoid deficiency. Virilization
because of excess androgen production
Excess 11-deoxycortisol and
11-deoxycorticosterone. Excess mineralocorticoid
activity. Salt and water retention
Decrease in glucocorticoid inactivation in
mineralocorticoid-sensitive cells, leading to excess
mineralocorticoid activity
glucocorticoid action within the cell, whereas increased
11β-hydroxysteroid dehydrogenase type II activity decreases
glucocorticoid action.
Mineralocorticoid Synthesis and Release
Aldosterone synthesis and release in the adrenal zona glomeru-
losa are predominantly regulated by angiotensin II and extracel-
lular K+ and, to a lesser extent, by ACTH (Figure 65–5).
Aldosterone is part of the renin–angiotensin–aldosterone sys-
tem, which is responsible for preserving circulatory homeostasis
in response to a loss of salt and water (please review Chapter 45).
A decrease in the effective intravascular blood volume leads to
decreased renal perfusion pressure, which is sensed by the juxta-
glomerular apparatus (baroreceptor) and triggers the release of
renin. Renin (pronounced REE-nin) release is also regulated by
NaCl concentration in the macula densa, plasma electrolyte con-
centrations, angiotensin II levels, and sympathetic tone. Renin is
an enzyme synthesized in the juxtaglomerular cells of the kid-
ney that cleaves angiotensinogen (a protein produced by the
liver) to angiotensin I, which is later converted by angiotensin-
converting enzyme to angiotensin II. This renin–angiotensin
system is part of an extremely powerful feedback system for long-
term control of blood pressure and volume homeostasis. Together,
angiotensin II, aldosterone, and antidiuretic hormone (ADH;
arginine vasopressin) produce vasoconstriction, and renal reten-
tion of Na+ and water. The increase in circulating angiotensin II
binds to the angiotensin II receptor in the adrenocortical cells of
the zona glomerulosa, stimulating phospholipase C. This results
in an increase in intracellular Ca2+, leading to stimulation of
aldosterone synthesis and release (Figure 65–5).
Potassium is also a major physiologic stimulus for aldoster-
one production, illustrating a classic example of hormone
regulation by the ion it controls (please review Chapter 46).
Aldosterone increases potassium excretion in urine, feces,
sweat, and saliva, preventing hyperkalemia during periods of
high potassium intake or after potassium release from skeletal
muscle during strenuous exercise. In turn, increases in circu-
 CHAPTER 65 Adrenal Gland 659

A. 21 Hydroxylase deficiency Cholesterol

Pregnenolone

Progesterone 17-Hydroxypregnenolone

Cortisol Aldosterone 17-Hydroxyprogesterone Dehydroepiandrosterone

Deoxycortisol

B. 11 β-hydroxylase deficiency Cholesterol

Pregnenolone

Progesterone 17-Hydroxypregnenolone

Deoxycorticosterone 17-Hydroxyprogesterone 17-Hydroxyprogesterone

11-Deoxycortisol
Corticosterone 11-Deoxycortisol Androstenedione

Cortisol
Cortisol

Dehydroepiandrosterone

FIGURE 65–3 Alterations in steroid hormone synthesis in 21-hydroxylase and 11β-hydroxylase enzymatic deficiency. A)
21-Hydroxylase deficiency accounts for 95% of genetic abnormalities in adrenal steroid hormone synthesis. 21-Hydroxylase converts progesterone
to deoxycorticosterone and 17-hydroxyprogesterone to 11-deoxycortisol, the precursor metabolites for the synthesis of cortisol and aldosterone.
Thus, more pregnenolone is shunted to the DHEA–androstenedione pathway (more androgen synthesis), resulting in virilization (presence of
masculine traits). In addition, aldosterone deficiency leads to sodium wasting. B) The second most frequent abnormality in glucocorticoid synthesis
is 11β-hydroxylase deficiency, the enzyme that converts 11-deoxycorticosterone to corticosterone and deoxycortisol to cortisol. 11β-Hydroxylase
deficiency results in excess deoxycorticosterone and 11-deoxycortisol production. Both metabolites have active mineralocorticoid activity. The
resulting excess in mineralocorticoid-like activity leads to salt and water retention and may lead to hypertension. Because of the loss in negative
feedback inhibition of ACTH release by cortisol, excess adrenal stimulation leads to increased synthesis of adrenal androgens (androstenedione
and dehydroepiandrosterone). (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

lating potassium concentrations stimulate the release of
aldosterone from the adrenal cortex.
The total amount of aldosterone released and the prevailing
plasma concentrations are markedly less than those of gluco-
corticoids. In addition, binding of aldosterone to plasma pro-
teins is minimal, resulting in a short plasma half-life.
Adrenal Androgen Synthesis and Release
The third class of steroid hormones produced by the zona fas-
ciculata and reticularis of the adrenal glands is the adrenal
androgens, including DHEA and DHEAS (Figure 65–2).
DHEA is the most abundant circulating hormone in the body
and is readily conjugated to its sulfate ester DHEAS. Regula-
tion of DHEA production is not completely understood, but
it is, in part, controlled by ACTH. The adrenal androgens are
converted into androstenedione and then into potent andro-
gens or estrogens in the peripheral tissues. Dihydrotestoster-
one and 17β-estradiol, the most potent androgen and
estrogen, are synthesized from DHEA. The importance of the
adrenal-derived androgens to the overall production of sex
steroid hormones is highlighted by the fact that approximately
660 SECTION IX Endocrine and Metabolic Physiology

Stress

Hypothalamus

CRH

Anterior
pituitary
gland
ACTH

Negative feedback

Adrenal gland

Cortisol

Bloodstream

FIGURE 65–4 Hypothalamic–pituitary–adrenal axis. Corticotropin-releasing hormone (CRH), produced by the hypothalamus and
released in the median eminence, stimulates the synthesis and processing of proopiomelanocortin, with resulting release of proopiomelanocortin
peptides that include adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH binds to the melanocortin-2 receptor in the adrenal
gland and stimulates the cholesterol-derived synthesis of adrenal steroid hormones. Glucocorticoids released into the systemic circulation exert
negative feedback inhibition of CRH and ACTH release from the hypothalamus and pituitary, respectively, in a classic example of negative
feedback hormone regulation. This closely regulated circuit is referred to as the HPA axis. (Modified with permission from Molina PE: Endocrine Physiology,
3rd ed. New York: McGraw-Hill Medical, 2010.)

50% of total androgens in the prostate of adult men are
derived from adrenal steroid precursors. Adrenal secretion of
DHEA and DHEAS increases in children at the age of
6–8 years, and values of circulating DHEAS peak between the
ages of 20 and 30 years. Thereafter, serum levels of DHEA
and DHEAS decrease.
STEROID HORMONE TARGET
ORGAN CELLULAR EFFECTS
Most of the physiologic effects of glucocorticoid and mineral-
ocorticoid hormones are mediated through binding to intrac-
ellular receptors that belong to a superfamily of steroid,
thyroid, retinoid, and orphan receptors and that operate as
ligand-activated transcription factors to regulate gene expres-
sion. Mineralocorticoid and glucocorticoid receptors are
closely related, and share similarities in their ligand- and
DNA-binding domain. They are classified into types I and II.
Type I receptors are specific for mineralocorticoids but have a
high affinity for glucocorticoids. Type II receptors are specific
for glucocorticoids and are expressed in virtually all cells.
The higher concentration of glucocorticoids, and the high
affinity of the mineralocorticoid receptor for glucocorticoids,
raises the issue of ligand–receptor specificity and resulting
physiologic action. Several factors are in place to enhance the
specificity of the mineralocorticoid receptor for aldosterone.
First, plasma glucocorticoids bind to CBG and albumin. This
plasma protein binding allows only a small amount (< 10%) of
the unbound hormone to freely cross cell membranes. Second,
aldosterone target cells possess enzymatic activity of
11β-hydroxysteroid dehydrogenase type II, the enzyme that
inactivates cortisol to cortisone (Figure 65–6). Third, the min-
eralocorticoid receptor discriminates between aldosterone
and glucocorticoids. Aldosterone dissociates from the miner-
alocorticoid receptor five times more slowly than do the
 CHAPTER 65 Adrenal Gland 661

Stimuli to renin

Liver

Kidney
Angiotensinogen
(453 aa)

Renin (enzyme)

Angiotensin I
(10 aa)

Angiotensin I
Angiotensin-converting Angiotensin-converting
enzyme enzyme
(endothelium) (endothelium)
Angiotensin II

Angiotensin II
(8 aa)

Adrenal
Cardiovascular cortex
system Aldosterone

Kidney

Vasoconstriction Salt and H2O

retention

Blood pressure

FIGURE 65–5 Regulation of aldosterone release by the renin–angiotensin–aldosterone system. A decrease in the effective circulating
blood volume triggers the release of renin from the juxtaglomerular apparatus in the kidney. Renin cleaves angiotensinogen, the hepatic
precursor of angiotensin peptides, to form angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE),
which is bound to the membrane of endothelial cells. Angiotensin II is a potent vasoconstrictor and stimulates the production of aldosterone in
the zona glomerulosa of the adrenal cortex. Aldosterone production is also stimulated by potassium and ACTH; aa = amino acids. (Reproduced with
permission from Widmaier EP, Raff H, Strang KT [editors]: Vander’s Human Physiology: The Mechanisms of Body Function, 11th ed. McGraw-Hill, 2007.)

glucocorticoids, despite their similar affinity constants. In SPECIFIC EFFECTS OF ADRENAL

other words, aldosterone is less easily displaced from the min-
eralocorticoid receptor than is cortisol. Together, these mecha-
nisms ensure that under normal conditions, mineralocorticoid
action is restricted to aldosterone. However, when production
and release of glucocorticoids is excessive, or when the conver-
sion of cortisol to its inactive metabolite cortisone is impaired,
the higher circulating and tissue cortisol levels may lead to
binding and stimulation of mineralocorticoid receptors.
CORTEX HORMONES
Glucocorticoids
Cortisol binds to the glucocorticoid receptor (type II glucocorti-
coid receptor) (Figure 65–6). The hormone–receptor complex
translocates to the nucleus, where it binds to specific DNA
sequences (glucocorticoid response elements) and exerts its
662 SECTION IX Endocrine and Metabolic Physiology

GC MC

Cell surface
11β-HSD 2

GC GC CS MC
GR MR MR MR

GRE MRE MRE

FIGURE 65–6 Steroid hormone receptors and mineralocorticoid specificity. Mineralocorticoids (MC; aldosterone) and glucocorticoid
(GC; cortisol) hormones bind to intracellular receptors that share 57% homology in the ligand-binding domain and 94% homology in the DNA-binding
domain. Cortisol binds the mineralocorticoid (MR) receptor with high affinity. Because more cortisol is produced than aldosterone, this could
complicate the regulation of aldosterone-specific effects. Nonspecificity is prevented by the presence of an enzyme: 11-hydroxysteroid dehydrogenase
type 2 (11β-HSD2) in mineralocorticoid target cells. This enzyme converts cortisol into its less active form cortisone (CS) that has less affinity for the
mineralocorticoid receptor (MR). Another factor that contributes to ensure that mineralocorticoid effects are kept under regulation is the fact that
aldosterone dissociates from the mineralocorticoid receptor more slowly than cortisol despite their similar affinity constants. In other words,
aldosterone is less easily displaced from the mineralocorticoid receptor than is cortisol. Thus, glucocorticoids and mineralocorticoids bind to
intracellular receptors (GR and MR, respectively), which dimerize prior to binding to glucocorticoid- or mineralocorticoid-responsive elements (GRE
and MRE, respectively) in the nucleus, thus modulating (increasing or suppressing) transcription of specific genes. Cortisol, because of its high-affinity
binding to the MR, can produce mineralocorticoid-like effects (sodium retention). Conversion to cortisone (CS) decreases the affinity for the receptor
shown by the ill-fit of CS with the MR. Decreased activity of the 11β-HSD2 leads to decreased conversion of cortisol to cortisone and increased
mineralocorticoid activity. (Modified with permission from Molina, PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010)

physiologic effects by altering transcription of genes. Because
virtually all cells express glucocorticoid receptors, the physio-
logic effects are multisystemic. Glucocorticoids affect interme-
diary metabolism, stimulate proteolysis and gluconeogenesis,
inhibit muscle protein synthesis, and increase fatty acid mobili-
zation. Their hallmark effect is to increase blood glucose con-
centrations, hence the name “glucocorticoids.” In the liver,
glucocorticoids increase the expression of gluconeogenic
enzymes. In muscle, glucocorticoids interfere with GLUT4
translocation to the plasma membrane, causing insulin resis-
tance. In bone and cartilage, glucocorticoids decrease the
insulin-like growth factor I, insulin-like growth factor–binding
protein 1, and growth hormone expression and action, and affect
thyroid hormone interactions. At high circulating levels, gluco-
corticoids are catabolic and result in loss of lean body mass
including bone and skeletal muscle. Glucocorticoids modulate
the immune response by increasing anti-inflammatory cytokine
synthesis and decreasing proinflammatory cytokine synthesis,
exerting an overall anti-inflammatory effect. Their anti-inflam-
matory effects have been exploited by the use of synthetic ana-
logs of glucocorticoids, such as prednisone, for the treatment of
chronic inflammatory diseases. The development of potent
inhaled steroids has been a major advance in the treatment of
asthma. In the vasculature, glucocorticoids affect reactivity to
vasoactive substances, such as angiotensin II and norepineph-
rine. This interaction becomes evident in patients with gluco-
corticoid deficiency and manifests as hypotension and decreased
sensitivity to vasoconstrictor administration. In the central ner-
vous system, glucocorticoids modulate perception and emotion
and may produce marked changes in behavior. Some of the main
physiologic effects of glucocorticoids are listed in Table 65–2. It
is important to note that some of these become evident only at
high circulating levels of cortisol.
Mineralocorticoids
The principal physiologic function of aldosterone is to regu-
late renal sodium reabsorption and potassium excretion, hence
the name “mineralocorticoid.” Aldosterone binds to the min-
eralocorticoid receptor in the principal cells of the distal tubule
and the collecting duct of the nephron, producing an increase
in sodium reabsorption and potassium excretion (Figure 65–7).
Aldosterone increases sodium entry at the apical membrane of
the cells of the distal nephron through the amiloride-sensitive
epithelial Na+ channel (ENaC). The Na+/K+-adenosine
triphosphatase (ATPase), located in the basolateral mem-
brane of the cells, maintains the intracellular sodium concen-
tration by extruding the reabsorbed sodium toward the
extracellular and blood compartments.
The specific effects of aldosterone are to increase the syn-
thesis of Na+ channels in the apical membrane, increase the
synthesis and activity of Na+/K+-ATPase in the basolateral
 CHAPTER 65 Adrenal Gland 663

TABLE 65–2 Physiologic effects of cortisol*.

System Effects

Metabolism Degrades muscle protein and increases nitrogen excretion

Increases gluconeogenesis and plasma glucose levels
Increases hepatic glycogen synthesis
Decreases glucose utilization (anti-insulin action)
Decreases amino acid utilization
Increases fat mobilization
Redistributes fat
Permissive effects on glucagon and catecholamine effect

Hemodynamic Maintains vascular integrity and reactivity

Maintains responsiveness to catecholamine pressor effects
Maintains fluid volume

Immune function Increases anti-inflammatory cytokine production

Decreases proinflammatory cytokine production
Decreases inflammation by inhibiting prostaglandin and leukotriene production
Inhibits bradykinin and serotonin inflammatory effects
Decreases circulating eosinophil, basophil, and lymphocyte counts (redistribution effect)
Impairs cell-mediated immunity
Increases neutrophil, platelet, and red blood cell counts

Central nervous system Modulates perception and emotion

Decreases CRH and ACTH release
CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone. *Some of the effects listed (particularly in Immune Function) occur only with very high cortisol levels.

Angiotensin II Principal cells

Extracellular
Aldosterone
fluid [K+]
Cortical collecting-
duct cells Interstitial Lumen
K+ space
Na+
Interstitium
Nucleus Apical
membrane
Na+/K+ -ATPase 3Na+
Na+
Na+
K+ 2K+
ENaC
Na+ Basolateral
membrane
Na+
K+
Na+
Lumen

FIGURE 65–7 Renal physiologic effects of aldosterone. Aldosterone diffuses across the plasma membrane and binds to its cytosolic
receptor. The receptor–hormone complex is translocated to the nucleus, where it interacts with the promoter region of target genes, activating
or repressing their transcriptional activity and thereby increasing transepithelial Na+ transport. Aldosterone increases Na+ entry at the apical
membrane of the cells of the distal nephron through the amiloride-sensitive epithelial Na+ channel (ENaC). Aldosterone promotes potassium
excretion through its effects on Na+/K+-ATPase and epithelial Na+ and K+ channels in collecting duct cells. An increase in the extracellular fluid K+
concentration stimulates the secretion of aldosterone, and a decrease in K+ inhibits aldosterone secretion. Angiotensin II has a synergistic effect
on the stimulation of aldosterone production induced by hyperkalemia. ATP, adenosine triphosphate. (Reproduced with permission from Gennari JF.
Current concepts: Hypokalemia. NEJM. 1998;339:451. Copyright Massachusetts Medical Society. All Rights reserved.)
664 SECTION IX Endocrine and Metabolic Physiology
membrane (which pulls cytosolic Na+ to the interstitium in
exchange for K+ transport into the cell), and increase the
expression of H+-ATPase in the apical membrane and the Cl−/
HCO3– exchanger in the basolateral membrane of intercalated
cells, described in Chapters 44 and 45. These cells express car-
bonic anhydrase and contribute to the acidification of urine
and alkalinization of plasma.
Mineralocorticoids act on fewer cell types than do glucocor-
ticoids. Their receptors are not as widely expressed as those for
glucocorticoids. Classic aldosterone-sensitive tissues include
epithelia in the distal parts of the nephron, the surface epithe-
lium of the distal colon, and the salivary and sweat gland ducts.
Additional effects of aldosterone include increased sodium
reabsorption in salivary and sweat glands, and increased K+
excretion from the colon.
Androgens
The physiologic effects of DHEA and DHEAS are not com-
pletely understood. Current knowledge indicates that low levels
of DHEA are associated with cardiovascular disease in men and
with an increased risk of premenopausal breast and ovarian can-
cer in women. In contrast, high levels of DHEA might increase
the risk of postmenopausal breast cancer. Exogenous adminis-
tration of DHEA to the elderly increases several hormone levels,
including insulinlike growth factor-1, testosterone, dihydrotes-
tosterone, and estradiol. The specific mechanisms through
which DHEA exerts its actions are not completely understood.
DISEASES OF OVERPRODUCTION
AND UNDERSECRETION OF
GLUCOCORTICOIDS
Glucocorticoid Excess
Glucocorticoid excess can be due to overproduction by an
adrenal tumor, overstimulation of adrenal glucocorticoid syn-
thesis by ACTH produced by a pituitary tumor or an ectopic
tumor, or the iatrogenic administration of excess synthetic
glucocorticoids. The clinical manifestation of glucocorticoid
excess, known as Cushing’s syndrome, can be separated into
two categories depending on its etiology.
ACTH-independent Cushing’s syndrome is usually due to
an adrenal neoplasm autonomously releasing cortisol despite
suppressed ACTH (due to cortisol negative feedback). Excess
exogenous glucocorticoid therapy is also a form of ACTH-
independent Cushing’s syndrome.
ACTH-dependent Cushing’s syndrome has two causes:
Cushing’s disease is reserved for Cushing’s syndrome caused
by excess secretion of ACTH by pituitary corticotroph tumors
and is the most common endogenous form of the syndrome.
ACTH production may also be ectopic (derived from extrapi-
tuitary tissue), most frequently because of small cell lung car-
cinoma. ACTH-dependent Cushing’s syndrome is characterized
by increased glucocorticoid levels due to excess stimulation by
ACTH leading to bilateral hyperplasia of the adrenal cortex.
Glucocorticoid Deficiency
Glucocorticoid deficiency can result from lack of ACTH stimu-
lation of adrenal glucocorticoid production (secondary defi-
ciency) or from adrenal dysfunction (primary deficiency).
Exogenous administration of synthetic analogs of glucocorti-
coids in the chronic treatment of some diseases will also suppress
CRH and ACTH, thereby leading to adrenal atrophy. Therefore,
the sudden discontinuation of treatment may be manifested as
an acute case of adrenal insufficiency, a medical emergency.
Most cases of ACTH deficiency involve deficiencies of other
pituitary hormones. Because aldosterone is mainly under the
regulation of angiotensin II and K+, individuals may not neces-
sarily manifest with simultaneous mineralocorticoid deficiency
when impaired ACTH release is the causative factor. Glucocor-
ticoid deficiency due to primary adrenal insufficiency is also
known as Addison’s disease, which can be the result of autoim-
mune or infectious destruction of the adrenal gland.
DISEASES OF OVERPRODUCTION
AND UNDERSECRETION OF
MINERALOCORTICOIDS
Aldosterone Excess
Primary hyperaldosteronism, also known as Conn’s syndrome,
is a condition in which autonomous benign tumors of the
adrenal glands hypersecrete aldosterone. The excess aldoster-
one leads to hypertension because of Na+ and H2O retention
and hypokalemia because of excess K+ secretion. The release
of renin is suppressed.
Secondary hyperaldosteronism is a renin-dependent phe-
nomenon. A decrease in the effective arterial blood volume,
associated with ascites or heart failure, leads to continuous
stimulation of the renin–angiotensin II–aldosterone system.
Aldosterone Deficiency
Primary hypoaldosteronism is most often due to primary
adrenal insufficiency as described above. Plasma renin levels
are elevated, so this condition is also referred to as hyper-
reninemic hypoaldosteronism.
Secondary hypoaldosteronism may be due to inadequate
stimulation of aldosterone secretion (hyporeninemic hypoal-
dosteronism) despite normal adrenal function. This condition
is usually associated with renal insufficiency.
DISEASES OF OVERPRODUCTION AND
UNDERSECRETION OF ADRENAL
ANDROGENS
Adrenal Androgen Excess
Congenital adrenal hyperplasia is an autosomal recessive disor-
der due to 21-hydroxylase deficiency in approximately 90% of
cases. In this condition, impaired cortisol production leads to a

lack of negative glucocorticoid feedback resulting in increased
ACTH release. Increased ACTH stimulation of adrenal hor-
mone synthesis leads to a buildup of cortisol precursors that
due to the lack of 21-hydroxylase activity get shunted to the
androgen synthetic pathway producing an androgen excess.
Steroid 21-hydroxylase (a cytochrome P450 enzyme) converts
17-hydroxyprogesterone to 11-deoxycortisol, and progester-
one to 11-deoxycorticosterone. Both 11-deoxycortisol and
11-deoxycorticosterone are precursors for cortisol and aldoster-
one, respectively. Total loss of 21-hydroxylase activity results in
cortisol and aldosterone deficiencies. If not detected and treated
in time, it can cause death in early infancy owing to shock,
hyponatremia, and hyperkalemia. Deficiency of 21-hydroxylase
leads to accumulation of steroid hormone precursors, and these
can be directed to the androgen hormone synthetic pathway.
Increased androgen production can lead to virilization in affected
girls and signs of postnatal androgen excess in both sexes, includ-
ing rapid linear growth and accelerated skeletal maturation.
HORMONES OF THE
ADRENAL MEDULLA
The adrenal medulla consists of cells that synthesize and
secrete the catecholamines epinephrine (in greater amounts)
and norepinephrine.
CHEMISTRY AND BIOSYNTHESIS
Catecholamines are tyrosine-derived hormones (Figure 65–8).
The transporters involved in packaging epinephrine into
secretory vesicles are the vesicular monoamine transporters,
which are expressed exclusively in neuroendocrine cells.
Because of the expression of these transporters in sympatho-
medullary tissues, their function can be used diagnostically
for radioimaging and localization of catecholamine-producing
tumors (pheochromocytomas). The synthesis of cate-
cholamines can be regulated by changes in the activity of
tyrosine hydroxylase by release from end-product inhibition
or by an increase in enzyme synthesis.
CATECHOLAMINE RELEASE,
TRANSPORT, AND METABOLISM
The release of catecholamines is a direct response to sympa-
thetic nerve stimulation of the adrenal medulla (please
review Chapter 19). Acetylcholine released from the pre-
ganglionic sympathetic nerve terminals binds to nicotinic
cholinergic receptors in the plasma membrane of the chro-
maffin cells, leading to the exocytosis of secretory granules,
which release catecholamines into the interstitial space, from
where they are transported in the circulation to their target
organs. Catecholamines have a short half-life and for the
most part circulate bound to albumin.
CHAPTER 65 Adrenal Gland 665
Catecholamines can undergo reuptake by extraneuronal sites,
degradation at target cells by catechol-O-methyltransferase
(COMT) or monoamino oxidase (MAO), or direct filtration
into the urine. The joint action of MAO and COMT on norepi-
nephrine and epinephrine, especially in the liver, produces the
metabolite vanillylmandelic acid (VMA), which is then
excreted in the urine; dopamine metabolized through this path-
way yields homovanillic acid. Because these metabolites are
water soluble and have high levels of urinary excretion, they can
play an important role in the clinical detection of tumors that
produce excess catecholamines. In humans, VMA is the major
end product of norepinephrine and epinephrine metabolism.
TARGET ORGAN CELLULAR EFFECTS
The physiologic effects of catecholamines are mediated by
binding to G protein–coupled adrenergic receptors distrib-
uted widely throughout the body (Table 65–3). Catecholamines
released from the adrenal medulla exert their effects almost
exclusively in peripheral tissues and not in the brain, because
catecholamines do not readily cross the blood–brain barrier.
Alpha-adrenergic Receptors
Alpha-adrenergic receptors have greater affinity for epineph-
rine than for norepinephrine or for isoproterenol, a synthetic
agonist. They are subdivided into α1- and α2-receptors.
α1-Adrenergic receptors are further subdivided into α1A,
α1B, and α1D. α1-Adrenergic receptors play important roles in
the regulation of several physiologic processes, including myo-
cardial contractility and chronotropy and hepatic glucose
metabolism (Table 65–4).
α2-Adrenergic receptors are also subdivided into three
groups, including α2A, α2B, and α2C (Table 65–3). Some of the
physiologic effects mediated by this subtype of receptor involve
actions at two counteracting α2-receptor subtypes. For example,
stimulation of α2A-receptors decreases sympathetic outflow and
blood pressure, whereas stimulation of α2B-receptors increases
blood pressure by direct vasoconstriction. α2-Adrenergic recep-
tors are implicated in diverse physiologic functions, particularly
in the cardiovascular system and the central nervous system.
Beta-adrenergic Receptors
Beta-adrenergic receptors have been subclassified as β1-, β2-,
and β3-receptors. They have greater affinity for isoproterenol
than for epinephrine or norepinephrine (Table 65–3). The
β1-adrenergic receptor plays an important role in regulating
contraction and relaxation of cardiac myocytes (Table 65–4).
The β2-adrenergic receptor mediates several physiologic
responses, including vasodilatation, bronchial smooth mus-
cle relaxation, and lipolysis, in various tissues. Abnormalities
in the function of this adrenergic receptor may lead to hyper-
tension. The β3-adrenergic receptor plays an important role
in mediating catecholamine-stimulated thermogenesis and
lipolysis.
666 SECTION IX Endocrine and Metabolic Physiology

HO

Tyrosine

COOH NH2
–
Tyrosine
hydroxylase

HO
HO
Dihydroxyphenylalanine (DOPA)

COOH NH2
DOPA
decarboxylase
HO
HO

Dopamine

Dopamine-β NH2
hydroxylase
HO
HO
Norepinephrine
OH

NH2
Phenylethanolamine
N-methyltransferase
HO
HO
Epinephrine
OH
N
CH3 H

FIGURE 65–8 Catecholamine synthetic pathway. Catecholamine synthesis from the precursor L-tyrosine involves four enzymatic
reactions that take place in the cytosol of chromaffin cells. These are the following: (1) hydroxylation of tyrosine to L-dihydrophenylalanine
(L-Dopa) by the enzyme tyrosine hydroxylase. This enzyme is found in the cytosol of catecholamine-producing cells and is the main control
point for catecholamine synthesis. The activity of this enzyme is inhibited by norepinephrine, providing feedback control of catecholamine
synthesis. (2) Decarboxylation of L-Dopa to dopamine by the enzyme dopa decarboxylase in a reaction that requires pyridoxal phosphate as
a cofactor. This end product is packaged into secretory vesicles. (3) Hydroxylation of dopamine to norepinephrine by the enzyme dopamine
β-hydroxylase, a membrane-bound enzyme found in synaptic vesicles that uses vitamin C as a cofactor. This reaction occurs inside the
secretory vesicles. (4) Methylation of norepinephrine to epinephrine by the enzyme phenylethanolamine N-methyltransferase. The activity of
this adrenal medullary enzyme, found in the cytosol of the chromaffin cell, is modulated by adjacent adrenal steroid production, underscoring
the importance of radial arterial flow from the cortex to the medulla. The latter enzymatic reaction occurs in the cytoplasm and thus requires
that norepinephrine leave the secretory granules by a passive transport mechanism. The epinephrine produced in the cytoplasm must reenter
the secretory vesicles through ATP-driven active transport. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill
Medical, 2010.)
 CHAPTER 65 Adrenal Gland 667

TABLE 65–3 Adrenergic receptors and signaling pathways.

Adrenergic Receptor G Protein Second Messenger

β-Adrenergic receptors β1, β2, β3 Gαs G protein Activate adenylate cyclase

α1-Adrenergic receptors α1A, α1B, α1D Mostly Gαq/11 family of G proteins Usually activate PLCα (thereby activating PKC via
DAG and increasing intracellular Ca2+ via IP3) or PLA2

α2-Adrenergic receptors α2A, α2B, α2C Mostly varied Gαi and Gα0 proteins May decrease the activity of adenylate cyclase
(opposing the effects of β-adrenergic receptors).
Activate K channels. Inhibit Ca2+ channels and
activate PLCβ or PLA2 (an effect similar to that of
α1-adrenergic receptors)
PL, phospholipase; PKC, protein kinase C; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate.

CATECHOLAMINE
PHYSIOLOGIC EFFECTS
Catecholamines are released from the adrenal medulla in
response to sympathetic stimulation and are central to the
stress response to a physical or psychological insult such as
severe blood loss, decrease in blood glucose concentration,
traumatic injury, surgical intervention, or a fearful experience.
Because catecholamines are part of the “fight–or-flight”
response, their physiologic effects include arousal, alerting,
papillary dilation, piloerection, sweating, bronchial dilation,
tachycardia, inhibition of smooth muscle activity in the gas-
trointestinal tract, constriction of the sphincters, and relax-
ation of the uterine muscles (Table 65–4). Catecholamines
ensure substrate mobilization from the liver, muscle, and fat
by stimulating the breakdown of glycogen (glycogenolysis)
and fat (lipolysis). Thus, an increase in circulating cate-
cholamines is associated with elevations in plasma glucose
and free fatty acid levels. Some of the most important effects of
catecholamines are exerted in the cardiovascular system,
where they increase heart rate (tachycardia), produce periph-
eral vasoconstriction, and elevate vascular resistance.
TABLE 65–4 Catecholamine physiologic effects.
α-Adrenergic Mediated β-Adrenergic Mediated
Vasoconstriction Vasodilation
Iris dilation Cardioacceleration
REGULATION OF
ADRENERGIC RECEPTORS
Chronic elevation of catecholamine levels leads to sustained
stimulation of adrenergic receptors, which can alter tissue
responsiveness. For example, chronic exposure to β-agonists,
as in asthmatic patients treated with isoproterenol, promotes
receptor desensitization. In contrast, treatment with
α-agonists, as found in some nasal decongestants, results in
tachyphylaxis. Persistent exposure to an agonist of the adren-
ergic receptor can also result in an actual loss of receptors
because of degradation or receptor desensitization. Adrener-
gic receptors can also undergo upregulation because of
increased transcription of the gene for the receptor. Two hor-
mones are known to produce this effect: glucocorticoids and
thyroid hormone. In addition, glucocorticoids and thyroid
hormone can regulate the expression of several types of adren-
ergic receptors through posttranscriptional events.
DISEASES OF OVERPRODUCTION
OF ADRENAL CATECHOLAMINES
Endocrine cells of the sympathoadrenal system are named
chromaffin cells, and the tumors arising from these cells are
called pheochromocytomas. Pheochromocytomas produce
catecholamines, and patients present with signs of excess cat-
echolamine effects, such as sustained or paroxysmal hyper-
tension associated with headache, sweating, or palpitations.

Intestinal relaxation Increased myocardial strength

Intestinal sphincter contraction Intestinal and bladder wall

relaxation CLINICAL CORRELATION
Pilomotor contraction Uterus relaxation
CASE A
Bladder sphincter contraction Bronchodilation
A term newborn infant presents with abnormal-appear-
Bronchoconstriction Calorigenesis
ing ambiguous genitalia that look more male than
Uterine smooth muscle Glycogenolysis female, including an enlarged clitoris. Blood tests reveal
contraction
hyponatremia, high 17-hydroxyprogesterone, and low
Cardiac contractility Lipolysis cortisol levels. CT scan reveals enlarged adrenal glands.
Hepatic glucose production Chromosomal and gonadal sex is assigned as female
668 SECTION IX Endocrine and Metabolic Physiology
gender. The diagnosis of congenital adrenal hyperplasia
is made.
Congenital adrenal hyperplasia is most frequently
(>90% of cases) the result of steroid 21-hydroxylase defi-
ciency due to a mutation. This is associated with ambig-
uous external genitalia in females or virilization during
the first 2–3 years of life in both girls and boys. Adrenal
insufficiency (cortisol deficiency) may present with or
without salt wasting (due to decreased aldosterone
synthesis). The lack of negative feedback inhibition of
ACTH release results in excess ACTH production and
stimulation of the early events in adrenal steroid hor-
mone synthesis and adrenal growth (hyperplasia). The
partial block in the synthetic pathway of cortisol and
aldosterone leads to shunting of pregnenolone to the
androgen hormone synthetic pathway, resulting in the
excess in progesterone causing increased androgen
synthesis. Treatment consists of replacement of gluco-
corticoids and, if desired or possible, surgical correction
of the external genitalia as soon as possible.
CASE B
A young adult male patient is admitted to the hospital
because of severe headache and hypertension (blood pres-
sure 220/100 mm Hg). The patient’s history includes com-
plaints of episodic mild headaches that resolved
spontaneously over the past 3 years. These have progres-
sively increased in severity and frequency and are accom-
panied by sweating, dizziness, palpitations, and pallor.
Measurements of catecholamines and their metabolites in
a 24-hour urine specimen were increased, leading to the
diagnosis of a pheochromocytoma. An MRI examination
of the abdominal revealed a large, unilateral adrenal mass.
Surgical resection of the adrenal was performed, reveal-
ing a large pheochromocytoma.
Pheochromocytomas are rare tumors that produce cat-
echolamines. They usually arise from the adrenal medulla,
but about 10% can arise in extra-adrenal chromaffin tis-
sue. The classic clinical presentation is the triad of epi-
sodic headache, sweating, and palpitations as a result of
the release of stored catecholamines from the tumor. An
unrecognized pheochromocytoma may lead to death as
the result of a hypertensive crisis, arrhythmia, or myocar-
dial infarction.
CHAPTER SUMMARY
■ Cortisol (adrenal glucocorticoid) production and release is
under ACTH regulation.
■ Aldosterone (adrenal mineralocorticoid) release is under
angiotensin II and K+ regulation.
■ Steroid hormone receptors undergo conformational changes
on hormone binding that allow them to bind to DNA and
stimulate gene transcription.
■ Specificity of the mineralocorticoid receptor is conferred by
conversion of cortisol to cortisone by 11β-hydroxysteroid
dehydrogenase.
■ Glucocorticoids facilitate fuel mobilization, decrease glucose
utilization, and produce immunosuppression.
■ Aldosterone regulates body sodium balance and stimulates
excretion of potassium.
■ Catecholamine release is under sympathetic neural control.
■ The response to stress by the host relies on close interaction
between the steroid hormones and catecholamines to ensure
adequate fuel mobilization and hemodynamic control.
STUDY QUESTIONS
1. Regulation of steroid hormone production by the adrenals
involves which of the following steps?
A) ACTH binding to a G protein–coupled receptor, stimulation
of cholesterol transfer to inner mitochondrial membrane,
and formation of pregnenolone
B) ACTH binding to a nuclear receptor, stimulation of
pregnenolone transfer to inner mitochondrial membrane,
and formation of DHEA
C) hydrolysis of cholesterol ester, stimulation of pregnenolone
transfer to inner mitochondrial membrane, and formation
of androstenedione
D) ACTH binding to a G protein–coupled receptor, increased
cholesterol ester hydrolysis, and pregnenolone transfer to
inner mitochondrial membrane
2. A deficiency in 21-hydroxylase activity would be associated with
which of the following?
A) central obesity, increased cortisol levels, and decreased
androstenedione
B) virilization, increased ACTH, and decreased
cortisol levels
C) decreased ACTH levels and decreased cortisol levels
D) hypertension, decreased ACTH, and increased cortisol
levels
E) virilization, hypertension, increased ACTH, and increased
cortisol levels
3. Regarding cortisol production and transport, which of the
following statements is true?
A) Most cortisol circulates unbound to protein.
B) Peak plasma levels occur at noon.
C) Most of the plasma cortisol is bound to transcortin.
D) More than 90% is excreted intact in the urine.
4. Physiologic effects of cortisol include
A) hypoglycemia, increased fatty acid mobilization, and
decreased central fat deposition
B) increased amino acid–derived gluconeogenesis,
increased glucose utilization, and hypoglycemia
C) hyperglycemia, decreased fatty acid mobilization, and
decreased central fat deposition
D) decreased glucose utilization, hyperglycemia,
and lipolysis

5. Regarding the production and release of aldosterone from the
adrenals, which of the following statements is correct?
A) Aldosterone production in the zona glomerulosa is mainly
under ACTH control.
B) Aldosterone production in the zona glomerulosa is mainly
under angiotensin II control.
C) Aldosterone production in the adrenal medulla is mainly
under angiotensin II control.
D) Aldosterone production in the zona glomerulosa is mainly
under K+ control.
CHAPTER 65 Adrenal Gland 669
6. Which of the following statements is true regarding
catecholamine synthesis and release from the adrenals?
A) Epinephrine accounts for 20% of total adrenal
catecholamine release.
B) Norepinephrine is derived from epinephrine through the
action of the enzyme phenylethanolamine
N-methyltransferase.
C) Catecholamine synthesis is regulated by tyrosine
hydroxylase.
D) 35% of catecholamines released are excreted intact in the
urine.
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 66
C H A P T E R

Endocrine Pancreas
Patricia E. Molina

O B J E C T I V E S

■ Identify the principal hormones secreted from the endocrine pancreas,

their cells of origin, and their chemical nature.
■ Understand the nutrient, neural, and hormonal mechanisms that regulate
pancreatic hormone release.
■ List the principal target organs for insulin and glucagon and their major
physiologic effects.
■ Identify the disease states caused by overproduction, underproduction, or
decreased sensitivity to insulin, and describe the principal manifestations
of each.

The pancreas is a mixed exocrine and endocrine gland that
plays a central role in digestion and in the metabolism, utiliza-
tion, and storage of energy substrates. Normal pancreatic
function is essential for the physiologic control of glucose
homeostasis, which, in turn involves interaction of several tis-
sues and hormones in the regulated balance between hepatic
glucose release (from glycogen breakdown and gluconeogen-
esis), dietary glucose absorption, and glucose uptake and dis-
posal from skeletal muscle and adipose tissue. The pancreatic
hormones insulin and glucagon play central roles in regulating
each of these processes; their overall effects are, in part, modi-
fied by other hormones such as growth hormone, cortisol, and
epinephrine.
FUNCTIONAL ANATOMY
The pancreas is a retroperitoneal gland located near the duo-
denum, composed of exocrine cells that are clustered in acini
(see Chapter 51). Embedded within the acini are richly vascu-
larized, small clusters of endocrine cells called the islets of
Langerhans, in which two endocrine cell types (β and α) pre-
dominate. The β-cells constitute about 73–75% of the total
mass of endocrine cells, and their principal secretory product
is insulin. The α-cells account for about 18–20% of the endo-
crine cells and are responsible for glucagon secretion. A small
number of δ-cells (4–6%) secrete somatostatin, and an even
smaller number of cells (1%) secrete pancreatic polypeptide.
The rich vascularization by fenestrated capillaries allows
ready access to the circulation for the hormones secreted by
the islet cells. Venous blood from the pancreas drains into the
hepatic portal vein. Therefore, the liver, a principal target
organ for the physiologic effects of pancreatic hormones, is
exposed to the highest concentrations of pancreatic hormones.
Following first-pass hepatic metabolism, the pancreatic endo-
crine hormones are distributed to the systemic circulation.
Parasympathetic, sympathetic, and sensory nerves richly
innervate the pancreatic islets, and the respective neurotrans-
mitters and neuropeptides released from their nerve termi-
nals exert important regulatory effects on pancreatic endocrine
hormone release. Acetylcholine, released from the parasym-
pathetic nerve terminals, stimulates the secretion of insulin,
glucagon, somatostatin, and pancreatic polypeptide. Norepi-
nephrine released from sympathetic nerve terminals inhibits
basal and glucose-stimulated insulin secretion and stimulates
glucagon and pancreatic polypeptide secretion.

671

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672 SECTION IX Endocrine and Metabolic Physiology

PANCREATIC HORMONES
INSULIN
Insulin Synthesis
Insulin is a polypeptide hormone with a highly conserved
amino acid sequence. It is produced from proinsulin cleavage
of the connecting C-peptide from the amino-terminal β-chain
and the carboxy-terminal α-chain (Figure 66–1A). C-peptide
links the α- and β-chains, allowing proper folding of the mol-
ecule and the formation of disulfide bonds between the two
chains. Removal of the C-peptide exposes the end of the insu-
lin chain that interacts with the insulin receptor. Both insulin
and the free C-peptide are packaged into secretory granules of
which about 5% are in a readily releasable pool and the rest
(>95%) in a reserve pool (Figure 66–1B). Insulin release from
granules from different pools leads to a biphasic pattern
response to glucose stimulation of the β-cell. Only a small pro-
portion of the cellular stores of insulin is released even under
maximal stimulatory conditions.
Stimulation of the pancreatic β-cell leads to release of equal
amounts of insulin and C-peptide into the portal circula-
tion. Insulin circulates in its free form and has a half-life of
3–8 minutes. It is degraded predominantly by the liver during
its first pass, which extracts about 40–80% of insulin delivered.
Additional degradation of insulin occurs in the kidneys as well
as at target tissues by insulin proteases following endocytosis
of the receptor-bound hormone. C-peptide is not readily
degraded in the liver. Thus, the relatively long half-life of
C-peptide (35 minutes) allows its release to be used as an index
of the secretory capacity of the endocrine pancreas.
Regulation of Insulin Release
The release of insulin throughout the day is pulsatile and
rhythmic in nature (Figure 66–1C). The pulsatile release of
insulin appears to be critical in the suppression of liver glucose
production and in insulin-mediated glucose disposal by adi-
pose tissue. Insulin release increases after a meal in response
to the increases in plasma levels of glucose and amino acids.
An increase in plasma glucose concentration is followed by a
transient stimulation of insulin secretion known as first-phase
secretion, which consists of a rapid burst of release to a
high peak and then a steep decline to a low secretion rate
(Figure 66–1B). This is followed by second-phase secretion,
which consists of a gradually increasing rate of secretion to a
plateau level. This biphasic response to glucose is a major
characteristic of glucose-stimulated insulin secretion. The first
phase occurs over a period of minutes, the second over an

A Proinsulin Insulin C Pulsatile insulin release

C peptide
900
Portal vein INS.

S 750
conc. (pM)

α-chain S
N-terminal S S
S S 450
S S S
S S 300
S
C-terminal 150
β-chain
0
B Biphasic insulin release 0 20 40 60 80 100 120
Time (minutes)
Immature glucose
Insulin release per beta cell

granules 1st phase

15
(granules/min)

10
2nd phase
5

0
Readily releasable 0 5 10 15 20
granules t (min)

FIGURE 66–1 Principal feature of insulin synthesis and release. A) Insulin synthesis starts with the translation of insulin mRNA into
an inactive protein called preproinsulin. Preproinsulin undergoes posttranslational modification in the endoplasmic reticulum (ER) to form
proinsulin. The active form of insulin is produced by modification of proinsulin by cleavage of the C-peptide structure linking the α- and
β-chains. Insulin is composed of two amino acid chains. The chains are held together by two disulfide (S–S) bonds. A third disulfide bond is
present within the α-chain. Both insulin and the cleaved C-peptide are packaged in secretory granules that accumulate in the β-cell cytosol
and are coreleased in response to glucose stimulation. B) Insulin release occurs in a biphasic mode from secretory granules that are immediately
available for release (<5%) and from granules that must undergo a series of preparatory reactions including mobilization to the plasma
membrane (>95%). These granule preparatory or maturation processes are modulated by intracellular levels of ATP, ADP, and Ca2+. C) Insulin
release in response to a meal is characterized by increased frequency and amplitude of pulsatile release. Shown are portal insulin concentrations
during basal state (left) and after ingestion of a mixed meal (right) in normal patients. (Modified with permission from Porksen N et al: Human insulin release
processes measured by intraportal sampling. Am J Physiol Endocrinol Metab 2002;282(3):E695–E702.)
 CHAPTER 66 Endocrine Pancreas 673

Glucose
1
GLUT2 carrier

Mitochondrion ATP
–
2
ATP-sensitive K+ channel
Endoplasmic reticulum K+

Ca2+ store
Depolarization

4 Ca2+ Ca2+
3
Secretory
granules
Voltage-gated Ca2+ channel
Ca2+

Exocytosis

Insulin
β CELL
FIGURE 66–2 Regulation of insulin release. Glucose is the principal stimulus for insulin release from the pancreatic β-cell. (1) It enters the β-cell
by a specific glucose-transporter protein (GLUT-2) and is immediately phosphorylated by glucokinase (not shown). The increased concentrations of
ATP and resulting greater ATP/ADP ratio lead to inhibition and (2) closure of the ATP-sensitive K+ channels (the target of sulfonylurea drugs), resulting
in depolarization of the plasma membrane and (3) opening of the voltage-dependent Ca2+ channels. As a result, there is an increased influx of
extracellular Ca2+ as well as (4) mobilization of Ca2+ from intracellular stores leading to the fusion of insulin-containing secretory granules with the
plasma membrane and the release of insulin (and C-peptide) into the circulation. PLC, phospholipase C; AC, adenylate cyclase; CCK, cholecystokinin;
GLP-1, glucagon-like peptide-1. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

hour or more. Secretion is the result of a combination of an
increase in the total amount of insulin released in each secre-
tory burst and an increased pulse frequency of a similar mag-
nitude (Figure 66–1C).
The pancreatic β-cell functions as a fuel sensor that responds
to changes in plasma levels of energy substrates (glucose
and amino acids), hormones (glucagon-like peptide 1 [GLP-1]
and epinephrine), and neurotransmitters (norepinephrine and
acetylcholine) (Figure 66–2). Glucose is the principal stimulus
for insulin release from the pancreatic β-cells.
The glucose-induced stimulation of insulin release is the
result of glucose metabolism by the β-cell and an increase in
the adenosine triphosphate (ATP)/ADP ratio in the cytosol.
Glucose enters the β-cell through a membrane-bound glucose
transporter (GLUT 2) (Figure 66–2). The production of ATP
from glucose oxidation results in an increase in intracellular
ATP/ADP that inhibits (closes) the ATP-sensitive K+ channels
(KATP) in the β-cell, reducing the efflux of K+. This process
results in membrane depolarization, activation (opening) of
voltage-dependent Ca2+ channels, and increased Ca2+ influx.
The increase in intracellular Ca2+ concentrations triggers the
exocytosis of insulin secretory granules and the release of
insulin into the extracellular space and into the circulation.
Regulation of K+ channels by ATP is mediated by the sulfonyl-
urea receptor, and is the basis for the therapeutic use of sulfo-
nylurea drugs in the treatment of type 2 diabetes mellitus.
The β-cell Ca2+ concentrations can also be increased by amino
acids through their metabolism and ATP generation, or by
direct depolarization of the plasma membrane. Other factors
that amplify the glucose-induced release of insulin from the
β-cell include acetylcholine, cholecystokinin, gastrointestinal
peptide, and GLP-1. Catecholamines and somatostatin inhibit
insulin.
Physiologic Effects of Insulin
Insulin produces a wide variety of effects that range from
immediate (within seconds), such as the modulation of ion
(K+) and glucose transport into the cell; early (within minutes),
such as the regulation of metabolic enzyme activity; moderate
(within minutes to hours), such as the modulation of enzyme
synthesis; to delayed (within hours to days), such as the effects
on growth and cellular differentiation. Overall, the actions of
insulin at target organs are anabolic and promote the synthesis
of carbohydrate, fat, and protein, and these effects are medi-
ated through binding to the insulin receptor (Table 66–1).
674 SECTION IX Endocrine and Metabolic Physiology

TABLE 66–1 Insulin effects on carbohydrate, fat, and protein metabolism.

Metabolic Effects Insulin Stimulates Insulin Inhibits

Carbohydrate Glucose transport in adipose tissue and muscle Glycogen breakdown in muscle and liver
metabolism Rate of glycolysis in muscle and adipose tissue Gluconeogenesis in the liver
Glycogen synthesis in adipose tissue, muscle,
and liver

Lipid metabolism Fatty acid and triacylglycerol synthesis in tissues Lipolysis in adipose tissue, lowering the plasma fatty
Uptake of triglycerides from the blood into adipose acid level
tissue and muscle Fatty acid oxidation in muscle and liver
Rate of cholesterol synthesis in the liver Ketogenesis

Protein metabolism Amino acid transport into tissues Protein degradation in muscle
Protein synthesis in muscle, adipose tissue, liver, Urea formation
and other tissues

Insulin Receptor pling of insulin receptor activation to signaling, mainly

the phosphatidylinositol 3-kinase (PI 3-kinase) and the
The insulin receptor belongs to the same family of the insu-
mitogen-activated protein kinase (MAPK) pathways
linlike growth factor receptor, and the insulin-related recep-
(Figure 66–3).
tor, all of which are involved in cell division, metabolism,
Activation of the PI 3-kinase pathway leads to activation of
and development (Figure 66–3). Insulin binding to the
enzymes that catalyze the cellular effects of insulin, particu-
receptor triggers receptor autophosphorylation on tyrosine
larly the metabolic effects of the hormone, including glucose
residues in the cytoplasmic domain (β-chain). The activated
transport, glycolysis, and glycogen synthesis, and regulation of
receptor phosphorylates tyrosine residues of several pro-
protein synthesis. Moreover, this pathway is involved in cell
teins known as insulin receptor substrates (IRS-1, -2, -3,
growth and transmits a strong antiapoptotic signal, promoting
-4). These IRS proteins facilitate the interaction of the insu-
cell survival. The other main signaling pathway that is acti-
lin receptor with intracellular substrates by serving as a scaf-
vated by insulin binding to its receptor is the MAPK pathway,
fold for recruitment of proteins involved in signal
which is involved in mediating the proliferative and differen-
transduction to downstream pathways. The result is cou-
tiation effects elicited by insulin.
The number of available insulin receptors is modulated by
Insulin exercise, diet, insulin, and other hormones. Chronic exposure
Insulin to high insulin levels, obesity, and excess growth hormone all
receptor
lead to a downregulation of insulin receptors. In contrast,
exercise and starvation upregulate the number of receptors.
The affinity of the receptor for insulin is increased following a
period of decreased insulin levels.
ATP

Insulin Effects at Target Organs

Early effects
The effects of insulin on skeletal muscle glucose utilization
P IRS-1 P dominate insulin action. Insulin mediates about 40% of glu-
cose disposal by the body, the great majority of which occurs
P P in skeletal muscle. The movement of glucose into the cell is
mediated by a family of carrier proteins, or glucose transport-
ers (GLUT), with their own unique tissue distribution. The
Other effector Various
main transporters and their predominant tissue distributions
systems and effects are summarized in Table 66–2.
secondary mediators
Insulin-stimulated glucose transport is mediated through
FIGURE 66–3 Intracellular responses triggered by insulin GLUT-4. Approximately 90% of GLUT-4 is sequestered intra-
binding to the insulin receptor. Red balls and balls labeled P cellularly in the absence of insulin or other stimuli such as
represent phosphate groups. IRS-1, insulin receptor substrate-1. exercise. Insulin binding to its receptor results in recruitment
(Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: of GLUT-4 from cytosolic vesicular compartments to the
Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.) plasma membrane.
 CHAPTER 66 Endocrine Pancreas 675

TABLE 66–2 Main features of glucose transporters.

Transporter Expression Function

GLUT-1 Ubiquitous, with particularly high levels in human erythrocytes Glucose uptake by skeletal muscle and fat under
and in the endothelial cells lining the blood vessels of the brain. basal conditions
Expressed in skeletal muscle and fat

GLUT-2 Low-affinity glucose transporter present in pancreatic β-cells, Functions in the glucose sensor system and
liver, intestine, and kidney ensures that glucose uptake by pancreatic β-cells
and hepatocytes occurs only when circulating
glucose levels are high

GLUT-3 Primarily in neurons Together, GLUT-1 and GLUT-3 are crucial in

allowing glucose to cross the blood–brain barrier
and enter neurons

GLUT-4 Predominantly in striated muscle and adipose tissue. In contrast to The major insulin-responsive transporter
the other GLUT isoforms, which are primarily localized on the cell
membrane, GLUT-4 transporter proteins are sequestered in
specialized storage vesicles that remain within the cell’s interior
under basal conditions
GLUT-5 Spermatozoa and small intestine Predominantly a fructose transporter

Intermediate effects
The intermediate effects of insulin are mediated by modula-
tion of protein phosphorylation of enzymes involved in meta-
bolic processes in muscle, fat, and liver (Table 66–1). In fat,
insulin inhibits lipolysis and ketogenesis by triggering the
dephosphorylation of hormone-sensitive lipase and stimulates
lipogenesis by activating acetyl-CoA carboxylase. In the
adipocytes, dephosphorylation of hormone-sensitive lipase
inhibits the breakdown of triglycerides to fatty acids and glyc-
erol, the rate-limiting step in the release of free fatty acids
mediated by lipolysis. This process thereby reduces the amount
of substrate that is available for ketogenesis. Insulin antago-
nizes catecholamine-induced lipolysis through the phospho-
rylation and activation of phosphodiesterase, leading to a
decrease in intracellular cAMP levels and a concomitant
decrease in protein kinase A activity.
In the liver, insulin stimulates the gene expression of
enzymes involved in glucose utilization (e.g., glucokinase,
pyruvate kinase, and lipogenic enzymes) and inhibits the
gene expression of enzymes involved in glucose production
(e.g., phosphoenolpyruvate carboxykinase and glucose-6-
phosphatase) (Figure 66–4). Insulin stimulates glycogen
synthesis by increasing phosphatase activity, leading to the
dephosphorylation of glycogen phosphorylase and glycogen
synthase. In addition, insulin-mediated dephosphorylation of
inhibitory sites on hepatic acetyl-CoA carboxylase increases
the production of malonyl-CoA and simultaneously reduces
the rate at which fatty acids can enter hepatic mitochondria for
oxidation and ketone body production.
In muscle, insulin stimulates glucose uptake and favors
protein synthesis though phosphorylation of a serine/threo-
nine protein kinase known as mammalian target of rapamy-
cin (mTOR). In addition, insulin favors lipid storage in
muscle as well as in adipose tissue. Insulin deficiency leads to
glucose accumulation in blood, a decrease in lipid storage,
and protein loss, resulting in negative nitrogen balance and
muscle wasting.
Long-term effects Sustained insulin stimulation enhances
the synthesis of lipogenic enzymes and the repression of gluco-
neogenic enzymes. The growth-promoting and mitogenic ef-
fects of insulin are long-term responses mediated through the
MAPK pathway.
GLUCAGON
Glucagon Synthesis
Glucagon is a 29–amino acid polypeptide hormone secreted
by the α-cells of the islets of Langerhans, which antagonizes
insulin’s action. The primary sequence of glucagon is highly
conserved among vertebrates. Glucagon is synthesized as
proglucagon and then proteolytically processed to yield
glucagon. The prohormone proglucagon is expressed in the
pancreas, and also in other tissues, such as enteroendocrine
cells in the intestinal tract and the brain. However, the
processing of the prohormone differs among tissues. The
two main products of proglucagon processing are glucagon
in the α-cells of the pancreas and GLP-1 in the intestinal
cells. GLP-1 is produced in the intestine in response to a
high concentration of glucose in the intestinal lumen. It is
known as an incretin, a mediator that amplifies insulin
release from the β-cell in response to a glucose load. Gluca-
gon has a short half-life (5–10 minutes) and is degraded
mostly in the liver.
Regulation of Glucagon Release
Glucagon release is inhibited by hyperglycemia (high blood
glucose levels) and stimulated by hypoglycemia (low blood
676 SECTION IX Endocrine and Metabolic Physiology

Glycogenolysis Glycolysis

Glycogen Glucose

G Glycogen I Glucokinase G
Glycogen
I synthase phosphorylase G Glucose-6-phosphate

Glucose-1-P
Fructose-6-phosphate
ATP Phospho-
ADP fructokinase G
Gluconeogenesis
Fructose-1,6-bisphosphate
(2) Pyruvate
Dihydroxyacetone
phosphate
(2) Oxaloacetate
I PEP carboxykinase G
(2) PEP
Glyceraldehyde-3-phosphate

(2) 3-Phosphoglycerate
1,3-Bisphosphoglycerate
(2) 1,3-Bisphosphoglycerate
3-Phosphoglycerate
Fructose-1,6-bisphosphate
Fructose-1,6-bisphosphate G
2-Phosphoglycerate
Fructose-6-phosphate

Phosphoenolpyruvate
Glucose-6-phosphate
I Glucose-6-phosphatase G I Pyruvate
kinase G
Glucose
Pyruvate
FIGURE 66–4 Glucagon and insulin effects on hepatic glucose metabolism. Binding of glucagon and insulin to their respective
receptors stimulates a cascade of protein phosphorylation steps that activate (or inhibit) key enzymes involved in the regulation of
glycogenolysis, gluconeogenesis, and glycolysis. The principal target enzymes for insulin- and glucagon-mediated effects are presented.
The overall result is an increase in hepatic glucose output. G, glucagon; I, insulin; PEP, phosphoenolpyruvate; ATP, adenosine triphosphate;
ADP, adenosine diphosphate. (Reproduced with permission from Jiang G, Zhang BB: Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol
Metab 2003;284(4):E671–E678.)

glucose levels). A meal rich in carbohydrates suppresses gluca-
gon release and stimulates insulin release from the β-cells
through intestinal release of GLP-1. Somatostatin also inhib-
its glucagon release. High amino acid levels following an
amino acid–rich meal stimulate glucagon release. Epinephrine
stimulates release of glucagon through a β2-adrenergic mecha-
nism (while it suppresses insulin release from β-cells through
an α2-adrenergic mechanism). Vagal (parasympathetic) stim-
ulation increases glucagon release.
Physiologic Effects of Glucagon
Glucagon mediates its effects by binding to the glucagon Gαs
protein–coupled receptor (Figure 66–5). The principal target
tissue for glucagon is the liver. Glucagon’s main physiologic
effect is to increase plasma glucose concentrations by stimulat-
ing de novo hepatic glucose production through gluconeogen-
esis and glycogen breakdown and decreasing glycolysis (Figures
66–4 and 66–5). Glucagon is the principal hormone involved in
prevention and counterregulation of hypoglycemia. The key
enzymatic steps regulated by glucagon that mediate the stimula-
tion of hepatic glucose output are summarized in Table 66–3.
Glucagon can exert effects on adipose tissue as well.
However, these are important primarily during periods of pro-
longed stress or food deprivation, particularly when insulin
release is suppressed. In the adipocyte, glucagon activates hor-
mone-sensitive lipase, the enzyme that breaks down triglycer-
ides (stored fat) into diacylglycerol and free fatty acids,
releasing them into the circulation. Glycerol released into the
circulation can be utilized in the liver for gluconeogenesis or
for reesterification. Free fatty acids are used as fuel by most
tissues, predominantly skeletal muscle and liver. In the liver,
free fatty acids are used for reesterification or they can
undergo β-oxidation and conversion into ketone bodies.
Thus, ketogenesis is regulated by the balance between the
effects of glucagon and insulin at their target organs.
 CHAPTER 66 Endocrine Pancreas 677

Glucagon

Adenylate
Phospholipase cyclase
C Gq

(PiP2) Receptor Gαs γ

β
Inositol 1.4.5 GDP
triphosphate Cytoplasm
(IP3) GTP cAMP

Ca2+

PKA Phosphorylase
PGC-1
PEPCK Kinase
G-6-Pase
a b
Phosphorylase

Glycolysis Glycogenesis Gluconeogenesis Glycogenolysis

Glucose
FIGURE 66–5 Glucagon receptor-mediated cellular effects. Glucagon binds to GPCR on target cells. The principal effects of glucagon
are mediated in hepatocytes where glucagon, through activation of adenylate cyclase and elevation in cAMP, leads to increased protein kinase
A (PKA) activity resulting in phosphorylation of enzymes responsible for control of glucose metabolism. Phosphorylase b is the inactive form of
the enzyme; phosphorylase a is the active form. Furthermore, there is a change in phospholipase C activity leading to a change in intracellular
Ca2+ release). The ultimate result is an increase in hepatic glucose production through increased gluconeogenesis and glycogenolysis. Additional
abbreviations: PGC-1, peroxisome proliferator-activated receptor coactivator-1; PEPCK, phosphoenolpyruvate carboxykinase; G-6-Pase, glucose-
6-phosphatase; PIP2, phosphatidylinositol 4,5-biphosphate. (Modified with permission from Cooper GM: The Cell: A Molecular Approach, 2nd ed. Sinauer, 2000.)

SOMATOSTATIN PANCREATIC POLYPEPTIDE

Somatostatin is a 14–amino acid peptide hormone produced
by the δ-cells of the pancreas. Its release is stimulated by high-
fat, high-carbohydrate, and particularly protein-rich meals,
and is inhibited by insulin. Somatostatin has a generalized
inhibitory effect on virtually all gastrointestinal and pancreatic
exocrine and endocrine functions.
Pancreatic polypeptide is a 36–amino acid peptide hormone
that belongs to a peptide family including neuropeptide Y
and peptide YY. It is produced in the endocrine type F cells
located in the periphery of pancreatic islets and is released into
the circulation after ingestion of food, exercise, and vagal
stimulation. The effects of pancreatic polypeptide include

TABLE 66–3 Effects of glucagon on hepatic glucose metabolism.

Effect on Target Enzyme Metabolic Response

Increased expression of glucose-6-phosphatase Frees glucose to enter the circulation

Suppression of glucokinase Decreases glucose entry into the glycolytic cascade

Phosphorylation (activation) of glycogen phosphorylase Stimulates glycogenolysis

Inhibition of glycogen synthase Inhibits glycogen synthesis

Stimulation of phosphoenolpyruvate carboxykinase expression Stimulates gluconeogenesis

Inactivation of phosphofructokinase-2 and activation of fructose-6-phosphatase. Inhibits glycolysis

PFK-2 is the kinase activity and fructose-2,6-bisphosphatase is the phosphatase Stimulates gluconeogenesis
activity of the bifunctional regulatory enzyme, phosphofructokinase-2/fructose-2,6-
bisphosphatase
Suppression of activity of the pyruvate kinase Decreases glycolysis
678 SECTION IX Endocrine and Metabolic Physiology
inhibition of pancreatic exocrine secretion, gallbladder con-
traction, modulation of gastric acid secretion, and gastrointes-
tinal motility. Pancreatic polypeptide crosses the blood–brain
barrier and has been postulated to play a role in regulating
feeding behavior.
AMYLIN
Amylin, or islet amyloid polypeptide, is a 37–amino acid
peptide hormone that belongs to the calcitonin family,
which includes calcitonin, calcitonin gene-related peptide,
and adrenomedullin. Amylin is synthesized as a small precur-
sor, undergoes posttranslational modification (amidation), is
stored in β-cell granules, and is released along with insulin
and C-peptide. Plasma amylin concentrations increase after a
meal or glucose infusion. Amylin appears to work with insulin
to regulate plasma glucose concentrations in the bloodstream,
suppressing the postprandial secretion of glucagon and slow-
ing gastric emptying. It is the main component of pancreatic
islet amyloid, found in the vast majority of patients with type 2
diabetes mellitus, and is thought to contribute to destruction
of the pancreatic β-cell.
DISEASES ASSOCIATED WITH
PANCREATIC HORMONES
HORMONE-PRODUCING TUMORS
Excess pancreatic hormone production and release are usually
due to hormone-producing tumors, with insulinoma being
the most frequent. Insulinomas produce excessive amounts of
insulin, and patients present with episodes of hypoglycemia,
confusion, aggressiveness, palpitations, sweating, convulsions,
and even unconsciousness. These symptoms are mostly
observed before breakfast and following physical exercise. The
compensatory or counterregulatory response of the body
includes the release of catecholamines, glucagon, cortisol, and
growth hormone.
Glucagonomas are unusual tumors that may produce symp-
toms of diabetes. Excessive glucagon production by the tumor
may also result in an overall catabolic effect on fat and muscle,
leading to severe weight loss and anorexia.
DIABETES MELLITUS
The most common disease resulting from impaired pancreatic
hormone release or sensitivity is diabetes mellitus. The two
forms of diabetes mellitus, type 1 (T1DM) and type 2 (T2DM),
are characterized by impaired insulin release, but for different
reasons. T1DM is the result of β-cell destruction. It accounts
for 2–5% of cases, and it occurs more frequently in younger
people, hence its archaic name, juvenile-onset diabetes. T1DM
is characterized by the development of ketoacidosis in the
absence of insulin therapy. T2DM results from impaired sensi-
tivity to insulin (insulin resistance) and a subsequent relative
loss of normal regulation of insulin secretion and accounts for
more than 90% of diabetes cases. It is usually associated with
obesity in adults and is characterized by mild hyperglycemia.
It rarely leads to ketoacidosis.
Type 1 Diabetes Mellitus
The pathophysiology of T1DM involves a complete lack of
insulin secretion due to autoimmune destruction of the islet
cells. This results in impaired entry of glucose into the cells
and accumulation of glucose in the blood. This leads to
increased plasma osmolarity and urinary loss of glucose,
accompanied by excess loss of water and sodium (polyuria).
The resulting dehydration triggers compensatory mecha-
nisms such as thirst (polydipsia). The inability of the cells to
utilize glucose resembles a state of cellular starvation, stimu-
lating hunger (polyphagia) and triggering the activation of
compensatory responses to increase the release and availabil-
ity of fuel substrates though activation of lipolysis and prote-
olysis.
Diabetic ketoacidosis is an acute pathologic event charac-
terized by elevated blood glucose levels and ketone bodies and
metabolic acidosis, resulting directly from decreased insulin
availability and simultaneous elevations of the counterregula-
tory hormones glucagon, catecholamines, cortisol, and growth
hormone. Diabetic ketoacidosis is precipitated by infections,
discontinuation of or inadequate insulin use, new-onset
(untreated) diabetes, and other events such as the stress asso-
ciated with surgery.
In diabetic ketoacidosis, gluconeogenesis in the liver pro-
ceeds unopposed by the physiologic presence of insulin. The
excess blood glucose increases osmolarity, which, if severe,
can result in diabetic coma. Low insulin levels and the high
levels of counterregulatory hormones glucagon, epinephrine,
and cortisol combine to increase the activity of hormone-sen-
sitive lipase, increase the release of free fatty acids, and
decrease the activity of acetyl-CoA carboxylase, thereby
impairing the reesterification of free fatty acids and promot-
ing fatty acid conversion into ketone bodies (Figure 66–6).
The steps involved in ketogenesis are β-oxidation of fatty
acids to acetyl-CoA, formation of acetoacetyl-CoA, and con-
version of acetoacetyl-CoA to 3-hydroxy-3-methylglutaryl-
CoA and then to acetoacetate, which is then reduced to
3-hydroxybutyrate. The enzymes involved in ketogenesis are
summarized in Table 66–4. Acetoacetate can be spontane-
ously decarboxylated to acetone, a highly fat-soluble com-
pound that is excreted slowly by the lungs and is responsible
for the fruity odor of the breath of individuals with diabetic
ketoacidosis.
Ketone bodies released into the blood can freely diffuse
across cell membranes and serve as an energy source for extra-
hepatic tissues including the brain, skeletal muscle, and
kidneys. Ketone bodies are filtered and reabsorbed in the kid-
ney. At physiologic pH, ketone bodies, with the exception of
 CHAPTER 66 Endocrine Pancreas 679

Acetyl CoA
carboxylase
Adipocyte Acetyl CoA Malonyl CoA
(FA synthesis)
Tryglycerides
β-oxidation Acetyl CoA
+ HSL
Acetoacetyl CoA
Free fatty acids
HMG CoA
Mitochondria
Acetoacetate

Hepatocyte
H
HO C CH2 O=C–CH3
CH2 CH2
COO- COO-
Acetoacetate
3-β -Hydroxybutyrate
CH3
O=C
CH3
Acetone
FIGURE 66–6 Process of ketogenesis in insulin deficiency. Insulin deficiency and high levels of counterregulatory hormones
glucagon, epinephrine, and cortisol combine to increase the activity of hormone-sensitive lipase, increase the release of free fatty acids, and
decrease the activity of acetyl-coenzyme A (CoA) carboxylase, thereby impairing the reesterification of free fatty acids and promoting fatty
acid conversion into ketone bodies. The excess supply of fatty acetyl-CoA and the deficiency in oxaloacetate increase the oxidation to ketone
bodies, with the resulting release of ketone bodies into the blood. Plus signs (+) denote steps that are favored by insulin deficiency. HSL,
hormone-sensitive lipase; FA, fatty acid; HMG, 3-hydroxy-3-methylglutaryl. (Reproduced with permission from Molina PE: Endocrine Physiology, 3rd ed.
New York: McGraw-Hill Medical, 2010.)

acetone, dissociate completely. The resulting liberation of H+
from ketone body metabolism exceeds the blood’s buffering
capacity, leading to metabolic acidosis with an increased
anion gap. If severe, this condition can lead to coma.
Type 2 Diabetes Mellitus
T2DM is the result of a decreased responsiveness of peripheral
tissues to insulin action (insulin resistance) and inadequate
responsiveness of the β-cells to glucose, which later is followed
by a net reduction in β-cell mass. Patients with type 2 diabetes
secrete normal amounts of insulin during fasting, but
in response to a meal or glucose load, they secrete less insulin
than nondiabetic patients. In addition to a relative reduction
in insulin release, the pattern of insulin release is also altered
following a meal, with pulses that are significantly smaller,
sluggish, and erratic, particularly after dinner. This abnormal-
ity results in significantly higher levels of fasting glucose in
these patients.
Regardless of the etiology (e.g., abnormalities in glucose
transport; abnormal insulin synthesis, processing, storage, or
secretion), the earliest physiologic indication of β-cell dys-
function is a delay in the acute insulin response to glucose.
The defect in the initial response to a glucose load leads to an
excessive rise in plasma glucose, which in turn produces a
compensatory and exaggerated second-phase hyperinsuline-
mic response. This initial period of sustained hyperinsuline-
mia downregulates the insulin receptors, decreasing
the sensitivity of tissues to insulin action and producing a state
of insulin resistance. The main pathologic defects in T2DM
are excessive hepatic glucose production, defective β-cell
secretory function, and peripheral insulin resistance.
INSULIN RESISTANCE
Insulin resistance is the inability of peripheral target tissues to
respond properly to normal circulating concentrations of
insulin. To maintain euglycemia, the pancreas compensates by
secreting increased amounts of insulin. In patients with T2DM,
insulin resistance precedes the onset of the disease by several
years. Compensating for insulin resistance by an increase
in insulin release is effective only temporarily. As insulin
resistance increases, impaired glucose tolerance develops.
Ultimately, failure or exhaustion of the pancreatic β-cell results
in a relative decrease in insulin secretion. The combination of
insulin resistance and impaired β-cell function characterizes
clinical T2DM.
680 SECTION IX Endocrine and Metabolic Physiology
TABLE 66–4 Three principal enzymes involved in
ketogenesis.
Enzyme Tissue Function
Hormone-sensitive Adipocytes Breaks down triglycerides,
lipase releasing fatty acids into the
circulation
Acetyl-CoA Liver Catalyzes the conversion of
carboxylase acetyl-CoA to malonyl-CoA,
the primary substrate of
fatty acid biosynthesis
HMG-CoA synthase Liver Involved in the
conversion of acetyl-CoA
to acetoacetate
CoA, coenzyme A; HMG, 3-hydroxy-3-methylglutaryl.
Exercise has been demonstrated to increase glucose trans-
port in skeletal muscle and to decrease insulin resistance in
patients with T2DM. The increase in glucose transport result-
ing from exercise is insulin-independent and involves the
enzyme AMP-activated protein kinase. AMP-activated pro-
tein kinase has been termed a master metabolic switch because
it phosphorylates key target proteins that control flux through
metabolic pathways. Repeated physical activity improves insu-
lin sensitivity by increasing skeletal muscle expression and/or
activity of key signaling proteins involved in the regulation of
glucose uptake and metabolism, lipid oxidation and/or turn-
over, and oxidative capacity.
CLINICAL CORRELATION
A middle-aged, overweight Hispanic man is referred for
evaluation following detection of an increased fasting
plasma glucose of 150 mg/dL by his primary care physi-
cian. Attempts of lifestyle modifications including exer-
cise and diet to reduce body weight over the past 7 months
have been unsuccessful. In addition, glycosylated hemo-
globin, an estimate of blood glucose control over the last
month, remains elevated at 7%. The diagnosis of T2DM is
established and treatment with oral hypoglycemic drugs
is initiated.
T2DM is the result of deficient insulin action (insulin
resistance) leading to fasting hyperglycemia and the
inability to have an adequate insulin-induced increase in
glucose uptake from plasma after a glucose load. The inci-
dence of T2DM has increased during the past several
decades due to an aging population, increased prevalence
of obesity, and decreased physical activity, among other
factors that include ethnicity, environmental, and genetic
risk factors. Diabetes mellitus is associated increased risk
factor for cardiovascular disease and long-term complica-
tions, including retinopathy, nephropathy, and neuropa-
thy. Treatment aims at the control of blood sugar, and is
monitored by prevailing levels of glycosylated hemoglo-
bin. Treatment can include sulfonylureas that increase
pancreatic insulin secretion, biguanides that decrease
hepatic glucose production, insulin sensitizers (glita-
zones) that attempt to restore insulin sensitivity, and drugs
that can decrease gastrointestinal absorption of glucose.
Finally, insulin injections are often used because pharma-
cological doses of insulin can increase glucose uptake
despite the relative insulin resistance. Newly available
analogs of GLP-1 can also be used to amplify the insulin
response to glucose.
CHAPTER SUMMARY
■ Insulin release is under nutrient, neural, and hormonal
regulation.
■ The pancreatic β-cell functions as a glucose sensor in the
process of insulin release.
■ The PI 3-kinase pathway mediates most of insulin’s metabolic
effects, and the MAPK pathway is mostly involved in mediating
the proliferative responses.
■ The principal metabolic effects of insulin are to increase
glucose utilization in skeletal muscle, suppress hepatic glucose
production, and inhibit lipolysis.
■ Glucagon antagonizes insulin’s effects by stimulating hepatic
glucose release.
■ T1DM results in hyperglycemia because of β-cell destruction
and loss of insulin.
■ T2DM results in hyperglycemia because of tissue resistance
to insulin action and an inadequate β-cell response to
hyperglycemia.
■ A disruption in the balance of insulin and glucagon can lead to
ketogenesis and hyperosmolar coma.
STUDY QUESTIONS
1. In a patient with severe hypoglycemia (38 mg/dL), the
differential diagnosis between self-administered insulin
overdose and a tumor that produces excess insulin can be
made by determining plasma levels of
A) insulin
B) somatostatin
C) C-peptide
D) gastrin
2. Physiologic responses to insulin include
A) stimulation of glucose transport in skeletal muscle,
red blood cells and the brain
B) inhibition of triglyceride synthesis in adipose tissue
C) stimulation of amino acid uptake by skeletal muscle
D) stimulation of glucose reabsorption in the kidney
 CHAPTER 66 Endocrine Pancreas 681

3. A 57-year-old female patient is brought to the emergency room 5. When would plasma insulin levels be expected to be highest?
with a history of frequent urination, weight loss, and decreased A) following a carbohydrate-rich meal
oral intake. At presentation, the patient is lethargic, dehydrated, B) after intravenous administration of somatostatin
hypotensive, and tachycardic. Her caretaker reports that she C) during a surgical procedure
was recovering from a recent bout of pneumonia. She had been D) following vigorous exercise
diagnosed with T2DM five years prior to this incident. Which of
the following laboratory findings is most likely?
A) plasma glucose of 40 mg/dL
B) plasma osmolarity of >350 mOsm/L
C) low blood pH
D) high plasma ketones
4. A 21-year-old male patient with T1DM is brought to the
emergency room for abdominal pain, nausea, and vomiting of
16-hour duration. On examination, you notice that his insulin
pump has stopped functioning. Which of the following is likely
to be associated with his presentation?
A) high plasma insulin levels
B) increased plasma C-peptide levels
C) increased serum ketones
D) increased blood pH
E) decreased hepatic glycogen breakdown
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 67
C H A P T E R

Male Reproductive System

Patricia E. Molina

O B J E C T I V E S

■ Describe the physiologic functions of the principal components of the male

reproductive system.
■ Describe the endocrine regulation of testicular function by gonadotropin-
releasing hormone, follicle-stimulating hormone, luteinizing hormone,
testosterone, and inhibin.
■ Identify the cell of origin for testosterone, its biosynthesis, and transport
within the blood, metabolism, and clearance. List other physiologically
produced androgens.
■ List the target organs or cell types, the cellular mechanism of action, and the
physiologic effects of testosterone.
■ Describe spermatogenesis and the role of different cell types in this process.
■ Understand the neural, vascular, and endocrine factors involved in the
erection and ejaculation response.
■ Compare and contrast the actions of testosterone, dihydrotestosterone,
estradiol, and müllerian inhibitory factor in the process of sexual
differentiation.
■ Identify the causes and consequences of androgen overproduction and
underproduction in prepubertal and postpubescent adult males.

In utero sexual differentiation, maturation, spermatogenesis,
and ultimately reproduction are all functions of the male repro-
ductive system. The two principal functions of the testes, the
male sex organs, are the production of sperm and the synthesis
of testosterone. These processes ensure fertility and maintain
male sexual characteristics. Testicular function is regulated by
the gonadotropins, follicle-stimulating hormone (FSH) and
luteinizing hormone (LH) as well as paracrine, neural, and
other endocrine factors.
FUNCTIONAL ANATOMY
The male reproductive organs include the testes (the principal
male sex organs), the vas deferens, the ejaculatory ducts, the
penis, and the accessory glands, which include the prostate and
bulbourethral glands (Figure 67–1). The testes consist of
numerous lobules made of convoluted tubes (seminiferous
tubules) supported by loose connective tissue. The seminiferous
tubules represent approximately 80–85% of the testicular mass.
The Leydig cells, embedded in the connective tissue, are the
endocrine cells responsible for the production of the most impor-
tant circulating androgen, testosterone, a steroid hormone. The
tubules consist of a basement layer lined with epithelial cells
forming the walls of the seminiferous tubules. These walls are
lined with germ cells (spermatogonia) and Sertoli cells.
Sertoli cells form tight junctions that functionally divide the
seminiferous tubules into two compartments or environments
for the development of spermatozoa. The basal compartment
below the tight junctions has contact with the circulatory sys-
tem and is the space in which spermatogonia develop to pri-
mary spermatocytes. The tight junctions open at specific
times and allow progression of spermatocytes to the adluminal
compartment, where meiosis is completed. In the adluminal

683

Ch67_683-694.indd 683 11/30/10 4:02:03 AM

684 SECTION IX Endocrine and Metabolic Physiology

Vas Ejaculatory Seminal

deferens duct vesicle
Urinary Ureter
bladder

Pubic
bone
Efferent ductules
Epididymis
Seminiferous
tubule
Prostate
gland
Bulbourethral
Epididymis gland
Penis Rete
Urethra Testis testis

Vas
deferens

FIGURE 67–1 Functional anatomy of the male reproductive system. The male reproductive organs include the testes, the vas
deferens, the ejaculatory ducts, the penis, and the accessory glands, which include the prostate and bulbourethral glands. The testes consist of
numerous lobules made of tubuli seminiferi supported by loose connective tissue. The tubuli seminiferi are united to form larger ducts called
the tubuli recti. These larger tubules form a close anastomosing network of tubes called the rete testis, terminating in the ductuli efferentes.
The tubular network carries the seminal fluid from the testis to the epididymis, from where spermatozoa enter the vas deferens and then enter
the urethra through the ejaculatory ducts. The penis is composed of two functional compartments: the paired corpora cavernosa and the
corpus spongiosum. The corpora cavernosa form the greater part of the substance of the penis and consist of bundles of smooth muscle fibers
intertwined to form trabeculae, and containing numerous arteries and nerves. (Modified with permission from Widmaier EP, Raff H, Strang KT [editors]: Vander’s
Human Physiology: The Mechanisms of Body Function, 11th ed. McGraw-Hill, 2007.)

compartment, spermatocytes are protected by a blood–testis

barrier formed by tight junctions between the Sertoli cells. TABLE 67–1 Contribution of the genitourinary
The principal functions of Sertoli cells are as follows: system and accessory organs to sperm production.
• provide support for germ cells, forming an environment in Organ Function
which they develop and mature;
Genitourinary system
• provide the signals that initiate spermatogenesis and sustain
spermatid development; Efferent ductules, vas deferens, Movement of spermatozoa
ejaculatory duct, urethra Fluid reabsorption
• modulate pituitary gland function and, in turn, control of
spermatogenesis. Epididymis H+ secretion and acidification of
luminal fluid
The seminiferous tubules are united to form larger ducts that Capacitation of spermatozoa;
form a close anastomosing network of tubes (Figure 67–1). This glycoconjugation
tubular network carries the seminal fluid containing sperm Reservoir for mature
spermatozoa
from the testis to the epididymis; from here, spermatozoa enter Phagocytosis of aging
the vas deferens and then the ejaculatory ducts. The ejacula- spermatozoa
tory ducts move semen (sperm-containing fluid) into the ure- Accessory glands
thra. In addition to serving as a route of transport, the tubular
network or excretory system and the accessory organs play Seminal vesicle Secretion and storage of
fructose-rich product (preferred
important roles in the production of sperm-containing semen energy substrate for sperm),
through absorptive and secretory processes. As summarized in prostaglandins, ascorbic acid,
Table 67–1, these absorptive and secretory processes contribute fibrinogen- and thrombin-like
to the final composition of sperm-containing semen. Sperm proteins
account for approximately 10% of the volume of the ejaculated Prostate Secretion and storage of fluid
semen that is composed of testicular and epididymal fluid rich in acid phosphatase and
protease (prostate-specific
together with the secretory products of male accessory glands. antigen)
Most of the volume of the ejaculate is formed by the seminal
vesicles with the remainder consisting of epididymal fluids and Cowper’s glands Secretion of mucus into the
urethra on arousal
secretions from the prostate gland and bulbourethral glands.
 CHAPTER 67 Male Reproductive System 685

The penis is composed of two functional compartments: the N

paired corpora cavernosa and the corpus spongiosum. The LH & FSH
corpora cavernosa form the greater part of the substance of
the penis and consist of bundles of smooth muscle fibers inter-
α
twined in a collagenous extracellular matrix. Interspersed GDP
β γ β γ
within this parenchyma is a complex network of endothelial C
cell–lined sinuses, arteries, and nerve terminals. The penis is
innervated by somatic and autonomic (both sympathetic and αi
parasympathetic) nerve fibers. The somatic innervation sup- GTP
plies the penis with sensory fibers and supplies the perineal
skeletal muscles with motor fibers. Autonomic nerves mediate
vascular dilation leading to penile erection, stimulate prostatic Adenylate cyclase Increase in translation
secretions, and control smooth muscle contraction of the vas of mRNAs for proteins
deferens during ejaculation. involved in cell growth and
differentiation, androgen
cAMP binding protein synthesis
(Sertoli cells), and
GONADOTROPIN REGULATION testosterone synthesis
(Leydig cells)
OF GONADAL FUNCTION PKA

The primary functions of the Leydig and Sertoli cells are to Gene expression
Protein regulation
produce the hormones involved in the regulation of reproduc- P
phosphorylation P
tive function and virilization and to produce spermatozoa.
These functions are regulated by the pituitary gonadotropins
Transcription Nucleus
FSH and LH. factors
The gonadotropins produce their physiologic responses by
binding to cell membrane G protein–coupled receptors
located in the Leydig and Sertoli cells (Figure 67–2). LH is the
principal regulator of testosterone production by the Leydig
cells. FSH plays an important role in the development of the Leydig & Sertoli Cells
immature testis, particularly by controlling Sertoli cell prolif-
eration and seminiferous tube growth. Because the tubules FIGURE 67–2 Receptor-mediated effects of gonadotropins
account for about 80% of the volume of the testis, FSH is of at target tissues. Model of signal transductional pathways of the
major importance in determining testicular size. FSH is gonadotropin receptor. On binding of FSH to the FSH receptor, the
Gαs subunit dissociates. Together with GTP, this complex directly
important in the initiation of spermatogenesis during puberty,
activates adenylyl cyclase, thereby leading to cAMP synthesis. cAMP
and is necessary for the production of androgen-binding activates protein kinase A (PKA), producing the dissociation of the
protein (ABP) by Sertoli cells and for the development of the catalytic subunit from the regulatory subunit. The active catalytic site
blood–testis barrier. of PKA can activate proteins by phosphorylation, and in the nucleus it
can phosphorylate transcription factors and affect gene transcription.

CONTROL OF GONADOTROPIN
SYNTHESIS AND RELEASE
FSH and LH are glycoproteins consisting of a common
α-subunit, required for receptor binding, and a unique
β-subunit, which confers their biologic specificity. The synthe-
sis and release of the gonadotropins are regulated by the pulsa-
tile release of gonadotropin-releasing hormone (GnRH)
from the hypothalamus, as well as by circulating hormones or
their metabolites, as illustrated in Figure 67–3.
LH stimulates testosterone production by the Leydig cell.
Testosterone released into the circulation inhibits LH release
in a negative feedback loop. The negative feedback inhibition
of FSH release is mediated mainly by inhibin, a Sertoli cell–
derived peptide.
In addition to the negative feedback inhibition produced by
gonadal androgens, inhibin and activin contribute to the reg-
As a result, LH and FSH mediate several biologic responses at their
target cells. LH is the principal regulator of testosterone production
by the Leydig cells. FSH plays an important role in the development
of the immature testis, particularly by controlling Sertoli cell
proliferation and seminiferous tube growth. (Modified with permission
from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)
ulation of gonadotropin release. Inhibins are heterodimer
glycoproteins consisting of an α- and a β-subunit (βA or βB).
Inhibin B is the physiologically important form in males.
Inhibin is produced and released from the Sertoli cells in
response to FSH stimulation, and its main function is to sup-
press FSH release in a classic negative feedback loop. Inhibin
secretion appears to be dependent on Sertoli cell prolifera-
tion, maintenance, and spermatogenesis, all of these func-
tions regulated by FSH. Inhibin B levels correlate with total
sperm count and testicular volume and can be used as an
686 SECTION IX Endocrine and Metabolic Physiology
FIGURE 67–3 Negative feedback regulation of
gonadotropin synthesis and release. Gonadotropin
release from the anterior pituitary gland is under
control by hypothalamic GnRH release. LH stimulates
Leydig cell production and release of testosterone. FSH
stimulates inhibin production and release from the
Sertoli cells. These two mediators regulate LH and FSH
release. The negative feedback inhibition of LH release
exerted by testosterone is mediated directly (through
androgen receptors) and indirectly (by local aromatase
conversion of testosterone to 17β-estradiol). Inhibin
produces negative feedback inhibition of FSH release.
(Modified with permission from Molina PE: Endocrine Physiology,
3rd ed. New York: McGraw-Hill Medical, 2010.)
index of spermatogenesis. Activins belong to the same family
of peptides as the inhibins and are homodimers or heterodi-
mers of the β-subunit of the inhibins. The peptide and their
receptor are expressed in a wide variety of tissues. Activin
facilitates GnRH-mediated FSH release from the anterior
pituitary.
GONADAL FUNCTION
The three principal hormones produced by the testis are tes-
tosterone, estradiol, and inhibin. Testosterone, a steroid hor-
mone produced by the Leydig cells, is the principal and most
important testicular and circulating androgen. Most of the
testosterone released into the circulation is bound to plasma
proteins, primarily sex hormone–binding globulin (SHBG)
and albumin. In the testes, testosterone is bound to androgen-
binding protein, a protein with great similarity to SHBG and a
product of the same gene. At its target cells, testosterone can
Hypothalamus
GnRH
Pituitary gland
LH
FSH
LH FSH
Negative
feedback
Negative
feedback
Sertoli cell
Inhibin
Leydig cell
Testosterone
Blood vessels
Testes
either have a direct androgen receptor–mediated effect or be
metabolized to either 17β-estradiol through the action of aro-
matase or to 5α-dihydrotestosterone (DHT) through the
action of 5α-reductase (Figure 67–4).
Aromatase is expressed in the Sertoli cells as well as in
extragonadal tissues. 17β-Estradiol produced by the testis
accounts for approximately 20% of the total circulating
estrogens in males. The majority of estradiol in males is
produced in adipose tissue through the aromatization of tes-
tosterone and, to a smaller extent, of adrenal-derived andros-
tenedione. Although some of the 17β-estradiol produced in
peripheral tissues is released into the circulation, not all
estrogens produced from testosterone are involved in medi-
ating endocrine responses. Some are involved in intracrine
regulation of physiologic responses through estrogen recep-
tor stimulation (Figure 67–4). An example is testosterone-
induced negative feedback regulation of FSH release from
the anterior pituitary, which is mostly mediated by aromati-
zation of testosterone to estrogen. Another important exam-

Estradiol Testosterone
DHEAS
Aromatase 5α-
Sulfatase Reductase
DHEA DHT
Estradiol
AR
3β-OHD AR
4A ER
17β-OHD
Testosterone
AR AR
Erβ/ERα
AR
transcription
Testosterone target cells
FIGURE 67–4 Receptor-mediated effects of testosterone
at target tissues. Testosterone (a steroid hormone) enters the cell
by passive diffusion. It can be converted to dihydrotestosterone
(DHT) by 5α-reductase and bind to the androgen receptor (AR), or
it can be converted to 17β-estradiol by aromatase. 17β-Estradiol
can be released to act on a neighboring cell’s estrogen receptors
(ER) (paracrine mechanism); it can enter the circulation (endocrine
effects) or it can bind to either the estrogen receptor α or β
and subsequently bind to the nucleus and affect transcription.
Intracellular testosterone can arise from androstenedione
(Δ4A), DHEA, or DHEAS. The desulfated DHEA is converted to
androstenedione by 3β-hydroxysteroid dehydrogenase (3β-OHD)
and androstenedione transformed into testosterone by
17β-hydroxysteroid dehydrogenase (17β-OHD). Testosterone,
DHT, and estradiol all bind to cytosolic steroid receptors. The
cytosolic androgen (and estrogen) receptor is complexed to
regulatory proteins (heat shock proteins). Hormone binding results
in the dissociation of the heat shock protein complex, dimerization
of the receptor, nuclear translocation, and DNA binding to
regulatory elements. The final result is the activation of gene
transcription. (Modified with permission from Molina PE: Endocrine Physiology,
3rd ed. New York: McGraw-Hill Medical, 2010.)
ple is the effect of testosterone on bones, where epiphysial
closure is mediated through osteoblast and chondroblast aro-
matase conversion of testosterone to estradiol. The conver-
sion of testosterone to DHT by 5α-reductase produces the
most potent natural androgen (Figure 67–4). Because andro-
gens stimulate the growth of prostate cancer cells and are also
involved in benign prostatic hyperplasia, the inhibition of
enzymatic conversion of testosterone to DHT has been used
effectively as a target for pharmacologic interventions. Finas-
teride and dutasteride, 5α-reductase inhibitors, are cur-
rently used for the treatment of benign prostatic hyperplasia
and prostate cancer.
Testosterone, dehydroepiandrosterone (DHEA), and
androstenedione are degraded primarily by the liver.
Biotransformation involves reduction to 17-ketosteroids con-
jugated (glucuronidation) prior to excretion (Figure 67–5).
CHAPTER 67 Male Reproductive System 687
PHYSIOLOGIC EFFECTS OF
ANDROGENS AT TARGET ORGANS
Testosterone and DHT affect sexual development, matura-
tion, and function, and contribute to the maintenance of fertil-
ity and secondary sexual characteristics in the adult male. In
addition, they exert anabolic effects in muscle and bone. Both
testosterone and DHT bind to the same androgen (nuclear)
receptor, on target cells (see Figure 67–4). DHT is the most
potent activator of the androgen receptor. However, distinct
physiologic responses can be attributed to each hormone
(Table 67–2), in part determined by the local conversion of
testosterone to DHT by 5α-reductase.
SEXUAL DEVELOPMENT
AND DIFFERENTIATION
Sexual differentiation in humans is genetically and hormonally
controlled (Figure 67–6). Genes on the Y chromosome signal
primordial cells in the embryonic gonad ridge to differentiate
into Sertoli cells and stimulate newly migrated germ cells to
differentiate as spermatogonia, developing into a testis. The
cells of the embryonic testis secrete hormones that lead to
the development of male secondary sexual characteristics. The
Sertoli cells secrete müllerian inhibitory factor or substance
(MIF or MIS) causing regression of the müllerian ducts.
The Leydig cells secrete testosterone causing differentiation
and growth of the Wolffian duct structures. DHT causes
growth of the prostate and penis and fusion of the labioscrotal
folds (Figure 67–6).
The key events involved in fetal development and sexual dif-
ferentiation can be summarized as follows.
Sex Determination
Mammalian sex determination leading to the development of
male or female phenotype involves three sequential processes:
• determination of the genetic sex of the embryo when an
X- or a Y-bearing sperm fertilizes the oocyte;
• determination of the fate of the bipotential or nondifferenti-
ated gonad and thus of gonadal sex;
• differentiation of male or female internal and external geni-
talia, or determination of phenotypic sex.
The determination of genetic sex is mediated through the
chromosomal set, which in the normal male is 46,XY. The sub-
sequent sexual differentiation is determined by genetic factors.
One of the first genes involved in sexual differentiation is
on the Y chromosome and is called SRY (sex-regulating
region of the Y). The product of the SRY gene is a protein that
stimulates the neutral gonadal tissues to differentiate into tes-
tes, thereby determining gonadal sex. SRY is necessary and
sufficient to initiate the male development cascade. If the SRY
gene is mutated or missing on the Y chromosome, the embryo
develops into a female.
688 SECTION IX Endocrine and Metabolic Physiology

LH

Mitochondria Cholesterol

StAR

Pregnenolone
P450 scc 3β-Hydroxysteroid dehydrogenase
Progesterone
17α-Hydroxylase
• Estrone
Androstenedione
• Epiandrosterone,
17β-HSD Androsterone,
Etiocholanolone
Testosterone

OH

FIGURE 67–5 Key steps in testosterone

biosynthesis and metabolism. Diagrammatic
representation of the typical biochemical 5α-Reductase
O OH
pathway and key enzymes involved in Leydig cell
steroidogenesis that facilitate the biosynthesis of Testosterone
testosterone from the precursor cholesterol. 3α-Hydroxysteroid
Testosterone finally diffuses out of the Leydig cell dehydrogenase
3α-Androstenediol
and reaches the interstitial space and the O
H (weak androgen)
peripheral circulation. In target cells, testosterone
can be converted to the most potent androgen, Dihydrotestosterone (DHT)
dihydrotestosterone (DHT), by 5α-reductase or to
17β-estradiol by aromatase. Testosterone,
dehydroepiandrosterone (DHEA), Aromatase
androstenedione, and 17β-estradiol are
degraded in the liver to 17-ketosteroids or polar
metabolites that are excreted in the urine. StAR, OH
steroidogenic acute regulatory protein; scc,
side-chain cleavage; HSD, hydroxysteroid
Estrone 16-OH-estrone Estriol
dehydrogenase; COMT, catechol-O-
methyltransferase. (Modified with permission from
Molina PE: Endocrine Physiology, 3rd ed. New York:
OH Catecholestrogen 2-Methoxyestrone
17β-Estradiol COMT
McGraw-Hill Medical, 2010.)

Sexual Differentiation gonads have differentiated into testes, the secretion of testicu-
lar hormones is sufficient to promote masculinization of the
Human male gonad differentiation begins in the sixth week of
embryo. The production of testosterone and MIF during a
gestation with the development of precursor Sertoli cells.
critical time in early gestation ensures male development. Ini-
These cells aggregate to form the seminiferous cords, which
tially, both the male (mesonephric or Wolffian) and female
are then infiltrated by primordial germ cells. By the end of the
(paramesonephric or müllerian) internal genital ducts are
ninth week, the mesenchyme that separates the seminiferous
present. In females, the mesonephric ducts regress and the
cords gives rise to the interstitial cells, which differentiate as
paramesonephric ducts develop into the uterine tubes, uterus,
steroid-secreting Leydig cells. Gonadotropic control of fetal
and upper vagina. In males, starting at the eighth week of ges-
testicular steroidogenesis is mediated initially by placenta-
tation, MIF mediates the regression of the paramesonephric
derived human chorionic gonadotropin (hCG) and later by
or müllerian ducts. The mesonephric duct system (Wolffian
fetal LH. The resulting increase in fetal testosterone produc-
ducts) remains and forms the vas deferens, epididymis, and
tion stimulates Leydig cell proliferation, increases the expres-
seminal vesicle. This process is dependent primarily on tes-
sion of steroidogenic enzymes, and increases the expression of
tosterone. In the female, in the absence of androgens, the
the androgen receptor in the target tissues.
Wolffian ducts regress and the müllerian ducts are spared
The postgonadal phase of sexual differentiation or external
from apoptosis, developing into the uterus, fallopian tubes,
genitalia differentiation is hormone dependent. Once the
 CHAPTER 67 Male Reproductive System 689

TABLE 67–2 Specific actions of testosterone, dihydrotestosterone, and estradiol.

Testosterone DHT (5α-Reductase Activity) 17β-Estradiol (Aromatase Activity)

Embryonic development of Wolffian duct–derived structures Embryonic development of the prostate Epiphyseal closure

Postpubertal secretory activity Descent of the testes Prevention of osteoporosis

Pubertal growth of larynx and deepening of voice Phallic growth Feedback regulation of GnRH secretion

Anabolic effects on muscle and erythropoiesis Male pattern balding

Inhibition of breast development Development of pubic and underarm hair

Stimulation of spermatogenesis; libido Activity of sebaceous glands

Feedback inhibition of GnRH, LH, and FSH release

DHT, dihydrotestosterone; GnRH, gonadotropin-releasing hormone. The enzyme activities that metabolize testosterone to DHT or estradiol are in parentheses.

and vagina. Estrogens do not appear to be essential for nor-
mal sexual differentiation of either sex, as shown by normal
genital development in males with a mutant estrogen receptor
gene or with aromatase deficiency. The differentiation of
external male genitalia is regulated particularly through the
actions of DHT.
Following müllerian duct regression and androgen-
dependent virilization of the urogenital system, the testes
migrate from their site of origin next to the kidney into the
scrotum. This is the critical and final event involved in male
sexual differentiation and is completed during the late gesta-
tional period, and is mediated by testosterone and insulin-like
peptide 3. In humans, failure of complete testicular descent
into the scrotum (cryptorchidism) is one of the most common
congenital abnormalities, involving approximately 3% of male
births. Testicular descent into the scrotum is important because
spermatogenesis requires lower temperatures (as in the scro-
tum) than those found intra-abdominally. If untreated, cryp-
torchidism can lead to infertility, and it has been associated
with an increased risk of testicular tumors.

Epididymis,
Wolffian ducts seminal vesicles,
Sex vas deferens
determination Prostate & penis growth
SRY Testosterone Fusion of labioscrotal folds
Urogenital Leydig
ridge Bipotential Testis Insl3
cells Testicular descent
gonad
Sertoli MIF
cells
Uterus, fallopian
Mullerian ducts tubes, cervix,
vagina

Sertoli cell Leydig cell

activity activity

MIF Testosterone Testes descent

Insl3 Male external genital External genital
differentiation growth
Wolffian duct differentiation
Germ cell Mullerian duct
migration regression
4 5 6 7 8 9 10 11 12 13 14 15 40
Gestational period (weeks)

FIGURE 67–6 Male sexual differentiation. The bipotential gonad is differentiated into testes by the sex-determining region gene on the Y
chromosome (SRY). This period of sex determination is followed by gonad differentiation of the different cell types of the testis. The Sertoli cells of
the testis secrete müllerian-inhibiting factor (MIF). The Leydig cells produce testosterone and insulin-like growth factor 3. MIF produces regression
of the müllerian ducts. Testosterone stimulates the growth and differentiation of the Wolffian ducts, and growth of the penis and prostate. Insl3
participates in testicular descent, the final step in male sexual development. DHT produced from testosterone also participates in testis descent
and development of the prostate. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)
690 SECTION IX Endocrine and Metabolic Physiology
Sexual Maturation and Function
Puberty
Puberty is the physiologic transition between childhood and
adulthood and involves the development of fertility, secondary
sexual characteristics and the pubertal growth spurt. The
process takes place over a period of about 4 years. Puberty is
triggered by increased pulsatile secretion of GnRH by the hypo-
thalamus, leading to increases in serum gonadotropins and,
thus, to increases in gonadal secretion of sex steroids. The hypo-
thalamic–pituitary–gonadal system is active during the neona-
tal period but enters a dormant state in the juvenile, prepubertal
period. During the initial phase of puberty, plasma levels of LH
increase primarily during sleep. These sleep-associated surges
are later present throughout the day and mediate or result in an
increase in circulating testosterone levels.
Puberty is preceded by adrenarche, a period characterized by
increased adrenal production of DHEA and androstenedione at
around 6–8 years of age. The peak concentrations of DHEA and
androstenedione are reached during late puberty and early adult-
hood. During this stage, there is some conversion of adrenal-
derived androgens to testosterone, resulting in a small increase in
circulating testosterone levels. The signal that triggers the increase
in the synthesis of DHEA and androstenedione is not known.
The increase in pulsatile release of GnRH from the hypothal-
amus into the hypophysial-portal blood is essential for the onset
of puberty and is thought to be facilitated by leptin, a hormone
secreted from adipose tissue. The increase in the amplitude of
GnRH pulses triggers a cascade of events including increases in
the amplitude of FSH and LH pulses, followed by marked
increases in gonadal sex hormone production. As a result of the
increase in testosterone production during puberty, growth
hormone release is increased. Together, growth hormone and
gonadal steroids are responsible for normal pubertal growth
spurt during which the growth velocity increases from 4–6 cm
per year to as much as 10–15 cm per year. The physiologic
changes associated with puberty are summarized as follows:
• Leydig cell maturation and initiation of spermatogenesis;
• testis enlargement, and reddening and wrinkling of scrotal
skin;
• pubic hair growth from base of the penis;
• penis enlargement;
• prostate, seminal vesicle, and epididymis growth;
• facial (mustache and beard) and extremities hair growth, re-
gression of scalp line;
• larynx enlargement, thickening of the vocal cords, and
deepening of the voice;
• enhanced linear growth;
• increased muscle mass and hematocrit;
• increased libido and sexual potency.
Maturity and senescence
Sexual maturity in males is achieved at approximately age
16–18 years. During this stage, sperm production is optimal,
plasma gonadotropins are normal, and most sexual anatomic
changes have been completed. Beginning at age 40, there is a
gradual decline in circulating testosterone levels, followed at
age 50 by a reduction in sperm production. This period of
gradual androgen decline is called the andropause and is
characterized by diminished sexual desire and erectile capac-
ity, decreased intellectual activity, fatigue, depression,
decreased lean body mass, skin alterations, decreased body
hair, decreased bone mineral density resulting in osteoporosis,
and increased visceral fat and obesity.
FERTILITY AND SECONDARY SEXUAL
CHARACTERISTICS
Spermatogenesis
Spermatogenesis is the process of continuous germ cell dif-
ferentiation to produce spermatozoa (Figure 67–7). Spermato-
genesis is initiated at the time of puberty and is associated with
the transition from a relatively hypogonadotropic state in the
prepubertal phase of development to the eugonadotropic state
in adulthood. It is compartmentalized within the blood–testis
barrier. It is under FSH regulation of the Sertoli cell and
requires testosterone production from the Leydig cells. Sper-
matogenesis involves four basic processes:
• Proliferation of spermatogonia (stem cells) giving rise to
spermatocytes (diploid cells)—Spermatogonia, derived
from primordial germ cells, line the seminiferous tubule near
the basement membrane. One or two divisions of sper-
matogonia occur to maintain their population in a stem cell
pool, some cells stay in the “resting” pool, whereas others
proliferate several times and undergo 1–5 stages of division
and differentiation becoming spermatocytes (Figure 67–7).
The “resting” or stem cell spermatogonia remain dormant
for a time and then join a new proliferation cycle of sper-
matogonia. These cycles of spermatogonial divisions occur
before the previous generation of cells has completed sper-
matogenesis, so that multiple stages of the process are occur-
ring simultaneously in the seminiferous tubules. This overlap
ensures a residual population of spermatogonia that main-
tain the ability of the testis to continuously produce sperm.
• Meiosis of spermatocytes to yield spermatids (haploid
cells; 23 chromosomes): The primary spermatocytes un-
dergo two divisions; the first meiotic division produces two
secondary spermatocytes. Division of the secondary sper-
matocytes completes meiosis and produces the spermatids.
• Spermiogenesis, or maturation and development of sper-
matids into spermatozoa (sperm): This phase is character-
ized by nuclear and cytoplasmic changes that provide
spermatozoa with key elements for their function, including
formation of the acrosome, as summarized in Table 67–3.
• Spermiation: This is the final process of release of mature
sperm from the Sertoli cells into the tubule lumen and in-
volves movement of the germ cells from the basal to the
adluminal region of the seminiferous tubule into the com-
partment protected by the blood–testis barrier. The mitotic
phase occurs in the basal compartment, whereas the meiotic
 CHAPTER 67 Male Reproductive System 691

Head
Tail sheath Nucleus
Spermatogonia Centrioles
Mitosis Mitochondria
Acrosome
Flaggellum
Primary spermatocyte Midpiece

First meiotic Tail

70 days

division
Secondary Spermatozoa
Second spermatocyte
meiotic Lumen of tubule
division
Spermatids

Spermatozoa
Spermatids Residual body

Secondary
Spermatocyte

Primary
Spermatocyte

Spermatogonia

FIGURE 67–7 Schematic representation of key events in spermatogenesis. The process of spermatogenesis involves proliferation
(mitosis) of spermatogonia, producing primary spermatocytes (diploid cells; 46 chromosomes). Spermatocytes undergo two meiotic divisions
to yield spermatids, or haploid cells (23 chromosomes). Spermatids undergo a process of maturation (spermiogenesis) and development into
spermatozoa. During this last phase, spermatozoa acquire the key elements for their function (Table 67–3). This continuous process takes about
70 days. At any given time, cells from all steps of spermatogenesis can be identified in the testes. (Modified with permission from Junqueira LC, Carneiro J:
Basic Histology: Text & Atlas, 11th ed. McGraw-Hill, 2005.)

and postmeiotic phases occur in the luminal compartment.
The overall results of spermatogenesis are the following: cell
proliferation and maintenance of a reserve germ cell popu-
lation, reduction in chromosome number and genetic varia-
tion through meiosis, and production of spermatozoa.
The complete maturation of sperm and the development of
its capacity to fertilize the ovum are a function of additional
processes occurring after sperm is released from the Sertoli
cells. These processes are a function of the accessory glands and

Regulation of Spermatogenesis TABLE 67–3 Key events in spermiogenesis and their

Spermatogenesis is dependent on gonadotropin stimulation functional importance in sperm function.
and testosterone production. FSH stimulates proliferation
Key Event Functional Importance
and secretory activity of the Sertoli cells, whereas LH stimu-
lates the production of testosterone. Testosterone in turn is a Nuclear chromatin condensation Haploid chromatin carries either
paracrine stimulator of spermatogenesis through receptor- X or Y chromosome
mediated events in the Sertoli cells. The LH-induced increase Acrosome development The acrosome is a large secretory
in intratesticular testosterone plays an essential role in the vesicle that overlies the nucleus
in the apical region of the sperm
initiation and maintenance of spermatogenesis by the Sertoli head and contains enzymes
cells. Androgens produced by the Leydig cells bind to needed for mucus penetration
androgen-binding globulin (ABG), a protein produced by and fertilization
the Sertoli cell in response to FSH stimulation and secreted Repositioning of spermatids; Microtubular structure provides
into the lumen of the seminiferous tubules. Testosterone is development and growth of motility, allowing sperm
produced by Leydig cells, which are interstitial cells that flagellum movement (3 mm/min) through
reside adjacent to the seminiferous tubules. Sertoli cells the genital tract
require the presence of testosterone for spermatogenesis, Formation of mitochondrial Provides energy (fructose-derived
underscoring the importance of paracrine mechanisms of sheath around flagellum ATP) for flagellar movement
hormone action. ATP, adenosine triphosphate.
692 SECTION IX Endocrine and Metabolic Physiology
the excretory system, summarized in Table 67–1. The develop-
ment and function of these organs are androgen dependent.
ANABOLIC AND METABOLIC
EFFECTS OF ANDROGENS
In bone, the main physiologic effect of testosterone is to reduce
bone resorption. This action is mediated both by direct effects
of testosterone on the androgen receptor and by localized aro-
matization of testosterone to estrogen. Testosterone increases
osteoblast lifespan and proliferation. Testosterone-derived
estrogen is the critical sex hormone in the pubertal growth
spurt, skeletal maturation, accrual of peak bone mass, and
maintenance of bone mass in the adult. It stimulates chondro-
genesis in the epiphysial growth plate, increasing pubertal linear
growth. At puberty, estrogen promotes the gradual, progressive
closure of the epiphysial growth plate and the termination of
chondrogenesis. In the adult, estrogen is important in main-
taining the constancy of bone mass through its effects on
remodeling and bone turnover. Testosterone decreases osteo-
blast and osteoclast apoptosis; stimulates osteoblast prolifera-
tion, enhancing bone formation; and increases periosteal
apposition of bone. It increases protein synthesis and decreases
protein breakdown, having an overall anabolic effect in muscle.
Testosterone inhibits lipid uptake and lipoprotein lipase
activity in adipocytes, stimulates lipolysis by increasing the
number of lipolytic β-adrenergic receptors, and inhibits dif-
ferentiation of adipocyte precursor cells. DHEA stimulates
resting metabolic rate and lipid oxidation and enhances glu-
cose disposal by increasing the expression of glucose trans-
porters on the plasma membrane of adipocytes.
NEUROENDOCRINE AND
VASCULAR CONTROL OF
ERECTION AND EJACULATION
The physiologic process of human reproduction involves the
fertilization of a mature ovum through the deposition of
sperm-containing semen in the vagina of the female. This
event involves penile erection and ejaculation of the sperm-
containing semen at the time of copulation. Penile erection
results from smooth muscle relaxation mediated by a spinal
reflex involving central nervous processing and integration of
tactile, olfactory, auditory, and mental stimuli. Corporeal
vasodilatation and corporeal smooth muscle relaxation allow
increased blood flow into the corpus cavernosum. Corporeal
vasodilatation is mediated by the parasympathetic nervous
system. The concordant contraction of the perineal skeletal
muscles leads to a temporary increase in corpus cavernosum
blood pressure above mean systolic arterial pressure, helping
to increase penile firmness.
Parasympathetic fibers directly innervating the corporeal
smooth muscle and sinusoidal endothelial cells release acetyl-
choline, stimulating the production of constitutive endothelial
nitric oxide. Nitric oxide produced locally in the smooth mus-
cle cell, or reaching it by diffusion from the adjacent endothe-
lial cells, is the major mediator of smooth muscle relaxation
through activation of guanylate cyclase and increased
production of cyclic guanosine monophosphate (cGMP). The
inhibition of cGMP phosphodiesterase (PDE5), the enzyme
that degrades cGMP, with drugs such as sildenafil preserves
smooth muscle relaxation and prolongs the erection period.
This is used commercially to treat erectile dysfunction.
The ejaculation phase of the sexual response consists of two
sequential processes: emission and ejaculation. Emission is
the deposition of seminal fluid into the posterior urethra and is
mediated by simultaneous contractions of the ampulla of the
vas deferens, the seminal vesicles, and the smooth muscles of
the prostate. The second process is ejaculation, which results in
expulsion of the seminal fluid from the posterior urethra
through the penile meatus. This process is controlled by sym-
pathetic innervation of the genital organs and occurs as a result
of a spinal cord reflex arc. Detumescence of the penis following
ejaculation, and maintenance of the flaccid penis in the absence
of sexual arousal, is produced by sympathetic corporeal vaso-
constriction and corporeal smooth muscle contraction by
noradrenergic, neuropeptide Y, and endothelin-1 fibers.
DISEASES OF TESTOSTERONE
EXCESS OR DEFICIENCY
Excess androgen activity in childhood leads to precocious
puberty, defined in boys as the appearance of male secondary
sex characteristics before age 9 (Table 67–2). Hypothalamic
tumors, activating mutations of the LH receptor, congenital
adrenal hyperplasia, and androgen-producing tumors are all
causes of premature virilization. Decreased testosterone pro-
duction, or hypogonadism, can be caused by disorders at the
hypothalamic/pituitary level (hypogonadotropic or secondary
hypogonadism) or by testicular dysfunction (hypergonadotro-
pic or primary hypogonadism).
Hypogonadotropic hypogonadism can be due to abnormali-
ties in hypothalamic GnRH secretion or impaired gonadotro-
pin secretion by the anterior pituitary. This condition may result
from genetic defects including Kallmann syndrome; abnormal-
ities of the GnRH receptor, LH, or FSH β-subunits; pituitary
tumors (including prolactinomas); trauma; or surgery.
Abnormal testicular function in the presence of elevated
gonadotropin levels (hypergonadotropic or primary hypogo-
nadism) is caused by testicular damage or impaired testicular
development, which can be either congenital or acquired follow-
ing chemotherapy or radiation. Causes include cryptorchidism,
gonadal dysgenesis, varicocele, enzyme defects in testosterone
biosynthesis, or LH receptor defects. Klinefelter syndrome is a
sex chromosome disorder, in which affected males carry an
additional X chromosome. This genetic abnormality results in
male hypogonadism, androgen deficiency, and impaired sper-

matogenesis. Klinefelter’s syndrome is the most common genetic
cause of human male infertility. Hyperprolactinemia from any
cause results in both reproductive and sexual dysfunction
because of prolactin inhibition of GnRH, FSH, and LH release,
resulting in hypogonadotropic hypogonadism.
CLINICAL PRESENTATION
Excess testosterone in the prepubescent male is associated
with the appearance of all the changes of puberty at a very
early age. These changes include enlargement of the penis and
testicles; appearance of pubic, underarm, and facial hair; spon-
taneous erections; production of sperm; development of acne;
and deepening of the voice.
Low levels of testosterone lead to symptoms, which differ
according to the time of onset. Androgen deficiency during
puberty results in lack of pubertal growth spurt, lack of deepen-
ing of the voice, female distribution of secondary hair, anemia,
underdeveloped muscles, and genitalia with delayed or absent
onset of spermatogenesis and sexual function. Hypogonadism,
as well as aromatase deficiency and the inability to synthesize
estradiol, result in lack of epiphyseal closure and continued
growth. Androgen deficiency in the adult after normal viriliza-
tion has been completed leads to a decrease in bone mineral
density (bone mass), decreased bone marrow activity resulting
in anemia, alterations in body composition associated with
muscle weakness and atrophy, changes in mood and cognitive
function, and regression of sexual function and spermatogen-
esis. In the adult male, androgen deficiency decreases noctur-
nal erections and libido.
CLINICAL CORRELATION
A 33-year-old father of two healthy children and his wife
are referred for evaluation more than a year after failure to
conceive despite being sexually active and not taking any
contraceptive measures. On physical examination, the
husband’s external genitalia are normal, but testes are
smaller and softer than normal for his age. He is very mus-
cular and admits to being a body builder. Blood labora-
tory values show low testosterone levels, low LH and FSH,
and normal prolactin levels. Semen analysis shows low
sperm count (oligospermia). A diagnosis of anabolic ste-
roid-induced hypogonadotropic hypogonadism is made.
Anabolic steroids are androgen hormone analogs that
produce negative feedback inhibition of LH and FSH release.
This in turn decreases testicular testosterone production
and spermatogenesis. Some anabolic steroids that are
abused by athletes are not aromatizable so that they are not
converted to estrogen and are different enough from native
testosterone to not be detected in the standard testosterone
assays. Cessation of anabolic hormone utilization restores
hypothalamic–gonadal function in most of the cases.
CHAPTER 67 Male Reproductive System 693
CHAPTER SUMMARY
■ The Sertoli cells support spermatogenesis and form the
blood–testis barrier.
■ Testicular function is under LH and FSH regulation.
■ LH and FSH production and release are under hypothalamic
GnRH stimulation and feedback inhibition by gonadal hormones.
■ The main functions of the testes are testosterone production
and spermatogenesis.
■ The main hormones produced by the testis are testosterone,
estradiol, and inhibin.
■ Testosterone can be metabolized to DHT, a more potent
androgen, or to 17β-estradiol, an estrogen.
■ Androgens exert their physiologic effects through modulation
of gene transcription.
■ Three essential testis-derived hormones regulate male sexual
development: androgens, MIF, and insulin-like peptide 3.
STUDY QUESTIONS
1. A 20-year-old male patient presents to the doctor’s office
complaining about continuous growth, lack of facial hair
development, and a smaller penis and testicles than his college
friends. Laboratory values include low total testosterone and
low LH. Thyroid-stimulating hormone and prolactin levels are
normal. He has no history of medications, drug use, or disease.
Continued growth in this case is due to
A) increased estrogen production
B) decreased inhibin release
C) decreased testosterone production
D) decreased sensitivity to LH stimulation
2. In the patient described above, it was observed that in addition
to being much taller than young adults his age, his arms were
very long. The excessive height and arm length resulting from
delayed epiphyseal growth plate closure is due to
A) increased DHT formation
B) decreased adrenal DHEA production
C) decreased estradiol production
D) increased estriol production
3. A college football player purchases online natural hormone
analogs to increase his muscle mass. After a year of hormone
analog injections, his muscle mass increases significantly, and
he develops acne. Consultation with the team’s physician leads
to a complete physical exam that reveals small testicular size.
Being a newlywed, he wants to determine his fertility status and
test results show low sperm count. Which of the following is the
underlying mechanism for these manifestations?
A) increased conversion of DHT to testosterone.
B) suppression of LH release from the pituitary
C) increased testicular testosterone concentrations
D) increasing aromatase activity
4. A 15-year-old male, underweight, high school student is brought to
the family physician due to what appears to be a delay in the onset
of puberty. The most likely mechanism underlying this defect is
A) decreased aromatase activity
B) increased DHT production
C) decreased leptin production
D) increased testosterone production
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 68
C H A P T E R

Female Reproductive
System
Patricia E. Molina

O B J E C T I V E S

■ Describe oogenesis, its relationship to follicular maturation, and the roles of

pituitary and ovarian factors in their regulation.
■ Describe the roles of pituitary hormones in regulation of ovarian function
including ovulation, formation and decline of the corpus luteum, and
estrogen and progesterone biosynthesis and secretion.
■ List the target organs and principal physiologic actions of estrogen and
progesterone and how they interact.
■ Identify the transport mechanisms and degradation pathways for estrogen
and progesterone.
■ Describe the cellular mechanisms of action for estrogen and progesterone.
■ Describe the endometrial changes (proliferative and secretory phases) that
occur throughout the menstrual cycle, and correlate them with the changes
in blood levels of pituitary and ovarian hormones.
■ Identify the pathways of sperm and egg transport required for fertilization
and for movement of the embryo to the uterus.
■ Describe the endocrine functions of the placenta, particularly the role of
placental hormones in rescue of the corpus luteum and maintenance of
pregnancy, and the fetal adrenal–placental interactions involved in estrogen
production.
■ Understand the roles of oxytocin, relaxin, and prostaglandins in the initiation
and maintenance of parturition.
■ Explain the hormonal regulation of mammary gland development during
puberty, pregnancy, and lactation, and explain the mechanisms that control
milk production and secretion.
■ Explain the physiologic basis for the effects of steroid hormone contraceptive
methods.
■ Describe the age-related changes in the female reproductive system,
including the mechanisms responsible for these changes, throughout life
from fetal development to senescence.

The principal functions of the female reproductive system are
to produce the ova for fertilization by sperm, and to provide
the appropriate conditions for embryo implantation, fetal
growth and development, and birth. Endocrine regulation of
the reproductive system is directed by the hypothalamic–
pituitary–ovarian axis. The ovarian cycle, which involves
changing patterns of hormone production and secretion,
regulates the hypothalamic–pituitary–gonadal axis in a
classical negative feedback pattern. In addition, the ovarian
cycle mediates the maturation and development of the repro-
ductive system throughout life. Throughout the cycle, a
selected ovarian follicle is rescued from its apoptotic fate to
undergo growth and development, culminating in ovulation.
The remnant of the follicle undergoes transformation into the

695

Ch68_695-714.indd 695 11/30/10 4:06:12 AM

696 SECTION IX Endocrine and Metabolic Physiology

corpus luteum, a temporary endocrine structure that plays a
central role in preparation for, and maintenance of the initial
stages of pregnancy. Parallel changes in endometrial morphol-
ogy and function (the menstrual cycle) occur throughout the
ovarian cycle in preparation for implantation of a fertilized
ovum. Ovarian and placental hormones maintain pregnancy
and prepare the breast for lactation.
FUNCTIONAL ANATOMY
The female reproductive organs include the ovaries, the uterus
and fallopian tubes, and the breasts or mammary glands
(Figure 68–1). Their growth, development, and function are
under hormonal regulation. The ovaries are the principal
female reproductive organs, and their functions are the stor-
age and release of the ovum and the production of the two
principal female sex steroid hormones, estrogen and proges-
terone. The ovaries consist of an outer cortex layer that
contains different-sized follicles and their apoptotic remnants
embedded in connective tissue and an inner medulla
containing vascular connective tissue. The primordial follicle
contains a primary oocyte surrounded by epithelial pregranu-
losa cells separated from the ovarian stroma by a basement
membrane. During follicular development, the epithelial cells
differentiate into granulosa cells, and a layer of cells from the
ovarian stroma is transformed into theca cells. The larger,
more mature follicles are filled with a transparent fluid and

A
Ampulla Fallopian
isthmus tube
Infundibulum Fundus of uterus
Fimbriae

Oviduct

Fimbriae
FIGURE 68–1. Functional anatomy of the Ovary
female reproductive tract. A) The female Ovarian ligament
reproductive organs include the ovaries, the Broad ligament Ovary
uterus and Fallopian tubes, and the breasts or Uterus
Perimetrium
mammary glands. The ovaries consist of an outer Layers of Myometrium Cervical canal
cortex layer that contains different-sized follicles uterus Endometrium
Vagina
and their remains undergoing apoptosis,
imbedded in connective tissue. The Fallopian tubes B
extend from each of the superior angles of the Primary
Mesovarium follicle Early antrum
uterus and consist of an isthmus, ampulla, and the Stroma formation
Primordial
infundibulum, which opens into the abdominal follicle Atretic
cavity and is surrounded by ovarian fimbria and follicle
attached to the ovary. The cilia of the epithelial
Graafian
lining of the Fallopian tubes contribute to the follicle
orientation of sperm movement, aiding in Blood
fertilization as well as facilitating the movement vessels
of the zygote (fertilized ovum) to the uterus for Corpus
implantation and fetal development. B) The albicans
ovary contains oocytes at different stages of Ovulation
development. Following ovulation, the follicle is Germinal
converted to the corpus luteum that contributes epithelium Ovary
to hormone production during the early pregnancy
period. C) The breast is organized in lobes made Mature corpus Early corpus
luteum Ductules or acini
of lobules, connected together by connective luteum Terminal duct
Terminal duct
lobular unit Lobule
tissue, blood vessels, and ducts. The lobules consist
of a cluster of rounded alveoli, which open into C
excretory lactiferous ducts and unite to form Breast Adipose tissue
larger ducts made of longitudinal and transverse Segmental duct
elastic fibers. These ducts converge toward the
Lactiferous duct
areola, beneath which they form ampular
Lactiferous sinus
dilatations, which serve as reservoirs for the milk.
Nipple
(A. Modified with permission from Molina PE: Endocrine
Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010. Fat
B. Modified with permission from Curtis O Byer, Louis W Lobule Alveoli
Shainberg, Grace Galliano, Louis Shainberg. Dimensions in unraveled Lactiferous Fat
Human Sexuality. 6th ed. McGraw-Hill; 2001. C. Modified Lobules Ampulla tubule
Duct
with permission from Gray H. Anatomy of the Human Body.
20th ed; 1918.)

consist of an external fibrovascular coat, connected with the
surrounding stroma of the ovary by a network of blood vessels;
and an internal coat, consisting of several layers of nucleated
cells (granulosa cells) anchored in the zona pellucida, a
glycoprotein-rich eosinophilic material surrounding the
oocyte. The zona pellucida forms the corona radiata, which,
close to the time of ovulation, is separated from the granulosa
cells and expelled with the oocyte. Formation of the follicles
begins before birth, and their development and maturation
continue uninterrupted from puberty to the end of a woman’s
reproductive life, as discussed later.
The female genital tract is derived from the müllerian ducts
and consists of the uterus, fallopian tubes, and vagina. The
fallopian tubes extend from each of the superior angles of the
uterus and consist of the isthmus, the ampulla, and
the infundibulum, which opens into the abdominal cavity and
is surrounded by ovarian fimbriae and attached to the ovary
(Figure 68–1). The epithelial lining of the fallopian tubes has
secretory and ciliated cells that contribute to sperm movement,
aiding in fertilization and facilitating the movement of the
zygote (fertilized ovum) to the uterus for implantation and
fetal development. These functions are also aided by the
rhythmic contraction of the smooth muscle walls.
The uterus is composed of a thick muscular coat and a
mucous membrane, or endometrium, lined by columnar
ciliated secretory epithelium. The endometrium undergoes
cycles of regeneration (proliferative phase), differentiation
(secretory phase), and shedding (menstrual phase)
approximately every 28 days in preparation for embryo
implantation.
The breast consists of glandular tissue organized in lobes
connected by fibrous tissue, with fat deposits interspersed
between the lobes (Figure 68–1). The lobules open into excre-
tory lactiferous ducts and unite to form larger ducts that con-
verge toward the areola, beneath which they form ampullar
dilatations, which serve as reservoirs for the milk.
GONADOTROPIN REGULATION
OF OVARIAN FUNCTION
Pulsatile release of gonadotropin-releasing hormone (GnRH)
from the hypothalamus stimulates pulsatile pituitary release of
luteinizing hormone (LH) and follicle-stimulating hormone
(FSH). Both FSH and LH stimulate ovarian production of
estradiol and progesterone through binding to a transmem-
brane G protein–coupled receptor. Estradiol and progester-
one are the two principal ovarian steroid hormones involved
in the regulation of ovarian function and control of the repro-
ductive cycle. The variations in pulsatile release of the gonado-
tropins result in a cyclic response of ovarian function. Each
cycle lasts approximately 28 days and can be divided into two
phases (follicular and luteal) of approximately 14 days each:
• Follicular phase: FSH is responsible for follicular recruit-
ment and growth and for estrogen synthesis during the
CHAPTER 68 Female Reproductive System 697
follicular phase of the ovarian cycle.
• Luteal phase: The peak in LH immediately precedes ovula-
tion and corpus luteum formation. The rise in LH results in
progesterone and estrogen production by the corpus luteum
during the early and midluteal phases of the menstrual
cycle. Activation of the LH receptors in theca cells stimu-
lates androstenedione production, providing the substrate
for the enzymatic conversion to 17β-estradiol that is medi-
ated by the enzyme aromatase in granulosa cells.
OVARIAN HORMONE SYNTHESIS
ESTROGEN
The production of estrogen involves coordinated enzymatic
activities between the theca and granulosa cells of the ovar-
ian follicle (Figure 68–2). During follicle growth, theca cells
express the enzymes necessary to convert cholesterol to andro-
gens (mainly androstenedione, a weak androgen) but lack the
enzymes necessary to convert androgens to estradiol. Granu-
losa cells can convert androgens to estradiol and they can pro-
duce progesterone, but they are unable to convert pregnenolone
or progesterone to androgens. Thus, theca cell–produced
androgens diffuse into the granulosa cells where they are aro-
matized to estradiol (Figure 68–2). More than 95% of circulat-
ing estradiol is directly secreted, with a smaller contribution
from peripheral conversion of estrone to estradiol in premeno-
pausal women.
ANDROGENS
Female androgens are derived from the adrenal glands (dehy-
droepiandrosterone and androstenedione), the ovaries
(androstenedione and testosterone), and peripheral conver-
sion of androstenedione and dehydroepiandrosterone to tes-
tosterone. Ovarian androgen secretion parallels that of
estrogen throughout the menstrual cycle. Most of the circulat-
ing testosterone in females is derived from the peripheral con-
version of androstenedione; 30–40% of testosterone is directly
secreted. The conversion of testosterone to dihydrotestoster-
one in peripheral tissues is limited in females because of their
higher levels of sex hormone–binding globulin (SHBG) than
in males, as well as by the peripheral conversion to estrogen by
aromatase, protecting females from virilization by dihydrotes-
tosterone.
PROGESTERONE
The preovulatory LH surge results in luteinization of granu-
losa and theca cells, altering the steroidogenic pathway so that
progesterone is the primary steroid hormone produced by
each of these cell types after luteinization. The changes leading
to the ability to produce progesterone include increased
expression of the enzymes involved in the conversion of cho-
lesterol to progesterone (cholesterol side-chain cleavage
698 SECTION IX Endocrine and Metabolic Physiology

Theca Cell LH/CG receptor

PI-4, 5P2
AC Gs Gq PLCβ
ATP
βγ βγ

cAMP DAG IP3

Ca2+

PKA PKC

Protein
P Protein P Protein

FIGURE 68–2 Theca and granulosa cells

coordinate the production of estrogen. The
cAMP/PKA pathway DAG/PKA pathway
secretion of estradiol by the dominant follicle
requires cooperation between theca cells, which
synthesize androstenedione and testosterone;
Cholesterol Progesterone Androstenedione
and granulosa cells of mature follicles, which
P450scc P450C17α
convert androgens to estradiol and estrone.
Androgen synthesis in theca cells results from Androstenedione Systemic circulation
the activity of three enzymes: cholesterol
side-chain cleavage (P450scc), 17α-hydroxylase- Basal lamina

lyase (P450C17), and 3β-hydroxysteroid

dehydrogenase (3β-HSD). Luteinizing hormone Androstenedione 17β-Estradiol
(LH) stimulates the steroidogenic pathway
leading to formation of androstenedione in the Aromatase
theca cells. In granulosa cells, the enzyme
Protein P Protein
17β-hydroxysteroid dehydrogenase transforms
androstenedione into testosterone in follicles
from the primary stage. In mature follicles, PKA
follicle-stimulating hormone (FSH) stimulates
the activity of aromatase, which transforms
testosterone into 17β-estradiol. AC, adenylate cAMP
cyclase; PLCβ, phospholipase Cβ; PI-4,5P2,
phosphatidylinositol 4,5-bisphosphate; ATP, ATP
βγ
adenosine triphosphate; cAMP, cyclic adenosine AC
Gαs
monophosphate; DAG, diacylglycerol; IP3,
Follicular fluid
inositol 1,4,5-trisphosphate; PKA, protein kinase
A; PKC, protein kinase C. (Modified with permission Granulosa Cell FSH receptor
from Molina PE: Endocrine Physiology, 3rd ed. New York:
McGraw-Hill Medical, 2010.)

cytochrome P450 complex and 3β-hydroxysteroid dehydro-
genase) and decreased expression of the enzymes that convert
progesterone to estrogens (17α-hydroxylase cytochrome P450
and aromatase cytochrome P450).
INHIBINS, ACTIVINS, AND FOLLISTATIN
Inhibin production by granulosa cells of mature follicles is
regulated by FSH and LH, and by local factors such as growth
factors (epidermal, transforming, and insulin-like) and
hormones (androstenedione, activin, and follistatin) in an
autocrine and paracrine way. Preantral follicles secrete
inhibin B exclusively, whereas small antral follicles secrete
both inhibin B and inhibin A. Inhibin B is a good marker of
granulosa cell function under the control of FSH, whereas
inhibin A is a marker of corpus luteum function under the
control of LH. Inhibins contribute to the regulation of LH
and FSH release through endocrine feedback regulation at
the anterior pituitary.
Activin production by the granulosa cells changes during
folliculogenesis. Activin promotes granulosa cell prolifera-
tion, upregulates FSH receptor expression on granulosa
cells, and modulates steroidogenesis in both granulosa and
theca cells. Activin is a physiologic antagonist to inhibin
and specifically stimulates pituitary FSH synthesis and
secretion.

OVARIAN CYCLE
During the ovarian cycle, throughout the reproductive life
span, a single mature oocyte is usually produced each month.
Most of the human oocytes (germ cells) present during pre-
natal development are destined to undergo atresia through
apoptosis, or programmed cell death. Only follicles that are
responsive to FSH stimulation (about 350) will enter the
final stage of development and progress to ovulation. The
ovarian cycle is divided into a follicular and a luteal phase.
The follicular phase begins on day 1 of the cycle, the first
day of menses, and corresponds to the growth and develop-
ment of a dominant follicle. At midcycle (day 14), the increas-
ing levels of estrogen stimulate a surge in LH release (positive
feedback), which results in ovulation 36 hours later.
After ovulation, during the luteal phase, the remnants of
the ovulatory follicle form the corpus luteum, a transient
endocrine structure that produces estradiol, progesterone,
and inhibin A and is under LH regulation. The end of the
luteal phase is marked by regression of the corpus luteum
and associated decreases in estradiol, inhibin A, and proges-
terone production. The hormonal changes that occur during
the ovarian cycle produce differential regulation of gonado-
tropin release.
OVARIAN REGULATION OF
GONADOTROPIN RELEASE
Gonadotropin release is under negative and positive feedback
regulation by estradiol, progesterone, and inhibins A and B.
The contributions of these ovarian hormones vary according
to the stage of the ovarian cycle.
Follicular Phase
During this phase, the dominant follicle produces high con-
centrations of 17β-estradiol and inhibin B. As concentrations
of estradiol and inhibin increase, they act on the hypothala-
mus and pituitary to decrease FSH secretion. The increase in
estradiol through positive feedback stimulates LH release dur-
ing midcycle (Figures 68–3 and 68–4). The midcycle LH surge
resulting from positive feedback of estradiol is due to an
increased responsiveness of gonadotropic cells to GnRH (fol-
lowing exposure to increasing estradiol), an increase in GnRH
receptor number, and a GnRH surge, triggered by the effect on
the hypothalamus of increasing estradiol. Progesterone also
exerts positive feedback by enhancing pituitary sensitivity to
GnRH and increasing GnRH release from the hypothalamus.
There is also a smaller pre-ovulatory FSH surge (Figure 68-4).
This is because GnRH-stimulated FSH release is restrained by
the inhibitory effect of inhibin.
Luteal Phase
The surge in LH levels induces ovulation and promotes
the survival of the corpus luteum during the luteal phase.
CHAPTER 68 Female Reproductive System 699
Following ovulation, as the corpus luteum develops and
synthesis and circulating levels of progesterone increase,
negative feedback inhibition of LH release is produced. With
the decline in LH levels comes the demise of the corpus luteum,
unless the corpus luteum is stimulated by human chorionic
gonadotropin (hCG), a placental hormone (described later) it
regresses.
OOGENESIS AND FORMATION
OF THE DOMINANT FOLLICLE
The fetal ovary begins germ cell development (oogenesis)
early in fetal life. During early intrauterine development
(15 weeks), primordial germ cells (oogonia) proliferate and
migrate to the genital ridge. On their arrival in the fetal ovary,
some of the oogonia continue mitotic proliferation, while oth-
ers begin to undergo apoptosis (Figure 68–5). Some of these
oogonia begin the first meiotic division but arrest at the diplo-
tene stage (end of prophase) at or near birth. The resulting
primary oocytes remain arrested in the first meiotic prophase
until puberty when they are recruited to grow and mature and
undergo meiosis to produce an ovum.
Primary oocytes are surrounded by a primordial follicle
consisting of a single layer of epithelial granulosa cells and a
less organized layer of mesenchymal theca cells. The pool of
primordial follicles in the female ovary reaches its maximum
number at about 20 weeks of gestational age and then
decreases in a logarithmic fashion throughout life until com-
plete depletion occurs during menopause. When reproduc-
tive life is initiated, less than 10% of the primordial follicles
remain.
Folliculogenesis, or formation of the dominant follicle,
consists of two stages: the gonadotropin-independent (pre-
antral) period and the gonadotropin-dependent (antral or
Graafian) period. Primordial follicular growth up to the
antral stage (up to 0.2 mm) occurs during fetal life and infancy
and is gonadotropin independent (Figure 68–5). Primary fol-
licles are formed when the flattened epithelial cells become
cuboidal and undergo mitosis. During the antral follicle
growth phase, there is further proliferation of the granulosa
cells, expression of FSH and steroid hormone receptors, and
association of the theca cells with the growing follicle and
granulosa cells, leading to formation of the secondary folli-
cles. Tertiary follicles are formed following further theca cell
hypertrophy and development. Their antrum is filled with
estrogen-rich fluid, and the theca interstitial cells start to
express FSH and LH receptors.
The mechanisms that trigger initiation of follicular growth are
thought to involve bidirectional communication between germ
and somatic cells through gap junctions and paracrine factors,
including cytokines and growth factors (insulin-like growth
factor-I [IGF-I], epidermal and fibroblast growth factors, and
interleukin-1β). When follicles reach a size of 2–5 mm, approxi-
mately 50% are rescued from apoptosis and enter the selection
growth phase. This final developmental phase of follicular
700 SECTION IX Endocrine and Metabolic Physiology

NE β -endorphin
NPY + – IL-1
Leptin GABA
DA

GnRH

LH FSH
FSH

LH FSH

LH
FSH
+Follicular 80 200
development;
Inhibin A(pg/mL)

Inhibin B(pg/mL)
60 150
ovulation
40 100
Theca cells
20 50

Granulosa 0 0
cells

50 1500
Progesterone(nmo/L)

Estradiol(pg/mL)
40
1000
30
20
500
10
0 0

Ovary
FIGURE 68–3 Hypothalamic–pituitary–ovarian axis. Gonadotropin synthesis and release and differential expression are under
both positive and negative feedback control by ovarian steroid and peptide hormones. Ovarian hormones can decrease gonadotropin release
both by modulating gonadotropin-releasing hormone (GnRH) pulse frequency from the hypothalamus and by affecting the ability of GnRH to
stimulate gonadotropin secretion from the pituitary itself. Estradiol enhances luteinizing hormone (LH) and inhibits follicle-stimulating hormone
(FSH) release, whereas inhibins A and B (gonadal glycoprotein hormones) reduce FSH secretion. After ovulation, ovarian progesterone
production predominates. Progesterone increases hypothalamic opioid activity and slows GnRH pulse secretion, favoring FSH production and
decreasing LH release. Inhibin B peaks early in the follicular phase, whereas inhibin A peaks in the midluteal phase. The increasing inhibin B levels
in the midfollicular phase act at the pituitary gonadotroph to offset activin signaling and suppress FSH biosynthesis from early follicular phase
levels. It also prevents a larger FSH surge in response to estrogen-induced positive feedback on GnRH pulses. The decrease in inhibin A at the
end of the luteal phase creates an environment in which FSH levels can again increase. A variety other CNS and peripheral factors can alter GnRH
release. NE, norepinephrine; NPY, neuropeptide Y; IL-1, interleukin-1; GABA, γ-aminobutyric acid; DA, dopamine. (Modified with permission from Molina
PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

growth, in which antral follicles are protected from apoptosis,
begins approximately 85 days before ovulation in the luteal
phase of the cycle preceding ovulation (Figure 68–5).
During this gonadotropin-regulated growth phase, follicles
grow exponentially, and FSH stimulates estrogen production
from granulosa cells through the induction of the aromatase
enzyme that catalyzes androgen conversion into estrogens,
with stimulation of follicular fluid formation, cell prolifera-
tion, and LH receptor expression in the dominant follicle. The
average time between primary follicle development and ovula-
tion is 10–14 days (Figure 68–5).
Follicles undergo cyclic recruitment and selection, leading
to the emergence of the preovulatory follicle(s). The increase
in circulating FSH stimulates antral follicle growth. One of
the leading follicles grows faster than the rest and produces
higher levels of estrogens and inhibins. While the reason for
why one follicle becomes dominant is unclear, this follicle is
likely to be more sensitive to FSH. In turn, the estrogens and
inhibins produced by the largest follicle suppress pituitary
FSH released during the midfollicular phase. The decrease in
FSH then leads to apoptosis of the remaining growing antral
follicles. Once a follicle is recruited for growth, the oocyte
enters a growth phase that leads to the completion of the first
meiotic division. The resumption of meiosis is mediated by
the surge in LH. LH acts on mature follicles to terminate the
program of gene expression associated with folliculogenesis.
 CHAPTER 68 Female Reproductive System 701

DAY OF MENSTRUAL CYCLE

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28–0

OVARY FOLLICULAR PHASE LUTEAL PHASE

Serum hormone concentrations

Progesterone

Estradiol

LH

FSH

Inhibin

UTERUS PROLIFERATIVE SECRETORY

PHASE PHASE

MENSTRUAL Spiral
PHASE artery
Gland Bleeding

Bleeding

Vein Basal artery

4 14 28
Time (days)
FIGURE 68–4 Hormonal events during the ovarian and endometrial cycles. Plasma concentrations of FSH, estrogen, LH, and progesterone,
during the human menstrual cycle and the corresponding proliferative and secretory changes in the endometrium and ovarian follicular development,
ovulation, and corpus luteum formation. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

The transcription of genes that control granulosa cell prolif-
eration and those that encode steroidogenic enzymes is rap-
idly turned off by LH. In addition, LH induces genes involved
in ovulation and luteinization. At this stage, mRNA transcrip-
tion virtually ceases and does not resume until 1–3 days after
the egg has been fertilized, when the final phases of meiosis
are completed. One preovulatory follicle is selected every
cycle, approximately 350 times during the female reproduc-
tive life span.
Ovulation
Ovulation involves rupture of the wall of the follicle at the
surface of the ovary, releasing the oocyte and corona radiata
702 SECTION IX Endocrine and Metabolic Physiology

Basal lamina
Granulosa precursors 25 μ m primordial follicle
Oocyte
Birth to 6 months postpartum
Granulosa cells 60 μm primary follicle

Basal lamina
Theca cells Puberty to menopause
Granulosa cells 150 μm primary
Antral fluid follicle

Oocyte
Zona pellucida
Theca externa
Theca interna
Granulosa cells
5,000 μm antral (graafian) follicle
Antrum 2–4 weeks prior to ovulation
Cumulus oophorus
Zona pellucida
FIGURE 68–5 Follicle growth and Oocyte
development. Folliculogenesis, or formation of
the dominant follicle, consists of two stages: the
18
gonadotropin-independent (preantral) period and
16
the gonadotropin-dependent (antral or Graafian) PREOVULATORY

period. Primordial follicular growth up to the antral Follicle size (mm)

14

stage occurs during fetal life and infancy and is 12

DOMINANT
gonadotropin independent. The final developmental 10
phase of follicular growth, in which antral follicles
8
are protected from apoptosis, begins approximately
6 SELECTED
85 days before ovulation. One dominant follicle is
ATR ATR ATR
recruited in the luteal phase of the cycle preceding 4 – –
ATR ATR ATR ATR ATR ATR
ovulation. The larger, more mature follicles are filled 2

with a transparent albuminous fluid, consisting of RECRUITMENT SELECTION EARLY DOMINANCE LATE DOMINANCE
FINAL MATURATION
an external fibrovascular coat, connected with the Late luteal Early follicular Midfollicular Late follicular
surrounding stroma of the ovary by a network of
blood vessels; and an internal coat, consisting of
several layers of nucleated cells (granulosa cells)
Follicular diameter (mm)

anchored in the zona pellucida, a glycoprotein-rich

2-5
eosinophilic material surrounding the oocyte. The
zona pellucida forms the corona radiata, which
10 days
close to the time of ovulation is separated from the 1-2 Gonadotropin-independent
Gonadotropin-
granulosa cells and expelled with the oocyte during dependent
15 days
ovulation. Ovulation entails rupture of the wall of 0.5-0.9 Early antral
the follicle at the surface of the ovary, releasing the 0.2-0.4 20 days
25 days
oocyte and corona radiata into the peritoneal cavity. 0.15
ATR, atretic; LH, luteinizing hormone; FSH, follicle- Preantral LH
stimulating hormone; Ovul, ovulation; M, menstrual Ovul Ovul Ovul FSH Ovul
phase. (Modified with permission from Molina PE: Endocrine M M M

Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.) First cycle Second cycle Third cycle

into the peritoneal cavity, close to the opening of the fallo-
pian tubes. The ovum is enclosed by an outer layer of cumu-
lus cells and an inner, thick extracellular glycoprotein coat,
the zona pellucida. Ciliary movement on the mucous mem-
brane of the fimbria aids movement of the ovum into the
fallopian tubes.
Throughout the preovulatory stage, the oocyte, granu-
losa cells, and theca cells acquire specific functional char-
acteristics. The oocyte becomes competent to undergo
meiosis, granulosa cells acquire the ability to produce estro-
gens and respond to LH via the LH receptor, and theca cells
begin to synthesize increasing amounts of androgens that
serve as substrates for the aromatase enzyme in the granu-
losa cells.
The sequence of temporal events that occurs during ovula-
tion is initiated in the responsive preovulatory follicle by a
surge of LH, which starts 34–36 hours before and peaks 12–24
hours before ovulation. This leads to follicular rupture and
promotes follicular remodeling to form a corpus luteum. In
addition, the surge in LH stimulates resumption of meiosis up
to the second meiotic metaphase following extrusion of the
first polar body (remnants of one X chromosome) before ovu-
lation. Meiosis is again arrested and then completed with the
release of the second polar body following fertilization.

Formation of the Corpus Luteum
The surge in LH release produces reorganization of the follicle
and formation of the corpus luteum, composed of small (theca
lutein) and large (granulosa-lutein) cells, fibroblasts, endothe-
lial cells, and immune cells. On rupture of the follicle (follow-
ing ovulation), small amounts of bleeding into the antral cavity
lead to the formation of the corpus hemorrhagicum and the
invasion by macrophages and mesenchymal cells, leading to
revascularization of the corpus luteum. The granulosa-lutein
cells transform into the corpus luteum, a temporary endocrine
gland. The corpus luteum continues to autonomously produce
and secrete progesterone and estradiol, playing a key role in
regulating the length of the ovarian cycle, maintaining gesta-
tion in its early stages, and suppressing LH and FSH release
through the inhibition of GnRH release.
During the initial gestational period, placental production
of hCG prevents the regression of the corpus luteum, trans-
forming the corpus luteum of the ovarian cycle into the cor-
pus luteum of pregnancy. hCG stimulates the granulosa-lutein
cells to produce progesterone, 17-hydroxyprogesterone, estro-
gen, inhibin A, and relaxin, a polypeptide hormone from the
insulin/IGF hormone family. Relaxin regulates the synthesis
and release of metalloproteinases, mediators of tissue (uterus,
mammary gland, fetal membranes, birth canal) growth and
remodeling, in preparation for birth and lactation.
Luteolysis
Luteolysis is a two-phase process of lysis or regression of the cor-
pus luteum and marks the end of the female reproductive cycle.
The process involves an initial decline in progesterone secretion
(functional luteolysis), followed by programmed luteal cell
apoptosis leading to gradual corpus luteum involution (struc-
tural or morphologic luteolysis) to form a small scar of connec-
tive tissue known as the corpus albicans. This sequence of
events takes place if fertilization does not occur within 1–2 days
of ovulation. If fertilization occurs, the corpus luteum continues
to grow and function for the first 2–3 months of pregnancy.
Thereafter, it slowly regresses as the placenta assumes the role
of hormone biosynthesis for the maintenance of pregnancy.
ENDOMETRIAL CYCLE
The ovarian cycle is accompanied by cyclic growth and shed-
ding of the endometrium controlled by estrogen and proges-
terone (Figure 68–4). Three distinct phases can be identified
in the endometrium throughout the menstrual cycle.
PROLIFERATIVE PHASE
The proliferative phase corresponds to the ovarian follicular
phase (Figure 68–4). It is characterized by estrogen-induced
endometrial epithelial cell proliferation and upregulation of
estradiol and progesterone receptor expression to reach a peak
by the time of ovulation. This is the initial phase of endome-
CHAPTER 68 Female Reproductive System 703
trial maturation in preparation for implantation of the embryo.
The preovulatory endometrial proliferation leads to relative
hypertrophy of the uterine mucosa.
SECRETORY PHASE
This phase corresponds to the ovarian luteal phase and is
characterized by progesterone-induced differentiation of
the endometrial epithelial cells into secretory cells. During
the secretory phase, there is a short, well-defined period of
uterine receptivity for embryo implantation. Toward the end
of the secretory phase, glandular expression of estrogen recep-
tors is markedly decreased, reflecting the suppressive effect of
increasing progesterone levels.
MENSTRUAL PHASE
The menstrual period is characterized by shedding of the
endometrium, resulting from proteolysis and ischemia in its
superficial layer. Proteolytic enzymes accumulate in mem-
brane-bound lysosomes during the first half of the postovula-
tory period. The integrity of the lysosomal membrane is lost
with the decline in estrogen and progesterone on day 25, result-
ing in lysis of the glandular and stromal cells and the vascular
endothelium. Ischemia due to vasoconstriction of endometrial
vessels during the early part of the menstrual period results in
rupture of the capillaries, leading to bleeding. In addition, a
significant increase in prostaglandin F2α in the late secretory
endometrium contributes by releasing acid hydrolases from
lysosomes and enhancing myometrial contractions, aiding in
the expulsion of degenerated endometrium.
FERTILIZATION
Fertilization is the union of the two germ cells, the ovum and
the sperm, restoring chromosome number to 46 and initiat-
ing the development of a new individual. The final steps of
mammalian oogenesis (and of spermatogenesis) prepare eggs
(and sperm) for fertilization. In preparation for ovulation,
fully grown oocytes undergo “meiotic maturation,” prepar-
ing them to interact with sperm. A very low proportion of the
sperm deposited into the vagina migrates up the female
reproductive tract to the site of fertilization in the ampullary–
isthmic junction of the fallopian tubes (Figure 68–6). During
this journey, sperm undergo activation (capacitation), a
series of changes in the sperm plasma membrane that increase
its affinity for the zona pellucida, enabling the sperm to bind
to the ovum and undergo the acrosome reaction. In the fal-
lopian tubes, sperm bind to the zona pellucida, leading to
fusion of the ovum and sperm plasma membranes to form a
single “activated” cell, the zygote (Figure 68–6). This simple
process requires several events:
• Sperm acrosome reaction and penetration of the ovum’s
zona pellucida: Sperm binding to the zona pellucida primes
the sperm cell to initiate the acrosome reaction. The
704 SECTION IX Endocrine and Metabolic Physiology

Perivitelline
Sperm
3 space
Zona
pellucida
Cortical
Ovum granules

Zona
pellucida

Ovum
4
FIGURE 68–6 Fertilization and embryo
migration. Sperm binds to the zona pellucida
and undergoes the acrosome reaction, releasing 5
its enzymatic contents, which are necessary for
penetration of the zona pellucida. In addition,
cortical granules in the ovum release their
Inner cell
contents, preventing multiple sperm from mass of
fertilizing one ovum. Once the sperm penetrates blastocyst
the zona pellucida and begins entry into the
perivitelline space, the sperm repositions itself Day 3 Day 2
Day 4 Day 1
from its original orientation with binding at the
tip of the head to binding in an equatorial or
sideways position, leading to fusion with the egg Blastocyst 4 cells 2 cells
plasma membrane and formation of the zygote. Morula Zygote
Day 7
This leads to completion of the meiotic division Fertilization Day 0
and initiation of mitotic divisions while the Embryo
zygote is being propelled through the fallopian
tubes through both ciliary movements by the
epithelium and rhythmic contractions of the Blastocyst
implanting
smooth muscle walls. The embryo enters the Acrosomal Ovulated
uterine cavity (where implantation occurs) as a reaction egg
blastocyst on day 4 following fertilization.
(Modified with permission from Molina PE: Endocrine Muscle layer
Endometrium Uterine wall
Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

acrosome reaction involves fusion of the acrosome with the sperm and ovum pronuclei reconstitutes a diploid cell,
sperm plasma membrane and exocytosis of its enzymatic called the zygote.
contents (proteases and glycosidases) and is required for
During migration of the zygote through the fallopian tubes
sperm penetration. During or after the acrosome reaction,
toward the site of implantation in the uterine cavity, mitosis
the fertilizing sperm detaches from the zona pellucida. It
yields a morula and then a blastocyst. The outer cells of the
penetrates through the zona pellucida and fuses with the
blastocyst are the trophoblast cells, which participate in the
ovum plasma membrane.
implantation process and form the fetal components of the
• Cortical and zona reaction: Fusion of the sperm and the
placenta. If fertilization does not take place, both the ovum
ovum triggers the second meiotic division of the ovum,
and sperm degenerate relatively rapidly in the female
leading to the formation of the mature oocyte and the sec-
reproductive tract.
ond polar body. In addition, this fusion triggers mecha-
nisms that prevent fertilization of the ovum by multiple
sperm, such as exocytosis of cortical granules (cortical re- IMPLANTATION
action) from the oocyte, resulting in proteolysis of zona
pellucida glycoproteins, as well as cross-linking of pro- The human embryo (blastocyst) enters the uterus three days
teins forming the perivitelline barrier. The fusion of the before implantation. The window of implantation corresponds
 CHAPTER 68 Female Reproductive System 705

to the short period of endometrial receptivity for the embryo,
between days 20 and 24 of the menstrual cycle. Outside of this
period, implantation fails. Many of the physiologic events
crucial to successful implantation are due to cyclic changes in
ovarian hormone levels, leading to morphologic and func-
tional maturation of the endometrium.
PHYSIOLOGIC EFFECTS OF
OVARIAN HORMONES
ESTROGEN
Estrogen Synthesis, Transport,
and Metabolism
The primary source of estradiol in women is the granulosa cell
of the ovaries. However, both granulosa and theca cells and
both gonadotropins (FSH and LH) are required for the produc-
tion of estrogen. The theca cells secrete androgens that diffuse
to the granulosa cells to be aromatized to estrogens (Figure 68–2).
In premenopausal women, 17β-estradiol produced by the ova-
ries is the chief circulating estrogen. Serum estradiol concen-
trations are low in preadolescent girls and increase at menarche,
defined as the time of the first menstrual bleed. Estradiol pro-
duction varies cyclically throughout the menstrual cycle. The
highest rates of production and serum concentrations are in the
preovulatory phase and the lowest during the premenstrual
phase (Figure 68–4). Estradiol levels increase during pregnancy.
After menopause, serum estradiol concentrations decrease to
values similar to or lower than those in men of a similar age.
Most of the estradiol released into the blood circulates bound
to SHBG and to albumin, with only 2–3% circulating in the free
form. Estradiol (as well as androstenedione) is converted to
estrone (a weak estrogen) in peripheral tissues (Figure 68–7).
Estrogen Receptor–Mediated
(Genomic) Effects
The estrogen receptors are members of the superfamily of
steroid hormone receptors (see Figure 60–6). Two subtypes
of estrogen receptors have been identified that differ in

CH3 CH3 CH3

C O C O H C OH

O HO HO
H H
Progesterone Pregnenolone Pregnandiol
H
O

HO
Estradiol

FIGURE 68–7 Metabolic fate of

HO progesterone and estrogen. Progesterone
Estrone and estrogen are degraded primarily in the
H liver. Estradiol and androstenedione are
O O
OH converted to estrone (a weak estrogen) in
peripheral tissues. Estrone is converted to
HO
estriol, primarily in the liver. Estrogens are
HO HO metabolized by sulfation or glucuronidation,
2-Hydroxyestrone Estriol and the conjugates are excreted into the
O urine. Estrogen can also be metabolized
through hydroxylation and subsequent
CH2O methylation to form catecholestrogens and
methoxyestrogens (not shown). (Modified
HO with permission from Molina PE: Endocrine Physiology,
2-Methoxyestrone 3rd ed. New York: McGraw-Hill Medical, 2010.)
706 SECTION IX Endocrine and Metabolic Physiology

structure and tissue distribution and are encoded by differ-
ent genes. Estrogen receptor alpha (α) is considered the
classic estrogen receptor. It is found predominantly in endo-
metrium, breast cancer cells, and ovarian stroma. Estrogen
receptor beta (β) is found predominantly in granulosa cells
and developing spermatids, as well as in several nonrepro-
ductive target tissues, including the kidney, intestinal
mucosa, lung parenchyma, bone marrow, bone, brain,
endothelial cells, and prostate gland.
Estrogen receptors are mostly nuclear, but are also found in
the cytoplasm. Similar to other steroid hormones, free estro-
gen diffuses into the cell and binds to the ligand-binding
domain of the receptor, which dissociates from its cytoplasmic
chaperone proteins. The estrogen receptor complex then
translocates into the cell nucleus, where it binds as homodim-
ers or heterodimers to specific sequences of DNA called estro-
gen response elements, regulating gene transcription. The
physiologic effects of estrogens that are mediated through
transcriptional activation take minutes or hours to occur.
Nongenomic Effects of Estrogen
Some rapid effects of estrogen cannot be explained by a tran-
scriptional mechanism (nongenomic) and are the result of
direct estrogenic action on cell membranes mediated by cell
membrane forms of estrogen receptor. Although these recep-
tors remain largely uncharacterized, they are thought to
resemble their intracellular counterparts.
Physiologic Actions of Estrogen
at Target Organs
Reproductive system
Estrogen exerts multiple effects in reproductive organs
(Figure 68–8):
• Uterus: Estrogen promotes proliferation of the endometri-
um by stimulating mitosis and angiogenesis. It sensitizes
uterine smooth muscle to the effects of oxytocin by
increasing the expression of oxytocin receptors and contrac-
tile proteins. Estrogen increases watery cervical mucus
production.
• Ovary: Estrogen exerts potent mitotic effects on granulosa
cells and augments the FSH-mediated differentiation pro-
cess (an autocrine action).
• Breast: Estrogen stimulates growth and differentiation of
the ductal epithelium, induces mitotic activity of ductal
cylindrical cells, and stimulates the growth of connective
tissue (Figure 68–9). The density of estrogen receptors in
breast tissue is highest in the follicular phase of the men-
strual cycle and decreases after ovulation. Estrogen can also

Neuroprotection

Influence on mood
Reduction of
intraocular pressure

Slowing of
skin aging

FIGURE 68–8 Systemic effects Arterial vasodilation

of estrogen. In addition to its Maintenance of
reproductive organ effects, estrogen bone density
has neuroprotective effects and
Cardioprotection
reduces perimenopausal mood
fluctuations in women. Estrogen is
Growth and proliferation
cardioprotective and may protect of breast tissue: risk factor
against colon cancer, and it has for breast cancer
Increased production of
vasodilatory effects. In the liver, liver proteins such as
estrogen stimulates the uptake of coagulation factors and
serum lipoproteins and the production hepatic lipoprotein
of coagulation factors. Estrogen receptors Putative reduction
protects against bone loss. In the skin, in risk of colon cancer
it increases skin turgor and collagen
production and reduces the depth of
wrinkles. (Reproduced with permission from
Gruber CJ et al. Mechanisms of Disease:
production and actions of estrogens. NEJM. Growth and differentiation of, and
2002;346:340. Copyright Massachusetts Medical water retention in primary sex organs:
Society. All rights reserved. risk factor for endometrial cancer

Atrophic ducts
Estrogen
GH, IGF-I
EGF
Lactogenesis Ductal growth
Progesterone,
Prolactin Estrogen, Cortisol, maturation &
Prolactin, Thyroid
Pregnancy & IGF-I, hPL,
hormone
post-partum Cortisol,
lactation Insulin
Oxytocin
Lobuloalveolar growth
indirectly affect mammary gland development by increas-
ing prolactin and progesterone levels and inducing proges-
terone receptors in mammary epithelium. The growth-
promoting effects of estrogen have been implicated in breast
and endometrial cancer.
• Other body systems:
a) Liver: Estrogen affects the expression of apoprotein
genes and increases lipoprotein receptor expression,
resulting in a decrease in serum concentrations of total
cholesterol and low-density lipoprotein (LDL) choles-
terol, increases in serum high-density lipoprotein
cholesterol and triglyceride concentrations, and decreas-
es in serum lipoprotein A concentrations. It regulates
the hepatic expression of genes involved in coagulation
and fibrinolysis. Estrogen decreases plasma concentra-
tions of fibrinogen, antithrombin III and protein S, and
plasminogen activator inhibitor type 1. Elevated plasma
estrogen levels are associated with an overall increase in
the potential for fibrinolysis. Estrogen stimulates the
synthesis of transport proteins (thyroxine-binding
globulin and transcortin).
b) Central nervous system: Estrogen has neuroprotective
actions, and its age-associated decline is associated with
a decline in cognitive function.
c) Bone: Overall, the effects of estrogen are antiresorptive.
Estrogen promotes bone maturation and closure of
epiphysial plates in long bones at the end of puberty. It
conserves bone mass by suppressing bone turnover and
maintaining balanced rates of bone formation and bone
resorption. Estrogen affects the generation, life span,
and functional activity of both osteoclasts and osteoblasts.
It decreases osteoclast formation and activity and
increases osteoclast apoptosis.
CHAPTER 68 Female Reproductive System 707
Puberty
FIGURE 68–9 Hormonal regulation of breast
development and lactogenesis. Mammary gland
development is initiated at puberty through the
actions of estradiol and growth factors and is
further regulated during pregnancy through the
effects of prolactin and human placental lactogen
(hPL). Throughout pregnancy, progesterone inhibits
lactogenesis. This inhibitory effect is removed
following parturition, when prolactin levels act
unopposed to stimulate lactogenesis. Through
Sexual neuroendocrine reflexes, suckling stimulates the
release of oxytocin from the posterior pituitary,
pregnancy
producing the milk “let-down” reflex. GH, growth
hormone; IGF-I, insulin-like growth factor I; EGF,
epidermal growth factor. (Modified with permission from
Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill
Medical, 2010.)
PROGESTERONE
Progesterone is produced by both theca and granulosa cells
and is the predominant ovarian hormone produced in the
luteal phase, a period during which plasma concentrations
increase 10-fold. Production of progesterone by the corpus
luteum is mainly under LH stimulation. The majority (80%) of
progesterone secreted circulates bound to albumin. The prin-
cipal targets of progesterone are the reproductive tract and the
hypothalamic–pituitary axis. The degradation of progesterone
is similar to that of androgens and estrogens and occurs
primarily in the liver.
Progesterone Receptor–Mediated Effects
Progesterone appears to exert most of its effects by directly
regulating transcription of genes through two specific pro-
gesterone receptor proteins, termed A and B. These proges-
terone receptor proteins arise from a single gene and act as
ligand-inducible transcription factors, regulating the expres-
sion of genes by binding specific progesterone responsive
elements on the DNA. The expression of progesterone recep-
tors is upregulated by estrogen and downregulated by
progesterone in most target tissues. Previous exposure to
estrogen induces the production of receptors for progester-
one and is required for progesterone to act on the reproduc-
tive tract.
Progesterone receptor expression in the uterus is increased
during the first half of the menstrual cycle. During the sec-
ond half, as serum progesterone levels increase, total proges-
terone receptor levels in the uterus decrease. In the mid and
late luteal phases, the density of progesterone receptors in
the luminal and glandular epithelium declines markedly to
708 SECTION IX Endocrine and Metabolic Physiology
undetectable levels; on the other hand, stromal and myome-
trial cells continue to express high levels of progesterone
receptor despite high circulating progesterone and absent
estrogen receptor.
In general, progesterone acts on the reproductive tract
to prepare it for initiation and maintenance of pregnancy.
The major physiologic roles of progesterone are mediated in
the uterus and ovary, where it stimulates the release of mature
oocytes, facilitates implantation, and maintains pregnancy
through stimulation of uterine growth and differentiation and
suppression of myometrial contractility. In the brain, proges-
terone modulates sexual behavior. Increased progesterone lev-
els during the luteal phase increase both core and skin
temperatures. This results in a biphasic pattern of body core
temperature throughout the menstrual cycle, with a higher
temperature in the luteal phase of the cycle.
Physiologic Actions of Progesterone
at Target Organs
• Effects on the uterus during early pregnancy: Progester-
one induces stromal differentiation; stimulates glandular
secretions, changing the pattern of proteins secreted by
endometrial cells; and modulates cyclic proliferation during
the menstrual cycle.
Progesterone induces uterine cell proliferation and differ-
entiation in early pregnancy through regulation of localized
growth factor synthesis and cell type–specific expression
of their receptors, thereby regulating cellular sensitivity to
the autocrine or paracrine effects of growth factors and
producing an environment that supports early embryonic
development.
• Promotion and maintenance of implantation: Progester-
one plays a major role in preparing the endometrium for
implantation of a fertilized ovum. It facilitates implantation
by stimulating the synthesis of enzymes responsible for lysis
of the zona pellucida. Finally, it promotes and maintains im-
plantation through effects on both the maternal uterus and
the developing blastocyst.
• Effects on uterine contractility: Progesterone induces
quiescence of the myometrium by increasing resting
membrane potential and preventing electrical coupling
between myometrial cells. It also prevents uterine contrac-
tions by blocking the ability of estradiol to induce mem-
brane expression of α-adrenergic receptors (α-adrenergic
activation causes contractions). Progesterone decreases
prostaglandin synthesis and increases the rate of prosta-
glandin inactivation through the stimulation of prosta-
glandin 15-dehydrogenase and opposes the stimulatory
effects of estrogen on endometrial prostaglandin F2α
expression in the luteal phase of the menstrual cycle.
Progesterone maintains the levels of relaxin, inhibiting
spontaneous or prostaglandin-induced myometrial con-
traction, and contributes to the maintenance of implanta-
tion and early pregnancy by increasing the collagen
framework and distensibility of the uterus.
At the end of pregnancy, the decrease in progesterone levels
is associated with increased prostaglandin synthase activity
and prostaglandin F2α production, enhancing uterine con-
tractility. The antiprogestin mifepristone antagonizes the
actions of progesterone on prostaglandin synthesis and catab-
olism and stimulates prostaglandin production, thereby pro-
ducing its abortive effects.
• Effects on lactation: In the mammary gland, progesterone
stimulates lobular–alveolar development in preparation for
milk secretion but suppresses milk protein synthesis before
parturition. Progesterone antagonizes prolactin’s effects in
mid to late pregnancy, preventing the synthesis of milk pro-
teins. The sudden decrease in circulating progesterone that
occurs with parturition is associated with a concurrent in-
crease in prolactin secretion and the onset of lactation.
• Antiestrogen actions: Progesterone antagonizes estrogen
induction of many of the known hormone-responsive genes.
This effect is mediated by downregulation of estrogen re-
ceptor protein concentrations, decreasing the active estro-
gen concentration (and antagonizing the action of estrogen
receptor at the molecular level), particularly in the uterus.
THE PLACENTA
Structure and Physiologic Function
The placenta is derived from two major cell types, which are the
source of the principal placental hormones. The outer cell mass
of the blastocyst, the precursor to the trophoblast, is in contact
with the endometrium and undergoes proliferation and tissue
penetration during implantation. The trophoblast has two cell
populations: an inner cytotrophoblast and an outer invasive
syncytiotrophoblast. The maternal side of the placenta contains
fetal chorionic villi that provide an extensive surface area for
nutrient and gas exchange between the fetal and maternal circu-
lation. The villi are covered with multinucleated syncytiotro-
phoblast and trophoblast stem cells, stromal cells, and blood
vessels. The villous cytotrophoblast cells are entirely secluded
from maternal elements, with the exception of any molecules
that might be transported across the placenta by the syncytiotro-
phoblast. By contrast, the extravillous trophoblast cells are con-
tinuously exposed to maternal tissues. The middle layer of the
placenta consists of densely packed cytotrophoblast cell columns
and serves as structural support for the underlying villi.
The physiologic functions of the placenta can be classified
as follows:
• supportive, transporting nutrients and oxygen necessary for
fetal growth; removing of waste products;
• immune, suppressing the local immune system to prevent
immunologic rejection of the fetus by the mother;
• endocrine, including hormone synthesis, transport, and
metabolism to promote fetal growth and survival.

Inability of the placental unit to perform these functions leads
to multiple complications of human pregnancy, including abor-
tion, miscarriage, impaired fetal growth, and preeclampsia.
Endocrine Function of the Placenta
The placenta produces cytokines, hormones, and growth fac-
tors that are essential for regulation of the fetomaternal unit.
In addition, the placenta expresses enzymes involved in hor-
mone metabolism, playing an important role in protection of
the fetus from maternal adrenal-derived androgens through
aromatase activity and from glucocorticoids through the activ-
ity of 11β-hydroxysteroid dehydrogenase type II. The princi-
pal placental hormones are as follows:
• hCG: hCG is a heterodimeric glycoprotein from the same
hormone family as LH, FSH, and TSH. It is produced by the
syncytiotrophoblast and released into the fetal and maternal
circulation. It is known as the hormone of pregnancy and
is the basis for the pregnancy test. hCG is detected in serum
at days 6–8 after implantation, and its levels peak at 60–90
days of gestation, declining thereafter. hCG has structural
and functional similarity to LH, has a much longer half-life,
and exerts its physiologic effects primarily through binding
to the LH receptors. The main function of hCG is to main-
tain the corpus luteum to ensure the production of proges-
terone until placental production takes over. Maternal hCG
levels are a useful index of functional status of the tropho-
blast (placental health).
• Human placental lactogen and growth hormone: hPL is
produced by the syncytiotrophoblast and is secreted into
both the maternal and fetal circulations after the sixth week
of pregnancy. In the fetus, hPL modulates embryonic
development, contributes to regulation of intermediary
metabolism, and stimulates the production of IGFs, insulin,
adrenocortical hormones, and pulmonary surfactant. Dur-
ing pregnancy, hGH-V, a GH variant expressed by the pla-
centa, becomes the predominant GH in the mother. This
hormone has structural and functional similarity to pitu-
itary GH and is not released into the fetus. Starting from the
15th to the 20th week of gestation up to term of pregnancy,
placental GH gradually replaces maternal pituitary GH,
which becomes undetectable. hGH-V stimulates IGF-I pro-
duction and modulates maternal intermediary metabolism,
increasing the availability of glucose and amino acids to the
fetus. Placental GH is not detectable in the fetal circulation,
and thus it does not appear to have a direct effect on fetal
growth.
• Progesterone: The major source of progesterone during the
initial phase of pregnancy is the corpus luteum under hCG
regulation. Starting from about week 8 of gestation, the pla-
centa (syncytiotrophoblast) becomes the principal source of
progesterone, leading to increasing levels of maternal pro-
gesterone throughout pregnancy. Because the placenta is
unable to produce cholesterol from acetate, cholesterol for
placental progesterone synthesis is derived from circulating
CHAPTER 68 Female Reproductive System 709
LDL. As discussed earlier, progesterone plays an important
role in maintaining uterine quiescence during pregnancy,
inhibiting prostaglandin synthesis, and modulating the
immune response to preserve pregnancy.
• Estrogen: The main source of estrogen during the initial
phase of pregnancy is the corpus luteum, being replaced
later by placental production. The production of estrogen by
the placenta requires coordinated interaction between fetal
and maternal adrenal gland steroid hormone production
(fetoplacental unit of steroid biosynthesis). The placenta
lacks 17α-hydroxylase activity and is thus unable to convert
progesterone to estrogen or to produce androgens. This lack
of placental androgen production protects the female fetus
from masculinization; protection is also aided by the strong
aromatase activity that converts maternal and fetal adrenal-
derived androgens to estrogens. Therefore, maternal and
fetal adrenal-derived androgens (dehydroepiandrosterone
sulfate [DHEAS]) are required for placental 17β-estradiol
and estriol production. Estriol is synthesized through
the aromatization of 16α-hydroxyandrostenedione derived
from 16α-hydroxyepiandrosterone sulfate produced by the
fetal liver and desulfated in the placenta (Figure 68–10);
16α-hydroxyepiandrosterone sulfate is derived from
DHEAS produced in the fetal adrenal gland. The enzymes
involved are placental sulfatase (DHEAS deconjugation),
3β-hydroxysteroid dehydrogenase (pregnenolone to proges-
terone conversion), and aromatase. The principal physio-
logic effects of estrogen during pregnancy include stimula-
tion of uterine growth, prostaglandin synthesis, thickening
of the vaginal epithelium, sensitization to oxytocin effects,
growth and development of the mammary epithelium, and
inhibition of milk production.
• Corticotropin-releasing hormone (CRH): CRH is pro-
duced by the syncytiotrophoblast and trophoblast cells of
the placenta. Its structure and function are similar to those
of hypothalamus-derived CRH. The CRH concentration in-
creases throughout pregnancy and peaks during labor. Pla-
cental production of CRH has been linked to the length of
gestation in humans. CRH is secreted into the maternal cir-
culation in large amounts during the third trimester of preg-
nancy and may play an important role in the onset of labor.
PREGNANCY AND LACTATION
Hormonal Control of Parturition
Uterine contractility during pregnancy and parturition can be
divided into at least four distinct phases:
• Phase 0: During pregnancy, the uterus is maintained in a
relatively quiescent state, mainly through the effects of pro-
gesterone. Additional factors involved in modulation of
uterine activity during this period are prostacyclin, relaxin,
parathyroid hormone-related peptide, and CRH. The initia-
tion of parturition results from the transition from the qui-
escent phase (phase 0) to a phase of activation (phase 1).
710 SECTION IX Endocrine and Metabolic Physiology

Mother Placenta Fetus

Pregnenolone
sulfate
Acetate Cholesterol LDL
cholesterol
Estriol
glucosiduronate

Pregnenolone
DHEA

Progesterone

16α -OHDEA

Urinary
excretion

16α -OHDEAS
Estriol

FIGURE 68–10 Fetoplacental unit hormone synthesis. The production of estrogen by the placenta requires the coordinated interaction
between fetal and maternal adrenal gland steroid hormone production. The placenta lacks 17α-hydroxylase and is thus unable to convert
progesterone to estrogen or to produce androgens. Maternal and fetal adrenal-derived androgens (dehydroepiandrosterone sulfate, DHEAS) are
required for 17β-estradiol and estrone production. Estriol is synthesized through the aromatization of 16α-hydroxyandrostenedione derived from
16α-hydroxyepiandrosterone sulfate (16α-OHDEAS) produced by the fetal liver and desulfated in the placenta; 16α-hydroxyepiandrosterone
sulfate in turn is derived from DHEAS produced in the fetal adrenal gland. LDL, low-density lipoprotein; 16α-OHDEA, 16α-hydroxyepiandrosterone.
(Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

• Phase 1: This phase of parturition is associated with activa-
tion of uterine function and is characterized by release from
the inhibitory mechanisms maintaining uterine quiescence
throughout pregnancy and activation of factors promoting
uterine activity. These factors include uterine stretch and
tension caused by the fully grown fetus, activation of the fe-
tal hypothalamic–pituitary–adrenal axis, and increased
prostaglandin synthesis. Mechanical stretch or hormonal
priming leads to upregulation of gene expression of proteins
that facilitate smooth muscle contraction, including con-
nexins (key components of gap junctions), prostaglandin
and oxytocin receptors, and ion channel proteins.
• Phase 2: This phase of parturition is a period of active uter-
ine contraction and is stimulated by prostaglandins, oxyto-
cin, and CRH. Prostaglandins, particularly those produced
in the intrauterine tissues, play a central role in the initiation
and progression of labor. They induce myometrial contrac-
tility and help produce the changes associated with cervical
softening at the onset of labor.
• Phase 3: This postpartum phase involves uterine involution
after delivery of the fetus and placenta and is mainly due to
the effects of oxytocin.
Mammary Gland Development
Mammary gland development involves cell proliferation, dif-
ferentiation, and morphogenesis. Most mammary gland devel-
opment occurs postnatally and involves branching and
extension of ductal growth points and secretory lobules into a
fatty stroma. This process is regulated by the associated altera-
tions in hormones and growth factors during the various
reproductive states (puberty and pregnancy) (Figure 68–9).
Ductal elongation is mediated by estrogen, GH, IGF-I, and
epidermal growth factor. Ductal branching and alveolar bud-
ding are regulated by progesterone, prolactin, and thyroid
hormone. Progesterone stimulates ductal side branching and
alveolar development. Prolactin acts directly on mammary
epithelium to induce alveolar development. Both progesterone

and prolactin synergize to stimulate proliferation of ductal
epithelium.
During pregnancy, prolactin, progesterone, and hPL act on
duct lobular units to promote expansion and differentiation of
their secretory function. This stage of mammary differentia-
tion into a secretory function is called stage I lactogenesis.
The elevated levels of progesterone prevent milk production
during this period.
The second stage (stage II lactogenesis) is initiated after
termination of pregnancy. The sudden decrease in circulating
progesterone that accompanies parturition in association with
the concurrent increase in prolactin secretion marks the onset
of lactation. The decrease in progesterone levels results in
removal of the inhibition of synthesis of α-lactalbumin and
β-casein. In the presence of prolactin, insulin, and glucocorti-
coids, the synthesis of milk proteins is established. Continuous
milk production is maintained by prolactin secretion from the
anterior pituitary throughout the period of lactation. The high
prolactin levels are in part due to increased lactotroph synthe-
sis resulting from the high estrogen levels during pregnancy.
Prolactin is the main regulator of milk protein synthesis
through its effects on the prolactin receptor located on mam-
mary epithelial cells. Prolactin release is under negative con-
trol by dopamine; thus, pharmacologic analogs of dopamine
such as bromocriptine inhibit lactogenesis. Weaning, or cessa-
tion of the lactation period, is followed by involution of the
terminal duct lobular units mediated by alveolar cell apoptosis
and gland remodeling, returning the breast to its mature qui-
escent state.
Hormonal Control of Milk Secretion
and Ejection
The onset of adequate milk production during the postpartum
period requires developed mammary epithelium, persistent
elevation in plasma prolactin, and a decrease in circulating
levels of progesterone. Milk secretion from the mammary
glands is triggered by stimulation of tactile receptors in the
nipples by suckling. Sensory impulses are transmitted to the
secretory oxytocinergic neurons in the hypothalamus, which
in response release oxytocin into the systemic circulation.
Oxytocin produces contraction of the myoepithelial cells of
the lactiferous ducts, sinuses, and breast tissue alveoli.
AGE-RELATED CHANGES IN THE
FEMALE REPRODUCTIVE SYSTEM
PUBERTY
Female puberty is initiated by low-amplitude nocturnal pulses
of gonadotropin release. The increased synthesis and secretion
of estrogen by the ovary cause the progressive skeletal matura-
tion that eventually leads to epiphysial fusion and the termina-
tion of linear growth. The onset of puberty causes a rapid
increase in bone mass that correlates with bone age. The initial
CHAPTER 68 Female Reproductive System 711
stage of puberty (at age 8–13) in girls involves breast develop-
ment, accompanied by ovarian and follicular growth. This is
followed by androgen- plus estrogen-induced pubic and axil-
lary hair growth and the onset of menses (approximately at
age 13), indicating sufficient estrogen production to stimulate
endometrial proliferation. The first cycles are usually anovula-
tory, becoming fully ovulatory after 2–3 years. In girls, serum
leptin concentrations increase as pubertal development pro-
gresses, and this increase in leptin levels parallels the increase
in body fat mass.
MENOPAUSE
Menopause is the permanent cessation of menstruation
resulting from loss of ovarian follicular activity. It is preceded
by a perimenopausal period, starting when the first features
of impending menopause begin (i.e., irregular menstrual
bleeding and cycle frequency) and lasting until at least 1 year
after the final menstrual period. During the menopausal
transition, gonadotropins, estradiol, and inhibin show a
marked degree of variability in their circulating levels. Within
1–2 years after the final menstrual period or the onset of
menopause, FSH levels are markedly increased, LH levels are
moderately high, and estradiol and inhibin levels are low or
undetectable. Postmenopausally, adrenal androstenedione is
the major source of estrogen, and serum testosterone levels
fall moderately.
Starting from the mid-thirties, ovarian follicular apoptosis
accelerates, leading to a steady decline in ovarian estradiol
production (Figure 68–11). This loss of ovarian function
results in a 90% loss of circulating estradiol. However, extrago-
nadal estrogen synthesis increases as a function of age and
body weight, and most of the estradiol is formed by extrago-
nadal conversion of testosterone. The predominant estrogen
in menopausal women is the weak estrogen estrone, produced
through aromatase conversion of androstenedione.
The decline in ovarian function associated with the peri-
menopausal period is also responsible for an early decline in
the release of inhibin B leading to an increase in follicular
phase FSH. The decrease in serum inhibin B is believed to
reflect the age-related decrease in ovarian follicle reserve,
which is the primary source of serum inhibin B. The later rise
in serum LH during the menopausal transition is due to the
cessation of ovarian follicle development. Despite a 30%
decrease in GnRH pulse frequency with aging, there is an
increase in the overall amount of GnRH secreted. FSH levels
gradually increase with age in women who continue to cycle
regularly. The consequences of loss of ovarian function during
reproductive life may be severe. Symptoms include hot flushes,
night sweats, vaginal dryness and dyspareunia (painful
intercourse), loss of libido, loss of bone mass with subsequent
osteoporosis, and abnormalities of cardiovascular function,
including a substantial increase in the risk of ischemic heart
disease. As already mentioned, estrogens (like androgens) have
general metabolic roles that are not directly involved in repro-
ductive processes. These include actions on vascular function,
712 SECTION IX Endocrine and Metabolic Physiology

Hormonal changes in menopause

Ovarian estradiol Adrenal estrone
Androgen: estrogen ratio
Progesterone levels

Negative feedback GnRH

FIGURE 68–11 Changes in
gonadotropin and ovarian
hormone production associated
with aging. Lower levels of inhibin
LH and FSH
B and estradiol result in impaired Aromatase
negative feedback regulation of
gonadotropin release, increasing
Testosterone Estradiol
FSH and LH. Production of Androstenedione Estrone
androstenedione and testosterone
during early menopause continues, Inhibin B Ovary
Adipose tissue
with some conversion to estradiol by Estradiol
aromatase activity in adipose tissue.
Adrenal-derived androstenedione is
converted to estrone, principally in Androstenedione
adipose tissue. (Reproduced with DHEA
permission from Gruber CJ et al. Production Progesterone
and actions of estrogens. NEJM. Adrenals
2002;346:340.)

lipid and carbohydrate metabolism, and bone mineralization

and epiphysial closure at sites such as breast, bone, vasculature,
and brain. Within these sites, aromatase action can generate
high levels of estradiol locally without significantly affecting
circulating levels. Circulating C19 steroid precursors are essen-
tial substrates for extragonadal estrogen synthesis. The levels
of these androgenic precursors decline markedly with advanc-
ing age in women, possibly from the mid to late reproductive
years. This is thought to contribute to the greater risk of bone
mineral loss and fracture, and possibly the decline in cognitive
function, in women as compared with men.
CONTRACEPTION AND THE
FEMALE REPRODUCTIVE TRACT
The multiple steps involved in the regulation of ovarian
hormone production, the consequent modifications of the
endometrium, and the regulation of uterine motility are all
under tight control, ensuring ovulation, fertilization, implan-
tation, and maintenance of pregnancy. Multiple approaches
have been implemented for contraception. Some of the princi-
pal interventions are summarized in Table 68–1.

TABLE 68–1 Principal contraceptive methods.

Method Mechanism Involved

Steroid contraceptives Suppression of LH surge preventing ovulation

Intrauterine devices Prevent blastocyst implantation by altering the endometrial lining

Some release progesterone, modifying the endometrial lining

Barrier methods: condoms, foam, and Prevent fertilization by either interfering with the access of sperm to the uterine cavity or
diaphragms destroying sperm in the vaginal cavity

Sterilization Surgically disrupts the continuity of the fallopian tubes, impairing access of the fertilized ovum to
the uterine cavity and implantation

Abortive Antiprogestin mifepristone produces an increase in prostaglandin F2α synthesis, leading to

expulsion of the embryo

Rhythm Relies on changes in mucus thickness and body temperature throughout the menstrual cycle,
indicating a “safe” period for intercourse

DISEASES OF OVERPRODUCTION
AND UNDERSECRETION OF
OVARIAN HORMONES
Alterations in female reproductive endocrine function are of
multiple etiologies and produce manifestations that range
from precocious puberty to infertility, depending on the age at
presentation. The most frequent are abnormalities in the men-
strual cycle, consisting of either absent menstruation (amen-
orrhea) or excess bleeding (metrorrhagia), and infertility.
Abnormalities of ovarian development and function are usu-
ally caused by defective development of the gonads and rarely
by defects in the synthesis of ovarian steroids. In general,
increased ovarian hormone production can be due to increased
gonadotropin release (hypergonadotropic hypergonadism)
related to tumors, brain inflammatory diseases, and head
injury, among other causes, or it can result from excess hor-
mone production by ovarian tumors. Decreased ovarian
hormone production can be genetic (e.g., FSH and LH recep-
tor gene mutations, mutation of the β-subunit of FSH, enzy-
matic deficiencies) or acquired (e.g., radiation) despite
adequate gonadotropin release (hypergonadotropic hypogo-
nadism). Decreased ovarian hormone production due to
impaired gonadotropin release (hypogonadotropic hypogo-
nadism) is rare and may result from GnRH receptor gene
mutations, lesions in the hypothalamic area, and other causes.
CLINICAL CORRELATION
CASE A
A postmenopausal woman presents with a history of acute
low back pain. She had menopause at 20 years prior to con-
sultation and has never received hormone replacement
therapy. She reports a history of a wrist fracture four years
before this visit. Lumbar spine films reveal a new vertebral
fracture. Dual-energy x-ray absorptiometry of the hip
shows a low bone mineral density. The diagnosis of osteo-
porosis is made.
Postmenopausal osteoporosis is a common disease with a
spectrum ranging from asymptomatic bone loss to disabling
hip fracture. Osteoporosis is a disease of increased skeletal
fragility accompanied by low bone mineral density measured
by dual-energy x-ray absorptiometry. Fractures occur because
of microarchitectural deterioration resulting from deteriora-
tion in the trabecular and cortical skeleton. Risk factors for
osteoporosis include low calcium and vitamin D intakes,
sedentary life, smoking, alcohol use, and low estrogen.
CASE B
A 19-year-old female ballet dancer is brought to the clinic
because she has never started menstruating. Height is normal
CHAPTER 68 Female Reproductive System 713
for her age and according to height of her parents. Body mass
index is 19%. Physical examination does not reveal abnormal-
ities in her clitoris or vagina. No physical problems are identi-
fied. Laboratory values are negative for elevations in prolactin.
The diagnosis of “exercise”-induced amenorrhea is made.
A frequent cause of amenorrhea in adolescents is hypo-
thalamic amenorrhea. Energy deficit results in suppression
of hypothalamic secretion of GnRH in anorexia nervosa,
exercise-induced amenorrhea, and amenorrhea associated
with chronic illness. This is in part mediated by leptin defi-
ciency due to decreased adipose tissue. Leptin is a hormone
secreted by adipose tissue and signals energy availability.
Young athletes, particularly ballet dancers, who start train-
ing at a young age, may present with primary amenorrhea,
and this is frequently associated with low BMI and body
weight. Additional factors that can contribute to lack of
menses are the decreased androgen aromatization to estro-
gen resulting from low fat mass.
CHAPTER SUMMARY
■ Gonadotropin release is under negative and positive feedback
regulation by ovarian steroid and peptide hormones.
■ Estrogen synthesis requires LH and FSH regulation of
coordinated metabolism by granulosa and theca cells of the
ovarian follicle.
■ LH and FSH rescue selected ovarian follicles from apoptosis
and stimulate their growth and maturation.
■ The corpus luteum is a temporary endocrine organ that plays a
central role during the initial stages of pregnancy.
■ The ovarian cycle produces cyclic changes in steroid hormone
production, which in parallel produce marked morphologic
and functional changes in the endometrium, preparing it for
embryo implantation.
■ Estrogen has important systemic effects affecting the risk of
cardiovascular disease, osteoporosis, and endometrial and
breast cancer.
■ Progesterone ensures uterine quiescence and prevents
lactogenesis during pregnancy.
■ Mammary gland morphologic development occurs during
puberty and is functionally modified during pregnancy by
prolactin and hPL, ensuring lactogenesis.
STUDY QUESTIONS
1. A 30-year-old female patient arrives at your office because of
missed menstrual periods for 2 months. Her history indicates
regular menstrual periods in the past. During physical
examination, you suspect that she may be pregnant. Which of the
following laboratory values would be compatible with your
diagnosis?
A) low plasma progesterone and high LH
B) high prolactin, low LH, and low progesterone
C) high urinary estradiol and low progesterone
D) high urinary hCG and increased plasma progesterone
714 SECTION IX Endocrine and Metabolic Physiology
2. A 5-month pregnant woman is referred to your office with newly
diagnosed hypertension. You are concerned that the fetus and
placenta may be compromised. To assess fetal and placental
health, which of the following hormone measurements would be
most informative?
A) urinary estriol and serum hCG
B) serum progesterone and prolactin
C) serum LH and hPL
D) urinary estriol and serum progesterone
3. Increased fasting plasma glucose levels in pregnant women with
no history of diabetes may be related to
A) increased estrogen production
B) decreased progesterone clearance
C) increased hPL/GH-V production
D) increased insulin degradation
4. The effects of progesterone on the myometrium during
pregnancy include
A) preventing electrical coupling between myometrial cells.
B) increased estradiol-induced α-adrenergic receptor
expression
C) decreased prostaglandin inactivation
D) increased prostaglandin synthase activity
5. Systemic and hepatic effects of estrogen include
A) increased serum concentrations of total cholesterol and
LDL
B) increased lipoprotein receptor expression
C) increased plasma concentrations of fibrinogen and
antithrombin III
D) decreased synthesis of thyroxine-binding globulin and
transcortin
 69
C H A P T E R

Endocrine Integration
of Energy and Electrolyte
Balance
Patricia E. Molina

O B J E C T I V E S

■ Identify the normal range of plasma glucose concentrations and the

hormonal regulation of its metabolism, storage, and mobilization.
■ Identify the specific roles of insulin, glucagon, glucocorticoids,
catecholamines, growth hormone, and thyroid hormone in the regulation of
energy substrate utilization, storage, and mobilization.
■ Describe the hormonal regulation of energy substrate metabolism during the
fed and fasted states and understand the consequences of its dysregulation.
■ Identify the mechanisms involved in the maintenance of long-term
energy balance.
■ Identify the normal range of dietary sodium intake, its body distribution, and
routes of excretion. Explain the roles of antidiuretic hormone, aldosterone,
angiotensin, and atrial natriuretic hormone in the regulation of sodium balance.
■ Identify the normal range of dietary potassium intake, its body distribution,
and routes of excretion. Explain the hormonal regulation of plasma potassium
concentration, distribution, and balance in the acute and chronic settings.

NEUROENDOCRINE REGULATION energy metabolism to different extents, according to age, sex,

OF ENERGY STORAGE,
MOBILIZATION, AND UTILIZATION
Two distinct phases directly related to the ingestion of a meal
alternate throughout the day in the regulation of energy metab-
olism. The fed state reflects overall anabolic metabolism, dur-
ing which energy is stored in the form of energy-rich compounds
(adenosine triphosphate [ATP], phosphocreatinine), glycogen,
fat, and proteins. The fasted or catabolic phase is the period
during which endogenous energy sources are utilized.
The anabolic and catabolic phases alternate to preserve ade-
quate glucose supply to the brain as well as sufficient energy to
maintain body functions, such as thermoregulation (maintain-
ing a constant core temperature), food digestion, and physical
activity. The two hormones at the core of maintaining this bal-
ance are insulin and glucagon; in particular, their ratio plays a
critical role in the dynamic regulation of substrate metabolism
(summarized in Table 69–1). However, several other established
and newly discovered hormones participate in the regulation of
nutritional state, and metabolic demands of the individual.
Because the autonomic nervous system also interacts with the
endocrine system in the modulation of glucose and fat metabo-
lism, the system is involved in neuroendocrine regulation. The
autonomic nervous system exerts its effects both directly and
indirectly. For example, activation of the sympathetic nervous
system through norepinephrine release from nerve terminals
and epinephrine release from the adrenal medulla stimulates
skeletal muscle glycogenolysis, glucagon release, and hepatic glu-
cose output while inhibiting the release of insulin (Figure 69–1).
NEUROENDOCRINE REGULATION
OF ENERGY METABOLISM
DURING THE FED STATE
Glucose
Blood glucose regulation occurs through interactions among
hormonal, neural, and hepatic autoregulatory mechanisms. Fol-
lowing a meal (postprandial state), in response to the increase

715

Ch69_715-728.indd 715 11/26/10 10:39:05 AM

716 SECTION IX Endocrine and Metabolic Physiology

TABLE 69–1 Regulation of metabolic processes acids are provided. GH and testosterone are of particular
by insulin/glucagon ratios. importance during growth and development, as well as during
adulthood and senescence.
Anabolic Metabolic Catabolic
(↑ I:G) Process (↓ I:G)
NEUROENDOCRINE REGULATION
↑ ↓
OF ENERGY METABOLISM
Glycogen synthesis
(liver and muscle)

↓ Glycogen breakdown ↑ DURING THE FASTED STATE

↓ Gluconeogenesis
↑ Fatty acid synthesis and
triglycerides (hepatocytes
and adipose tissue)
↑ Muscle protein synthesis
↑ Lipogenesis and
triglyceride formation
↓ Lipolysis
↓ Free fatty acid oxidation
↓ Ketone body formation
↓ Muscle proteolysis
I, insulin; G, glucagon.
↑ During the fasted postabsorptive state, catabolism of stored
↓ energy sources provides the energy required for bodily func-
tions. The amount of energy expended by an awake, resting indi-
vidual, measured 12–14 hours following the last meal, and at
↓ normal (or thermoneutral) body temperature is called the basal
metabolic rate (BMR). The BMR is the amount of energy
↓
required to maintain breathing, brain activity, enzymatic activity,
and other functions without any physical movement of the indi-
↑
vidual. Any deviation from the basal condition, such as changes
↑ in body temperature (fever or hypothermia), the level of activity
↑ of the individual (exercise or sleeping), or time from the last meal
(fed or fasted), will affect the metabolic rate. In addition, BMR
↑
can be directly affected by hormone action, particularly thyroid
hormones, which increase Na+/K+-ATPase activity and body
temperature, resulting in an increase in the BMR.

in pancreatic insulin release, glucose uptake is increased in

muscle, fat, and the liver; hepatic glucose output is suppressed;
and glycogen synthesis is increased.
Glucose disposal by insulin-sensitive tissues is regulated
initially by an increase in glucose transport and enzyme phos-
phorylation leading to the activation of glycogen synthase,
phosphofructokinase, and pyruvate dehydrogenase (see
Figure 66–5). The majority of insulin-stimulated glucose
taken up is stored as glycogen.
Fat
Most of the body’s energy reserve is stored in adipose tissue in
the form of triacylglycerol in the adipocytes. The principal hor-
mone involved in lipogenesis is insulin, through activation of
lipogenic enzymes. Opposing the effects of insulin are growth
hormone and leptin (described later), which inhibit lipogenesis.
The balance between lipogenesis and lipolysis followed by fatty
acid oxidation determines the overall accumulation of body fat.
Both processes are under hormonal and cytokine regulation.
Protein
The balance between protein synthesis and degradation is
regulated by interactions among hormonal, nutritional, neu-
ral, and inflammatory mediators. Hormonally, regulation of
protein metabolism is predominantly under the influence of
insulin, hGH, and insulin-like growth factor-I (IGF-I).
During the fed state, insulin acts primarily to inhibit proteoly-
sis, and GH stimulates protein synthesis. IGF-I has antiprote-
olytic effects during the postabsorptive state that progress to
stimulation of protein synthesis in the fed state or when amino
Glucose
In the resting postabsorptive state, release of glucose from the
liver through glycogenolysis and gluconeogenesis is the key
regulated process. During fasting, hepatic glucose production is
increased and peripheral glucose utilization is inhibited. Initially,
hepatic glucose output is derived from breakdown of hepatic gly-
cogen stores through glycogenolysis. Following an overnight
fast, glycogenolysis provides approximately 50% of the overall
hepatic glucose output. As hepatic glycogen stores are depleted
during a period of prolonged fasting (approximately 60 hours),
the contribution of glycogenolysis to hepatic glucose output
becomes negligible, with hepatic gluconeogenesis predominat-
ing. Glycogenolysis depends on the relative activities of glycogen
synthase and phosphorylase (see Figure 66–4). Gluconeogenesis
is regulated by the activities of fructose-1,6-diphosphatase, phos-
phoenolpyruvate carboxykinase, pyruvate kinase, and pyruvate
dehydrogenase, and by the availability of the principal gluconeo-
genic precursors, lactate, glycerol, glutamine, and alanine.
A smaller, yet significant amount (approximately 25%) of sys-
temic glucose production in the postabsorptive state is derived
from renal gluconeogenesis. Usually, the kidney is not a net pro-
ducer of glucose. The proximal tubule cells produce glucose at a
rate similar to that of glucose utilization by the renal medulla.
Fat
After an overnight fast, most of the resting energy requirement is
provided by oxidation of fatty acids derived from adipose tissue.
Lipolysis in adipose tissue is mostly dependent on the concentra-
tions of hormones (epinephrine stimulates lipolysis, and insulin
inhibits lipolysis). During a period of acute energy deprivation
 CHAPTER 69 Endocrine Integration of Energy and Electrolyte Balance 717

Pancreas

Glucagon
Insulin

Paraventricular
glucose nucleus
CRH, ADH
Pituitary
Locus ceruleus
Cortisol GH (noradrenergic
system)
Glycogenolysis Norepinephrine
Gluconeogenesis Gluconeogenic
ACTH
substrates

Cortisol FIGURE 69–1 Neuroendocrine response

FFA to exercise. A. The principal pathways activated
by stress are the hypothalamic–pituitary–adrenal
Epinephrine Sympathetic
FFA Norepinephrine ganglion
axis and the sympathetic nervous system,
Lipolysis resulting in the release of corticotropin-releasing
Norepinephrine
Dorsal-root hormone (CRH), antidiuretic hormone (ADH),
Glycogenolysis Neuropeptides
Heart rate ganglion catecholamines, and growth hormone (GH). In
FA oxidation Neuropeptides
Protein synthesis Blood pressure the periphery, increased production and release
Peripheral of cortisol, glucagon, and catecholamines and
vasoconstriction suppressed release of insulin favor an overall
B catabolic response. Stimulation of hepatic
Protein Glycogen Fat glycogenolysis and gluconeogenesis, muscle
glycogenolysis, and adipose tissue lipolysis
Amino acids Glucose Glycerol Fatty acids
ensures the production and mobilization of
energy stores to meet the enhanced metabolic
ATP Glycolysis
demands of the individual. Reproductive and
NH2 growth functions are inhibited, conserving
Pyruvate
energy to sustain fundamental processes that
CO2
Urea ensure survival. B. Stimulation of hepatic
Acetyl coenzyme A glycogenolysis and gluconeogenesis, muscle
glycogenolysis and adipose tissue lipolysis
Krebs cycle CO2 ensure the production and mobilization of
ATP energy stores to sustain the enhanced metabolic
demands of the individual as shown in the
Oxidative metabolic pathway. ATP, adenosine triphosphate;
O2 H2O
phosphorylation FFA, free fatty acid; FA, fatty acid. (Modified with
permission from Molina PE: Endocrine Physiology, 3rd ed.
ATP New York: McGraw-Hill Medical, 2010.)

or prolonged starvation, lipolysis mobilizes triglycerides, provid-
ing nonesterified fatty acids as energy substrates for tissues such
as muscle, heart, and liver; and substrates for glucose (glycerol)
and lipoprotein (free fatty acids) synthesis to the liver. Unlike
most other tissues, the brain cannot utilize fatty acids for energy
when blood glucose levels become compromised. In this case,
ketone bodies provide the brain with an alternative source of
energy, providing close to two thirds of the brain’s energy needs
during periods of prolonged fasting and starvation.
The release of glycerol and free fatty acids from adipose tis-
sue is inhibited by insulin and stimulated primarily by cate-
cholamines. During fasting, or more frequently during periods
of acute glucose deficiency (insulin-induced hypoglycemia)
or increased energy demand (as with strenuous exercise), cat-
echolamines play an important role in the stimulation of lipoly-
sis (Figure 69–1). The amount of energy stored as triglycerides
in adipose tissue is substantial. For example, an adult with 15 kg
of body fat has enough energy to support the whole body
energy requirements (8.37 MJ; 2,000 kcal) for about 2 months.
Protein
Unlike excess fat and glucose, which are stored as fat and gly-
cogen in adipose tissue, liver, and muscle, there is no storage
718 SECTION IX Endocrine and Metabolic Physiology
pool for body protein. Therefore, under catabolic conditions,
essential proteins are catabolized. Cortisol, epinephrine, and
glucagon together favor muscle protein breakdown and
hepatic amino acid uptake, some of which can be utilized for
gluconeogenesis.
COUNTERREGULATION
TO ACUTE STRESS
During acute decreases in plasma glucose (hypoglycemia) or in
response to acute stress, the role of the counterregulatory hor-
mones glucagon, epinephrine, growth hormone, and cortisol
becomes evident. Glucagon’s primary role is to stimulate hepatic
gluconeogenesis and glycogenolysis, resulting in an overall
increase in hepatic glucose output. GH and cortisol facilitate
glucose production and limit glucose utilization. Their effects
are not immediate; thus, they are mostly involved in defense
against prolonged hypoglycemia. Cortisol exerts permissive
effects on the lipolytic action of catecholamines and GH in adi-
pose tissue and on the glycogenolytic action of catecholamines
in skeletal muscle. In addition, cortisol induces hepatic enzy-
matic gene expression required for enhanced gluconeogenic
rates and exerts permissive effects on the stimulation of gluco-
neogenesis in the liver by glucagon and epinephrine.
Epinephrine stimulates hepatic glycogenolysis and hepatic
and renal gluconeogenesis, largely by mobilizing gluconeo-
genic precursors including lactate, alanine, glutamine, and
glycerol. It also limits glucose utilization by insulin-sensitive
tissues. The role of epinephrine is critical when glucagon
release is deficient. Together, glucagon and epinephrine act
within minutes to raise plasma glucose concentrations.
The contribution of the activation of the autonomic nervous
system is more easily understood when described in the context
of acute and severe hypoglycemia. The decrease in plasma glu-
cose concentrations (hypoglycemia) within and below the phys-
iologic postabsorptive concentration range of about 70–110 mg/
dL (3.9–6.1 mmol/L) triggers the activation of a counterregula-
tory neuroendocrine response. The release of counterregula-
tory hormones glucagon, epinephrine, GH, and cortisol
contributes to the increase in hepatic glucose output and the
suppression of tissue glucose uptake, partly through an increase
in tissue fatty acid oxidation. As plasma glucose levels are
restored, peripheral glucose sensors in the portal vein, small
intestine, and liver decrease firing. This afferent signal is trans-
mitted to the hypothalamus and to the nucleus solitarius in the
medulla through the vagus nerve, conveying information on the
prevailing peripheral glucose levels. In the hypothalamus, glu-
cose sensors contribute to the central nervous system integra-
tion of these signals. This initiates an appropriate response
through the inhibition of hepatic and adrenal nerve activity,
with consequently decreased release of adrenomedullary cate-
cholamines. The decreased sympathetic activation allows hyper-
glycemia to induce pancreatic insulin secretion. Thus, glucose
acts as a feedback signal contributing to integration of the neu-
roendocrine mechanisms that regulate its homeostasis.
MAINTENANCE OF LONG-TERM
ENERGY BALANCE AND FAT STORAGE
The balanced transition from fed to fasted and the consump-
tion of adequate energy commensurate with the level of physi-
cal activity ensure that adequate energy reserves are available
for short-term increases in metabolic demands, such as those
described for exercise. An imbalance in either energy intake or
expenditure leads to one of the following two extremes: loss of
lean body mass or wasting syndrome and obesity. In the
absence of chronic physical or psychiatric illness, development
of a wasting syndrome is infrequent. Obesity is an important
health problem that increases the risk of several diseases.
Because of the rising incidence of obesity in our society, a brief
discussion follows on the endocrine physiologic responses
implicated in the development of this condition.
Obesity
Obesity is defined as a significant increase above the ideal
weight. The increase in body mass index (BMI), an indicator
of the adiposity or fatness that accompanies obesity, has
become an important worldwide health problem. Life expec-
tancy is reduced when BMI is significantly increased. Obesity
is associated with an increased risk of type 2 diabetes melli-
tus, dyslipidemia, hypertension, heart disease, and cancer.
Approximately 30% of the US population is considered obese,
according to the definition of the World Health Organization.
Body weight and the excess weight gain leading to obesity
are determined by interactions among genetic, environmental,
and psychosocial factors that affect the physiologic mediators
of energy intake and expenditure, several of which pertain to
the endocrine system. Energy expended by the individual can
be in the form of work (physical activity) or heat production
(thermogenesis), which can be affected by environmental
temperature, diet, and the neuroendocrine system (cate-
cholamines and thyroid hormone). The uncoupling of ATP
production from mitochondrial respiration dissipates heat
and affects the efficiency with which the body utilizes energy
substrates. The expression of proteins involved in this process
(uncoupling protein-1 expressed in brown adipose tissue and
uncoupling protein-3 in skeletal muscle) is modulated by cat-
echolamines, thyroid hormones, and leptin.
The role of genetics in the predisposition to obesity has been
demonstrated convincingly. Susceptibility genes have been
identified that increase the risk of developing obesity, and their
relevance has been shown in studies in which pairs of twins
were exposed to periods of positive and negative energy bal-
ance. The differences in the rate of weight gain, the proportion
of weight gained, and the sites of fat deposition showed greater
similarity within pairs than between pairs, indicating a close
genetic relationship. Although a clear correlation between
energy expenditure and weight gain has not been demon-
strated, increasing physical activity, which represents
20–50% of total energy expenditure, has been actively pro-
moted as an approach to prevent obesity and improve insulin
 CHAPTER 69 Endocrine Integration of Energy and Electrolyte Balance
responsiveness. Environmental factors are also thought to
unmask genetic tendencies toward obesity.
The responsiveness to hormones that regulate lipolysis
varies according to the distribution of fat depots. The lipoly-
tic response to norepinephrine is greater in abdominal than
in gluteal or femoral adipose tissue in both men and women.
The exaggerated release of free fatty acids from abdominal
adipocytes directly into the portal system, an increased
hepatic gluconeogenesis, and hepatic glucose release, and
hyperinsulinemia are hallmarks of patients with upper-body
obesity. The endocrine properties of the different fat depots
may be more important than the anatomic location. The
severity of medical complications is more closely related to
body fat distribution, being greater in individuals with
abdominal (visceral) obesity than those with an excess total
body fat. Differential fat deposition leading to upper-body or
abdominal obesity is reflected in a high waist–hip ratio, an
index used for predicting risks associated with fat accumula-
tion. The presence of visceral obesity, insulin resistance, dys-
lipidemia, and hypertension is collectively termed the
metabolic syndrome.
Excess energy intake in relation to the energy expended by
the organism leads to the accumulation of fat. The fat mass
itself is determined by the balance between breakdown
(lipolysis) and synthesis (lipogenesis). The sympathetic ner-
vous system is the principal stimulator of lipolysis, particu-
larly when the energy demands of the individual are
increased. When intake exceeds energy utilization, lipogen-
esis occurs in liver and adipose tissue. Lipogenesis is influ-
enced by diet (increased by carbohydrate-rich diets) and
hormones (principally GH, insulin, and leptin) through
modification of transcription factors (e.g., peroxisome pro-
liferator-activated receptor-γ [PPAR-γ]). The transcription
factor PPAR, the target for the insulin sensitizer thiazolidin-
edione drugs, affects gene transcription of several enzymes
involved in glucose and fat metabolism and is involved in
preadipocyte differentiation into mature fat cells. The main
hormones involved in fat storage are insulin (which stimu-
lates lipogenesis), and GH and leptin (which reduce lipogen-
esis). Other hormones involved in the regulation of body fat
stores include testosterone, dehydroepiandrosterone, and
thyroid hormone.
Regulation of Energy Intake
Regulation of energy intake is mediated by several factors.
Central integration of peripheral signals, including those
mediated by mechanoreceptors and chemoreceptors, signals
the presence and energy density of food in the gastrointestinal
tract. Hypothalamic glucose sensors monitor fluctuations in
circulating glucose concentrations. Hormones signal the cen-
tral release of peptides that regulate appetite and satiety. Two
hormones that have been identified as crucial in the long-term
regulation of energy balance are insulin and leptin, the prod-
uct of the ob gene (discussed later). Both hormones are
released in proportion to body fat (Figure 69–2). In the brain,
719
they modulate the expression of hypothalamic neuropeptides
known to regulate feeding behavior and body weight, resulting
in inhibition of food intake and increase in energy expendi-
ture. While insulin release is directly correlated to meals, that
of leptin does not correlate with food intake but reflects body
fat mass (Figure 69–2).
Hypothalamic Integration
The hypothalamus receives innervation from several areas,
notably the nucleus tractus solitarius and area postrema in
the brainstem. These areas relay many neural and hormonal
signals from the gastrointestinal tract. Mechanical stretch
receptors sense stretch of the stomach and other areas of the
intestine. Gastrointestinal hormones such as cholecystokinin
(CCK), released following a meal in response to the presence
of lipids or protein in the intestinal lumen, are involved in
afferent signaling to the brain regarding the intestinal nutri-
tional content. The nucleus tractus solitarius also relays taste
information to the hypothalamus and other centers. Other sig-
nals regarding smell, sight, memory of food, and the social
context under which it is ingested are also integrated and may
also influence energy intake by modulating output from the
hypothalamus. Integration of these signals results in the acti-
vation of gene expression of mediators implicated in the regu-
lation of satiety and development of obesity. These genes
control thermogenesis (uncoupling proteins), hormone syn-
thesis (ghrelin, leptin, and CCK and adiponectin), and neu-
rotransmitter (neuropeptide Y) availability, as summarized in
Table 69–2.
The relative contributions of these mediators to the regula-
tion of caloric intake, energy expenditure, body weight, and fat
mass are not completely understood. However, important new
discoveries, such as the secretory function of adipose tissue,
have provided new insight into potential factors contributing
to obesity. Adipose tissue is an endocrine tissue participating in
a complex network regulating energy homeostasis, glucose and
lipid metabolism, vascular homeostasis, immune response,
and even reproduction. Among the hormones identified that
are produced by adipose tissue are leptin, cytokines (TNF-α,
interleukin-6), adipsin and acylation-stimulating protein,
angiotensinogen, plasminogen activator inhibitor-1, adi-
ponectin, resistin, and steroid hormones (Table 69–2). Secre-
tion of almost all of these hormones and cytokines is
dysregulated as a consequence of both excess and deficiency in
the mass of adipose tissue, suggesting that they are involved in
the pathophysiology of both obesity and cachexia. Of particu-
lar interest are the contributions of the proinflammatory cytok-
ines, such as TNF-α, to the development of insulin resistance
in obese individuals and the potential role of leptin as a regula-
tor of fat mass.
Leptin
Leptin is a peptide hormone (146 amino acids) thought to
serve as an indicator of energy stores, as well as a modulator of
720 SECTION IX Endocrine and Metabolic Physiology

Arcuate
nucleus Nucleus
of the
solitary tract
Hypothalamus
Vagus
nerves
Spinal
nerves Neurons
PVN in other
hypothalamic
Orexigenic areas

Anorexigenic
Ghrelin ARC NPY/
AgRP
Leptin Insulin POMC/
CART

PYY CCK NPY-Y1R MC3 R Ghrelin R Hunger Thermogenic response

NPY-Y2R MC4 R Leptin R
NPY-Y4R Insulin R Meal size Energy stores
GLP-1R
Meal duration Substrate metabolism

Intake Expenditure

Stretch
Chemoreceptors
Nutrients

– + – +
– Insulin
Ghrelin + Leptin
PYY3-36

Stomach
Adipose tissue Pancreas
(or duodenum)

FIGURE 69–2 The brain integrates multiple peripheral and neural signals to control the regulation of energy homeostasis,
maintaining a balance between food intake and energy expenditure. The hypothalamus receives innervation from several areas, notably the
nucleus tractus solitarius and area postrema in the brainstem, that relay many neural and hormonal signals from the gastrointestinal tract, such
as mechanical signals indicating stretch of the stomach and other areas of the intestine; and hormonal signals indicating the presence of food in
the gut, such as CCK. Additional signals regarding smell, sight, memory of food, and the social context under which it is ingested are also
integrated and may also influence energy intake by modulating output from the hypothalamus. Collectively, these signals act on two subsets of
neurons that control food intake in the arcuate nucleus of the hypothalamus (ARC), which stimulate and inhibit energy intake. Orexigenic
(appetite-stimulating) neurotransmitters are agouti-related peptide (AgRP) and neuropeptide Y (NPY). Anorexigenic (appetite-suppressant)
neurotransmitters are cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) neurotransmitters. Both
neuronal populations innervate the paraventricular nucleus (PVN), which, in turn, sends signals to other areas of the brain. These include
hypothalamic areas such as the ventromedial nucleus, dorsomedial nucleus, and the lateral hypothalamic area, which modulate this control
system. Brain circuits integrate information from the NTS and multiple hypothalamic nuclei to regulate overall body homeostasis. Leptin and
insulin decrease appetite by inhibiting the production of neuropeptide Y (NPY) and AgRP, while stimulating melanocortin-producing neurons in
the arcuate nucleus region of the hypothalamus. NPY and AgRP stimulate eating, and melanocortins inhibit eating. Ghrelin stimulates appetite
by activating the NPY/AgRP-expressing neurons. PYY3-36, released from the colon, inhibits these neurons and transiently decreases appetite.
Integration of these signals results in regulation of energy intake, satiety, control of thermogenesis, and energy expenditure.

energy balance. The specific effects of leptin on fat metabo-
lism are as follows:
• decrease in fat storage;
• increase in sympathetic-mediated energy expenditure;
• increase in expression of uncoupling proteins;
• decrease in triglyceride content by increasing fatty acid
oxidation;
• decrease in activity and expression of esterification and
lipogenic enzymes;
• decrease in lipogenic activity of insulin, favoring lipolysis.
 CHAPTER 69 Endocrine Integration of Energy and Electrolyte Balance 721

TABLE 69–2 Mediators implicated in regulation of energy intake.

Mediator Regulation and Target Effect

Gastrointestinal tract

Cholecystokinin Released in the duodenum during a meal. Stimulates the vagus nerve projecting
to the NTS and signals within the hypothalamus to induce satiety

Ghrelin Released from the GI tract before meals. Plasma levels are low in obese patients.
Stimulates growth hormone release, decreases fat oxidation, increases food
intake and adiposity. Overall has antileptin action

PYY3-36 Member of the neuropeptide Y family, released in the distal small intestine
and colon in response to food. Blood levels remain elevated between meals.
Decreases food intake at the arcuate nucleus in the hypothalamus

Adipose tissue

Adiponectin (adipocyte complement-related Produced by adipose tissue (decreased in obese patients; plasma levels correlate negatively
protein of 30 kDa, AdipoQ) with triglycerides). Increases insulin sensitivity and tissue fat oxidation, resulting in reduced
circulating fatty acid levels and reduced intramyocellular and liver triglyceride content

Acylation-stimulating protein Produced by adipose tissue. Paracrine signal increases efficiency of triacylglycerol
synthesis in adipocytes, resulting in more rapid postprandial lipid clearance

Leptin Produced in adipose tissue. Acts on neuropeptide Y, AgRP-containing neurons, and

α-MSH neurons in the arcuate nucleus of the hypothalamus to decrease food intake

Resistin Peptide hormone induced during adipogenesis. It antagonizes insulin action

Hypothalamus

Neuropeptide Y (NPY) Produced by hypothalamic neurons that express AgRP. Release is under leptin, insulin,
and cortisol regulation. Stimulates food intake via the NPY5 receptor

α-MSH Product of POMC in hypothalamic neuronal subset under leptin regulation.

Decreases food intake through melanocortin-4 receptors in the hypothalamus

Cocaine- and amphetamine-regulated Leptin and amphetamines stimulate production of this peptide
transcript (CART) by hypothalamic POMC-expressing neurons. Reduces food intake

Agouti-related peptide (AgRP) Released from hypothalamic NPY-expressing neurons. Inhibits

neuronal melanocortin-4 receptors and increases food intake

Orexins (A and B) Produced by neurons in the lateral hypothalamus perifornical area. Regulated
by glucose, leptin, neuropeptide Y, and POMC neurons. They stimulate food intake
NTS, nucleus tractus solitarius; GI, gastrointestinal; PYY, polypeptide YY; AgRP, agouti-related peptide; MSH, melanocyte-stimulating hormone; POMC, proopiomelanocortin.

Leptin produced by white adipose tissue functions as a sig-
nal that provides information about the level of energy stores
(adipose tissue mass). The signal is integrated by hypotha-
lamic neurons, and an effector response, most likely involving
modulation of appetite centers and sympathetic nervous sys-
tem activity, regulates the two main determinants of energy
balance: intake and expenditure. Leptin secretion exhibits a
circadian rhythm, with a nocturnal rise over daytime secre-
tion. These changes in leptin plasma concentrations are not
influenced by meal ingestion and meal-induced increases in
the circulating insulin concentration.
The effects of leptin are mediated through the leptin recep-
tor, a member of the gp130 family of cytokine receptors, which
activates a gene transcription factor on two populations of
hypothalamic neurons. This process results in reduced expres-
sion of two orexigenic (feeding-inducing) neuropep-
tides, neuropeptide Y and agouti-related peptide (AgRP);
and enhanced expression of two anorexigenic peptides,
α-melanocyte-stimulating hormone (α-MSH) and cocaine-
and amphetamine-regulated transcript (CART). Thus, lep-
tin-induced inhibition of food intake results from both the
suppression of orexigenic and the induction of anorexigenic
neuropeptides (Figure 69–2).
The feedback regulatory loop for leptin’s effects has been
well established in rodents; however, many unsolved questions
remain about its applicability to body weight regulation in
humans. The role of leptin in humans appears to be mostly
one of the adaptations to low energy intake rather than a brake
on overconsumption and obesity. Leptin concentrations
decrease during fasting and energy-restricted diets, indepen-
dent of body fat changes, stimulating an increase in food intake
before body energy stores become depleted. Because leptin
levels do not increase in response to individual meals, it is not
thought to serve as a meal-related satiety signal. Finally, it is
notable that obese individuals have high plasma leptin con-
centrations that do not result in the expected reduction in
food intake and increase in energy expenditure, suggesting
that obesity is related to leptin resistance.
722 SECTION IX Endocrine and Metabolic Physiology
Ghrelin
Ghrelin is a hormone produced by the enteroendocrine cells
of the stomach, and to a lesser extent by the pituitary, and
hypothalamus. Circulating levels of ghrelin decrease during
meals and are highest in the fasted state. Ghrelin levels are
decreased in obese individuals and increased in individuals
consuming low calorie diets, chronic strenuous exercise, can-
cer anorexia, and anorexia nervosa. In humans, ghrelin has
been shown to be a potent growth hormone secretagogue and
appetite stimulant.
ELECTROLYTE BALANCE
REGULATION OF SODIUM BALANCE
Sodium is the primary electrolyte that regulates extracellular
fluid (ECF) levels and osmolarity in the body. Regulation of
extracellular Na+ concentration controls the distribution of
water between the ECF and intracellular fluid (ICF) and main-
tains cell volume, ensuring normal physiologic function.
Sodium is maintained in the ECF by the action of Na+/K+-
ATPase, whereas water crosses cell membranes through ubiq-
uitously expressed aquaporins (maintaining ICF and ECF
isotonicity). The overall mass of Na+ is under aldosterone reg-
ulation, whereas the Na+ concentration in plasma is under
antidiuretic hormone (ADH) regulation. Thus, low Na+ con-
centrations do not necessarily mean that total Na+ mass is low.
In chronic heart failure, osmolarity can be low, yet Na+ mass
can be high because of excess water and Na+ in the ECF, with
greater increases in total body water than in Na+ mass.
Hormonal Regulation
of Sodium and Water Balance
The system that controls total body water is a negative feed-
back homeostatic mechanism, of which thirst and ADH are
the major effectors. Two stimuli regulate the system: tonicity
of the ECF through osmoreceptors and intravascular volume
through stretch or baroreceptors.
The system works primarily to maintain intravascular vol-
ume and to a lesser extent to maintain tonicity. Thirst is stimu-
lated by an increase in tonicity (1–2% changes are sufficient to
elicit thirst) and by reductions in the ECF volume. Water intake
is inhibited by hypotonicity and ECF volume expansion.
Sudden decreases in blood volume are sensed by mechano-
receptors in the left ventricle, carotid sinus, aortic arch, and
renal afferent arterioles (Figure 69–3). These mechanorecep-
tors respond to decreased stretch resulting from decreases in
systemic arterial pressure, stroke volume, renal perfusion, or
peripheral vascular resistance by triggering an increase in
sympathetic outflow from the central nervous system, activa-
tion of the renin–angiotensin–aldosterone system, and
nonosmotic release of antidiuretic hormone, as well as stimu-
lation of thirst. Low blood pressure results in decreased renal
perfusion pressure and lower glomerular filtration rates, which
stimulate the release of renin from juxtaglomerular cells in the
afferent and efferent arterioles.
Antidiuretic hormone ADH directly controls water ex-
cretion by the kidneys. ADH secretion and compensatory
thirst are stimulated by hypothalamic osmoreceptors and by
decreased stimulation of aortic and carotid stretch receptors.
Release of ADH is inhibited by increased stretch of mechano-
receptors (stretch receptors) in the atria of the heart. ADH
stimulates insertion of aquaporins into the cell membrane, in-
creases water reabsorption in the collecting ducts, and concen-
trates excreted urine.
Angiotensin II Angiotensin II increases blood pressure by
several mechanisms, including direct vasoconstriction, poten-
tiation of the activity of the sympathetic nervous system at both
the central and peripheral levels, stimulation of aldosterone
synthesis and release with consequent sodium reabsorption by
the kidney, stimulation of ADH release and increased water re-
tention, and intrarenal efferent arteriolar constriction.
Aldosterone Aldosterone increases sodium reabsorption and
potassium excretion in the distal tubule and the collecting duct of
the nephron, playing a central role in determining total body Na+
mass, and thus long-term blood pressure regulation. Aldosterone
release from the adrenals is stimulated by angiotensin II.
Atrial natriuretic factor Atrial natriuretic factor is a pep-
tide hormone produced in atrial myocardial cells and released in
response to increased stretch, usually resulting from increased
intravascular volume. It increases renal Na+ excretion and water
loss through an increase in glomerular filtration rate and a de-
crease in Na+ reabsorption in the medullary collecting duct.
Abnormalities in Sodium
and Water Balance
Abnormalities in sodium and water balance can be classified
into four categories. Excess Na+ is characterized by expansion
of the ECF volume and frequently by low effective circulating
blood volume (i.e., heart failure, hypoalbuminemia, renal
insufficiency). Deficit in Na+ is characterized by reduced ECF
volume. Excess water is due to either excess intake or
enhanced ADH release and is manifested by hyponatremia
and hypoosmolarity. Water deficit is due to lack of intake or
excess loss (renal and nonrenal) and is manifested by hyper-
natremia and hyperosmolarity.
REGULATION OF POTASSIUM BALANCE
Potassium is the most abundant cation in the body and the
main intracellular electrolyte. Most (98%) of the potassium in
the body is sequestered within cells. The ratio of extracellular to
intracellular potassium (1:10) is maintained by a sodium–
 CHAPTER 69 Endocrine Integration of Energy and Electrolyte Balance 723

Cardioregulatory
center

Glossopharyngeal
& vagal afferents
from baroreceptors
Sympathetic trunk

Sympathetic ganglia

AVP
Sympathetic
nerves
Aldosterone FIGURE 69–3 Neuroendocrine control
of blood volume. Sudden decreases in blood
volume are sensed by mechanoreceptors in the
left ventricle, carotid sinus, aortic arch, and renal
afferent arterioles, triggering an increase in
Renin
Angiotensin II sympathetic outflow from the central nervous
production system, activation of the renin–angiotensin–
Peripheral
vasoconstriction aldosterone system, nonosmotic release of
arginine vasopressin (AVP), and stimulation of
thirst. The decreases in renal perfusion pressure
and glomerular filtration rates stimulate the
release of renin, the enzyme responsible for
the conversion of angiotensinogen to
angiotensin I (later converted by angiotensin-
converting enzyme to angiotensin II).
Angiotensin II, aldosterone, and ADH produce
vasoconstriction, venoconstriction, and renal
Water reabsorption retention of Na+ and water. (Modified with
Na reabsorption permission from Molina PE: Endocrine Physiology, 3rd ed.
K+ excretion New York: McGraw-Hill Medical, 2010.)

potassium pump and is the major determinant of resting mem-
brane potential. Small losses (1%, or 35 mmol) of total body
potassium content can seriously disturb the delicate balance
between intracellular and extracellular potassium and can result
in profound physiologic changes. The tissues most severely
affected by potassium imbalance are muscle and renal tubular
cells. Manifestations of hypokalemia include generalized mus-
cle weakness, paralytic ileus, and cardiac arrhythmias.
Intake, Distribution, and
Excretion of Potassium
The daily intake of potassium in the Western diet is about
80–120 mmol, and this exceeds the minimum daily require-
ment. Only a small fraction (10%) of potassium is excreted
through the gastrointestinal tract and the majority is excreted by
the kidney. Thus, the kidney is responsible for long-term potas-
sium homeostasis, as well as for regulating the serum potassium
concentration. On a short-term basis, serum potassium is also
regulated by the shift of potassium between the ICF and ECF.
This short-term regulation of serum potassium is principally
controlled by insulin and catecholamines through regulation of
the transcellular distribution of potassium. Dietary potassium,
which is rapidly absorbed by the gut, increases serum potassium
transiently. The release of insulin and catecholamines during a
meal quickly shifts the potassium into the cells.
The principal site for the regulation of K+ excretion is the
distal tubule, where secretion is indirectly but tightly coupled
724 SECTION IX Endocrine and Metabolic Physiology

to sodium reabsorption via the amiloride-sensitive sodium
channel, and under regulation by aldosterone. Because the
kidney is the major regulator of potassium homeostasis, renal
dysfunction results in abnormal levels of serum potassium.
Potassium contributes to regulation of its balance by stimu-
lating aldosterone secretion by the zona glomerulosa cells of
the adrenal cortex. Aldosterone enhances renal and colonic
K+ secretion, promoting the loss of K+ in the urine and stool
(Figure 69–4). Sustained hyperkalemia does not occur in
individuals with normal renal function despite marked
increases in potassium intake because of an adaptive change in
distal tubular K+ secretion, such that intake is matched by
rapid and equivalent increases in K+ excretion. The mecha-
nisms involved in the chronic adaptation to increased levels of
K+ include changes in apical K+ and Na+ conductance and in
basolateral Na+/K+-ATPase pump activity, an increase in api-
cal Na+ delivery and reabsorption, and an increase in K+ excre-
tion per nephron to match K+ intake.
Hormonal Regulation
of Potassium Balance
Total body stores of potassium and its cellular distribution in
the body are closely regulated by key hormones.
Aldosterone Aldosterone increases the synthesis and activity
of Na+/K+-ATPase in the basolateral membrane of the distal tu-
bule, promoting the exchange of cytosolic Na+ for K+. The overall
result is an increase in Na+ reabsorption and an increase in K+
excretion.
Insulin Insulin stimulates entry of K+ into the cell through
activation of the electroneutral Na+/H+ antiporter, leading to
Na influx. The increase in intracellular Na+ produced by insu-
lin triggers the activation of the electrogenic Na+/K+-ATPase,
which extrudes Na+ from the cell in exchange for K+. The treat-
ment of patients with diabetic ketoacidosis with high insulin
doses produces a significant influx of K+ into the cells that may
result in hypokalemia, manifested by changes in the electro-
cardiogram.
Catecholamines Catecholamines (β-adrenergic receptor
stimulation) increase cellular potassium uptake by stimulating
cell membrane Na+/K+-ATPase. Indirectly, catecholamines
stimulate glycogenolysis, resulting in a rise in plasma glucose
concentrations, release of insulin from the pancreas, and insu-
lin-mediated effects on K+ redistribution. Stimulation of the
α-adrenergic receptor shifts K+ out of the cell and can also af-
fect K+ distribution through inhibition of pancreatic insulin
release.
Insulin and catecholamines are both stimulated by the inges-
tion of glucose- and potassium-rich foods, thereby maintain-
ing K+ homeostasis despite large dietary intake. These hormones
are essential in moving potassium primarily into the intracel-
lular compartment of the liver and striated muscle cells.

β-Adrenergic Potassium concentration in extracellular fluid

catecholamines
Insulin Aldosterone
Cortical
Na+ collecting-
K+
duct cells K+
Na+
Na+
H+
Na+/K+ Na+/K+
-ATPase Na+ -ATPase
Na+
K+ K+

Na+

Na+
K+
Muscle Na+
cell
Lumen

A B
FIGURE 69–4 Key hormones involved in normal potassium homeostasis. A) Insulin stimulates entry of K+ into the cell through the
activation of the electroneutral Na+/H+ antiporter. The increase in intracellular Na+ produced by insulin triggers the activation of the electrogenic
Na+/K+-ATPase, which extrudes Na+ from the cell in exchange for K+. Catecholamines (β-adrenergic receptor stimulation) increase cellular
potassium uptake by stimulating cell membrane Na+/K+-ATPase. Stimulation of the α-adrenergic receptor shifts K+ out of the cell. B) Aldosterone
promotes potassium excretion through its effects on the Na+/K+-adenosine triphosphatase (ATPase) and epithelial sodium and potassium
channels in collecting duct cells. Angiotensin II has a synergistic effect on the stimulation of aldosterone production induced by hyperkalemia.
(Reproduced with permission from Gennari F. Current concepts: Hypokalemia. NEJM. 1998;339:451. Copyright Massachusetts Medical Society. All Rights reserved.)
 CHAPTER 69 Endocrine Integration of Energy and Electrolyte Balance
Acid–Base and Osmolar Regulation
of Potassium Distribution
Intracellular potassium homeostasis is also affected by changes
in acid–base balance and osmolarity. Sudden changes in
plasma osmolarity redistribute water between the ICF and
ECF. This movement of water out of a cell creates a solvent
drag phenomenon, pulling K+ out of the cell and therefore
increasing serum potassium. Similarly, metabolic acidosis
caused by a loss of bicarbonate or a gain in hydrogen ion con-
centration [H+] leads to a shift of K+ across cell membranes
and hyperkalemia. However, integrity of renal function and
stimulation of aldosterone release rapidly correct this imbal-
ance. In diabetic ketoacidosis, there is a net loss of K+ from the
body because of osmotic diuresis, despite elevations in ECF K+
concentrations (hyperkalemia), because of insulin deficiency.
Following aggressive insulin treatment, hypokalemia becomes
apparent. Opposite effects are observed during alkalosis. In
metabolic alkalosis, the excess bicarbonate causes H+ in the
ECF to fall, leading to entry of Na+ into the cell in exchange for
H+. Na+ is pumped out of the cell by the Na+/K+-ATPase in
exchange for K+ movement into the cell, creating a shift of K+
into the cells.
Hypokalemia is a common electrolyte abnormality encoun-
tered in clinical practice. It is almost always the result of potas-
sium depletion induced by abnormal fluid losses (i.e., vomiting,
colonic diarrhea, profuse sweating, diuretic use, or nasogastric
suction). Patients present with muscle weakness and changes
in the electrocardiogram. More rarely, hypokalemia occurs
because of an abrupt shift of potassium from the ECF into
cells, frequently as an effect of prescription drugs. Hyper-
kalemia, also a common electrolyte disorder, is caused by
renal dysfunction, decreased aldosterone production by the
adrenal gland, potassium shifting from the intracellular to the
extracellular compartment, and some drugs. Patients can pres-
ent asymptomatic or have altered electrocardiogram.
NEUROENDOCRINE REGULATION
OF THE STRESS RESPONSE
Alterations in the environment or in the host that require
adaptation involve the synchronized interaction of virtually all
aspects of neuroendocrine function that have been described
(Figure 69–5). The adaptation to a biologic, psychosocial, or
environmental insult to the host is referred to as the stress
response; in the acute setting, it is also termed the fight-or-
flight response. It is now clear that this stress response can be
chronic, with a significant cost to the health of the individual
(Figure 69–5).
Chronic activation of the mechanisms that restore homeo-
stasis results in excessive and, in some cases, inadequate
responses that ultimately alter the function of virtually all
organ systems (e.g., hypertension, autoimmune disorders,
metabolic syndrome) (Figure 69–5). Many of the effects of this
725
dysregulated state are mediated by chronic activation of the
hypothalamic–pituitary–adrenal (HPA) axis and the sympa-
thetic nervous system, producing marked alterations in endo-
crine function, such as the following:
• Inhibition of reproduction function: Enhanced release of
corticotropin-releasing hormone (CRH) and β-endorphin
suppresses GnRH release directly and indirectly through
the release of glucocorticoids. Glucocorticoids decrease the
release of luteinizing hormone and produce gonadotropin
resistance at the gonads. This suppression in gonadal func-
tion is evident in patients with anorexia nervosa, athletes,
and ballet dancers.
• Inhibition of the GH–IGF-I axis: Chronic activation of the
HPA axis suppresses GH release and inhibits the effects of
IGF-I at target tissues.
• Suppression of thyroid function: CRH and cortisol sup-
press the production of thyroid-stimulating hormone and
inhibit the activity of peripheral 5ʹ-deiodinase, leading to
the euthyroid sick syndrome.
• Dysregulation of energy substrate metabolism: An in-
crease in catecholamines stimulates lipolysis and decreases
triglyceride synthesis in white adipose tissue. In the liver,
increased epinephrine levels stimulate hepatic glycogenoly-
sis and, together with high cortisol levels, increase hepatic
glucose output. High cortisol levels resulting from activa-
tion of the HPA increase gluconeogenesis, produce insulin
resistance in peripheral tissues, inhibit the lipolytic action of
GH, and inhibit bone osteoblastic activation (remodeling)
by sex steroids. This leads to increases in visceral adiposity
and loss of BMD and lean body mass. This aspect of the
stress response may be of particular importance in the treat-
ment of diabetic patients during stressful periods such as
surgery or infection.
• Alterations in the Immune Response: The significant in-
crease in circulating cortisol levels affects virtually all as-
pects of the immune response, including cytokine pro-
duction, leukocyte trafficking and recruitment, and
production of chemokines. Overall, glucocorticoids exert
an anti-inflammatory response. Activation of the auto-
nomic nervous system also affects the immune response
through effects on neutrophil demargination and cytokine
production.
Short-term activation of these stress response mechanisms
ensures that energy substrates are available to meet the increased
metabolic demands of the individual. However, prolonged
duration and increased magnitude of these activities lead to
erosion of lean body mass and tissue injury. Nevertheless,
impaired activation or lack of responsiveness of the HPA and
autonomic nervous system can also be deleterious, as in the
case of the critically ill patient. Thus, the overall regulation of
the neuroendocrine responses that mediate the physiologic
functions involved in maintaining and restoring homeostasis is
critically important in situations such as illness, trauma, sur-
gery, or fasting.
726 SECTION IX Endocrine and Metabolic Physiology

Stress
Developmental history
Nutrition
Genetic variation
Aging

CRH Stress system LC

ADH NE

Systemic sympathetic
HPA axis adrenomedullary systems

Cortisol NE, E
Target tissues
GH and/or
IGF-I Metabolic syndrome
(insulin resistance, visceral obesity, sarcopenia) Sleep apnea
LH, T, E2
TSH, T3
TG APR ABP
LDL Cytokines Coagulopathy
Osteopenia
Polycystic HDL
or
ovary syndrome
osteoporosis

Endothelial dysfunction
and inflammation

Atherosclerosis
Cardiovascular and
neurovascular disease

FIGURE 69–5 Neuroendocrine responses to chronic or severe stress. Chronic activation of the neuroendocrine response to restore
homeostasis influences virtually all organ systems. The short-term activation of these stress response mechanisms ensures that energy
substrates are available to meet the increased metabolic demands of the individual. However, prolonged duration and increased magnitude
of these activities lead to erosion of lean body mass and tissue injury. ABP, arterial blood pressure; ACTH, adrenocorticotropic hormone; APR,
acute-phase reactants; ADH, antidiuretic hormone; CRH, corticotropin-releasing hormone; iCRH, immune CRH; E, epinephrine; E2, estradiol; GH,
growth hormone; HPA, hypothalamic–pituitary–adrenal; IGF-I, insulinlike growth factor I; IL-6, interleukin 6; LC, locus ceruleus; LH, luteinizing
hormone; NE, norepinephrine; T, testosterone; TG, triglycerides. (Adapted with permission from Chrousos G. Stress and disorders of the stress system. Nat Rev
Endocrinol. 2009;5(7):347–381, 2009.)

CLINICAL CORRELATION
A woman with type 1 diabetes mellitus on an insulin
pump is brought to the emergency room after she fainted
during her daily exercise class. First responders adminis-
tered intravenous glucose solutions after obtaining a
blood sample for analysis. On examination, she is tachy-
cardic and agitated, and has sweaty palms. Laboratory
values showed high insulin and low plasma glucose levels.
A diagnosis of insulin-induced hypoglycemia is made.
Diabetic patients treated with insulin are at risk for
developing insulin-induced hypoglycemia. These epi-
sodes are sometimes asymptomatic and occur during
night time, over time diminishing the autonomic responses
to hypoglycemic episodes. Hypoglycemia deprives the
brain of its preferred substrate, glucose, leading to rapid
activation of neuroendocrine responses aimed at restoring
glycemia including increased release of glucagon, epi-
nephrine, and growth hormone. Together, these counter-
regulatory hormones increase hepatic glucose output
(from gluconeogenesis and glycogenolysis) and peripheral
glycogenolysis and lipolysis. The activation of the sympa-
thetic nervous system leads to increased heart rate. Insu-
lin-induced hypoglycemic episodes are more frequent in
patients treated with insulin than in those treated with
oral hypoglycemics.
 CHAPTER 69 Endocrine Integration of Energy and Electrolyte Balance
CHAPTER SUMMARY
■ Energy substrate mobilization, utilization, and storage are
under neuroendocrine regulation.
■ Hepatic glycogen and adipose tissue triglycerides are the
principal sites of energy storage.
■ The central nervous system integrates the counterregulatory
response to acute decreases in energy substrate availability.
■ Regulation of sodium balance determines blood volume and
blood pressure control.
■ The kidney is responsible for long-term potassium homeostasis
and serum potassium concentration.
■ Insulin and catecholamines regulate the cellular distribution
of potassium.
STUDY QUESTIONS
1. Which of the following neuroendocrine responses contributes to
meeting the enhanced energy demands during exercise?
A) glucagon stimulation of hepatic glycogen synthesis
B) epinephrine stimulation of hepatic glycogenolysis
C) norepinephrine-induced stimulation of insulin release
D) cortisol inhibition of gluconeogenesis
727
2. Which of the following processes takes place immediately after a
balanced meal?
A) suppression of pancreatic insulin release
B) increased muscle and fat glucose uptake
C) increased hepatic glycogenolysis
D) suppressed lipogenesis
3. Activation of the renin–angiotensin–aldosterone system during
loss of effective intravascular volume results in all of the
following except
A) increased renal sodium and fluid retention
B) potentiation of the activity of the sympathetic nervous
system
C) peripheral venodilatation
D) enhanced ADH release
4. Regulation of body potassium content and distribution can be
affected by all of the following except
A) aldosterone-induced increase in K+ excretion
B) insulin stimulation of intracellular K+ efflux
C) β-adrenergic stimulation of cell membrane Na+/K+-ATPase
D) sudden changes in plasma osmolarity
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 SECTION X INTEGRATIVE PHYSIOLOGY

70
C H A P T E R

Control of Body
Temperature
Hershel Raff and Michael Levitzky

O B J E C T I V E S

■ Understand the mass balance characteristics of the control of internal body

temperature.
■ List and define the four mechanisms of heat transfer from the skin to the
environment.
■ Explain the feedback control of internal body temperature.
■ Understand the short-term response to cold (to increase heat production and
minimize heat loss) and heat (to decrease heat production and maximize
heat loss).
■ Describe the adaptations to cold and warm environments.
■ Understand the mechanisms of fever.

Like all mammals, humans are endotherms, meaning they gen-
erate their own internal heat. Humans are also homeotherms—
they maintain body temperature within a narrow range despite
large swings in environmental temperature. The maintenance
of internal body temperature within a narrow range is therefore
one of the most important regulated variables in humans. This
is because enzymatic reactions, and optimal cell and organ
function, occur in a fairly small range of temperatures. Despite
wide swings in environmental temperature, the core body tem-
perature—the internal temperature in the organs such as the
liver (often estimated by rectal or tympanic membrane
temperature)—is usually maintained within ±0.6°C (±1.0°F).
The core temperature averages about 37°C (98.6°F) for humans,
although it varies from person to person. The maintenance of a
stable body temperature involves a negative feedback control
system with a very high gain since the perturbation to the sys-
tem (changes in environmental temperature) can be very large
compared with the maintenance of a stable internal body tem-
perature. In fact, the gain of the body temperature control
system is 25–30—compare this with the gain of only 4 for the
blood pressure restoration in response to moderate hemorrhage
shown in Figure 1–5. Furthermore, there is usually a daily (cir-
cadian) rhythm in body temperature with a low point in the
early morning and a high point in the early evening. Body tem-
perature also varies depending on the level of muscular activity
and with the menstrual cycle in women.
The core body temperature is the central compartment of a
mass balance system (see Figure 1–4) composed of heat gained
from the environment and produced in the body by cellular
metabolism, and the heat lost to the environment. Since body
temperature is usually quite stable in the steady state, heat pro-
duction is approximately equal to heat loss.

729

Ch70_729-734.indd 729 11/26/10 10:39:16 AM

730 SECTION X Integrative Physiology
MECHANISMS
OF HEAT LOSS OR GAIN
Most of the gain or loss of heat between the body and the envi-
ronment is through the skin. Heat is mainly transferred to the
skin from the internal environment by the circulatory system.
There are four general mechanisms of heat transfer between
the body and the environment. Radiation is the emission of
heat to and from the skin by electromagnetic waves—the rate
of the temperature transfer by radiation is proportional to the
temperature difference between the body surface and the envi-
ronment. Conduction is intermolecular thermal heat transfer
and usually occurs between the skin and air. One loses heat
more rapidly when immersed in water because conduction
between the skin and water is faster than that between skin and
air. Convection is the loss or gain of heat by the movement of
air or water over the body. Because heat rises, air carries heat
away from the body by convection. This is one reason why
having a fan circulating air in a room helps one to keep cool on
a hot day. Finally, evaporation of water from the skin and the
respiratory tract can carry a large amount of heat generated by
the body because of the amount of heat required to transform
water from the liquid to the gas phase. Air circulation also
improves the rate of evaporation of sweat from the skin.
FEEDBACK MECHANISMS
REGULATING BODY TEMPERATURE
As mentioned above, the control of the internal body tempera-
ture is a classic example of negative feedback control. If you
recall from Chapter 1, feedback control systems involve sen-
sors that detect the regulated variable (in this case, body tem-
perature) with afferent input to the controller, a controller (in
this case, in the brain), and efferent input to the effectors that
can alter the rate of heat gain or loss.
Figure 70–1 summarizes the regulation of body temperature.
The sensors are located in the skin (peripheral thermorecep-
tors) and the brain (central thermoreceptors), primarily in
the hypothalamus. It is the central thermoreceptors that sense
core temperature and provide input to control body tempera-
ture, whereas the peripheral thermoreceptors provide the brain
with information about changes in environmental tempera-
ture. The main temperature control center is also located in the
hypothalamus. The most important effectors are the sympa-
thetic nerves to sweat glands, arterioles of the skin, and the
adrenal medulla, as well as motor neurons to skeletal muscles.
Heat production in humans is usually by metabolism. The
basal metabolic rate can be altered by circulating thyroid hor-
mone (see Chapter 63), and by shivering thermogenesis,
driven by innervation of skeletal muscle. Shivering is the
rhythmic, involuntary contraction and relaxation of skeletal
muscles that generates heat due to increased metabolic rate. Of
course, one can voluntarily increase heat production from
skeletal muscle with movement.
EFFECTOR MECHANISMS
REGULATING TEMPERATURE
Body temperature can be increased when the body is cold by
decreasing heat loss and/or by increasing heat production.
Decreasing heat loss is accomplished primarily by vasoconstric-
tion of the arterioles of the skin, minimizing heat transfer to the
environment. Another mechanism of heat conservation is the
reduction of body surface area by, for example, curling up, and
behavioral responses such as putting on warm clothes or mov-
ing to a warmer environment. As mentioned above, the short-
term increase in heat production is accomplished primarily by
an increase in voluntary movement and by shivering.
Body temperature can be decreased when the body is hot by
increasing heat loss and/or by decreasing heat production.
Increasing heat loss is accomplished primarily by vasodilation of
arterioles in the skin, thereby increasing heat transfer from the
blood to the skin and then to the environment, and by sweating
to lose heat by increased evaporation. Sweat production is
increased by increasing activity of autonomic nerves innervat-
ing sweat glands in the skin. The principal mechanism to
decrease heat production is a decrease in voluntary movement.
Now let us return to Figure 70–1 to summarize the control
of body temperature. When first exposed to a cold environ-
ment, the thermal sensors in the skin signal the brain to
decrease blood flow to and sweat production from the skin,
thus minimizing heat loss. If the core temperature decreases,
shivering and increases in adrenal medullary epinephrine can
increase to increase heat production, although the latter is a
minor pathway in humans. When one is exposed to a hot envi-
ronment, thermal sensors in the skin can increase blood flow
to the skin and sweat production, thus increasing heat loss. If
core temperature increases, sweat production can increase
profusely to greatly increase heat loss by evaporation. How-
ever, if evaporation cannot occur or is difficult because the air
is already saturated or nearly saturated with water vapor,
sweating is not a very effective means of heat loss.
ADAPTATION TO A HOT
OR COLD ENVIRONMENT
Humans can adapt to a variety of environments. You will learn
in the next chapter that humans can adapt when chronically
exposed to low oxygen (hypoxia) at altitude. Humans also
have the ability to adapt to changes in environmental tempera-
ture. Adaptation to a hot environment is much better under-
stood than adaptation to a cold environment.
Most people have difficulty when first exposed to a very hot
environment and have difficulty exercising. The core tempera-
ture can increase and a feeling of malaise and weakness can
ensue. Heat stroke can occur if core temperature increases
above 41°C and body functions begin to fail. After days to
weeks of exposure to a hot environment, people do better—this
process of acclimatization allows us to improve performance

Begin
Cerebral cortex
Skin temperature
Peripheral
thermoreceptors
Hypothalamus
Via
sympathetic
nerves
Adrenal medulla
Epinephrine
FIGURE 70–1 Summary of temperature-regulating mechanisms beginning with peripheral and central thermoreceptors. The
dashed arrow from the adrenal medulla indicates that this pathway is of minor importance in humans. (Reproduced with permission from Widmaier EP,
Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
during hot weather. When the environment is warmer than
skin temperature, the only efficient way to lose heat is by
increased evaporation from sweating. Over a few months in a
hot environment, the ability to sweat increases dramatically
(up to a 4-fold increase). Since sweat contains electrolytes, and
specifically sodium, an increase in blood aldosterone occurs,
which not only increases sodium reabsorption in the kidney
(see Chapter 44), but also increases sodium and chloride reab-
sorption from sweat in the sweat glands. The increase in aldos-
terone can lead to hypokalemia due to increased renal
potassium excretion and loss of potassium in sweat, however,
so increased dietary potassium intake is important during
acclimatization to a hot environment. This is particularly true
when working or exercising. You have probably observed mar-
athon runners lose the ability to function when performing
heroic exercise in a hot environment, particularly when they
have not had time to acclimatize to hot weather.
The adaptation to a cold environment is not as well under-
stood particularly since modern humans have the ability to
wear highly efficient warm clothing and to heat their environ-
ments. It is known that constriction of the blood vessels in the
skin and the inhibition of sweat production does minimize heat
lost to a cold environment. There may be the ability to increase
basal metabolic rate, although the role of changes in hormones
such as catecholamines and thyroid hormone in this response
is controversial. Probably the most common cause of lethal
hypothermia is immersion in cold water for an extended
period of time. Wearing a wetsuit is one way to avoid this.
CHAPTER 70 Control of Body Temperature 731
Voluntary motor responses
Begin
Core temperature
Central
thermoreceptors
Involuntary motor responses
Via
motor
nerves
Sweat glands Skin arterioles Skeletal muscles
FEVER
Fever is an increase in body temperature that occurs usually
due to a pathophysiological process such as infection. It is due
to an increase in the hypothalamic set point for temperature
so that body temperature increases to a new plateau at which
body temperature is then regulated. Although infection is the
most common cause of fever, there are other etiologies includ-
ing a form of severe hyperthyroidism called thyroid storm (see
Chapter 63).
Figure 70–2 summarizes the development of fever due to
infection. Pyrogens are circulating factors that cause fever.
Although some bacteria release exogenous pyrogens such as
lipopolysaccharides (endotoxins), the unifying cause of fever
during infection is the release of small proteins called endog-
enous pyrogens from macrophages and other immune cells.
Macrophages activated during infection are an integral part of
the immune response. Examples of endogenous pyrogens are
cytokines such as the interleukins and tumor necrosis factor.
These endogenous pyrogens can activate vagal afferents to the
hypothalamus, and can also circulate to the brain to directly
alter the hypothalamic set point for temperature. Since these
pyrogens are peptides, they must be able to signal the hypo-
thalamus despite the existence of the blood–brain barrier.
One theory to explain this is that the areas in the brain that can
sense cytokines, such as the circumventricular organs near
the hypothalamus, have a “leaky” blood–brain barrier (see
Chapter 27). Endogenous pyrogens can be sensed and the
732 SECTION X Integrative Physiology

Infection
to curling up increase body temperature in the same way as
exposure to cold. Although it is not known exactly why an
increase in body temperature is beneficial during infection, it
is thought that some of the cells of the immune system operate
more efficiently at higher body temperature. When a fever
Liver Multiple organs
Macrophages Macrophages
“breaks” and the set point of the hypothalamus returns to nor-
mal, the body must dissipate heat to return body temperature
to normal. Therefore, profuse sweating can occur as one recov-
Secrete Secrete
endogenous pyrogens endogenous pyrogens
ers from the acute phase of an infection.
(IL–1, IL–6, ? others) (IL–1, IL–6, ? others) There are a variety of drugs that can be used to lower tem-
perature during a fever. Aspirin inhibits prostaglandin synthe-
Firing of neural sis throughout the body. In addition to the action of
receptors Plasma IL–1, IL–6, ? others prostaglandins in the resetting of the hypothalamic set point
Vagus Systemic
for temperature, local production of prostaglandins is thought
nerve circulation to be involved in the muscle and joint aches that occur with
fever, which is why aspirin is effective in treating those symp-
Hypothalamus toms. Acetaminophen is a potent inhibitor of prostaglandin
Temperature setpoint
synthesis within the brain, so it also is effective in treating
fever. Glucocorticoid therapy with drugs such as prednisone
can also inhibit fever due to their inhibition of the immune
response (see Table 65–2), as well as their inhibition of prosta-
glandin synthesis. If fever is long-lasting and excessive (>40°C
Skeletal muscles Skin arterioles
Curl up, Vasoconstriction [>104°F]), tissue damage and organ failure can ensue, so
put on clothes heroic measures may be instituted to lower body temperature.
Shivering and blankets An example of this is immersion in cold water to decrease
body temperature. Finally, high fever can be much more dan-
gerous in the elderly.
Heat production Heat loss

Heat production greater than heat loss
Heat retention
Body temperature
FIGURE 70–2 Pathways by which infection causes fever. IL-1,
interleukin 1; IL-6, interleukin 6. (Reproduced with permission from Widmaier
EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
appropriate change in hypothalamic set point occurs, possibly
due to release of prostaglandins in or near the hypothalamic
controller that results in an alteration in the set point for body
temperature.
Once the hypothalamic set point is increased, the body tem-
perature is lower than the set point, so the hypothalamus
“thinks” that the body is too cold. The brain then activates all
of the mechanisms previously described to increase body tem-
perature when cold. This is why one can feel cold just before
and during the onset of fever despite the fact that body tem-
perature is normal or even increasing. The increase in heat
production due to shivering and the decrease in heat loss due
CLINICAL CORRELATION
A 32-year-old woman is brought into an emergency room
by her husband. She is confused, and complaining of palpi-
tations, (rapid, strong heart beats) shortness of breath, and
excessive sweating. Her blood pressure and heart rate are
markedly increased and her body temperature is danger-
ously high at 40.3°C. The woman is placed on a cooling bed
to try to lower her body temperature. The emergency room
doctor suspects an infection and orders the appropriate
blood testing. However, a medical student notices that the
woman’s eyes are bulging out and immediately suspects
that the woman may have severe thyrotoxicosis (a patho-
logical increase in thyroid hormone secretion). When the
student interviews the patient and her husband, it is discov-
ered that the woman always feels warm in a cold room and
often has palpitations. Blood tests are immediately ordered
and show a suppressed serum thyroid-stimulating hor-
mone (TSH) and an increased serum thyroxine level indi-
cating primary hyperthyroidism.
Hyperthyroidism is a very common disease, particularly
in women. By far the most common cause is primary
hyperthyroidism defined as an increase in thyroid gland
function independent of TSH, the anterior pituitary hor-
mone that controls most aspects of thyroid hormone syn-
thesis and gland function. The most common cause of

primary hyperthyroidism is Graves disease (see Chapter
63). It is caused by an autoimmune phenomenon in which
antibodies that activate the TSH receptor on the thyroid
follicular cell are produced and stimulate thyroid hor-
mone synthesis and secretion just as TSH normally would.
The increase in thyroid hormone in the blood then sup-
presses pituitary TSH release due to negative feedback.
The immune dysfunction can also result in a lymphocytic
infiltration of the muscles and fat behind the eyes. The
resultant swelling pushes the eyes forward (away from the
eye socket) resulting in the eyes bulging out—this is called
proptosis or exophthalmos. To confirm the cause of thyro-
toxicosis is Graves disease, a radioactive iodine uptake test
is performed by having the patient ingest a small amount
of radioactive iodine to measure the amount and distribu-
tion of iodine that accumulates in the thyroid gland. Iodine
is required for the synthesis of thyroid hormone and its
uptake is stimulated by activation of the TSH receptor (see
Table 63–1 and Figure 63–3). The iodine uptake is uni-
formly increased in Graves disease and in our patient. The
combination of the blood tests and uniformly increased
thyroid uptake, plus other tests and physical findings such
as proptosis, strongly suggests that the patient has Graves
disease. In fact, her increase in body temperature, her
mental confusion, and other symptoms define her as the
most extreme form of thyrotoxicosis called thyroid storm.
The short-term goal in treating this patient is decreasing
her body temperature and heart rate. This is accomplished
by giving drugs that decrease thyroid hormone synthesis,
beta-adrenergic blocking drugs to lower her heart rate,
stroke volume, and blood pressure, and glucocorticoid ther-
apy that is immunosuppressive and also decreases the con-
version of thyroxine to triiodothyronine the more potent
endogenous thyroid hormone. The long-term goal is nor-
malizing the thyroid function. This is usually accomplished
by giving radioactive iodine to destroy the thyroid. Alterna-
tive therapies are drugs that inhibit thyroid hormone syn-
thesis or, in an extreme case, a surgical thyroidectomy.
Why was this woman’s body temperature so elevated?
Thyroid hormone causes an increase in metabolic rate in
virtually all organs of the body. This results in an increase
in heat production. When severe enough, the ability to lose
heat to the environment by sweating cannot keep up with
the increase in heat produced by increased metabolism,
and the body temperature increases. This can be extremely
dangerous, and urgent treatment is usually required.
CHAPTER SUMMARY
■ Internal body temperature is the central compartment of a
mass balance system—heat loss usually equals heat gain.
■ Heat transfer between the skin and environment occurs by
radiation, conduction, convection, and evaporation.
CHAPTER 70 Control of Body Temperature 733
■ Feedback control of body temperature involves sensors
(thermoreceptors) in the skin and hypothalamus, a central
controller in the hypothalamus, and effectors consisting of
autonomic (sympathetic) control of blood flow to the skin and
sweat production.
■ Adaptation to hot weather involves increasing the capacity to
sweat to lose heat by evaporation.
■ Fever due to infection results from pyrogens released from
bacteria and from macrophages—these pyrogens increase the
set point of the hypothalamic controller such that heat
production and body temperature increase.
STUDY QUESTIONS
1. Which of the following will increase body temperature?
A) an increase in heat loss from the skin to the environment
B) a decrease in basal metabolic rate
C) a decrease in circulating thyroid hormone
D) shivering
2. All of the following are mechanisms to increase heat transfer
from the skin to the environment except
A) vasoconstriction
B) radiation
C) conduction
D) convection
3. Which of the following is false?
A) Sweating increases due to an increase in sympathetic
nerve input.
B) Skin arterioles vasoconstrict primarily due to input from
motor nerves.
C) The hypothalamus is the location of the central controller
of body temperature.
D) The hypothalamus is the location of the central
thermoreceptors.
4. All of the following will reduce fever except
A) aspirin-induced decrease in hypothalamic
prostaglandin synthesis
B) acetaminophen-induced decrease in hypothalamic
prostaglandin synthesis
C) an increase in endotoxin in the blood
D) cortisol-induced suppression of immune function
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 71
C H A P T E R

Hypoxia and Hyperbaria

Michael Levitzky and Hershel Raff

O B J E C T I V E S

■ Discuss the physiologic responses to hypoxia and hyperbaria.

■ Identify the physiologic stresses involved in the ascent to altitude.
■ Predict the initial responses of the central nervous, cardiovascular, and
respiratory systems to the ascent to altitude.
■ Describe the acclimatization of the cardiovascular, respiratory, and renal
systems to residence at high altitudes.
■ Identify the physiologic stresses involved in diving.
■ Predict the responses of the respiratory, cardiovascular, and renal systems to
various types of diving.

HYPOXIA inspired air passes through the airways, it is warmed to body

temperature and completely humidified. Therefore, the partial
Hypoxia means low oxygen. As was discussed in Chapter 37, pressure exerted by the water vapor in the air entering the
tissue hypoxia has many causes that can be classified into four alveoli is 47 mm Hg.
main types (see Table 37–7). One of these is low arterial partial The alveolar Po2 can therefore be calculated by using the
pressure of oxygen (“hypoxic hypoxia”) that may result from alveolar air equation discussed in Chapter 33:
a low alveolar partial pressure of oxygen. Other causes of P
Pao2 = Pio2 – ____
Aco2
hypoxic hypoxia are described in Chapter 37. The most com- R
+ [F] (1)
mon reason for decreased inspired oxygen in a healthy indi-
The inspired Po2 is equal to 0.21 times the total barometric
vidual is ascent to altitude.
pressure (if ambient air is breathed) after the subtraction of the
water vapor pressure of 47 mm Hg:
ALTITUDE AND Pio2 = 0.21 × (PB – 47mm Hg) (2)

ACCLIMATIZATION The alveolar Pco2 decreases at greater altitudes because

The barometric pressure decreases at greater altitudes because
the total pressure at any altitude is proportional to the weight
of the air above it. There is a greater change in barometric
pressure per change in altitude closer to the earth’s surface
than at very great altitudes because air, which is attracted to
the earth’s surface by gravity, is compressible.
The fractional concentration of oxygen in the atmosphere
does not change appreciably with altitude; it is therefore 21%
of the total pressure of dry ambient air at any altitude. As
hypoxic stimulation of the arterial chemoreceptors increases
alveolar ventilation (hyperventilation). As shown in
Figure 71–1, the decrease in alveolar Pco2 brings the alveolar
Po2 closer to the inspired Po2, as calculated by equation (1). For
example, at an altitude of 15,000 ft, the total barometric pres-
sure is about 429 mm Hg. The inspired Po2 is therefore 0.21 ×
(429 – 47) mm Hg, or 80.2 mm Hg. The alveolar Pco2 is likely
to be decreased to about 32 mm Hg, resulting in a Pao2 of about
45 mm Hg. At 18,000 ft, the total barometric pressure is about
380 mm Hg; at 20,000 ft, it is 349 mm Hg.

735

Ch71_735-744.indd 735 12/8/10 10:07:11 PM

736 SECTION X Integrative Physiology
Altitude (1000 feet)
0 5 10 15 20
20
Highest permanent habitation
Denver
18
16 Inspired gas PO2
Mt. Blanc
Partial pressure (kPa)
14
Silver hut
12 Alveolar
gas PO2
10
8
6 Alveolar gas PCO2
4 vascular distention and engorgement of the lung secondary
2
0 0
0 1 2 3 4 5
Altitude (km)
FIGURE 71–1 Calculated inspired and alveolar partial
pressures of oxygen and carbon dioxide at rest plotted versus
increasing altitude. Note that as increasing arterial chemoreceptor
drive decreases alveolar PCO2, alveolar PO2 is closer to inspired PO2.
(Adapted with permission from Lumb AB: Nunn’s Applied Respiratory Physiology, 5th
ed. Oxford: Butterworth-Heinemann, 2000 [Figure 16.1, p. 359].)
ACUTE EFFECTS OF ALTITUDE
Ascent to altitude causes significant alterations in the central
nervous system, the cardiovascular system, the respiratory
system, and the regulation of body fluids by the renal system.
Because low temperatures are commonly encountered at alti-
tude, the temperature regulatory mechanisms discussed in
Chapter 70 are also usually involved.
If a healthy person were to ascend rapidly to altitudes greater
than 3,000–4,500 m (approximately 10,000–15,000 ft) above sea
level, he or she would suffer a deterioration of nervous system
function. Similar problems could occur if cabin pressure is lost in
an airplane. The symptoms are mainly due to hypoxia; they may
include sleepiness, laziness, a false sense of well-being, impaired
judgment, blunted pain perception, increasing errors on simple
tasks, decreased visual acuity, clumsiness, and tremors. Severe
hypoxia may result in a loss of consciousness or even death.
If an unacclimatized person (a person who has not adapted
to being at altitude) ascends to altitudes greater than
3,000–4,500 m above sea level, he or she may suffer from a
group of symptoms known collectively as acute mountain
sickness. The symptoms include headache, dizziness, breath-
lessness at rest, weakness, malaise, nausea, anorexia, sweating,
palpitations, impaired vision, partial deafness, sleeplessness,
fluid retention, and dyspnea on exertion. These symptoms are
a result of hypoxia and hypocapnia, and alkalosis or cerebral
edema, or both.
CARDIOVASCULAR SYSTEM
25 30
There is an increase in cardiac output, heart rate, and sys-
140
temic blood pressure at altitude. These effects are probably a
result of increased sympathetic stimulation of the cardiovas-
120 cular system secondary to arterial chemoreceptor stimula-
Partial pressure (mm Hg)
tion. There may also be a direct stimulatory effect of hypoxia
100 on the myocardium. Alveolar hypoxia results in hypoxic
pulmonary vasoconstriction (see Chapter 34). The
80 increased cardiac output, along with hypoxic pulmonary
vasoconstriction and sympathetic stimulation of larger pul-
Everest
60 monary vessels, results in an increase in mean pulmonary
artery pressure and tends to abolish any preexisting zone 1
(see Figure 34–7) by recruiting previously unperfused capil-
40
laries. Undesirable consequences of these effects include
20 to the pulmonary hypertension, which may lead to high-
altitude pulmonary edema and a greatly increased right
ventricular workload. People who are more susceptible to
6 7 8 9
high-altitude pulmonary edema also seem to have greater
hypoxic pulmonary vasoconstriction responses than less
susceptible individuals. Analysis of high-altitude pulmonary
edema fluid shows that it contains large-molecular-weight
proteins, which indicates that the edema is caused by
increased capillary permeability as well as increased capil-
lary hydrostatic pressure. The increased capillary permeabil-
ity may result from capillary stress failure caused by high
pulmonary artery pressure and blood flow and by altered
release of cytokines or other mediators.
The effects of ascent to high altitude on the cerebral circu-
lation are complex. Hypoxic stimulation of the arterial
chemoreceptors causes hypocapnia and respiratory alkalo-
sis, as already discussed. Cerebral arterial hypocapnia not
only could cause constriction of the cerebral blood vessels,
but would also cause alkalosis of the cerebrospinal fluid.
Most of the central nervous system symptoms of acute moun-
tain sickness could be attributed to cerebral hypoperfusion,
alkalosis, or both. However, it now appears that in most cases
the symptoms of acute mountain sickness result from cere-
bral hyperperfusion and edema. This hyperperfusion is
mainly a result of vasodilation, which is the direct effect of
hypoxia on the cerebral blood vessels. As the cerebral arteri-
oles dilate, the hydrostatic pressure in the cerebral capillaries
increases, increasing the tendency of fluid to leave the cere-
bral capillaries and cause cerebral edema. The hyperperfusion
and cerebral edema increase intracranial pressure, compress-
ing and distorting intracranial structures. This may lead to a
general increase in sympathetic activity in the body, increas-
ing the possibility of pulmonary edema and promoting renal
salt and water retention.
RESPIRATORY SYSTEM
The decreased arterial partial pressures of oxygen that occur at
altitude stimulate the arterial chemoreceptors and increase

alveolar ventilation; the central chemoreceptors are not
responsive to hypoxia, as was discussed in Chapter 38.
Although the arterial chemoreceptors are not very sensitive to
changes in arterial Po2 above approximately 60 mm Hg (see
Figure 38–8), at an arterial Po2 of 45 mm Hg, minute ventila-
tion is approximately doubled. Because carbon dioxide pro-
duction is initially normal (it does increase with the increased
work of breathing caused by greater alveolar ventilation), alve-
olar and arterial Pco2 decrease to approximately 20 mm Hg,
causing respiratory alkalosis. Arterial hypocapnia also results
in “diffusion” of carbon dioxide from the cerebrospinal fluid
into the blood (see Figure 38–6), causing an increase in the pH
of the cerebrospinal fluid. Therefore, not only are the central
chemoreceptors unresponsive to the hypoxia of altitude, but
their activity is also depressed by the secondary hypocapnia
and the alkalosis of the cerebrospinal fluid.
Increased tidal volumes and respiratory rates increase the
elastic work of breathing. High ventilatory rates may be
accompanied by active expiration, resulting in dynamic com-
pression of airways. This airway compression, coupled with
arterial chemoreceptor-mediated reflex parasympathetic
bronchoconstriction in response to the arterial hypoxemia,
results in increased resistance work of breathing. More tur-
bulent airflow, which is likely to be encountered at higher
ventilatory rates, may also contribute to increased resistance
work. Maximum airflow rates may increase because of
decreased gas density at altitude. The deeper inspirations
and expirations would likely result in a more uniform
regional distribution of alveolar ventilation; previously col-
lapsed or poorly ventilated alveoli would be better ventilated.
The increased pulmonary blood flow seen acutely at high
altitude, coupled with the more uniform alveolar ventilation,
would be expected to improve regional ventilation–perfu-
sion matching. Surprisingly, studies have not shown striking
differences in VA/Qc relationships at high altitude, although
they do appear to improve.
At high altitude, the partial pressure gradient for oxygen
diffusion is decreased because the alveolar Po2 is decreased
more than the mixed venous Po2. This decrease in the partial
pressure gradient is partly offset by effects of increases in car-
diac output and increased pulmonary artery pressure, which
increase the surface area available for diffusion by recruit-
ment of unperfused capillaries and decrease the time erythro-
cytes spend in pulmonary capillaries.
Oxygen loading in the lung may be compromised at alveolar
partial pressures of oxygen low enough to be below the flat part
of the oxyhemoglobin dissociation curve (see Figure 36–1),
causing a low arterial oxygen content. Hypocapnia may aid
somewhat in oxygen loading in the lung but will interfere with
oxygen unloading at the tissues (see Figure 36–2). The main
short-term compensatory mechanism for maintenance of oxy-
gen delivery is the increased cardiac output. The hemoglobin
concentration may also increase slightly within the first 2 days.
This is a result of hemoconcentration secondary to fluid shift-
ing into the extravascular space, not an increase in erythrocyte
production.
CHAPTER 71 Hypoxia and Hyperbaria 737
Prevention and Treatment
of Acute Mountain Sickness
Acetazolamide, a carbonic anhydrase inhibitor, taken for a
few days before ascending to altitude can prevent the symp-
toms of acute mountain sickness in many people. The mecha-
nism by which it does this is unclear because acetazolamide
has several actions that may help prevent acute mountain sick-
ness. It decreases reabsorption of bicarbonate by the proximal
tubule of the kidney. This may lead to a moderate metabolic
acidosis that may partly offset the respiratory alkalosis and
therefore also help stimulate ventilation. Acetazolamide is also
a diuretic, so it may help prevent fluid retention and edema. It
is likely that both proposed mechanisms are involved. Acetazo-
lamide may also inhibit hypoxic pulmonary vasoconstriction.
By far the most important treatment of acute mountain
sickness is increasing alveolar Po2. This can be performed at
altitude by breathing increased concentrations of oxygen from
a gas cylinder. Descent to lower altitudes is most effective in
treating acute mountain sickness.
Acclimatization to Altitude
Longer-term compensation to high altitude begins to occur
after several hours of ascent and continues for days or even
weeks. The immediate responses to the ascent and the early
and late adaptive responses are summarized in Table 71–1.
Renal compensation for respiratory alkalosis begins within
a day: renal excretion of base is increased, and hydrogen ions
are conserved. A second major compensatory mechanism is
erythropoiesis. Within 3–5 days, new red blood cells are pro-
duced, increasing the hematocrit and the oxygen-carrying
capacity. Much of this response is due to an increase in the
secretion of the hormone erythropoietin from the kidney due
to local renal hypoxia; erythropoietin then stimulates red cell
production in bone marrow (see function 5 in Chapter 39).
(Commonly known as “Epo,” this protein is available for injec-
tion and has been used for “blood doping” in athletes.) Thus,
although the arterial Po2 is not improved, the arterial oxygen
content increases because of the increased blood hemoglobin
concentration. This is at the cost of a higher blood viscosity
and ventricular workload. Increased concentrations of 2,3-BPG
(DPG) may help release oxygen at the tissues (Figure 36–2).
Hypoxic stimulation of the arterial chemoreceptors persists
and may be augmented during the acclimatization. A more
immediate finding is that the ventilatory response curve to car-
bon dioxide shifts to the left (Figure 38–4). That is, for any given
alveolar or arterial Pco2, the ventilatory response is greater after
several days at high altitude. The current theory for the increase
in ventilation that occurs during acclimatization is that carotid
body chemoreceptor sensitivity to hypoxia increases through
cellular mechanisms that are not well established. The increase in
alveolar ventilation results in an increase in alveolar, and hence
arterial, Po2. It is this adaptive response that allows people to
live at altitude for long periods of time. The central nervous sys-
tem symptoms usually abate at the same time as the resolution of
738 SECTION X Integrative Physiology

TABLE 71–1 Physiologic responses to high altitude relative to sea-level control values.a
Immediate Early Adaptive (72 Hours) Late Adaptive (2–6 Weeks)

Minute ventilation ↑ ↑ ↑

Respiratory rate Variable Variable Variable

Tidal volume ↑ ↑ ↑

Arterial PO2 ↓ ↓ ↓

Arterial PCO2 ↓ ↓ ↓

Arterial pH ↑ ↑↔ ↑↔

Arterial HCO3− ↔ ↓ ↓

Evaluation of lung function

Vital capacity ↔ ↔ ↔

Maximum airflow rates ↑ ↑ ↑

Functional residual capacity ↔ ↔ ↔

Ventilatory response to inhaled CO2 ↔ ↑ ↑

Ventilatory response to hypoxia ↔ ↔ ↔

Pulmonary vascular resistance ↑ ↑ ↑

Oxygen transport

Hemoglobin ↔ ↑ ↑

Erythropoietin ↑ ↔ ↔

P50 ↓ ↑ ↑

2,3-BPG ↔ ↑ ↑

Cardiac output ↑ ↔ ↔↓

Central nervous system

Headaches, nausea, insomnia ↑ ↔ ↔

Perception, judgment ↓ ↔ ↔

Cerebral edema ↑ ↔ ↔
a
These values apply to native sea-level inhabitants. ↑, increased; ↓, decreased; ↔, no change.
Adapted with permission from Guenter CA. Pulmonary Medicine, 2nd ed. Philadelphia, PA: Lippincott; 1982.

the cerebral edema and higher intracranial pressure. This is likely

due to increased reabsorption of cerebrospinal fluid, autoregula-
tion of cerebral blood flow, and a sympathetically mediated vaso-
constriction that for some reason takes several days to develop. It
is also possible that the cerebral vessels produce less nitric oxide,
which may mediate the cerebral vasodilatation in response to
hypoxia (see Chapter 27).
The increased cardiac output, heart rate, and systemic blood
pressure return to normal levels after a few days at high alti-
tude. This probably reflects a decrease in sympathetic activity
or downregulation of adrenergic receptors. Nevertheless,
hypoxic pulmonary vasoconstriction and pulmonary hyper-
tension persist (along with increased blood viscosity due to
higher hematocrit), leading to right ventricular hypertrophy
and frequently chronic cor pulmonale (right ventricular fail-
ure secondary to pulmonary hypertension).
HYPERBARIA
Hyperbaria means increased ambient pressure. Healthy peo-
ple can experience hyperbaric conditions during underwater
diving. Hyperbaric chambers are used clinically to increase
ambient gas pressures as treatment for decompression illness
(discussed below) or to enhance wound healing (hyperbaric
oxygen therapy or HBOT).
DIVING
The major physiologic stresses involved in diving include
increased ambient pressure, decreased effects of gravity
because of buoyancy, altered respiration, hypothermia, and
sensory impairment. The severity of the stress depends on the

depth attained, the length of the dive, and whether the breath
is held or breathing apparatus is used. The physiologic stresses
of elevated ambient pressure, decreased effects of gravity, and
altered respiration are the focus of this discussion.
PHYSICAL PRINCIPLES
The pressure at the bottom of a column of liquid is propor-
tional to the height of the column (h), the density of the liquid
(ρ), and the acceleration of gravity (g):
Pressure = h × p × g (3)
For example, for each 10 m (33 ft) of seawater, ambient pres-
sure increases by 1 atm. Thus, at a depth of 10 m of seawater,
total ambient pressure is equal to 1,520 mm Hg or twice the
barometric pressure at sea level.
The tissues of the body are composed mainly of water and
are therefore incompressible, but gases are compressible and
follow Boyle’s law. Thus, in a breath-hold dive, the volume of
gas in the lungs is inversely proportional to the depth attained.
At 10 m of depth (2 atm), lung volume is cut in half; at 20 m
(3 atm), it is one third the original lung volume. As a gas is
compressed, its density increases.
As the total pressure increases, the partial pressures of the
constituent gases also increase, according to Dalton’s law (see
Chapter 33). The biologic effects of gases are generally depen-
dent on their partial pressures rather than on their fractional
concentrations. Also, as the partial pressures of a gas increases,
the amount dissolved in the tissues of the body increases,
according to Henry’s law (see Chapter 35).
EFFECTS OF IMMERSION
UP TO THE NECK
Merely immersing oneself up to the neck in water causes pro-
found alterations in the cardiovascular and pulmonary sys-
tems. These effects are mainly a result of an increase in pressure
outside the thorax, abdomen, and limbs.
Cardiovascular and Renal Effects
During immersion up to the neck, increased pressure outside
the limbs and abdomen results in less pooling of systemic
venous blood in gravity-dependent regions of the body (see
Chapter 30). If the water temperature is below body temper-
ature, a sympathetically mediated venoconstriction occurs,
also augmenting venous return (see Chapter 70). The
increased venous return increases the central blood volume
by approximately 500 mL. Right atrial pressure increases
from about –2 to +16 mm Hg. As a result of this increase in
preload, the cardiac output and stroke volume increase by
about 30%. The increases in pulmonary blood flow and pul-
monary blood volume result in increased mean pulmonary
artery pressure, capillary recruitment, an increase in the dif-
fusing capacity, and a somewhat improved matching of ven-
tilation and perfusion.
CHAPTER 71 Hypoxia and Hyperbaria 739
An additional effect of neck-deep immersion is immersion
diuresis. Within a few minutes of immersion, urine flow
increases 4–5-fold. These findings are consistent with stimula-
tion of stretch receptors in the cardiac atria and elsewhere in
thoracic vessels by the increased thoracic blood volume. This,
in turn, is believed to decrease the secretion of antidiuretic
hormone (ADH) by the posterior pituitary gland or to cause
the release of natriuretic hormones from the cardiac atria
(see Chapter 45).
Respiratory Effects
The pressure outside the chest wall of a person standing or
seated in neck-deep water is greater than atmospheric,
averaging about 20 cm H2O (14.7 mm Hg). This positive
pressure outside the chest opposes the normal outward elas-
tic recoil of the chest wall and decreases the functional
residual capacity by about 50%. This occurs at the expense
of the expiratory reserve volume, which may be decreased
by as much as 70%. The intrapleural pressure is less nega-
tive at the functional residual capacity because of decreased
outward elastic recoil of the chest wall. The work that must
be done to bring air into the lungs is greatly increased
because extra inspiratory work is necessary to overcome the
positive pressure outside the chest. Immersion up to the
neck in water results in an increase in the work of breathing
by about 60%.
The hydrostatic pressure effects of water outside the chest
prevent a submerged person, who is trying to breathe through
a tube that is communicating with the air above the surface of
the water, from descending more than about 3 ft. This is
true even if the increased airway resistance offered by the tube
were negligible and if the person avoided increasing the effec-
tive dead space by occluding the mouth end of the tube and
exhaling directly into the water (or by using a one-way valve).
The reason is that the maximal inspiratory pressure that nor-
mal individuals can generate is about 80–100 cm H2O (i.e.,
intrapleural pressures of –80 to –100 cm H2O). Because 100 cm
is 1 m (39.37 in), the maximum depth a person can attain
while breathing through a tube in this manner is a little more
than 1 m (3 ft).
BREATH-HOLD DIVING
During a breath-hold dive, the total pressure of gases within
the lungs is approximately equal to the increased ambient
pressure. Therefore, the volume within the thorax must decrease
proportionately and partial pressures of gases must increase.
The Diving Reflex
Many subjects demonstrate a profound vagally mediated
bradycardia (decreased heart rate) and increased systemic
vascular resistance with face immersion (especially into
cold water), as well as apnea. This “diving reflex” is initiated
by sensors in the face or nose with afferents to the brain via
the trigeminal nerves. A similar response is seen when
740 SECTION X Integrative Physiology
Face immersion
FIGURE 71–2 The author’s (MGL) electrocardiographic response to face immersion in ice water (the diving reflex). The experiment
was performed in the prone position, and face immersion was performed without changing the position of the head to avoid the effects of
changes in baroreceptor activity. The heart rate decreased from about 75 to about 43 beats/min. (Time between the vertical ticks above or below
the ECG = 3sec.) (Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)
aquatic mammals such as whales and seals dive. The reflex
decreases the workload of the heart and severely limits per-
fusion to all systemic vascular beds except for the strongest
autoregulators—namely, the heart and brain. The cardiovas-
cular effects of the diving reflex are similar to those produced
by stimulation of the arterial chemoreceptors when no
increase in ventilation can occur, except that the diving reflex
also appears to cause the spleen to slowly contract, which
releases erythrocytes stored in the spleen into the venous
blood. This increases the oxygen-carrying capacity of the
blood and therefore the oxygen content of the blood at the
same arterial Po2. The bradycardic component of the diving
reflex is demonstrated in Figure 71–2.
Gas Exchange
Breath-hold divers usually hyperventilate before a dive so
that the typical alveolar Po2 and Pco2 might be 120 and
30 mm Hg, respectively. Indeed, breath-hold divers must
take care not to hyperventilate so much that their Pco2 gets so
low that they do not reach their “breakpoint” until after they
lose consciousness from arterial hypoxemia. (The break-
point is the point at which an individual can no longer vol-
untarily hold his or her breath, which is mainly determined
by Paco2.) During a breath-hold dive to a depth of 10 m
(33 ft), lung volume decreases and gases are compressed.
Total gas pressure approximately doubles: thus, after
20 seconds at 10 m, the alveolar Po2 may be 160–180 mm Hg;
even after 1 minute at 10 m, the alveolar Po2 is well above
100 mm Hg. The alveolar Pco2 (that would be less than
40 mm Hg at the surface because of hyperventilation before
the dive) also increases to above 40 mm Hg during descent,
reversing the gradient for CO2 transfer. Carbon dioxide
therefore diffuses from the alveoli into the pulmonary capil-
lary blood. The alveolar Pco2 therefore does not increase as
much as would be predicted by the compression of gases
caused by the increased pressure as CO2 diffuses into the
blood. This is believed to result from the much greater solu-
bility of CO2 than O2 in the blood. Thus, the transfer of oxy-
gen from alveolus to blood is undisturbed until ascent;
however, the normal transfer of carbon dioxide from blood
to alveolus is reversed during descent and results in signifi-
cant retention of carbon dioxide in the blood.
During ascent, the ambient pressure decreases rapidly, lung
volume increases, and alveolar gas partial pressures decrease
accordingly. Alveolar Pco2 decreases, allowing CO2 to diffuse
from pulmonary capillary blood into the alveoli. However,
the rapid decrease in alveolar Po2 during ascent may result in a
decrease in arterial Po2 sufficient to cause the breath-hold diver
to lose consciousness. This loss of consciousness can occur
rapidly and without warning and usually occurs as divers
ascend to a depth of approximately 5 m or less. It is therefore
known as “shallow water blackout.”
THE USE OF UNDERWATER
BREATHING APPARATUS
Self-contained underwater breathing apparatus, or scuba
gear, mainly consists of a tank of compressed gas that can be
delivered by a demand regulator to the diver when the diver’s
mouth pressure decreases during inspiration to slightly less
than the ambient pressure. Expired gas is simply released into
the water as bubbles. Therefore, during a dive with scuba gear,
gas pressure within the lungs remains close to the ambient pres-
sure at any particular depth. As a result, the physiologic stresses
on the respiratory system during scuba diving are mainly a
consequence of elevated gas densities and partial pressures.
During scuba diving, the inspiratory work of breathing is
not a great problem at moderate depths because gas is deliv-
ered at ambient pressures. At very great depths, however,
increased gas density becomes a problem because it increases
the airway resistance work of breathing during turbulent flow.
For example, in long-term experiments performed with sub-
jects simulating dives of over 600 m (2,000 ft) inside hyper-
baric chambers, all subjects reported that they could breathe
only through their mouths; the work of breathing through the
nose was too great. This is one reason for replacing nitrogen
with helium for deep dives. Helium is only about one seventh
as dense as nitrogen.
The respiratory control system’s sensitivity to carbon diox-
ide is decreased at great depths because of increased gas

densities and high arterial Po2 and because divers learn to sup-
press carbon dioxide stimuli to conserve compressed gas.
CLINICAL PROBLEMS
ASSOCIATED WITH DIVING
Clinical problems that may be encountered in diving, particu-
larly to great depths, include barotrauma, decompression ill-
ness, nitrogen narcosis, oxygen toxicity, and high-pressure
nervous syndrome (HPNS).
Barotrauma occurs when ambient pressure increases or
decreases, but the pressure in a closed unventilated area of the
body that cannot equilibrate with ambient pressure does not.
The barotrauma of descent is called “squeeze.” It can affect the
middle ear, if the Eustachian tube is clogged or edematous, so
that a person cannot equilibrate pressure in the middle ear; the
sinuses; the lungs, resulting in pulmonary congestion, edema,
or hemorrhage; and even cavities in the teeth. The barotrauma
of ascent can occur if gases are trapped in areas of the body
and begin to expand as the diver ascends. If a diver does not
exhale while ascending, expanding pulmonary gas may over-
distend and rupture the lung (“burst lung”). This may result in
hemorrhage, pneumothorax, or air embolism. Gases trapped
in the gastrointestinal tract may cause abdominal discomfort
and eructation (belching) or flatus as they expand. Barotrauma
of the ears, sinuses, and teeth may also occur on rapid ascent
from great depths.
Decompression illness occurs when gas bubbles form in the
blood and body tissues as the ambient pressure decreases. The
term “decompression illness” encompasses two different prob-
lems, both of which involve gas bubbles. Arterial gas embo-
lism is gas bubbles in the arterial blood. Because bubbles do
not seem to form in the arterial blood itself, arterial gas embo-
lism usually occurs when airway obstruction prevents expand-
ing gas from being exhaled. As expanding alveoli rupture, gas
bubbles may enter pulmonary capillaries and be carried into
the arterial blood. Arterial gas embolism is a likely conse-
quence of an ascending diver neglecting to exhale on rapid
ascent. Bubbles resulting from arterial gas embolism may be
carried to cerebral blood vessels where they may cause a stroke.
The second component of decompression illness, decompres-
sion sickness, occurs when bubbles form in tissues of the body.
During a dive, the increasing ambient pressure causes an ele-
vation of the partial pressure of nitrogen in the body. The high
partial pressure of nitrogen causes this normally poorly solu-
ble gas to dissolve in the body tissues and fluids according to
Henry’s law (discussed in Chapter 35). This is especially the
case in body fat, which has a relatively high nitrogen solubility.
At great depths, body tissues become supersaturated with
nitrogen.
During a fast ascent, ambient pressure decreases rapidly and
nitrogen comes out of solution, forming bubbles in body tis-
sues and fluids. The effect is the same as opening a bottle of a
carbonated beverage. During the production of a carbonated
beverage, it is exposed to higher-than-atmospheric pressures
CHAPTER 71 Hypoxia and Hyperbaria 741
of gases, mainly carbon dioxide, and then capped. The total
pressure in the gas layer above the liquid remains greater than
atmospheric pressure. The partial pressures of gases dissolved
in the liquid phase are in equilibrium with the partial pres-
sures in the gas phase. Gases dissolve in the liquid phase
according to Henry’s law. When the bottle is uncapped, the
pressure in the gas phase suddenly decreases and the gas dis-
solved in the liquid phase comes out of solution, forming bub-
bles.
The bubbles formed in decompression sickness may enter
the venous blood or affect the joints of the extremities. Bub-
bles that enter the venous blood are usually trapped in the
pulmonary circulation and rarely cause symptoms. The symp-
toms that do occasionally occur, which are known as “the
chokes” by divers, include substernal chest pain, dyspnea, and
cough and may be accompanied by pulmonary hypertension,
pulmonary edema, and hypoxemia. This is obviously an
extremely dangerous form of decompression illness. Even
more dangerous, of course, are bubbles in the circulation of
the central nervous system, which may result in brain damage
and paralysis. They may result from alveolar rupture and
arterial gas embolism, as discussed previously, or be carried
from the venous blood to the arterial side through a patent
foramen ovale (see Chapter 30) or an intrapulmonary shunt.
Bubbles that form in the joints of the limbs cause pain (“the
bends”). Osteonecrosis of joints may also be caused by inad-
equate decompression.
The treatment for decompression illness is immediate
recompression in a hyperbaric chamber that forces the gas in
bubbles back into solution, followed by slow decompression.
Decompression illness may be prevented by slow ascents from
great depths (using decompression tables) and by substituting
helium for nitrogen in inspired gas mixtures. Helium is only
about half as soluble as nitrogen in body tissues.
Gas bubbles, although they are sterile, are perceived by the
body as foreign. They elicit inflammatory and other responses,
including platelet activation, blood clotting, the release of
cytokines and other mediators, leukocyte aggregation, free
radical production, and endothelial damage. These responses
are not reversed by recompression and may continue unless
additional treatment is initiated.
Divers who ascend from submersion with no immediate
effects of decompression may subsequently suffer decompres-
sion illness if they ride in an airplane within a few hours of the
dive. Commercial airplanes normally maintain cabin pres-
sures well below 760 mm Hg, with cabin pressures similar to
those at altitudes 5,000–8,000 ft above sea level. This is why
people with pulmonary impairment may need to use supple-
mental oxygen during an airplane flight.
Very high partial pressures of nitrogen directly affect the
central nervous system, causing euphoria, loss of memory,
clumsiness, and irrational behavior. This nitrogen narcosis or
“rapture of the deep” occurs at depths of 30 m (100 ft) or more
and at greater depths may result in numbness of the limbs, dis-
orientation, motor impairment, and ultimately unconscious-
ness. The mechanism of nitrogen narcosis is unknown.
742 SECTION X Integrative Physiology
Oxygen toxicity can be caused by inhalation of 100% oxy-
gen at 760 mm Hg, or of lower oxygen concentrations at higher
ambient pressures. It can cause central nervous system, visual
system, and alveolar damage, although pulmonary manifesta-
tions are rare among divers. The mechanism of oxygen toxic-
ity is controversial but probably involves the formation of
superoxide anions or other free radicals.
Exposure to very high ambient pressures, such as those
encountered at very great depths (greater than 75 m), is associ-
ated with tremors, decreased mental ability, nausea, vomiting,
dizziness, and decreased manual dexterity. This high-pressure
nervous syndrome (HPNS) usually occurs when nitrogen has
been replaced by helium to decrease gas density, prevent nitro-
gen narcosis, and help avoid decompression sickness. Small
amounts of nitrogen added to the inspired gas mixture help
counteract the problem. One hypothesis explaining HPNS is
that the syndrome may result from alterations in cerebral neu-
rotransmission.
A person inside an intact submarine is not at risk for any of
the clinical problems associated with diving discussed above.
The rigid walls of a submarine allow its inhabitants to reside at
an ambient pressure similar to that at the surface.
CLINICAL CORRELATION
Physicians on a medical mission in the mountains of
South America treat a 65-year-old man who has lived at
altitudes above 3,600 m (about 12,000 ft) since he was
born. He has a chronic headache, feels dizzy and tired,
has trouble remembering things, and does not sleep
well. He is cyanotic (his skin and mucosa appear to be
blue; see Chapter 36), and has peripheral edema. His
jugular veins are distended even though he is sitting
upright. An electrocardiogram indicates right axis
deviation (a frontal plane mean electrical axis greater
than +105°).
The patient has chronic mountain sickness (also known
as Monge’s disease) with chronic cor pulmonale. Chronic
cor pulmonale is right ventricular failure secondary to
pulmonary hypertension, in this case exacerbated by
polycythemia (increased hematocrit resulting from
increased production of red blood cells). His pulmonary
hypertension is mainly a result of the effects of chronic
hypoxic pulmonary vasoconstriction, which not only
causes constriction of pulmonary arterioles, but also
causes structural changes in the affected blood vessels
over time. He has polycythemia because of chronic hypox-
emia leading to erythropoiesis. The increase in hemat-
ocrit resulted in higher blood viscosity. His low arterial Po2
combined with his increased hematocrit (see Chapter 36)
explains his cyanosis. The workload of his right ventricle
is much greater than that of a healthy individual who has
always lived at sea level because the increased pulmonary
artery pressure and increased blood viscosity have greatly
increased his right ventricular afterload. This has resulted
in right ventricular hypertrophy, which explains his right
axis deviation. This has resulted in right ventricular fail-
ure. As the right ventricle failed, it could no longer keep up
with venous return, leading to increased venous pressure,
which explains his distended jugular veins, and increased
capillary hydrostatic pressure, particularly in lower parts of
the body. This caused his peripheral edema. His headache,
sleep difficulties, and problems with his memory are a
result of insufficient oxygen delivery to his brain. The most
effective treatment for chronic mountain sickness is to have
the patient move to a lower altitude, but this may not be
possible for psychosocial reasons. Other treatments may
include repetitive removal of red blood cells, and possibly
acetazolamide.
CHAPTER SUMMARY
■ The main physiologic stresses of altitude are hypoxia and
secondary hypocapnia and respiratory alkalosis; acclimatiza-
tion occurs mainly by renal compensation for the respiratory
alkalosis, erythropoiesis, elevated 2,3-BPG concentrations, and
resolution of cerebral edema.
■ The main physiologic stresses of diving are caused by
increased ambient pressures causing gas compression, leading
to increased partial pressures and densities and viscosities
of gases.
STUDY QUESTIONS
1. Three hours after climbing from sea level to an altitude of
3,500 m, a healthy person breathing ambient air would likely
have a lower-than-normal
A) pulmonary artery pressure
B) alveolar ventilation
C) arterial pH
D) arterial Pco
2
E) work of breathing
2. Which of the following would be lower-than-normal sea-level
values in a healthy person breathing ambient air after 5 days at
an altitude of 15,000 ft?
A) plasma bicarbonate concentration
B) hematocrit
C) pulmonary vascular resistance
D) 2,3-BPG (2,3-DPG)
E) alveolar ventilation
3. Immersion in cold water up to the neck decreases
A) the inspiratory work of breathing
B) venous return
C) the functional residual capacity
D) the inspiratory reserve volume
E) right atrial pressure

4. During the descent phase of a 1-minute breath-hold dive to a
depth of 10 m
A) lung volume is increasing
B) alveolar pressure is increasing
C) the partial pressure gradient for diffusion of oxygen from the
alveoli into the pulmonary capillary blood is decreasing
D) the partial pressure gradient for carbon dioxide diffusion
from the pulmonary capillary blood into the alveoli is
increasing
CHAPTER 71 Hypoxia and Hyperbaria 743
5. When a healthy person immerses his or her face in cold water
A) vagal tone to the cardiac pacemakers decreases
B) sympathetic stimulation of most of the systemic vascular
beds, except for the coronary and cerebral beds, increases
C) heart rate increases
D) systemic vascular resistance decreases
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Exercise
Michael Levitzky and Kathleen H. McDonough
O B J E C T I V E S
■ Identify the physiologic demands of exercise.
■ Predict the physiologic responses to acute exercise.
■ Describe the effects of long-term exercise programs (training) on the
physiologic response to exercise.
Exercise increases the metabolism of the working muscles.
Physical activity increases the requirement for oxygen and the
production of carbon dioxide. Moderate to severe levels of
exercise also cause increased lactic acid production. The
respiratory and cardiovascular systems must increase the
amount of oxygen supplied to the exercising tissues and
increase the removal of carbon dioxide and hydrogen ions
from the body. Although the muscular and cardiopulmonary
systems are the primary responders to exercise, there are also
adjustments in intermediary metabolism and fluid and elec-
trolyte balance that allow the individual to maintain an
increase in physical activity.
MUSCLE METABOLISM
During exercise, increases in cardiac output (CO) and the
supply of substrates for energy are coordinated primarily by
the sympathetic nervous system. Epinephrine increases glu-
cose output from the liver and fatty acid output from adipose
tissue, providing more substrate for oxidative metabolism by
the exercising muscle. Muscle also has an intracellular supply
of glycogen that provides glucose-6-phosphate for energy.
Oxidative phosphorylation of glucose supports the initial
few minutes of exercise and, during the intermediate phase,
both glucose and fatty acids are used in approximately equal
proportions. More prolonged exercise is mainly supported by
fatty acid oxidation. With strenuous and prolonged exercise,
oxygen delivery may be limiting and glycolysis and lactic acid
formation become more important sources of energy. Anaer-
obic metabolism provides only 2–3 molecules of ATP per
Ch72_745-752.indd 745
72
C H A P T E R
molecule of glucose (2 molecules when glucose is the substrate
and 3 when the glucose-6-phosphate produced by hydrolysis
of glycogen is the substrate), as opposed to the 32 molecules of
ATP produced per molecule of glucose by oxidative phospho-
rylation. Therefore, anaerobic metabolism cannot be sus-
tained for long periods of time. During strenuous exercise,
glycolysis can maintain ATP production for muscular activity
at least for a short time and, on completion of the exercise ses-
sion, the oxygen debt is then repaid by the increased oxygen
consumption that continues in spite of the cessation of the
higher rate of skeletal muscle contraction. Lactate produced
during the anaerobic phase can be converted to glucose by the
liver and glycogen and triacylglycerol stores are subsequently
restored.
ACUTE EFFECTS OF INCREASES
IN PHYSICAL ACTIVITY
The response to exercise in an untrained person is mainly a
function of increased CO and alveolar ventilation to meet the
demand for increased oxygen delivery and carbon dioxide and
hydrogen ion removal.
CARDIOVASCULAR SYSTEM
The CO increases during exercise to provide more blood flow
to the exercising muscles. In most situations, blood flow to the
skin increases in order to help dissipate the heat generated by
muscle metabolism. CO increases nearly linearly with work
745
11/26/10 10:38:23 AM
746 SECTION X Integrative Physiology

rate up to 4–5-fold in a healthy untrained person during max-

Cardiac output (L/min)

25 imal exercise (Figure 72–1); it may increase even more in a

Trained trained athlete.
20
Untrained The CO increases immediately with the onset of exercise
or even in anticipation of exercise. The cerebral cortex initi-
ates the command to exercise, resulting in increased skeletal
muscle activity and metabolism (Figure 72–2). At the same
5 time, the cerebral cortex exerts a “central command” on the
medullary cardiovascular centers from corticohypothalamic
Work rate pathways that decreases parasympathetic activity to the heart
and increases sympathetic activity to the heart and blood
vessels. The set point of the arterial baroreceptor reflex is
Heart rate (beats/min)

200
Untrained Trained increased, which allows arterial pressure to be regulated to a
higher-than-resting level. It is also possible that chemorecep-
tor and mechanoreceptor afferents from active skeletal mus-
70 cles influence the medullary cardiovascular centers. Such
inputs would also contribute to the increases in sympathetic
activity and mean arterial pressure that accompany exercise
and may also contribute to increasing the baroreceptor reflex
Work rate
set point.
Heart rate and stroke volume increase to support the increase
in CO. Heart rate increases linearly with increasing work rate
Stroke volume (ml)

Trained up to about three times that at rest; stroke volume does not
125
increase linearly with workload, but plateaus at an increase of
Untrained
approximately 50%. The increase in heart rate is mediated by
70
reduced parasympathetic and augmented sympathetic activity
to the SA node; the increased stroke volume occurs primarily
by a sympathetically mediated increase in myocardial contrac-
O2 consumption tility and ejection fraction, with the Frank–Starling mecha-
FIGURE 72–1 Changes in cardiac output, heart rate, and nism (see Figure 24–4) playing a lesser role.
stroke volume with increasing workload in untrained and trained The distribution of the left ventricular output changes dur-
individuals. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: ing exercise to support increased local oxygen consumption
Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.) (Figure 72–3). Blood flow to the exercising skeletal muscle

Begin
FIGURE 72–2 Control
of the cardiovascular Brain Exercising skeletal muscles
system during exercise. “Exercise centers” Contractions
“Exercise centers” in the brain
(mainly in the cerebral cortex
and hypothalamus) adjust Afferent Stimulate Local chemical
autonomic control to the input mechanoreceptors changes
Arterial baroreceptors Medullary in the muscles
heart and blood vessels and
Reset upward cardiovascular
increase the baroreceptor center
reflex set point via the Afferent
medullary cardiovascular input Stimulate Dilate
chemoreceptors arterioles
center. Afferent input from in the muscles in the muscle
Parasympathetic output to heart
mechanoreceptors and Sympathetic output to heart, veins,
chemoreceptors in the and arterioles in abdominal
exercising muscles also organs and kidneys Muscle blood flow
influences the medullary
cardiovascular center.
(Reproduced with permission from Cardiac output
Widmaier EP, Raff H, Strang KT: Vasoconstriction in
Vander’s Human Physiology, 11th
abdominal organs
and kidneys
ed. McGraw-Hill, 2008.)
 CHAPTER 72 Exercise 747

Flow during Rest Exercise Recovery

strenuous exercise

Minute ventilation (L/min)

(ml/min)

750 (4%)
Flow
at rest (2)
(ml/min) 750 (4%)

Brain 650 (13%)

(1)
Heart 215 (4%) 12,500 (73%)

Skeletal muscle 1030 (20%)

Time
Skin 430 (9%)
FIGURE 72–4 Changes in ventilation during exercise.
Note the instantaneous increase at the onset of exercise (1) and the
Kidneys 950 (20%)
instantaneous decrease at the end of exercise (2). (Reproduced with
permission from Widmaier EP, Raff H, Strang KT. Van der’s Human Physiology. 11th ed.
Abdominal McGraw-Hill; 2008.)
1200 (24%)
organs 1900 (11%)

Other 525 (10%)
Total 5000 600 (3%)
600 (3%)
400 (2%)
17,500
FIGURE 72–3 Distribution of the left ventricular output at
rest and during strenuous exercise. Flows at rest are typical for a
70-kg individual. The numbers in parentheses represent the percent
of the total for each organ. (Reproduced with permission from Widmaier EP,
Raff H, Strang KT. Van der’s Human Physiology. 11th ed. McGraw-Hill; 2008.)
(including the respiratory muscles), heart, and skin increases
significantly, while blood flow to the kidneys, gastrointestinal
tract, and other abdominal organs decreases significantly.
Blood flow to the brain is not significantly altered. The increase
in blood flow to the exercising muscles occurs primarily by
local metabolic regulation; the increased blood flow to the
skin occurs primarily by withdrawal of sympathetic tone. The
decreased blood flow to the kidneys and other abdominal
organs occurs by sympathetically mediated vasoconstriction.
Venous return must increase in order for the CO to increase.
Three mechanisms combine to increase venous return:
increased activity in the exercising skeletal muscle compressing
veins and squeezing blood through one-way valves toward the
heart (the skeletal muscle pump), increased tidal volume and
breathing frequency increasing the abdominal–thoracic pres-
sure difference so that intrapleural pressure is more negative
and abdominal pressure more positive during inspiration (the
thoracoabdominal pump), and a sympathetically mediated
increase in venous tone, which decreases venous capacitance.
The dilation of skeletal muscle arterioles also lowers resistance
to blood flow from the arterial to the venous vessels.
Mean arterial blood pressure (MABP) increases moder-
ately with increasing exercise, indicating that the increase in
CO must be slightly greater than the decrease in systemic
vascular resistance (SVR) caused by dilation of blood vessels
supplying the exercising muscle:
MABP – RAP = CO × SVR (1)
Right atrial pressure (RAP) does not usually change sig-
nificantly during exercise; it may increase slightly during
strenuous exercise because of the large increase in venous
return (preload).
The increased MABP is characterized by an increase in
pulse pressure without a significant change in diastolic pres-
sure. The pulse pressure mainly increases because of the
greater stroke volumes noted above and because of more rapid
aortic pressure development (increased dP/dt) caused by
increased ventricular contractility. Furthermore, the set point
for the baroreceptor reflex increases to allow the increased sys-
temic blood pressure (see Figure 72–2).
RESPIRATORY SYSTEM
Minute ventilation increases (hyperpnea) linearly with both
oxygen consumption and carbon dioxide production up to a
level of about 60% of the maximal work capacity. Above that,
minute ventilation increases faster than oxygen consumption but
continues to rise proportionally to the increase in carbon dioxide
production. This increase in ventilation above oxygen consump-
tion at high work levels is caused in part by the increased lactic
acid production that occurs as a result of anaerobic metabolism.
The hydrogen ions liberated in this process directly stimulate the
arterial chemoreceptors. In addition, the buffering of hydrogen
ions by bicarbonate ions results in production of carbon dioxide
in addition to that derived from aerobic metabolism.
The ventilatory response to constant work rate exercise con-
sists of three phases (Figure 72–4). At the beginning of exercise,
there is an immediate increase in ventilation, which may even
occur in anticipation of physical activity. This is followed by a
phase of slowly increasing ventilation, ultimately increasing to a
final steady-state phase if the exercise is not too strenuous. The
748 SECTION X Integrative Physiology
initial immediate increase in ventilation may constitute as much
as 50% of the total steady-state response. The increase in min-
ute ventilation is usually a result of increases in both tidal vol-
ume and breathing frequency.
The mechanisms by which exercise increases minute ventila-
tion are summarized in Table 72–1. No single factor can fully
account for the ventilatory response to exercise, and much of the
response remains unexplained. The immediate increase in ven-
tilation occurs too quickly to be due to changes in metabolism
or blood gases. This “neural component” consists in part of col-
lateral fibers to the respiratory muscles from the motor cortex
neurons that primarily innervate the exercising skeletal muscles.
It may also be partly accounted for by a conditioned reflex; that
is, a learned response to exercise. Input to the respiratory centers
from proprioceptors located in the joints and muscles of the
exercising limbs may play a role. The ventilatory and cardiovas-
cular responses to exercise may be coordinated (and in part ini-
tiated) in an “exercise center” in the hypothalamus.
The arterial chemoreceptors do not appear to play a role in
the initial ventilatory response to exercise. In mild or moder-
ate exercise, average arterial Pco2 and Po2 are not altered signifi-
cantly (see Figure 72–5), even during the increasing ventilation
phase (the “humoral component”). It is possible that the arte-
rial chemoreceptors are responding to greater oscillations in
the blood gases during exercise. Other potential afferent stim-
uli to ventilation during moderate exercise are summarized in
Table 72–1.
The work of breathing is increased during exercise. Larger
tidal volumes result in increased work necessary to overcome
the elastic recoil of the lungs and chest wall during inspiration
because the lungs are less compliant at higher lung volumes and
because the elastic recoil of the chest wall is inward at high tho-
racic volumes. The high airflow rates generated during exercise
result in a much greater airway resistance component of the
work of breathing because of greater turbulence and dynamic
compression of airways secondary to active expiration. .
In normal adults, the resting minute ventilation (VE ) of 5–6
L/min can be increased to as much as 150 L/min during short
periods of maximal exercise. Maximal increases in CO during
exercise are only in the range of four to five times the resting
level in healthy adults compared with this 25-fold potential
increase in minute ventilation. Therefore, it is the cardiovas-
cular system rather than the respiratory system that is the lim-
iting factor in exercise by healthy people. However, significant
decreases in respiratory function that can occur with a variety
of pulmonary diseases often limits exercise capacity. The
breathing frequency may increase to 40–50 breaths/min in
healthy adults (and as high as 70 breaths/min in children) with
strenuous exercise.
Arterial Pco2 is stable until anaerobic metabolism results in
appreciable lactic acid generation (Figure 72–5). The hydro-
gen ions liberated directly stimulate alveolar ventilation via
the arterial chemoreceptors and may cause arterial Pco2 to fall
below the resting arterial Pco2.
As CO increases, mean pulmonary arterial and mean left
atrial pressures increase, but the increase is not as great as the
TABLE 72–1 Ventilatory response to exercise.
Immediate response—“neural component”
Central command
Learned or conditioned reflex
Direct connections from motor cortex—collaterals from motor
neurons to muscles
Coordination in hypothalamus
Proprioceptors or mechanoreceptors in limbs—probably not
muscle spindles or Golgi tendon organs
Subsequent increase
During moderate exercise
Arterial chemoreceptors
PO2—usually no change in mean
PCO2—usually no change in mean
[H+]—usually no change unless cross anaerobic threshold
[K+]—released from exercising muscle cells could stimulate
arterial chemoreceptors—minor role
Oscillations in arterial PO2 and PCO2
Metaboreceptors
Nociceptors—H+, K+, bradykinin, arachidonic acid released during
exercise could stimulate pain receptors
Cardiac receptors
Venous chemoreceptors
Temperature receptors
During exercise severe enough to exceed anaerobic threshold
Lactic acid buffered by HCO3− produces CO2
Arterial chemoreceptors
↑ PCO2
↑ [H+]
Central chemoreceptors
↑ PCO2 → ↑ H+
Potentiation of chemoreceptor responses during exercise
Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New
York: McGraw-Hill Medical, 2007.
increase in pulmonary blood flow. This indicates a decrease in
pulmonary vascular resistance that occurs passively by
recruitment and distention of pulmonary vessels. It results in
more uniform distribution of pulmonary blood flow and more
uniform matching of ventilation and perfusion throughout
the lung. Because ventilation increases more than perfusion in
moderate to strenuous
. . exercise, the whole lung ventilation–
perfusion ratio (VA /QC ) increases to a range of 2.0–4.0. Thus,
the location of the perfusion is better matched to the location
of the ventilation during exercise, but the ventilation–perfusion
ratios increase in most alveolar–capillary units.
The diffusing capacities for oxygen and carbon dioxide
normally increase substantially during exercise. The increase
in diffusing capacity during exercise is largely a result of the
increase in pulmonary blood flow. Recruitment of capillaries,
especially in upper regions of the lungs, increases the surface
area available for diffusion. Increased linear velocity of blood
flow through pulmonary capillaries reduces the time that red

100
80
ventilation
(L/min)
Minute
60
40
20
0
Arterial PO2
110
(mmHg)
100
90
Arterial PCO2
40
(mmHg)
30
Arterial [H+]
60
(nmol/L)
48
36
O2 consumption (ml/min)
Rest Maximal
exercise
FIGURE 72–5 Effect of exercise on minute ventilation, arterial
oxygen and carbon dioxide partial pressures, and arterial
hydrogen ion concentration with increasing exercise workloads.
Note that the average arterial carbon dioxide levels are not altered
significantly until exercise is sufficiently strenuous to produce increased
levels of lactic acid. As the additional hydrogen ions stimulate the
arterial chemoreceptors, arterial carbon dioxide levels decrease; the
individual is therefore hyperventilating. (Reproduced with permission from
Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)
blood cells spend in contact with the alveolar air, decreasing
the perfusion limitation of gas transfer. The alveolar–arterial
oxygen difference usually increases during exercise.
. .This is
probably because of a number of factors, including VA /QC mis-
match, diffusion limitation of gas transfer, a decreased mixed
venous Po2 , an increased alveolar Po2 , and alterations in the
oxyhemoglobin dissociation curve.
The loading of carbon dioxide into the blood and the unload-
ing of oxygen from the blood are enhanced in exercising mus-
cles. Oxygen unloading is improved because the tissue Po2 in the
exercising muscle is decreased, resulting in an increased diffu-
sion gradient for oxygen. Oxygen unloading is also enhanced
by the rightward shift of the oxyhemoglobin dissociation curve
caused by the increased local Pco2 (the Bohr effect), hydrogen
ion concentrations, and temperatures found in exercising mus-
cle. Low capillary Po2 also leads to improved carbon dioxide
loading because lower oxyhemoglobin levels shift the carbon
dioxide dissociation curve to the left (the Haldane effect).
Exercise strenuous enough to cause a significant degree of
anaerobic metabolism results in metabolic acidosis second-
ary to the increased lactic acid production. As discussed previ-
ously, the hydrogen ions generated by this process stimulate
CHAPTER 72 Exercise 749
the arterial chemoreceptors (especially the carotid bodies)
and cause a further compensatory increase in alveolar ventila-
tion, maintaining arterial pH near the normal level.
FLUID AND ELECTROLYTE BALANCE
Exercise causes a decrease in plasma volume, particularly if
the exercise is performed in a warm environment. The
increased metabolism generates heat. As was discussed in
Chapter 70, evaporation of water in perspiration produced by
sweat glands is a primary mechanism of heat loss by the body.
A 70-kg person can lose more than 2 L/h of water via perspira-
tion. A second cause of decreased plasma volume during exer-
cise is increased filtration of plasma fluid from capillaries into
the interstitial space. Capillary hydrostatic pressure increases
in exercising muscles because of arteriolar vasodilation and to
a lesser extent because MABP increases. Also, the circulating
blood volume decreases because as body temperature increases,
compliance of the veins of skin increases to help dissipate heat,
resulting in a greater amount of blood in the skin.
Perspiration is hypotonic to plasma, so relatively more water
is lost than ions. The composition of sweat is variable from
person to person and is also dependent on the rate of sweat
production. At higher flows, sweat contains increased concen-
trations of sodium and chloride, and less potassium although
it remains hypotonic to plasma. Training (see the next section)
and heat acclimatization lead to production of more dilute
sweat, which helps conserve sodium and chloride and increase
exercise tolerance; this effect is probably mediated by aldoster-
one release in response to sodium ion loss.
Ingesting sodium chloride with water improves recovery from
exercise and/or heat stress dehydration. Drinking water without
salt decreases extracellular fluid osmolality and decreases thirst,
delaying rehydration. This is the basis of sports drinks that con-
tain sodium chloride and potassium; some also contain carbo-
hydrates for energy. However, overhydration causing dangerous
hyponatremia during exercise is a significant problem particu-
larly in those new to strenuous, sustained exercise.
TRAINING EFFECTS
The ability to perform physical exercise increases with train-
ing. Most of the changes that occur as a result of physical train-
ing are a function of alterations in the cardiovascular system
and in muscle metabolism (Figure 72–1). The maximal oxy-
gen uptake increases with physical training mainly as a result
of a higher maximal CO. As stated earlier, the maximal CO is
probably the limiting factor in exercise. Physical training
decreases the resting heart rate and increases the resting stroke
volume; an elite cross-country skier can have a resting heart
rate as low as 40 beats/min. The maximal heart rate does not
appear to be affected by physical training, but the heart rate of
a trained person is lower than that of an untrained person at
most levels of physical activity. Stroke volume is increased.
750 SECTION X Integrative Physiology
The arterial hemoglobin concentration and the hematocrit do
not appear to change with physical training at sea level, but the
arteriovenous oxygen content difference can increase with
physical training. This is probably a function of the greater
effects of local pH, Pco2 , and temperature in the exercising
muscles, as well as an increased ability of the muscles to use
oxygen. Blood volume is usually higher after an exercise–
training program.
Physical training augments the oxidative capacity of skeletal
muscle by inducing mitochondrial proliferation and increasing
the concentration of oxidative enzymes and the synthesis of gly-
cogen and triglyceride. These alterations result in lower concen-
trations of blood lactate in trained subjects than those found in
untrained people, reflecting increased aerobic energy produc-
tion. Nevertheless, blood lactate levels during maximal exercise
may be higher in trained athletes than in untrained people.
Maximal ventilation and resting ventilation do not appear to
be affected by physical training, but ventilation at submaximal
loads is decreased, probably because of the lower lactic acid
levels of the trained person during submaximal exercise. The
strength and endurance of the respiratory muscles appear to
improve with training. Total lung capacity is not affected by
training; vital capacity may be normal or elevated. Pulmonary
diffusing capacity is often elevated in athletes, probably as a
result of their increased blood volumes and maximal COs.
There are many changes in other physiologic systems that
can occur with training. One of the most important is the
female athlete triad that, by definition, occurs in women. The
triad is amenorrhea (lack of menstrual cycles), osteoporosis
(significant decreases in bone mineral density), and disor-
dered eating. This triad is found primarily in elite female ath-
letes with low body energy stores. The amenorrhea (or
oligomenorrhea—irregular menses) is caused primarily by a
decrease in luteinizing hormone (LH) release from the ante-
rior pituitary. Although the precise signal for this is not known,
a decrease in the hormone leptin, released by adipose tissue,
resulting in a reduction of gonadotropin-releasing hormone
(GnRH) pulsatility has been implicated. Exercise by itself does
not cause amenorrhea—it contributes to the negative caloric
balance due to decreased caloric intake. The loss of bone mass
is primarily due to low estrogen levels because of decreased
LH (see Chapter 68). This greatly increases the risk of stress
fractures in female athletes. Unfortunately, some of this loss of
bone mass is not reversible even if normal menses and estro-
gen secretion occur with treatment. It is generally appreciated
that eating disorders are more common in athletes. In women,
these are primarily anorexia nervosa (refusal to maintain
caloric input to maintain body weight) and bulimia nervosa
(characterized by self-induced vomiting, as well as laxative
and diuretic abuse). Although these extreme eating disorders
are not a requisite for the triad, caloric intake is usually sig-
nificantly lower than the increased energy expenditure in ath-
letes. The treatment of the female athlete triad generally
includes alterations in training type and intensity, increased
caloric intake, and even administration of birth control pills or
estrogen to try to restore bone mass.
CLINICAL CORRELATION
A 58-year-old man, complaining of chest pain on exertion,
was referred to a cardiologist for a graded exercise stress
test. The patient’s electrocardiogram, blood pressure, heart
rate, tidal volume, respiratory rate, and arterial oxygen sat-
uration by pulse oximetry were monitored during the test,
which used a treadmill to provide an incremental work-
load. At the stage of the test when the workload had dou-
bled, the patient complained of chest pain and the stress
test was stopped. During the test, his heart rate increased
from 75 to 135/min, and his blood pressure increased from
150/90 to 180/95 mm Hg. His electrocardiogram was nor-
mal at rest, but showed significant ST segment depression
at the highest exercise level (see Chapter 25). His oxygen
consumption increased from 300 mL/min to 1.5 L/min
during the test. Pulse oximetry did not show significant
oxygen desaturation.
Exercise stress tests are used to help diagnose cardiovas-
cular and pulmonary disease, as well as to determine the
severity of the disease and the efficacy of treatment. Patients
may be asymptomatic at rest because of the physiologic
reserves of the cardiovascular and respiratory systems; these
reserves are often decreased in cardiopulmonary disease.
The data obtained during the increased workload of an
exercise stress test can be useful in differentiating whether
the problem is cardiovascular, respiratory, or both. In this
case, the problem was cardiovascular, with coronary artery
disease the most likely diagnosis. The respiratory system
was able to meet the increased demand for alveolar ventila-
tion in order to supply more oxygen and remove more car-
bon dioxide. However, the increased cardiac work led to ST
segment depression, indicating an inability of the coronary
arteries to dilate sufficiently to provide additional blood
flow to meet the higher myocardial oxygen demand. The
cardiac workload, particularly the left ventricular work-
load, is increased during exercise because of the increases
in contractility and heart rate and stroke volume to increase
the cardiac output, and because the increase in blood pres-
sure increases the afterload. Furthermore, left ventricular
coronary perfusion mainly occurs during diastole, which is
much shorter at higher heart rates.
Treatment of coronary artery disease is dependent on the
severity of the disease and may include low doses of aspirin
to prevent blood clotting, drugs to decrease blood pressure
and blood cholesterol, or interventions such as angioplasty
(to open clogged arteries) with or without stents (to keep
them opened), or coronary artery bypass surgery.
CHAPTER SUMMARY
■ The main physiologic stresses of exercise are increased oxygen
demand and removal of carbon dioxide and hydrogen ions, and
dissipation of heat produced by muscle metabolism.
 CHAPTER 72 Exercise 751

■ The response to exercise is mainly an increase in cardiac output 2. Which of the following would be expected to have the largest
and alveolar ventilation. percent increase as a healthy person transitions from rest to
■ In a healthy young person, exercise is limited by the cardiovas- moderate exercise?
cular system, not the respiratory system. A) heart rate
■ Prolonged exercise decreases plasma volume, particularly in a B) stroke volume
warm environment. C) cardiac output
■ Training improves exercise performance mainly by improving D) mean arterial blood pressure
the cardiovascular response. E) diastolic arterial blood pressure
■ The female athlete triad is the combination of menstrual 3. Which of the following would be expected to decrease as a
disorders and low estrogen, decreases in bone mass, and healthy untrained person undergoes an exercise–training
decreased caloric intake despite increased energy expenditure program?
leading to a low body fat mass. A) resting stroke volume
B) resting cardiac output
C) resting heart rate
STUDY QUESTIONS D) maximal oxygen uptake
E) maximal alveolar ventilation
1. Which of the following would be expected to decrease as an
untrained person transitions from rest to moderate exercise?
A) pulmonary vascular resistance
B) pulmonary blood flow
C) alveolar ventilation
D) tidal volume
E) diffusing capacity
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Aging
Hershel Raff
O B J E C T I V E S
■ Understand the changes in the nervous, muscular, cardiovascular, respiratory,
renal, gastrointestinal, and endocrine function that occur with aging.
■ Appreciate the pathophysiology of Alzheimer disease.
The life expectancy in most areas of the world has increased
over the past few centuries. Much of this is due to the devel-
opment of vaccines against infectious diseases as well as the
development of antibiotics and antiviral therapy resulting in
decreased infant mortality. Furthermore, improvements in
the treatment of other chronic conditions such as cancer and
cardiovascular disorders, as well as improved sanitation, have
increased life expectancy. Along with this increase of lifespan,
there are many chronic diseases associated with aging such as
type 2 diabetes mellitus and osteoporosis that have increased
in frequency. Successful or healthy aging promotes the con-
cept that aging is not an illness, but a natural phenomenon
that can be influenced by lifestyle, genetics, and environmen-
tal factors. In general, functional reserves such as exercise
capacity decrease with age and, eventually, function itself
declines and the susceptibility to disease increases. It is also
important to note that the effects of aging are quite variable
between males and females, ethnic groups, and populations.
Table 73–1 summarizes some aging-related changes in the
organ systems you have learned about in this book.
NEURAL SYSTEM
It is generally accepted that healthy individuals lose some cogni-
tive abilities with age. However, this is different from the devel-
opment of neurological diseases and syndromes associated with
aging. Reflexes can slow, resulting in an increased response time.
Normal aging can often include a decline in visual, auditory, gus-
tatory, and olfactory acuity, as well as deterioration in gait and
balance. This is why fall prevention is so critical in the elderly.
Ch73_753-756.indd 753
73
C H A P T E R
One of the important pathological causes of neurological
decline associated with aging is dementia that is defined as a
significant loss of memory recall and other cognitive func-
tions. Although there are many types of dementia, Alzheimer
disease, a pathological deterioration of cognitive and behav-
ioral function associated with aging, is the most common type.
This condition is associated with the development of amyloid
plaques and neurofibrillary tangles in the central nervous
system that leads to inflammation and neurotoxicity.
MUSCULAR SYSTEM
There is an overall loss of skeletal muscle mass (sarcopenia)
with normal aging—this results in a decrease in lean body
mass. In addition, there is a loss of mitochondria, tendon
strength, and elasticity. There is also loss of blood vessel den-
sity and cellular respiratory enzyme activity, leading to a
decrease in the ability to extract oxygen during exercise and
decreased force production.
CARDIOVASCULAR SYSTEMS
One of the hallmarks of healthy aging is an increase in systolic
blood pressure with either no change or a decline in diastolic
blood pressure (Figure 73–1). This increase in pulse pressure
indicates a loss of vascular compliance. Calcification of blood
vessels increases with age. When extreme, this “stiffening” of
the vascular bed is defined as arteriosclerosis. Table 73–2 lists
other common cardiovascular changes with aging.
753
11/26/10 10:37:45 AM
754 SECTION X Integrative Physiology

TABLE 73–1 Aging-related changes. TABLE 73–2 Cardiovascular changes with aging.
Organ System Aging-related Changes Heart Decrease in maximal heart rate during exercise
Decrease in maximal cardiac output during
Nervous system Degenerative changes in neurons exercise
Loss of dendrites and synaptic connections Decrease in left ventricular compliance
Decreases in sensation, memory recall, and Increase in valve calcifications
communication
Increase in calcification of coronary arteries
Diminished visual, gustatory, auditory, and
olfactory senses Vascular Increase in total peripheral resistance
Muscular Decrease in number of skeletal muscle fibers and Increase in “stiffness”, decrease in aortic compliance
decrease in strength and capillary density (rarefaction)

Cardiovascular See Table 73–2 CV control Blunted baroreceptor reflex

Decrease in response to beta-adrenergic
Respiratory Loss of elasticity of lungs (increase in stimulation
compliance)
Decrease in the number of alveoli and surface Blood Decrease in total body water and blood volume
area for gas exchange CV hormones Decrease in plasma renin activity, angiotensin,
Reduced vital capacity and increased dead space and aldosterone
Reduced ability to clear airways by coughing

Renal/urinary Decrease in number of functional nephrons

Decrease in glomerular filtration rate
Decrease in tubular secretion and reabsorption
Increased risk of dehydration
Increase in the frequency of incontinence
Gastrointestinal Decreased capacity to secrete pancreatic
enzymes
Decreased vitamin D and calcium absorption
(contributes to loss of bone mineral density)
Decrease in motility (contributes to constipation)
Endocrine Decrease in some hormones in the blood
(e.g., GH, androgens, DHEA)
Menopause and associated phenomena
(e.g., loss of bone mineral density)
Data from Shier D, Butler J, Lewis R. Hole’s Human Anatomy & Physiology 11th
Edition. McGraw Hill Higher Education. Boston, 2007 and Kane RL, Ouslander JG,
Abrass IB, Resnick B. Essentials of Clinical Geriatrics 6th Edition. McGraw Hill Medical,
New York, 2009.
200
150
Pressure (mmHg)
PULMONARY SYSTEM
Important changes in the structure and function of the pulmo-
nary system include loss of alveolar elastic recoil resulting in
increased lung compliance, decreased respiratory muscle
strength, changes in the rib cage and spinal column resulting
in decreased chest wall compliance, and loss of alveolar sur-
face area and pulmonary capillary volume. The decreases in
lung elastic recoil can lead to an increase in functional
residual and closing capacities.
One of the hallmarks of aging is an increase in the difference
between the partial pressure of alveolar oxygen (PAo2), which
is calculated using the alveolar air equation and does not
change significantly with age, and arterial oxygen (Pao2). This
increase in the so-called A–a oxygen gradient reflects a nearly
linear decrease in Pao2 with age. This is primarily due to an
increase in ventilation–perfusion mismatching resulting
from changes in pulmonary blood flow and volume, increases
in pulmonary compliance leading to airway and alveolar col-
lapse, and a decrease in diffusing capacity due to a decreased
surface area for gas exchange. When evaluating blood gases in
an elderly patient, it is important to realize that a lower Pao2

Systolic pressure may be a result of normal aging rather than due to a specific
disease that requires treatment.
Mean pressure
100

Diastolic pressure
50
RENAL/URINARY SYSTEM
After the age of about 30 years, the number of functional
glomeruli declines and, by age 80, may have decreased from a
0
0 20 40 60 80
peak of about 2.2 to about 1.2 million. In addition, there is a
Age (years) decrease in renal plasma flow due to changes in the small
FIGURE 73–1 Changes in arterial pressure with age in the renal arteries and the afferent arterioles. As a result, creatinine
US population. (Adapted with permission from National Institutes of Health clearance, an index of glomerular filtration rate, decreases
Publication #04-5230, August 2004.) by approximately 30%. There is also a decrease in urinary

diluting and concentrating capacity. Despite this, basal water
and electrolyte balance are usually not significantly altered
during healthy aging. The decrease in total body water is more
due to a loss of lean body mass rather than renal function.
The risk of dehydration is increased during healthy aging.
This is due to a decrease in the ability to maximally concentrate
the urine due to a decline in tubular function. Thirst is also
compromised with aging. Furthermore, the antidiuretic hor-
mone (arginine vasopressin) response to an increase in plasma
osmolality can be altered, and the ability to defend total body
water and blood volume during dehydration is compromised.
Incontinence is involuntary urination with many causes,
and is a significant health and hygiene problem in the elderly.
In men, the development of benign prostatic hyperplasia can
lead to difficulty in voiding. In women after menopause, estro-
gen deficiency is known to be associated with structural
changes in the vagina, urethra, and bladder, all of which
increase the risk of incontinence.
GASTROINTESTINAL SYSTEM
The changes in the gastrointestinal tract with aging are subtler
than the other systems described in this chapter. A loss of
swallowing coordination, combined with increased gastro-
esophageal reflux, can lead to an increased risk of aspiration
pneumonia. The colon tends to thicken, resulting in increased
contraction strength that may increase the risk of diverticuli,
which are pouches that can form from the wall of the colon
that can become infected and even burst, releasing luminal
contents into the peritoneal cavity. The decline in vitamin D
absorption and tendency to get less sunlight leads to vitamin
D insufficiency and a subsequent decrease in calcium absorp-
tion. This can exacerbate the decline in bone mineral density
that occurs with age. The subtle decline in liver function can
alter drug metabolism sufficiently to increase the risk of drug
toxicity. Although decreases in motility of the intestine are not
dramatic, there is an increase in the risk of constipation.
Finally, the maximal function of the exocrine pancreas can
result in a decrease in enzyme secretion into the small intes-
tine—this is usually not sufficient to alter the digestion and
absorption of proteins and fats.
ENDOCRINE SYSTEM
There are many hormonal changes that occur with aging. The
most dramatic is the cessation of ovarian function in women
that results in menopause described in detail in Chapter 68.
Briefly, loss of estrogen synthesis from the ovaries results in a
large increase in gonadotropin secretion from the anterior
pituitary due to loss of negative feedback. Low estrogen levels
result in many physiological changes, probably the most dra-
matic being loss of bone mineral density (osteopenia) that can
become severe enough to increase the risk of bone fractures
(osteoporosis). The low estrogen levels can lead to physiologi-
CHAPTER 73 Aging 755
cal changes in autonomic function and behavior, as well as sys-
temic consequences. There appears to be a higher incidence of
cardiovascular dysfunction after menopause. The decline in
male reproductive function (the andropause) is much more
subtle. Although there can be a decrease in plasma free and
total testosterone levels and sperm production, it is well known
that many men can remain fertile well into their 80s.
There is a subtle decline in insulin sensitivity such that fast-
ing blood glucose tends to increase, as does the risk of the
development of type 2 diabetes mellitus. Finally, growth hor-
mone and insulin-like growth factor I (IGF-1) concentra-
tions decline with aging. It has been hypothesized that these
contribute to the loss of muscle mass described earlier, and
some have advocated growth hormone replacement therapy in
the elderly with established growth hormone deficiency.
CLINICAL CORRELATION
(Adapted from Toy E et al: CASE FILES; Pathology. McGraw-
Hill, 2006):
An elderly man is found wandering around your campus
looking for his way home. You notice a wristband that says
he is 88 years old and a resident of a local nursing home. He
is not bleeding, has no obvious bruises, and is not limping.
In addition to being lost and disoriented, his sentences do
not make sense and his conversation is not coherent. He is
alert and cooperative, but confused. You call the nursing
home and they immediately call for an ambulance that
arrives in 10 minutes and takes the man to the emergency
room of the local hospital. The emergency room physician
makes a provisional diagnosis of dementia and examines
the patient. He has no obvious injuries nor does he have
neurological signs that would suggest a brain tumor or
stroke. A representative of the nursing home arrives at the
emergency room with the patient’s medical records that
indicate the man has Alzheimer disease.
Alzheimer disease is the most common cause of demen-
tia in the elderly. It usually starts with a slow loss of advanced
mental functions such as the ability to do mathematical
problems (e.g., pay bills, manage the check book or house-
hold finances) and word recall. There is often a change in
mood and behavior early in the disease. As the disease pro-
gresses, higher brain functions involving the cerebral cor-
tex are lost, leading to disorientation (demonstrated in our
patient) and memory loss. In late stages, patients often do
not speak or move.
Although there is a familial form of Alzheimer disease,
most cases in the elderly occur without a strong family his-
tory. When the brain is examined post mortem, atrophy of
the cerebral cortex is a common finding. The most com-
mon abnormalities found during histological examination
of the brain are neurofibrillary tangles and amyloid plaque
deposition. Neurofibrillary tangles are bundles of filaments
composed primarily of phosphorylated tau protein found
756 SECTION X Integrative Physiology

in the neuronal cytoplasm around the nucleus. Amyloid STUDY QUESTIONS

plaque deposits are extracellular, and contain several abnor- 1. Which of the following is true?
mal proteins. All of these abnormal proteins interfere with A) Both arterial and pulmonary compliance increase
normal neurological function. with aging.
Alzheimer disease usually progresses slowly for 10–20 B) Arterial compliance decreases and pulmonary
years. As in our patient, forgetfulness and difficulty with compliance increases with aging.
sentence formation (aphasia) are common signs. As the C) Arterial compliance increases and pulmonary
disease progresses, the loss of motor function ensues. compliance decreases with aging.
Patients develop difficulty with balance and walking, and D) Both arterial and pulmonary compliance decrease
are prone to fall. The cause of death is usually another pri- with aging.
mary disease, such as pneumonia, the susceptibility to 2. All of the following decrease with aging except
which increases dramatically due to the loss of motor func- A) number of glomeruli in the kidney
tions such as the ability to chew and swallow properly. B) creatinine clearance
C) renal plasma flow
D) risk of dehydration
3. The decrease in bone mineral density in elderly women is due
CHAPTER SUMMARY at least in part to
A) decrease in vitamin D absorption
■ It is normal for some memory and sensory functions to
B) increase in calcium absorption
decrease with age.
C) increase in estrogen secretion
■ There is typically a loss of muscle mass with aging. D) decrease in cortisol
■ An increase in arterial systolic and pulse pressure is typical 4. Which plasma hormone increases with aging?
with aging.
A) renin
■ Decreased lung elasticity increases the functional residual B) pituitary gonadotropins in women
capacity and decreased Pao2 increases the alveolar–arterial C) growth hormone
gradient for oxygen with aging. D) free testosterone in men
■ A decrease in renal glomerular number and creatinine
clearance occurs with aging.
■ In women, ovarian function invariably ceases, causing
menopause characterized by a decrease in estrogen in
the blood and loss of bone mass. A decrease in vitamin D
and calcium absorption further contributes to the loss of
bone mass.
 Answers to Study Questions

Chapter 1 Chapter 12
1. B 2. D 3. C 4. B 1. B 2. E 3. B 4. D 5. E

Chapter 2 Chapter 13
1. C 2. E 1. C 2. D 3. A 4. D 5. D

Chapter 3 Chapter 14
1. C 2. E 3. D 4. E 5. C 6. D 1. C 2. E 3. C 4. E

Chapter 4 Chapter 15
1. A 2. D 3. C 4. B 1. D 2. D 3. B 4. E 5. D 6. B 7. D

Chapter 5 Chapter 16
1. A 2. D 3. A 1. E 2. B 3. C 4. E 5. D 6. D 7. E

Chapter 6 Chapter 17
1. C 2. B 3. E 4. C 5. A 6. D 1. D 2. C 3. D 4. D 5. C 6. D

Chapter 7 Chapter 18
1. A 2. D 3. B 4. B 5. C 6. C 7. D 1. C 2. E 3. E 4. D 5. C

Chapter 8 Chapter 19
1. D 2. B 3. A 4. C 1. D 2. B 3. D 4. D

Chapter 9 Chapter 20
1. B 2. C 3. B 1. C 2. D 3. C 4. D 5. A 6. C

Chapter 10 Chapter 21
1. D 2. D 3. A 4. A 1. A 2. C 3. D 4. B 5. D 6. D

Chapter 11 Chapter 22
1. A 2. C 3. B 4. C 1. E 2. D 3. E 4. B 5. B

757

Answers_757-760.indd 757 11/30/10 2:15:02 PM

758 Answers to Study Questions

Chapter 23 Chapter 37
1. B 2. E 3. C 4. B 5. A 1. C 2. D 3. B 4. A

Chapter 24 Chapter 38
1. B 2. A 3. C 4. A 5. A 1. B 2. D 3. D 4. B

Chapter 25 Chapter 39
1. B 2. D 3. A 4. C 5. C 1. B. 2. C 3. C 4. C 5. D 6. B

Chapter 26 Chapter 40
1. E 2. E 3. D 4. C 5. A 1. D 2. B 3. B 4. C 5. C

Chapter 27 Chapter 41
1. B 2. C 3. A 4. C 5. C 1. D 2. A 3. C 4. B 5. C

Chapter 28 Chapter 42
1. E 2. B 3. A 4. D 5. E 1. C 2. D 3. B 4. D 5. A

Chapter 29 Chapter 43
1. A 2. B 3. E 4. A 5. A 1. C 2. D 3. A 4. C 5. A 6. B

Chapter 30 Chapter 44
1. E 2. B 3. C 4. E 5. E 1. B 2. B 3. D 4. A 5. B 6. C

Chapter 31 Chapter 45
1. F 2. E 1. D 2. A 3. A 4. C 5. A

Chapter 32 Chapter 46
1. C 2. D 3. A 4. C 5. B 6. D 1. D 2. C 3. B 4. B 5. D

Chapter 33 Chapter 47
1. F 2. D 3. C 4. C 5. A 1. B 2. A 3. D 4. C 5. C 6. B

Chapter 34 Chapter 48
1. C 2. E 3. B 4. B 5. E 1. C 2. B 3. A 4. A 5. D 6. D

Chapter 35 Chapter 49
1. E 2. A 3. B 4. A 1. A 2. D 3. A 4. B 5. E

Chapter 36 Chapter 50
1. E 2. D 3. E 4. A 1. A 2. E 3. E 4. D 5. B 6. A
 Answers to Study Questions 759

Chapter 51 Chapter 63
1. A 2. E 3. C 4. C 5. D 1. C 2. C 3. A 4. C

Chapter 52 Chapter 64
1. A 2. A 3. D 4. E 5. A 1. B 2. D 3. A 4. C 5. C

Chapter 53 Chapter 65
1. B 2. C 3. C 4. E 5. D 1. A 2. B 3. C 4. D 5. B 6. C

Chapter 54 Chapter 66
1. A 2. E 3. A 4. B 5. C 6. E 1. C 2. C 3. B 4. C 5. A

Chapter 55 Chapter 67
1. E 2. C 3. D 4. C 5. B 1. C 2. C 3. B 4. C

Chapter 56 Chapter 68
1. A 2. E 3. A 4. E 5. D 1. D 2. A 3. C 4. A 5. B

Chapter 57 Chapter 69
1. C 2. E 3. B 4. B 5. A 1. B 2. B 3. C 4. B

Chapter 58 Chapter 70
1. C 2. B 3. E 4. E 5. B 1. D 2. A 3. B 4. C

Chapter 59 Chapter 71
1. E 2. D 3. D 4. D 5. E 1. D 2. A 3. C 4. B 5. B

Chapter 60 Chapter 72
1. B 2. E 3. D 4. C 1. A 2. C 3. C

Chapter 61 Chapter 73
1. A 2. D 3. B 4. C 5. D 1. B 2. D 3. A 4. B

Chapter 62
1. B 2. A 3. C 4. B
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761 INDEX

Index
Page numbers followed by f or t indicate figures or tables, respectively.

A metabolic acidosis, renal response to, 482 adrenal medulla, hormones

A–a oxygen gradient, 754 metabolic alkalosis, factors, 482 adrenal catecholamines, overproduction
ABC transporters, 24 respiratory acidosis, 378, 481 diseases, 667
ABC5 transporter, 568 respiratory alkalosis, 378–379, 394, 481, 736 adrenergic receptors, regulation, 667
ABC8 transporter, 568 respiratory acidosis and alkalosis, renal catecholamine physiologic effects, 667,
Abducens nerves, 143 response to, 481–482 667t
Absence seizures, 185 Acidemia, 375, 380, 464, 469, 470 catecholamine release, transport, and
Absolute refractory state, 212 Acidosis, 375, 377, 647 metabolism, 665
Absorption process, 491 Acid-sensing ion channels (ASICs), 45 chemistry and biosynthesis, 665
Accessory muscles of inspiration, 315, 316 Acini, 308, 492 target organ cellular effects, 665–667
Acclimatization process, 730 Acromegaly, 630, 631 functional anatomy and zonation, 655
Accommodation, 136 ACTH-independent Cushing’s syndrome, 664 adrenal androgens diseases, 664–665
ACE inhibitors, 453, 461 Actin, 80, 83 adrenal cortex hormones, 656–664
Acetaminophen, 732 Actin filament, 80, 83 glucocorticoids diseases, 664
Acetazolamide, 737 Action potential, 10, 47 mineralocorticoids diseases, 664
Acetylcholine (ACh), 56, 60–61, 85, 86, 178, 188, cardiac muscle, 54–55 steroid hormone, target organ cellular
206, 216, 268, 346, 510, 519, 529, 544, 671 SA and AV node, 55–56 effects, 660–661
receptors, 57, 60, 62f compound, 54 Adrenal insufficiency, 664
synapse, 62f depolarization, 48 Adrenal medulla, 56, 63, 72f, 178f, 179, 182, 268,
Acetylcholinesterase (AChE), 61, 85f, 86, 103 externally recorded, 53f 405, 464, 715
Acetyl-CoA carboxylase, 675 positive feedback cycle, 48f Adrenergic receptors, 63
ACh. See Acetylcholine (ACh) propagated, 10 α-Agonists, 667
ACh-activated K channel (KACh), 57 refractory periods, 47, 51 β-Agonists, 667
ACh receptor channels (AChRs), 20 absolute and relative, 52f β-Adrenergic blockers, 222, 273
muscarinic AChRs, 20 regenerated, 39 β1-Adrenergic receptor blockers, 231
nicotinic AChRs, 20 threshold, 51 β1-Adrenergic receptor–protein kinase
ACh receptors (AChRs), 60 Activation gate, 213 A-dependent process, 451–452
Muscarinic AChRs, 60 Activation of microglia, 112 alpha-adrenergic receptors, 64, 267, 708
nicotinic AChRs, 60 Active expiration, 317 α1−Adrenergic receptors, 267, 665
Acid–base balance, 306, 375–382, 471–472 Active hyperemia, 265 α2−Adrenergic receptors, 665
acid–base chemistry, 375–377 Active membrane transport pathways, isoproterenol, 665
acid–base paths in vivo, 378f characteristics, 528t beta-adrenergic receptors, 64, 638, 692
aldosterone, influence of, 482–483 Active spread of action potentials, 39 β1−Adrenergic receptors, 665
chloride depletion, influence of, 482 Active transport, 4 β2−Adrenergic receptors, 268, 665
extracellular volume contraction, Activin, 686 β3−Adrenergic receptors, 665
influence of, 482 Acute cholecystitis, 572 and signaling pathways, 667t
fundamentals, 472–473 Acute mountain sickness, 736, 737, 742 Adrenergic sympathetic nerves, 323
and osmolar regulation of potassium prevention and treatment, 737 Adrenocorticotropic hormone
distribution, 725 Acute respiratory distress syndrome, 321 (ACTH), 623
regulation, 398, 471 Adaptation, 118 Adult respiratory distress syndrome, 321
renal excretion, 476–478 Addison’s disease, 664 Afferent arterioles, 409
hydrogen ion excretion on ammonium, Adenohypophysis, 623 Afferent fibers, 127
478–480 Adenoids, 308 Afterload, 87, 88, 95
phosphate and organic acids as urinary Adenoma, 470 aortic pressure, 95
buffers, 477–478 Adenosine, 102, 232, 264, 457 cardiac, 232, 301
quantification, 480 Adenosine triphosphate (ATP), 11, 45, and isotonic contraction, 219–220
titratable acidity, 480 79, 607 muscle, 96
urinary buffers, hydrogen ion excretion, 477 production, 745 result in less shortening, 95
renal handling, 474–476 Adenylyl cyclase (AC), 21, 25, 607 ventricular, 227
regulation, renal glutamine control, Adequate stimulus, 43, 117 effect of changes, 228–229
metabolism and, 480–481 ADH. See Antidiuretic hormone (ADH) Ageusia, 162
sources Adjuvant, 538 Aging, 712
carbohydrate and fat, anaerobic ADP/ATP ratio, 18 cardiovascular changes, 754t
metabolism, 474 Adrenal androgens, 664. See also Androgens cardiovascular systems, 753–754
dietary protein, metabolism, 473 Adrenal cortex, 268, 405, 452f, 454, 455, 457, changes in arterial pressure with age, 754f
dietary weak acids, metabolism, 473 467, 602, 626 clinical correlation, 755–756
GI secretions, 473–474 Adrenal cortex hormones endocrine system, 755
intravenous solutions, lactated Ringer’s, 474 androgens, 664 gastrointestinal system, 755
Acid–base disorders, 377, 481 glucocorticoids, 661–662 hormone production associated
acid–base disturbances, 381t deficiency, 664 with, 712f
metabolic acidosis, 377, 379, 382, 392, 481, 679, excess, 664 muscular system, 753
725, 737, 749 mineralocorticoids, 662–664 neural system, 753
metabolic alkalosis, 379, 481, 482, 483f Adrenal gland, 178, 656f pulmonary system, 754

761
762 INDEX

Aging (continued) Aminoglycoside antibiotics Anomic aphasia, 196

related changes, 754t gentamicin, 154 Anorexia nervosa, 722, 750
renal/urinary system, 754–755 streptomycin, 154 Anosmia, 161, 165
successful/healthy, 753 α-Amino-3-hydroxyl-5-methyl-4-isoxazole- ANS. See Autonomic nervous system (ANS)
Agouti-related peptide (AgRP), 721 propionate (AMPA), 194 Antagonists, 20
Air conduction, 153 channel, 74 Anterior insula, 162
Airway resistance, 322 receptors, 194 Anterior pituitary cell type, 625t
Akinesia, 171 Amiodarone, 639 Anterior pituitary gland, 613
Albumin, 208, 404, 412, 426, 431, 569, 576, 578, Ammonia (NH3), 477, 578 diseases of
637, 647, 660, 665, 705 homeostasis, 579f hormone-producing pituitary
Aldosterone, 268, 405, 454, 467, 480, 531, 626, metabolism, principles adenoma, 630
656, 724, 731. See also Mineralocorticoids extraintestinal production, 579 hypopituitarism, 630–631
action mechanism, 456f intestinal production, 578–579 function, evaluation of, 613
deficiency, 664 role and significance, 578 functional anatomy, 623
excess, 664 urea cycle, 579 hypothalamic control of, 623–624
renal physiologic effects, 663f urea disposition, 579–580 Anterior pituitary hormones, 615,
Alerting reaction, 289 production, sources, 578f 623–630, 625f
Alerting response, 290 Ammoniagenesis, 477, 479f deficiency of, 630
Alkalemia, 375, 376, 381, 464, 469, 470, 484 and excretion, 479f glycoproteins, 625–626
Alkaline phosphatase, 647 Ammonium ion (NH4+), 478 growth hormone, 626–629
Alkaline tide, 513 AMP-activated protein kinase, 680 measurements, 631
Alkalosis, 375, 376, 377, 379, 647. See also Amphipathic, 565 prolactin family, 629–630
Metabolic alkalosis; Respiratory alkalosis character of bile acids, 567, 596 proopiomelanocortin (POMC), 626
Allodynia, 116 lipids, 16 target organs, and physiologic effects, 624f
Alpha-adrenergic receptors, 64, 102, 323 term defined, 565 Anterior wall myocardial infarctions, 222
Altitude, 735 Ampulla, 150 Anterograde conduction, 110
acclimatization to, 737–738 Amygdala, 159, 161f, 173f, 192f, 194–196 Anterograde amnesia, 196
acute effects of, 736 Amylin, 678 Anticholinergics, 384
acute mountain sickness, 736 Amyloid plaques, 753, 755 Anticholinesterases, 61, 70
adaptive response, 737 Amyloid precursor protein (APP), 194 Anticoagulants, 209, 361
physiologic responses to, 738t Amylolytic enzymes, 517 Antidiuresis, renal water handling, 446f
symptoms, 736 Amylopectin, 584 Antidiuretic hormone (ADH), 27, 64, 268,
Alveolar air equation, 338, 355, 735 structure, 585f 404–406, 443, 444, 446, 448, 458–461, 615,
Alveolar–arterial PO2 difference, 355, 383 Amylose, 584 739, 755
Alveolar–capillary diffusion, 382 structure, 585f cellular mechanism of, 618f
Alveolar–capillary unit, 309 Amyotrophic lateral sclerosis (ALS), 63, 86, magnocellular neurons, 614, 617
Alveolar dead space, 347, 354, 361 130, 176 osmoreceptor control, 459
Alveolar ducts, 308 Anabolic metabolism, 715 physiologic effects of, 618–619
Alveolar edema, 382 Anaerobic metabolism, 745 production, disorders of, 620
Alveolar gas, 337 Anal canal, anatomy, 553f release, control of, 619–620
Alveolar hypercapnia, 348 Anandamide, 75 secretion, inappropriate
Alveolar hypoxia, 348 Anaphylactic shock, 301 syndrome of, 620
Alveolar macrophage, 310 Anaphylaxis, 307, 541 signals, integration of, 619f
Alveolar PO2, 735 Anatomic dead space, 308, 334, 335 synthesis and processing of, 616f
Alveolar pressure, 314, 735 Anatomic shunts, 355 Antigen–antibody complexes, 416
Alveolar sacs, 308 Androgen-binding protein (ABP), 685 Antileukotriene, 384
Alveolar septa, 308 Androgens, 664, 687 Antrum, 508, 548
Alveolar ventilation, 331, 334, 353, 481 anabolic and metabolic effects of, 692 Aortic arterial chemoreceptors, 386
anatomic dead space and, 334–335 physiologic effects, 687 Aortic baroreceptors, 287
and carbon dioxide, 337 sex determination, 687 Aortic insufficiency, 247
measurement of, 335 sexual development, 687 Aortic regurgitation, 247
and oxygen, 338 sexual differentiation, 688–689 Aortic stenosis, 245–247
physiologic dead space, 335–336 sexual maturation, 690 Aortic valve obstruction, 229
Bohr equation, 335 Andropause, 755 Aortic valve stenosis, 247, 282
regional distribution, 338–339 Anemia, 406, 693 Aphasias, 196, 756
closing volume, 339 Anemic hypoxia, 383 Apical epithelial cell membrane. See Luminal
Alveolar vessels, 343 Anergy, 538 epithelial cell membrane
Alzheimer’s disease, 63, 193–195, 753, 755 Angina pectoris, 231, 248, 272 Apical membrane, 29, 424
familial form, 755 Angioplasty, 750 Apical sodium-dependent bile salt transporter
Ambiguous genitalia, 667 Angiotensin (asbt), 569
Amenorrhea, 631, 750 angiotensin I, 451, 658 Apnea, 388, 739
Amiloride, 163, 470 angiotensin II, 268, 302, 451, 454–456, 658 Apneustic center, 387
Amiloride-sensitive epithelial Na+ channel Angiotensin converting enzyme (ACE), Apoproteins, 597
(ENaC), 163, 662 451, 658 Apoptosis, 493
Amino acids, 61 inhibitor, 282, 293, 309, 461 Aptotagmin, 66
essential, 583, 587–588 Angiotensin II receptor blockers (ARBs), Aquaporins (AQPs), 21, 27, 426, 442, 458
naturally occurring, 588f 293, 453, 470 key features of, 619t
nonessential, 560 Angiotensinogen, 451, 658 phosphorylation of, 618
transporters, 430, 531, 590 Angle-closure glaucoma, 133 Arachidonic acid metabolites, 455
γ-Aminobutyrate (GABA), 106, 159 Anion exchanger (AE), 24 Arcuate arteries, 409
synapse, 63f Anion gap, 381–382, 679 Area postrema, chemoreceptor trigger zone, 551
 INDEX 763

A receptors, 21 Aspirin, 117, 282, 732, 750 Axoplasmic transport, 60, 66

Areflexia, 168 Associative learning, 76 orthograde/retrograde., 66
Arginase, 579 Astereognosis, 195 Azotemia, 461
Arginine, 579 Asthma, 309, 326
Arginine succinate, 579 Astigmatism, 136 B
Arginine vasopressin (AVP), 444, 458, 615, 617, Astrocytes, 105, 106, 110, 176 Babinski sign, 169
755. See also Antidiuretic hormone (ADH) Astrocytic proliferation, 112 Bacteremias, 379
Aromatase, 686 Ataxia, 175, 183 Bacterial metabolism, 577
Arterial–alveolar CO2 difference, 336, 355 Atelectasis, 319, 348, 360, 388 Bacteroides, 538
Arterial baroreceptors, 287, 390 Atherosclerosis, 248, 261, 272, 462 β2-Adrenergic agonist, 384
pathway, 286f Athetosis, 171 β-Adrenergic blockers, 222, 273, 293
reflex, 286, 286f, 746 ATPase activity, 91 β1-Adrenergic receptor blockers, 231
Arterial blood gases, 380 ATP-binding cassette (ABC), 24 β1-Adrenergic receptor–protein kinase
clinical interpretation, 380–381 ATP-sensitive channels, 21 A-dependent process, 451–452
anion gap, 381–382, 679 ATP-sensitive K+ channels (KATP), 673 β1-Adrenergic receptors, 217
base excess, 381 Atrial fibrillation, 242, 420 β2-Adrenergic receptors, 268
Arterial blood pressure, 203, 210, 252, 290, Atrial flutter, 241 Balance concept. See Electrolyte balance concept;
300, 372, 444, 458, 460. See also Arterial Atrioventricular (AV) nodes, 54, 212, 236 Water, balance concept
pressure Atrophic gastritis, 538 Ballism, 171
regulation, 267, 288, 291, 398 Atropine, 60, 61, 72, 179, 432 β-Amyloid peptides (Αβ), 194
Arterial chemoreceptors, 289, 323, 351, 372, 390, Auditory agnosia, 121 Barbiturates, 63, 74
392, 394, 473, 736, 747 Auditory cortex, 153 Baroreceptors, 222, 297, 372, 450, 450f
carotid bodies, 749 Auditory meatus, external, 147 intrarenal, 451
Arterial–end-tidal CO2 difference, 355 Auditory ossicles, 147 Barotrauma, 741
Arterial gas embolism, 741 incus, 147 Basal electrical rhythm (BER), 549, 549f
Arterial hypocapnia, 737 malleus, 147 Basal ganglia, 167, 171, 172f, 173f, 183
Arterial oxygen, 754 stapes, 147 caudate nucleus, 171
Arterial pressure Auditory receptors, 149, 150, 152 globus pallidus, 171
auscultation technique, 260 electrical responses, 150 hyperkinetic diseases, 171
changes with age, 754f genesis of action potentials in, 150, 152 tremor, chorea, athetosis, ballism, 171
determinants, 260 sound transmission, 152 hypokinetic diseases, 171
arterial compliance, 261 Auditory (Eustachian) tube, 147, 153f akinesia and bradykinesia, 171
arterial pulse pressure, 260–261 Auscultation, 226, 235, 260f putamen, 171
mean arterial pressure, 260 Autoimmune disease, 86, 112, 634 substantia nigra, 171
Korotkoff sounds, 260 Autoimmunity, 538 pars compacta and pars reticulata,
long-term regulation, 290 Autonomic activity 171
fluid balance & arterial pressure, 291 reflex and central control, 183 subthalamic nucleus, 171
on urinary output rate, 291–292 Autonomic nerve activity, 181 Basal metabolic rate (BMR), 716
measurement, 259–260 responses of some effector organs to, 181–182t Basal stem cells, 159
regulation of, 285–286 Autonomic nervous system (ANS), 71, 80, 94, Basal tone, 264
short-term regulation, 286 177, 286, 523 Base deficit, 381
arterial baroreceptor reflex, 286–288 craniosacral division, 178 Base excess, 381
central command, 290 efferent fibers and motoneurons, 72f Basement membrane, 494
chemoreceptor reflexes, 289 intermediolateral column (IML), 177 circular muscle, 494
reflexes from receptors in heart & parasympathetic, 177 lamina propria, 494
lungs, 289 oculomotor, facial, glossopharyngeal mucosa, 494
reflex responses to pain, 290 nerves, 178 muscularis mucosae, 494
responses associated with emotion, 289 vagus nerves, 178 submucous (submucosal) plexus, 494
Arterial pulse pressure, 260 peripheral organization and transmitters Basilar membrane, 149
Arteriolar tone, 264 released by, 178 Basket cells, 109, 174
control of, 264 preganglionic and postganglionic neurons, 177 Basolateral membrane, 29, 424
basal tone, 264 sympathetic, 177 B cells, 536
flow responses caused by, 265–267 Autoregulation, 266, 415 Bell’s palsy, 162
hormonal influences, 268 Autotransfusion, 302 Benign prostatic hyperplasia, 755
angiotensin II, 268 AVP. See Arginine vasopressin (AVP) Benzocaine, 53
circulating catecholamines, 268 Axis deviations, ventricular, 240f Benzodiazepines
vasopressin, 268 Axon, 9, 10f, 106 diazepam (Valium) 63, 74
local influences on, 264, 266t conduction velocity, 107 Beta-adrenergic receptor blockers, 282
local metabolic influences, 264–265 degeneration, 111–112 Beta-adrenergic receptors, 94
local nonmetabolic influences, 265 of first-order neurons, 119f Beta2 (β2) receptors, 323
transmural pressure, 265 initial segment, 106 Bezoars, 551
neural influences, 267 reaction, 66 Bicarbonate
sympathetic vasoconstrictor nerves, 267 regeneration, 111–112 reabsorption, predominant proximal tubule
organ blood flow responses caused by, 267f of second-order neurons, 162 mechanism, 475f
Arteriosclerosis, 261, 753 sprouting, 111 secretion
Asbestosis, 329, 360 of sympathetic preganglionic neurons, 177 generic model, 474f
Ascending reticular system, 111f unmyelinated, 106, 615 renal contribution, 480t
Ascites, 284, 563, 664 Axonal conduction velocity, 107 Biguanides, 680
Ascorbic acid, 590 Axonal sprouting, 111 Bile
Aspartate, 430, 579 Axon collaterals, 130 composition
Aspiration, 329 Axon hillock, 72, 106 canalicular bile, 567–568
764 INDEX

Bile (continued) acidify/alkalinize process, 481t reticulospinal, 167

changes in, 571f cells, 207–208, 208t rubrospinal, 167
ductular bile, 568 flow, basic physics of, 202–203 tectospinal, 167
hepatic bile, 569 hemostasis, 208–209 vestibulospinal tracts, 167
concentration mechanism, 572f macrophages, 559 Breast milk lipase. See Cholesterol esterase
ducts, 562 plasma, 4, 208 Breathing work, 748
excretion and secretion, principles of adult, normal constituents, 209t elastic work, 737
role and significance, 565 pressure, 398–399, 411f resistance work, 737
relationship to cholesterol, 570f Blood–brain barrier, 106, 272, 392, 394, 575, Broca’s area, 195
solute entry pathways, 568f 675, 731 Brodmann’s area , 118, 141, 153, 169
Bile acids, 530, 561, 565 Blood gas analysis, 483 Bronchial blood flow, 341
circulation, quantitative aspects, 566 Blood glucose regulation, 715 Bronchial circulation, 341
conjugated bile acids, 566, 567f postprandial state, 715 Bronchioles, 307, 308
enterohepatic circulation, schematic, 561f Blood oxygen content, 363 Bronchitis, 326
conjugation, 566–567 Blood plasma, 4 chronic, 481
enterohepatic circulation Blood–testis barrier, 684, 685, 690 Bronchoconstriction, 737
hepatocyte transport mechanisms, 569 Blood urea nitrogen (BUN), 434 Brown-Séquard syndrome, 131
intestinal uptake mechanisms, 569 Body fluid compartments, 200, 437–438 Bruits, 258
synthesis and transport, regulation, 569–570 Body plethysmography, 325, 333, 334 Brush border, 29
metabolism from cholesterol, 565–566 Body temperature control, 729–734 hydrolysis, 585
physical forms, 567f clinical correlation, 732–733 membrane, 584, 586f, 596, 598
physicochemical properties, 567 effector mechanisms, 730 Buffer, 5, 375
primary, 566 feedback mechanisms, 730 Buffer systems, 4–5, 472
structures, 566f fever, 731–732 calcium-buffering system, 487
secondary, 566 infection pathway, 732f and pH, 4–5
structures, 566f heat loss/gain mechanisms, 730 phosphate and albumin, 472
Bile ducts, 562 hot/cold environment, adaptation, Bulbourethral glands, 683
Bile salt export pump (BSEP), 569 730–731 Bulimia nervosa, 750
Biliary colic, 572 Bohr effect, 366, 371, 376, 749 Bundle branch blocks, 242
Biliary ductules, 562 Bohr equation, 335, 355 α-Bungarotoxin, 70
Biliary system, 559, 561 Bone, 487 Burst lung, 741
functional anatomy, 562f fractures (See Osteoporosis)
motor functions marrow, 575 C
contraction, 571 mineral density (See Osteopenia Ca-activated K channels, 19, 75
sphincter of Oddi function, 571–572 and Osteoporosis) Ca-ATPase, 486
Bilirubin, 539 Bone conduction, 153 Cable properties, 39
conversion of heme, 576f Bone density, 652 Cadherins, 26, 74
cycling, 577f T score, 652 Caffeine, 21, 156
handling by hepatocytes, 577f Z score, 652 Ca2+ influx, 194
homeostasis Bone metabolism Ca2+ ion channels, 194
bacterial metabolism, 577 factors involved in regulation of, 650t Calbindins, 486
hyperbilirubinemia, 578 hormonal regulation, 651 Calcarine fissure, 141
urinary elimination, 577–578 childhood–adult, 651 Calcinosis, 650
metabolism, principles menopause, 652–653 Calcitonin, 487, 633, 652
hepatic transport mechanisms, 576 pregnancy and lactation, 651 Calcitonin gene–related peptide (CGRP), 64, 117,
hepatocyte conjugation, 576–577 Bone remodeling, 643, 646, 648f, 651 512, 555
role and significance, 575 Bone resorption, 644 Calcium, 79, 80, 643
pigment stones, 572 Bony labyrinth, 149 channels, 11, 55, 80, 86, 94, 102, 214, 607
Bilirubin diglucuronide, 576 Borborygmi, 540 blockers, 233, 273
Biliverdin reductase, 575 Botulinum toxin (Botox), 61 L-type, 94
Binding proteins. See Carrier proteins Botulism, 70 factors involved in regulation of, 650t
fatty acid binding protein (hepatic) FABP, 597 Bowman glands, 161 homeostasis, 647
Bioactive substances, excretion, 398 Bowman’s capsule, 400, 402, 440 clinical evaluation of abnormalities
Biogenic amines, 63 hydraulic pressure in, 412 in, 652t
Biological cell membrane oncotic pressure of fluid, 412 hormonal regulation of, 649
associated proteins in, 2f Bowman’s space, 423, 464 interaction of bone, kidney, and intestine
Biphasic action, 53 Boyle’s law, 313, 334, 739 in maintaining, 648–649
Birth, 300 Bradycardia, 221, 232, 241, 242, 289, 299, 739 role of calcitonin in, 650
Birth control pills, 261 Bradykinesia, 171–173 role of vitamin D in, 649–650
2,3-Bisphosphoglycerate (2,3-BPG), 364 Bradykinin, 116, 265, 307 malabsorption, 651
Bisphosphonates, 652 Brain, 105 reabsorption, 644
Bitemporal hemianopia, 144 endorphins in, 120 Calcium ATPase activity, 94
BK potassium channels, 466 Brain areas, concerned with somatic Calcium balance, 485–486
activity, 467f sensation, 119f effector sites
Black (or brown) widow spider venom Brain injury, 80 bone, 487
(BWSV), 61 Brain natriuretic peptide (BNP), 457 GI tract, 486
Bladder, 399 Brain rhythms hormonal control, 487–489
Blebs, 330 in wakefulness and sleep, 186 kidneys, 486
Blind spot, 134 distribution of sleep stages, 187 reabsorption, mechanism, 487f
Blobs, 141 sleep stages, 186–187 regulation, 485
Blood Brain stem pathways transcellular transport, generic method, 486f
 INDEX 765

Calcium-binding proteins, 80, 486 ejection fraction (EF), 245 arterial blood, 201
Calcium channel blockers, 222, 273, 293 end-systolic pressure–volume relationship, 245 blood flow, basic physics, 202–203
Calcium channels, 86 Cardiac cycle, 224 cardiac output, 201
Calcium reabsorption, 644 diastolic pressure, 225 distribution of, 201f
Calcium-sensing receptor, 643 end-diastolic volume, 225 effects of ascent to high altitude on, 736
Calmodulin, 79, 80, 99, 102, 193f, 607 heart sounds, 226 during exercise, 745–747
Calsequestrin, 86 atrial gallop rhythm, 226 hemorrhage, 6f, 301–302
Calyces, 399 isovolumetric contraction phase, 225 homeostatic role, 200–202
cAMP response element-binding protein left heart pump, 224 myocardium, 201
(CREB), 607 mitral valve, 225 pulmonary circulation, 201, 341–352
Canalicular bile, 567 peak systolic pressure, 225 systemic circulation, 201, 199–304
composition, 568 phases, 224 Cardiovascular transport
Canaliculi, 509, 512, 561 pressure–volume & length–tension endothelial cells, 254
Canal of Schlemm, 133 relationships, 226–227 Fick principle, 252
Canals of Hering, 568 ventricular afterload, 227 lymphatic system, 255
Cannabinoid receptors (CB1), 75 ventricular preload, 226 transcapillary fluid movement, 254–255
Capacitance, 34 pulse pressure, 225 factors influencing, 255f
Capacitance vessels, 207 QRS complex, 225 transcapillary solute diffusion, 253–254
Capillary filtration coefficient, 349 right heart pump, 225–226 Cardioversion, 244
Capillary hydrostatic pressure, 349 c wave, 226 Carotid bodies, 749
Capsaicin receptor, 45 jugular venous pulse, 226 Carotid chemoreceptors, 386
Ca pumps, 23 v wave, 226 Carotid massage, 232
Carbamoyl phosphate, 579 a wave, 226 Carotid sinus baroreceptors, 287
Carbohydrates ventricular diastole, 224 Carpal tunnel syndrome, 122
assimilation, basic principles ventricular systole, 225 Carrier proteins, 603
barriers to water-soluble macromolecules, Cardiac dipoles β-Casein, 711
584 and electrocardiographic records, 237–238 Cataplexy, 187
luminal digestion, 584–585 Cardiac excitation, abnormal, 240 Catecholamines, 63–64, 231, 346, 665, 724, 731
monosaccharide uptake pathways, 587 Cardiac function physiologic effects, 667t
oligosaccharides/disaccharides, brush sympathetic neural influences on, 231 synthetic pathway, 666f
border digestion, 585–586 techniques for assessment, 235 Catechol-O-methyltransferase (COMT), 63, 665
regulation, 587 Cardiac function curve, 230, 231, 282 C cells, 633
role and significance, 583 Cardiac glycoside, 22, 218 CCK. See Cholecystokinin (CCK)
sources in diet, 584 Cardiac index, 244 CCK-A receptors, 549
digestion and absorption, 583 Cardiac muscle, 79–81, 93–97 CCK-releasing peptide (CCK-RP), 519
Carbon dioxide production, 336, 747 contraction—force–velocity, 95–96 CD4 and CD8 molecules, 25, 536
Carbon dioxide inspired and alveolar partial contraction—length–tension, 94–95 Celiac disease, 538
pressures, 736 excitation–contraction coupling, 93–94 Cell adhesion molecules, 26
Carbon dioxide transport, by blood, increases in strength of contraction in, 96–97 Cell body
368, 371f involuntary, 80 soma, 106
bicarbonate, 370 isometric contractions, 94–95 Cell–cell interactions, 6
carbamino compounds, 369–370 isotonic contractions, 95–96 Cell membrane, 1, 15
dissociation curve, 370–371 Cardiac muscle cells, 212 receptors, 605–607
chloride shift, 372 contractility, 220–221 G protein–coupled receptors, 605f, 607
Haldane effect, 370 lusitropic effect, 221 intracellular receptors, 606f
isohydric shift, 370 excitation–contraction coupling, 217 receptor kinase, 606f
physically dissolved, 368–369 mechanics, 218 receptor-linked kinase receptors, 606f
Carbonic acid, 472 relating to ventricular function, 221 α-Cells, 671
Carbonic anhydrase, 472 relaxation, 217–218 β-Cells, 671, 678
carbonic anhydrase II, 512 Cardiac output (CO), 227, 253, 341, 745 δ-Cells, 671
inhibitor (See Acetazolamide) determinants of, 227–228, 230 Cellular processes, 9
Carbon monoxide, 364 cardiac function curves, 230–231 of hypothetical three-celled organism, 10f
diffusing capacity, 360 sinoatrial (SA) node, 228 messenger to control, 19
for metabolic acidosis, 379t measurement of, 244 phosphorylation of molecules, regulatory
partial pressures of, 358f, 359 cardiac index, 244 roles, 231
poisoning, 383 Fick principle, 244 Cellular respiration
Carboxyhemoglobin (COHb), 368 Cardiac pacemaker, 93, 205, 212, 216, 222 enzyme activity, 753
Carboxypeptidases, 588 Cardiac valve function, abnormal, 245–246 waste product of, 4
carboxypeptidase A, 588 Cardiogenic shock, 301 Central chemoreceptors, 289, 392, 394, 737
carboxypeptidase B, 588 Cardiomyopathy, 222, 282 Central command, 290
Carcinoma, 489, 653, 664 Cardiopulmonary baroreceptors, 289, 297 Central delay, 127
Cardia, 495, 548 Cardiopulmonary resuscitation (CPR), 244 Central nervous system (CNS), 9, 105, 115,
Cardiac action potentials, 54 Cardiovascular adaptations, normal, 298 125, 494
cell-to-cell conduction, 215f cardiovascular changes, with normal aging, 300 modulatory neurotransmitters, 74–75
conduction, 214–216 fetal circulation & changes at birth, 299–300 synapses, 72, 74f
velocity, 215 gender-dependent differences, 300–301 axon hillock, 72
Cardiac afterload, 232 pediatric cardiovascular characteristics, 300 cell body (soma), 72
Cardiac arrhythmias, 52, 240–244, 650, 723 during pregnancy, 299 convergence and divergence, 72, 73f
Cardiac cell membrane potentials, 212–214 respiratory activity, responses to, 298–299 Central sleep apnea, 187, 391
Cardiac contractility, estimations, 245 Cardiovascular adjustments, to hemorrhage, 281f Central swallowing center, 544
echocardiography, 245 Cardiovascular system Central tendon, 315
766 INDEX

Central thermoreceptors, 730 Cholecystectomy, 572 quantification of, 418–419

Central venous compartment, 275 Cholecystitis units, 417–418
Central venous pool, 258 acute/chronic, 572 Cl–HCO3— antiporters, 475
Central venous pressure, 258, 277, 289 Cholecystokinin (CCK), 64, 499, 501, 519, 571, Cl/HCO3— exchanger, 24
abnormal, clinical implications of, 281–282 594, 719 Climbing fibers, 175
and cardiac output and venous return, 279–281 CCK-A receptors, 549 Clonus, 130
influence on venous return, 277–278 CCK releasing peptide (CCK-RP), 519 Closing capacity, 339
Central venous volume, 258 cholecystokinin (CCK)-B receptors, 510 Closing volume, 325, 339
Centrosomes, 3 effects of, 519f Clostridium botulinum, 70
Cephalic, 511, 519 role, factors causing CCK release, 519 Clostridium difficile, 534, 539
Cerebellar ataxia, 183 Cholera, 25, 529, 533 Clotting function, 272
Cerebellar cortex Cholesterol, 16, 566, 570 CNS postsynaptic receptors
basket cells, 174 intestinal handling, 597f gammaaminobutyric acid (GABAAR), 20
Golgi cells, 174 Cholesterol 7a-hydroxylase, 566 for glycine (glyR), 20
granule cells, 174 Cholesterol esterase, 595 serotonin (5HT3R), 20
Purkinje cells, 174 Cholesterol stones, 572 CNS synapse, 74
stellate cells, 174 Cholic acid, 566, 569 α-γ Coactivation, 129
Cerebellar disease, 175 Choline acetyl transferase (CAT), 60 Cobalamin, 507. See Vitamin B12
Cerebellum, 167, 173–174 Cholinergic neurons, 178 CO2-bicarbonate system, 474
cellular organization, 174–175 Cholinergic parasympathetic nerve fibers, 206 buffer system, 472
functional divisions of, 174f Cholinergic parasympathetic postganglionic Cocaine, 64
inferior peduncles, 174 nerves, 323 Cocaine-and amphetamine-regulated transcript
neural connections in, 175f Cholinesterase inhibitors, 71, 91 (CART), 721
neuronal types in cerebellar cortex, 174f Chondrogenesis, 692 Cochlea, 147
superior, middle, 174 Chorda tympani branch of the facial nerve, 162 Cockcroft–Gault formula, 420, 421
vestibulocerebellum, 174f Chorea, 171 Cogwheel rigidity, 173
Cerebral circulation, 232, 736 Chorionic somatomammotropin, 626 Colipase, 517, 595
Cerebral cortex, 107–110, 110f, 169f, 385 Choroid plexus, 272 role of, 595f
Cerebral edema, 30, 736, 738 Chromaffin cells, 665 Colitis, 538
Cerebral hyperperfusion, 736 Chromatin, 3 Collecting duct system, 438, 443–444, 464
Cerebral ischemic response, 289 Chromatolysis, 66, 111 Colloid, 633
Cerebral palsy, 340 Chronic bronchitis, 309, 333, 360 Colloid osmotic (oncotic) pressure, 29, 254,
Cerebral vascular accidents, 299 Chronic cholecystitis, 572 412, 349
Cerebrocerebellum, 174f, 175 Chronic congestive heart failure (CHF), 282 Colon, 496
Cerebrospinal fluid (CSF), 4, 106, 183, 272, 289, Chronic cor pulmonale, 742 chloride secretion, 532f
393f, 736 Chronic hypertension, 292 colonocytes, 496
Cerumen, 154 Chronic obstructive pulmonary disease (COPD), defecation, 496
CFTR. See Cystic fibrosis transmembrane 360, 392 electrogenic sodium absorption, 531
regulator (CFTR) Chronic renal failure, 653 electroneutral NaCl absorption, 532f
Chandelier cells, 109 Chronic thyroiditis, 640 epithelial layers, morphology of, 493f
Channels, 11, 16–18 Chronotropic, 220, 638 functions, 553
cell–cell, 21–22 Chronotropic effect on heart rate, positive and haustrations, 496
chemosensitive, 20–21 negative, 217, 220 ion transport mechanisms, 528t
involved in synaptic release, 65 Chvostek’s sign, 647 Color agnosia, 121
mechanosensitive, 18–19 Chylomicrons, 496, 597 Color blindness, 143
voltage-sensitive, 19 lipid-bearing, 598 Colors
water, 21 secretion of, 597f hue, intensity, and saturation, 142
Charges. See also Anion gap triglyceride-rich, 629 Color vision, 134, 142–143
separation of, 34–35 Chymotrypsin, 588 Commensal, 538
Chemical synapses, 60, 68, 73 Cilia, 134, 159 Commensal bacteria, 492
Chemoreceptors, 115, 159, 289, 311, 380, 390, Ciliary muscle, 136 Common bile duct, 562
392, 473, 737, 746 Circadian rhythms, 185, 187–188, 610, Communication, 12
peripheral, 392, 394 615, 623 Comparator, 12
reflexes, 289 Circular muscle, 494 Compensation, 372, 380, 481
Chemoreceptor trigger zone, 551 Circulatory shock, 301, 301t, 372 acid–base disorders and, 481–482
Chemosensitive channels, 11, 17, 20, 24, 44, 73 Circumventricular organs, 731 short-term cardiovascular, 297
Chenodeoxycholic acid, 566 Cirrhosis, 580, 658 Complementary color, 142
Chest wall, 305 Cisternae, 86, 94 Complex cells, 142
Chest wall compliance, 754 Citrulline, 579 Compliance, 5, 259, 318
Chief cells, 494, 508–513, 588, 643 Clara cells, 307, 308 Compound action potential, 54
Chloride Clasp-knife effect, 130 Conditioned reflex, 748
reabsorption, 439, 731 Class 1 cytokine receptor superfamily, 628 Conducting airways, 305
transport pathways for, 440f, 442f, 443f Classic sensory pathways Conducting zone, 308
secretion, regulation, 533f specific/nonspecific, 110 Conduction, 51, 52, 54, 107, 153, 204, 214–216,
shift, 372 Clathrin-coated pit, 66 236, 241, 242, 730
Chloride–iodide transporting protein, 635. See Clearance, renal Conduit vessels, 207
also Iodide channel derivation of, 418f Congenital adrenal hyperplasia, 664, 668, 692
Chloride reabsorption, 731 measuring GFR, practical method Congestive heart failure, 281–283, 482, 620
Chloride shift, 372 creatinine clearance, 419 Connecting tubule, 406
Cholangiocytes, 562, 568 plasma creatinine and urea concentrations, Connexins, 21, 214
Cholecalciferol, 650 419–420 topology of, 21f
 INDEX 767

Connexons, 21 Cutaneous pain, 290 type I, 394, 587, 678–679, 726

Conn’s syndrome, 664 Cu/Zn superoxide dismutase (SOD-1), 176 type II, 292, 406, 679, 718, 753
Constant field equation, 39 Cyanide, 383 Diabetic coma, 678
Continuous positive airway pressure Cyanosis, 368, 383, 742 Diabetic ketoacidosis, 376, 379, 394, 678, 724
(CPAP), 190 Cyberneticists, 10 Diabetic neuropathy, 116
Contraception, 712 Cyclic 3′, 5′-adenosine monophosphate (cAMP), Diacylglycerol (DAG), 25, 101, 605f, 607,
principal methods for, 712t 11, 607, 618 676, 698f
Contractile element (CE), 87 Cyclic guanosine monophosphate (cGMP), Diads, 93
Contractility, 93 11, 692 Diaminopyridine, 70
Convection, 730 Cyclic nucleotide-gated channels, 11, 19, 44, 44f Diaphragm, 305, 315, 386
Convective transport, 252 Cyclic nucleotide–gated (CNG) nonspecific Diarrhea, 379, 533
Convergence, 72 cation channel, 44 Diastole, 55, 56, 94, 95, 204, 225, 227, 247,
Convergence movements, 144 Cystic duct, 562, 562f, 570, 572 259, 276, 300
Coordinated movement, 167 Cystic fibrosis, 24, 524, 584 ventricular, 204, 224
Core body temperature, 729 Cystic fibrosis transmembrane regulator (CFTR), Diastolic failure, 228
Coronary angioplasty, 273 24, 25, 521, 522, 524, 525, 532, 533, 568, 572 Diastolic murmur, 247
Coronary arteries, 269, 270, 272, 273 Cytochrome P450 sidechain cleavage (SCC) Diastolic pressure, 225
disease, 248, 272, 750 enzyme, 656 Diazepam (Valium), 63, 74
stent, 292 Cytokine receptor superfamily, class 1, 628 Diencephalon, 107, 189, 193, 613
Coronary artery bypass surgery, 750 Cytokines, 311, 384, 499t, 500, 536, 538, 731 Dietary fiber, 532, 539, 584
Coronary artery disease, 282, 750 Cytoplasm, 2 Dietary lipids, 565
Coronary artery stent, 292 Cytoplasmic/nuclear inclusions, 183 Dietary polymers, 584
Corpora cavernosa, 685 Cytoplasmic organelles, 3 Dietary potassium, 468, 723, 731
Cor pulmonale, 738 Cytosolic proteolysis, 590 Dietary salt restriction, 293
Corpus, 548 Diffusing capacity, 350, 360, 748, 750, 754
Corpus hemorrhagicum, 703 D Diffusion, 4
Corpus luteum, 696, 703 Dalton’s law, 336, 739 facilitated, 4, 26, 27, 531, 596
Correction, 6 D cells, 509, 510 simple, 4, 26, 27, 424
Cortical collecting tubule, 406 Dead space, 739 Digestion process, 491
Cortical radial arteries, 409 Deafness, 154 gastrointestinal motility, 491
Corticobulbar tract, 168 conductive, 154 Digitalis, 22, 37, 218
Corticohypothalamic pathway, 289 partial, 736 Digoxin, 420
Corticosteroids, 384 sensorineural, 154 Dihydropyridines (DHP), 55
Corticostriate pathway, 171 Decerebrate deficits in humans, 172f receptors, 80, 86, 94, 102f
Corticotropin-releasing hormone (CRH) or Decerebrate rigidity, 171 Dihydrotestosterone, 659, 664, 687, 688f,
factor (CRF), 626, 657, 725 Decerebration, 171, 172 689t, 697
Cortisol, 405, 456, 602, 604, 609, 626, 631, 657, Declarative memory, 75, 191, 196 Dihydroxyphenylalanine (DOPA), 63,
659, 662, 668, 718, 725, 726f Decomposition of movement, 175 64, 666
conversion to cortisone, 658 Decompression illness, 738, 741 1,25-Dihydroxyvitamin D, 398, 531
negative feedback, 664 Decompression sickness, 741 Diiodinated tyrosine (DIT), 636
physiologic effects, 663t Decorticate deficits in humans, 172f Diluting segment, 443
precursors, 665 Decorticate rigidity, 171 Dipalmitoyl phosphatidylcholine, 321
Cortisol-binding globulin (CBG), 658 Decortication, 171, 172f Disordered eating, 750
Cough, 390 Deep cerebellar nuclei, 175 Distal nephron
Coulomb (C), 34 Deep pain, 290 delivery of sodium, 467
Countercurrent exchange, 445 Deep tendon reflex, 126 flow rate, 468
Cranial nerves, 107, 125, 143, 155f, 164f, Deep vein thrombosis (DVT), 262, 360 Distal stump, 111
177, 619f Defecation, 299, 496, 553, 554, 556 Distal tubule, 406
functions of, 109t Defensins, 538 Distensibility, 5
Creatine phosphate (CP), 80 Defibrillation, 244 Diuresis, 430
Creatinine clearance, 419, 420, 754 Deglutition, 544, 545 Diuretics, 57, 293, 442, 443, 468, 469f, 737
Cretinism, 638 Dehydroepiandrosterone (DHEA), 686, 687 effects of, 468–469
Cribriform plate, 159 Deiodinases, 637 heavy use of, 482
Cricopharyngeal muscle, 545 Dementia, 194, 195, 580, 753, 755. See also Aging promoting calcium reabsorption, 487f
Crista ampullaris, 150 Alzheimer disease, 753 Diuretic therapy, 293
Critical micellar concentration (CMC), 567, Demyelinating diseases, 53 Divergence, 72
571, 596 Dendrites, 9, 106 Diverticula, 556, 755
Critical opening pressure, 345 Dendritic cells, 536 Diving
Crohn’s disease, 534, 538, 598 Dendritic spines, 106 breath-hold diving, 739–740
Cross-bridge cycling, 83 Denervation supersensitivity, 111 clinical problems, 741–742
Crossed extensor response, 130 Deoxycholic acid, 566 immersion up effects to neck, 739
Crura, 315 Dephosphorylation, 99 physical principles, 739
Crypt, 493 Depolarize membrane, 38 reflex, 739–740
Cryptorchidism, 689, 692 Depression, 70 electrocardiographic response, 740f
CSF. See Cerebrospinal fluid (CSF) Derecruitment of pulmonary capillaries, 345 underwater breathing apparatus, use, 740–741
Cuneate nuclei, 118 Desensitization, 69–70, 118, 608 DNA-binding transcription factors, 638
Cupula, 150 of acetylcholine receptors, 70f Dominant hemisphere, 195
Curare, 60 Desmopressin, 620 l-DOPA (levodopa), 173, 666
Cushing reflex, 289 Desmosomes, 214 DOPA decarboxylase, 63
Cushing’s disease, 664 Diabetes insipidus, 448, 620 Dopamine, 63, 629
Cushing’s syndrome, 630, 631, 664 Diabetes mellitus, 120, 442 Dopamine agonists, 631
768 INDEX

Dopamine beta-hydroxylase (DBH), 63 Elastase, 588 proliferative phase, 703

Dorsal cochlear nuclei, 153 Elasticity, 318 secretory phase, 703
Dorsal column–medial lemniscus pathway, 115 Elastic recoil, 314, 332, 748 Endopeptidases, 64, 65, 70, 588
Dorsal column system, 118 at functional residual capacity, 754 Endoperoxides, 307
Dorsal respiratory groups (DRG), 386 closing capacities, 754 Endoplasmic reticulum, 2, 15, 60, 66, 597, 603f,
Dorsal root ganglia, 125 Elastic work of breathing, 329, 737 607, 616, 672, 673f
Dorsal vagal complex, 509, 545 Elastin, 207 Endorphin, 64
Driving force, 35 Electrical dipoles, 237 β-Endorphin, 626
on ions crossing through membrane, 36f Electrical synapses, 73f Endothelial cells, 103, 206, 253, 254, 265, 401, 416,
Dry atmospheric air, 337 Electrocardiogram, 216, 224, 235–236, 750 451, 562, 597, 626, 692, 703, 706
D-Tubocurare, 70, 179 basic conventions, 236–237 Endothelin, 346
Dual-energy x-ray absorptiometry (DEXA), 652 Einthoven’s conventions, 237f endothelin-1, 102
Dubin–Johnson syndrome, 576 P, QRS, and T waves, 236 receptors, 102
Duchenne muscular dystrophy, 85 PR segment, 236 Endotherms, 729
Duct of Santorini, 518 QT interval, 236 Endotoxins, 731
Ductus arteriosus, 300 Electrocardiography, 216, 235 Endplate, 10f, 11, 68, 128f
Duodenal cluster unit, 495, 519 Electrochemical equilibrium potential, 36 End plate potential, 86
Duodenal I cells Electrochemical forces, 486 Endplate potential (EPP), 11, 68
cholecystokinin (CCK) release, 520f Electrochemical gradients, 16, 35 recording, 68–69
Duodenum, 495 Electroencephalogram (EEG), 185 End-stage renal disease (ESRD), 406
bicarbonate secretion, 533f Electrolytes, 2, 208, 731 End-systolic pressure–volume relationship, 245
Dutasteride, 687 balance concept, regulation, 397–398 End-tidal CO2, 336
DVT. See Deep vein thrombosis (DVT) exercise, effect on, 749 Energy intake, regulation of, 719
Dwarfism, 631 regulation mediators implicated in regulation, 721t
Dynamic cell processes, 9 of potassium balance, 722–725 Enkephalin, 64
Dynamic compliance, 319 of sodium balance, 722 En passant synapses, 72
Dynamic compression, 324 transport pathways, 527 ENS. See Enteric nervous system (ENS)
Dynamic equilibrium, 604 Electromotive force, 34 Enteric bacteria
Dynamic response, 126 Embolectomy, 361 metabolic effects, 539t
Dyneins, 66 Emboli, 262, 272 populations, 538t
Dynorphin, 64 Emesis, 552 Enteric flora, 538. See Microbiota
Dysdiadochokinesia, 175 Emmetropic eye, 137 Enteric nervous system (ENS), 494, 497, 510, 529,
Dysgeusia, 163 Emphysema, 319, 325, 326, 329, 332, 333, 339, 360 549, 554
Dyslexia, 195 End-capillary oxygen content, 355 enteric nerves, classification, 503t
Dyslipidemia, 718, 719 End-diastolic volume (EDV), 245 enteric neurotransmitters, 503
Dysmetria, 175 Endocardial (inner) surface, 55 little brain model, 502–503
Dyspareunia, 711 Endocrine physiology, 601–728 neurokinin A, 554
Dysphagia, 176, 556 endocrine function, assessment of pelvic nerves, 554
Dyspnea, 247, 283, 316, 329, 339, 350, 383, hormone measurements, interpretation, plexuses of, 497f
390, 470 610–611 pudendal nerves, 554
Dystonia, 61 hormone cellular effects, 605 schematic diagram, 502f
Dystrophin, 85 hormone chemistry, and mechanisms of action Enterochromaffin-like (ECL) cells, 503, 509, 529
amino acid–derived hormones, 603 Enteroendocrine cells, 464, 494, 502, 503, 509, 530
E hormone effects, 603 Enteroglucagon, 502
Ear hormone transport, 603–604, 604f Enterohepatic circulation, 561
anatomy, 147 protein/peptide hormones, 602 Enterokinase, 588, 589f
cochlea, 149–150, 150f steroid hormones, 602 Eosinophil chemotactic factors, 307
external ear, 147 hormone receptors, and signal transduction Epicardial (outer) surface, 55
middle ear, 147, 148f cell membrane receptors, 605–607 Epididymis, 684, 688, 689
inner ear, 149–150 hormone–receptor regulation, 608 Epilepsy, 52, 63, 185
cochlea, 147 intracellular receptors, 607–608 Epimerization, 566
saccule, 147 hormone release control Epinephrine (EPI), 56, 63, 268, 346, 405, 464, 665,
semicircular canals, 147 hormonal control, 608–609 666f, 676, 717f, 725, 731f
utricle, 147 neural control, 608 Epithelial cells, 619
vestibular system, 154 nutrient/ion regulation, 609–610 polarization, 425
Ear dust, 150 principles, 601 Epithelial salt and water, reabsorption, 425
Ebner gland, 162 Endocrine system, 601–602, 602f Epithelial sodium channel (ENaC), 21, 44,
ECF. See Extracellular fluid (ECF) disorders, 610 443, 531
Echocardiogram, 282 endocrine glands, 601 EPSPs. See Excitatory postsynaptic potentials
Echocardiography, 245 hormones, 601–602 (EPSPs)
Ectopeptidases, 588 physiologic functions and components, Equal pressure point, 325
Edema, 29, 207, 255, 261, 297, 736, 738. See also 601–602 Erectile dysfunction, 692
Pulmonary edema target organ, 602 Ergocalciferol, 650
Edinger–Westphal nucleus, 143 Endocytosis, 30 Error, 6
Edrophonium chloride (Tensilon), 71, 77 Endogenous opioid peptide, 626 Eructation, 741
Effective renal plasma flow, 419 Endogenous pyrogens, 731 Erythropoiesis, 737
Effector, 12 Endolymph, 149 Erythropoietin, 398, 406, 450, 602, 737
Efferent arterioles, 400, 402, 409, 411f, 722, 753 Endometrial cycle. See also Ovarian hormones Esophageal varices, 563
Efferent control, 45, 108 fertilization, 703–704 Esophageal motility, features of
Einthoven’s triangle, 236, 238, 240 implantation, 704–705 LES relaxation, 547
Elastance, 5 menstrual phase, 703 peristalsis, 545–547
 INDEX 769

swallowing, 545 External anal sphincter, 494, 554 infection pathway, 732f
Esophageal motility, principles External auditory meatus, 147 Fiber, 85, 584
role and significance, 543–544 External intercostal muscles, 315 dietary, 539
Esophagus, 493, 543 Extra-alveolar vessels, 343 types, 90–91
functional anatomy and innervation, 544f Extracellular fluid (ECF), 4, 437 Fibrillation, 272
lower esophageal sphincter (LES), 544 total body water, distribution, 438f Fibrosis, 319, 322, 326, 580
upper esophageal sphincter, 544 volume, 450, 453–454 Fibrous astrocytes, 105
Estradiol, 611, 686, 687f, 693, 697–699, 705, 707f, Extrafusal fibers, 126 Fick principle, 244, 252
711, 712f, 726f Eye Fick’s first law, 26
17β−Estradiol, 659 accommodation, 137–138, 138f of diffusion, 253, 357
Estrogen, 261, 755 anatomy, 133–134, 134f Fight–or-flight response, 667
deficiency, 652 aqueous humor, 133 Filtered load, 414–415, 430
estrogen receptor–mediated (genomic) effects, canal of Schlemm, 133 Filtration, 253
705–706 choroid, 133 Filtration fraction, 414
metabolic fate of, 705f ciliary body, 133 Filtration of inspired air, 308
nongenomic effects, 706 cornea, 133 Final common pathway, 131, 167
physiologic actions, 706–707 crystalline lens, 133 Finasteride, 687
replacement therapy, 652 eyeball Fixed/nonvolatile acids, 376
synthesis, 755 sclera, 133 Fixed obstructions, 326
transport, and metabolism, 705 image-forming mechanism, 135–136 Flaccid, 129
theca and granulosa cells coordination common defects, 136–137 Flaccid paralysis, 168
forproduction of, 698f iris, 133 Flippase, 16
Estrogen receptor beta (β), 706 lens suspensary ligament (zonule), 133 Flow, 5
Ethmoid bone, 165 movements, 143–144 Flow-induced distribution
Eubacteria, 538 convergence, 144 of blood volume and pressure, 277
Eukaryotic cell, 1, 2f extraocular muscles, 143f Flow–volume curves, 326–327, 329.
Eupnea, 315 saccades, 143 See also Respiratory system
Eustachian tube, 147 smooth pursuit, 144 effort-dependent, 326
Euthyroid, 638 vestibular, 144 effort-independent, 326
Evaporation, 439, 730, 731 pupil, 133 inspiratory and expiratory, 328f
Excitability, 6, 9, 33, 52, 68, 131, 212, 243, retina, 133 maximal expiratory, 328f
463, 485, 647 vitreous humor, 133 of varying intensities, 327f
Excitation–contraction coupling, 86, 93–94 Fluid balance model, 290
Excitatory amino acid transporter (EAAT), 62 F Fluoxetine hydrochloride (Prozac), 24, 64
Excitatory postsynaptic potentials (EPSPs), Facial nerves, 162, 163f, 178, 648, 653 Follicle-stimulating hormone (FSH), 64, 614f,
11, 20, 67, 86, 125 Facilitated diffusion, 4, 26, 27 615, 623, 625f, 683, 685, 691, 697, 698f, 700f,
Excitatory spinal pathways, 287 Facilitation, 70 711, 713
Exercise, 265, 745–752 Familial dysautonomia, 162 Follicular cell, 633, 733
capacity, 753 Familial Hyper KPP, 57 Foot plate, 147
cardiovascular system, control, 746f Fanconi syndrome, 427 Foot processes, 411
changes in Farad (F), 34 Foramen ovale, 299
cardiac output, 746f Faraday’s constant, 34, 36, 39 Force, 86
heart rate, 746f Fasciculations, 168, 176 Forced expiratory volume, 325
stroke volume, 746f Fat-soluble vitamins, 565, 593, 594, 596, 597 Forced vital capacity (FVC), 325
ventilation, 747f absorption of, 598 maneuver using rolling seal spirometer,
effect on minute ventilation, 749f Fatty acid, 597 326f
muscle metabolism, 745 oxidation, 93, 745 Fovea centralis, 134
neuroendocrine response to, 717f Feature detectors, 142 Fractionate, 130
physical activity, acute effects Feedback control mechanism, 604. See also Frank–Starling mechanism, 746
cardiovascular system, 745–747 Hormones, regulation Frontal operculum, 162
fluid and electrolyte balance, 749 negative feedback, 6, 608, 610 Fructose, 586
respiratory system, 747–749 positive feedback, 12, 610 Fruit juice paradox, 473
stress tests, 750 Feedback control systems, 6f, 730 FSH. See Follicle-stimulating
training effects, 749–750 feedback device, 128 hormone (FSH)
ventilatory response to, 748 feed-forward inhibition, 175 F-type H pump, 23
Exercise capacity, 753 Female athlete triad, 750 Functional magnetic resonance imaging
Exercise stress tests, 750 Female genital tract, 697 (fMRI), 191
Exocrine pancreas, 517 Female reproductive organs, 696 Functional residual capacity (FRC), 321–322,
amylolytic enzymes, 517 age-related changes, 711 332, 739
colipase/trypsin inhibitors, 517 menopause, 711–712 Fundus, 508, 548
lipases, 517 puberty, 711
nucleases, 517 functional anatomy, 696f G
proteases, 517 Feminization, 580 GABAA receptors, 63
Exocytosis, 30 Fenestrae, 411, 562 Gain, 6
Exogenous pyrogens, 731 Fermentation, 539 Galactorrhea, 630, 631
Exophthalmos, 639, 733 Fertility, 683 Gallbladder, 562, 570
Expiratory neurons, 386 Fertilization, 695 function, principles
Expiratory reserve volume (ERV), 332, 333f, and embryo migration, 704f role and significance, 570
334f, 739 Fetal development, 299 functional anatomy
Expired air, 337 Fetal hemoglobin (HbF), 364 epithelium, 570
Explicit memory, 75 Fever, 731–732 musculature, 570–571
770 INDEX
Gallbladder (continued)
motor functions
contraction, 571
sphincter of Oddi function, 571–572
neurohumoral control, 570f
storage of bile
bile concentration, mechanism, 571
effects on composition, 571
Gallstone disease, 571, 572
Gamma-aminobutyric acid (GABA), 63, 74
GABAA receptors, 20, 63, 74
GABAB receptors, 63, 74
Gamma-glutamyl transpeptidase (GGT), 568
Gamma loop, 171
Ganglionic synapse, 71
Gap junctions, 6, 21, 93, 101, 134, 214
Gases, diffusion of, 357
diffusing capacity, measurement of, 360
diffusion limitation, 358–359
diffusion of carbon dioxide, 359–360
diffusion of oxygen, 359
Fick’s law, 357–358
perfusion limitation, 359
Gαs protein–coupled receptor, 676
Gαs signaling pathway, 25
Gastric acid
secretion, regulation, 511f
cephalic phase, 511
gastric phase, 512
intestinal phase, 512
Gastric glands, 495, 508
chief cells, 588
pepsinogens, 588
pepsins, 588
structure, 508f
Gastric inhibitory peptide (GIP), 499
Gastric motility, features of
basal electrical rhythm, 549
during fasting, 551
gastric emptying, 550–551
mixing and grinding, 549–550
pylorus, role, 550–551
receptive relaxation, 549
vomiting, 551–552
Gastric motility, principles
patterns, 550
role and significance, 547–548
Gastric musculature, functional anatomy
innervation, 548–549
muscle layers, 548
Gastric pacemaker, 548f, 549f, 550
Gastric peristalsis, 594
Gastric phase, 512
Gastric pits, 508
Gastric secretion
anatomical considerations
gastric cell types, 508–509
innervation, 509
stomach, functional regions, 508
basic principles
gastric secretory products, 507–508
role and significance, 507
cellular basis of
acid secretion, 512–513
other products, 513–514
neural regulation, 510f
products, 508t
regulation, 509
in interdigestive phase, 510–511
postprandial secretion, 511–512
regulatory strata, 510
Gastrin, 64, 499, 501, 508, 547
biologically active forms, 501
Gastrin-releasing peptide (GRP), 504, 510, 519
Gastrocolic reflex, 549
Gastroesophageal reflux disease (GERD), 309,
495, 556, 755
Gastrointestinal hormones, 499
candidate, 502
enteroglucagon, 502
glucagon like peptide-1, 502
ileal brake, 502
pancreatic polypeptide, 502
peptide YY (tyrosine-tyrosine), 502
factors influencing release, 501t
sites of production, 500f
Gastrointestinal immune system, 492
Gastrointestinal system, 492f, 491–600
anatomy of, 494f
communication, specific modes
endocrine communication, 498–499
immune communication, 500
neurocrine regulation, 499–500
paracrine communication, 500
endocrine regulation, principles
candidate GI hormones, 502
gastrin/CCK family, 501
GI hormones, 500
motilin, 501
engineering considerations
cellular specialization, 492–494
hollow organs, design, 492
intestine division into functional
segments, 494
functions
digestion and absorption, 491–492
excretion, 492
host defense, 492
physiologic neurohumoral regulators, 499t
regulation, 498
gastrointestinal tract
chemical signals, characteristics, 498
crypt and villus structures, 493
epithelium, 493
esophagus, 493
lumen, 492
neurohumoral regulation, features, 498
paracrine and immune mediators, 503t
stratified squamous epithelium, 493
immune system, 492
neural control, 498f
neurocrine regulation, principles
enteric nervous system, little brain model,
502–503
enteric neurotransmitters, 503
organs and systems
colon, 496
duodenal cluster unit, 495–496
neuromuscular system, 497
oral cavity and esophagus, 495
small intestine, 496
splanchnic circulation and lymphatics,
496–497
stomach, 495
paracrine and immune regulation
important mediators, 503–504
mechanisms of activation, 504
regulatory systems, integration, 504
Gastrointestinal (GI) tract, 4, 5, 491–600
absorption, 5
chemical signals, characteristics, 498
crypt and villus structures, 493
epithelium, 493
esophagus, 493
liquids and absorption, 4
lumen, 492
neurohumoral regulation, features, 498
paracrine and immune mediators, 503t
stratified squamous epithelium, 493
Gate-control hypothesis, 120
Gating current, 49
G cells, 509
Gender-dependent differences in the
cardiovascular system, 300
General anesthetics, 74
chloroform, 74
ether, 74
halothane, 74
Generalized seizures, 185
Generator potential, 125
Geniculocalcarine tract, 141
Genomic effects, 637–638
GFR. See Glomerular filtration rate (GFR)
GH. See Growth hormone (GH)
GH–IGF-I axis, 725
GH insensitivity syndrome, 631
GH receptor antagonists, 631
Ghrelin, 501, 627, 722
Gibbs–Donnan equilibrium, 29
Gigantism, 630
GIP (glucose-dependent insulinotropic peptide),
499–502, 512
Glands, 508, 523
Glial cells, 105
microglia/macroglia, 105
principal types, in nervous system, 106f
Glia-like supporting (sustentacular) cells, 159
Glitazones, 680
Globulins, 208, 404, 603
Glomerular capillary hydraulic pressure, 412
Glomerular capillary plasma
pressure in, 413
Glomerular filtration
fenestrae, 411
filtered load, 414–415
forces involved, 413f
formation, 411–412
GFR, direct determinants, 412–414
summary of, 414t
Glomerular filtration rate (GFR), 404, 412, 414,
415, 418–420, 430, 449, 453, 456, 457, 462,
486, 754
autoregulation, 415f
filtration coefficient, 412
oncotic/colloid osmotic pressures, 412
resistance, changes effect, 415f
Starling forces, 412
Glomeruli, 159, 161, 400, 410, 412, 413, 416,
456, 754
Glomerulonephritis, 416
Glomerulus, 159, 161, 400, 401f, 403, 405, 409,
426, 453f, 579
Glossopharyngeal nerves, 162, 163f, 178, 386,
390, 545
Glucagon, 676, 715
effects on hepatic glucose metabolism,
676f, 677
physiologic effects, 676
receptor-mediated cellular effects, 677f
regulation of release, 675–676
synthesis, 675
Glucagon-like peptide 1 (GLP-1), 502, 673,
675, 676, 680
 INDEX 771

Glucagonomas, 678 G protein-coupled receptors (GPCRs), 18, 44, 62f, pumping action, 203–204
Glucoamylase, 585f 64, 71, 74, 75, 163, 521, 605f, 607, 618, 677f, Purkinje fibers, 216
Glucocorticoids, 608, 626, 651, 732 685, 697 rate, 232
diseases, 664 adrenergic receptors, 665 control of, 216–217
metabolism, 658 G proteins, 25, 44, 45, 71, 161, 164f, 533, 605, 607, sounds, 226
synthesis and release, 657–658 618, 625, 645, 665, 685 ventricular gallop rhythm, 226
Glucocorticoid therapy, 732 Gq/11 protein–coupled oxytocin receptors, 617 Heart failure, 228, 620, 664
Gluconeogenesis, 398, 405, 559, 676f, 716, 717f, Gracilis nucleus, 118 Heart rate, 232
718, 726 Gradient-limited systems, 426, 427 Heat stroke, 730
Glucose, 430 Granular cells, 403, 451–454 Helicobacter pylori, 514
glucose-6-phosphate, 745 Granule cells, 159, 174 Helicotrema, 149
liver synthesis of, 5 Graves’ disease, 634, 638–640, 733 Helium-dilution technique, 333
oligomers, 585–586 Gray rami communicans, 178 Hematocrit, 207, 372, 737
polymers, types, 584 Growth hormone (GH), 615, 623, 624, Hematuria, 416
tolerance test, 631 709, 755 Heme-containing proteins, 575
Glucose buffer function, 559 deficiency, 755 Heme oxygenase, 575
Glucose-dependent insulinotropic effects at target organs, 629 Hemianopia, 142
peptide, 499 insensitivity syndrome, 631 Hemiblocks, 242
Glucose tolerance test, 631 physiologic effects of, 628 Hemichannels, 21
Glucose transporter (GLUT), 23, 430, 675t receptor, 628–629 Hemochromatosis, 531
GLUT1, 27 receptor antagonists, 631 Hemoglobin, 363, 377, 472
GLUT2, 531, 587 regulation of, 627 chemical reaction of oxygen and, 364
GLUT3, 27 release and effects, 628f hemoglobin M, 368
GLUT4, 27, 662 stimulation of, 628t hemoglobin S, 364
GLUT5, 586, 587 Growth hormone-releasing hormone structure, 363–364
Na-GLUT, 27 (GHRH), 627 Hemophilia, 209
Glutamate, 61–63, 74, 106, 159 Gs protein–cAMP–protein kinase A, 220 Hemorrhage, 6, 171, 230, 280, 336, 348, 454
synapse, 62f Guanosine diphosphate (GDP), 25, 605, 607, Hemorrhagic shock, 618
Glutamate decarboxylase (GAD), 63 677f, 685f Hemorrhagic hypovolemic shock, 301
Glutamate receptors (gluRs), 20 Guanosine triphosphate (GTP), 25, 139, 605f, Hemostasis, 208–209, 563
metabotropic gluRs (mgluRs), 61 607, 677f, 685f activity of vitamin K, 209
NMDA gluRs, 61 Guanylate cyclase, 692 anticoagulants, 209
NMDA-type, 61, 74 Guanylin, 529, 530, 533, 534 blood clotting, 209
non-NMDA-type, 61, 74 Gustation, 161 calcium chelators, 209
umami taste, 44 Gustducin, 163 citrate, 209
Glutamine, 62, 405, 434, 478, 479f, 480 EDTA, 209
Glutarate, 579 H endogenous tissue plasminogen activator
Glycerophospholipids, 15, 16f Hair cells, 147, 150. See also Auditory receptors (tPA), 209
Glycine, 74 inner hair cells, 149 formation of thrombin, 209
Glycine receptors, 20, 63 outer hair cells, 149 heparin, 209
Glycogen phosphorylase, 675 role of tip link, 151f intrinsic pathway, 209
Glycogen synthase, 675 structure, 151f local vasoconstriction, 209
Glycolipids, 1 supporting (sustentacular) cells, 150 oxalate, 209
Glycoproteins, 1, 624 tectorial membrane, 149 platelet aggregation, 208–209
gonadotropins, 626 Haldane effect, 370, 749 thrombolytic agents, 209
thyroid-stimulating hormone, Halothane, 350 Henderson–Hasselbalch equation, 377, 380, 472
625–626 Haptocorrin, 291 Henle’s loop, 400, 402, 405, 406, 434, 435, 438,
Glycosphingolipids, 16 Hashimoto’s thyroiditis, 638 440, 442–444, 458, 464, 465, 468, 469, 475,
Goblet cells, 307–309, 494 H-ATPase, 475, 476 476, 486
Goiter, 639–640 Haustra, 496f, 553, 555 aquaporins, 442
Goldman–Hodgkin–Katz (GHK) Haustrations, 496 diluting segment, 443
equation, 39 hCG. See Human chorionic gonadotropin (hCG) loop diuretics, 442
Golgi apparatus, 2, 16, 17, 597, 603f Hearing bumetanide, 442
Golgi cells, 175 action potentials in, 153 furosemide (Lasix), 442
Golgi tendon organs, 117, 129 bone and air conduction, 152–153 Na–K–2Cl symporter, 442
Gonadal dysgenesis, 692 central pathway, 153 Henry’s law, 357, 739
Gonadal function, 686–687 loss (see Deafness) Heparin, 262, 307
Gonadotropin-releasing hormone (GnRH), 626, sound transmission, 152 Hepatic artery, 497, 560, 561f, 562
685, 697, 700, 750 sound waves, 152 Hepatic bile, 569
Gonadotropins, 623, 626, 685, 755 traveling waves, 153 Hepatic ducts, 562, 562f, 569
receptor-mediated effects of, 685f Heart, 203 Hepatic encephalopathy, 130, 580
regulation, of ovarian function, 697 autonomic neural influences, 205–206 Hepatic endothelial cells, 598
release, ovarian regulation of, 699 block, 242 fenestrae, 598
follicular phase, 699 conduction velocity, 215 Hepatic stellate cells, 562, 563, 580
luteal phase, 699 control of cardiac output, 205–206 Hepatic triad, 560
synthesis and release diastolic filling, 205 Hepatitis, 580
control of, 685–686 effective operation, requirements for, 205 Hepatitis C virus, 563
negative feedback regulation, 686f electrical activity of, 215f Hepatocytes, 496, 561, 565
Gout, 432 electrocardiograms, 216 transporters, 568t
G protein–activated inward rectifier GIRK excitation, 204–205 Hering–Breuer deflation reflex, 388
channel, 56 failure, 664 Hering–Breuer inflation reflex, 388
772 INDEX

Herpes simplex, 66 salt, 163 Hypertrophy, 292

Heteronymous hemianopia, 142, 144 sour, 163 Hyperventilation, 361, 378, 735, 740
Heterotrimeric guanine-binding (G) proteins, sweet, 163 syndrome, 378
161, 607 umami, 163 Hyperventilation syndrome, 378
Hexamethonium, 71, 179 Humoral hypercalcemia of malignancy, 489 Hypesthesia, 161
H/glutamate antiporter, 24, 27 Huntington’s disease, 63 Hypoaldosteronism, 664
High altitude pulmonary edema, 736 Hydraulic pressure in Bowman’s Hypocalcemia, 52, 57, 68, 484, 487, 644,
High-amplitude propagating contractions, 555 capsule, 412 647, 653
High-pressure nervous syndrome (HPNS), Hydrogen ions Hypocalcemic tetany, 653
741, 742 excretion of, 477f, 478 Hypocapnia, 372, 384, 736, 737
Hippocampus, 76, 108f, 191, 192f, 193–196 secretion generic model, 474f Hypogeusia, 162, 165
Histamine, 63, 64, 116, 188, 255, 307, 323, 346, tubular segments, contributions, 475t Hypoglycemia, 626, 627, 676, 717, 718, 726
510, 529 Hydrophobic groups, 16 Hypogonadism, 580, 630, 692, 693
H2 receptors, 510 Hydrostatic forces, 5 Hypogonadotropic hypogonadism, 692, 693, 713
antagonists, 510 Hydrostatic pressure, 5, 28, 254, 258, 348, 349, Hypokalemia, 463, 620, 664, 724, 725, 731
Histotoxic hypoxia, 383 412, 413 Hypomagnesemia, 644
H–K antiporters, 465 of interstitial fluid, 254 Hyponatremia, 30, 620, 665, 749
H+,K+-ATPase, 475, 512. See also Proton pump of intracapillary fluid, 254 Hyponatremic encephalopathy, 30
H/K pump, 23 Hydroxyapatite, 377, 487, 646 Hypoparathyroidism, 652t, 653
Holter monitor, 210 deposition of, 488 Hypoperfusion hypoxia, 383
Homeostasis, 1, 11 resorption of, 488 Hypophosphatemia, 651
energy, brain’s signals to control 11β-Hydroxylase, 657 Hypophysiotropic hormones, 613, 615
regulation, 720f enzymatic deficiency, 659f key aspects of, 615t
and feedback control, 12 21-Hydroxylase, 657 Hypophysis, 623
Homeotherms, 729 enzymatic deficiency, 659f Hypopituitarism, 630, 639
Homovanillic acid, 665 11β-Hydroxysteroid dehydrogenase, 658 Hyporeflexia, 168, 176
Homunculus, 118 type I, 658 Hyporeninemic hypoaldosteronism, 664
Hooke’s law, 5 type II, 658 Hyposmia, 161
Hormone-producing tumors, 678 5-Hydroxytryptamine (5-HT), (also see Hypothalamic integration, 719
Hormone–receptor agonists/antagonists, 605 serotonin) 64, 503, 529, 550 Hypothalamic neurons, 613
Hormone–receptor complex, 604, 605, 607, 608, Hyperaldosteronism Hypothalamic neuropeptides, 615
628, 661 primary, 470, 664 Hypothalamic nuclei, 613–615
Hormones, 498. See also Endocrine physiology; Hyperalgesia, 116 Hypothalamic peptides, 625
Endocrine system; Gastrointestinal Hyperbaria, 738 Hypothalamic–pituitary–adrenal axis, 660f
hormones; Ovarian hormones; Steroid Hyperbaric chambers, 738 Hypothalamic–pituitary–ovarian axis, 695, 700f
hormones Hyperbaric oxygen therapy (HBOT), 738 Hypothalamic–pituitary–thyroid axis, 634, 634f
affinity, 605 Hyperbilirubinemia, 577, 578 Hypothalamic tumors, 692
of anterior pituitary, 624–630 Hypercalcemia, 653 Hypothalamohypophysial tract, 613, 615
autocrine, 603 Hypercalcemia of malignancy, 645 Hypothalamo-pituitary hormone-mediated
biologic effect, 603 Hypercalciuria, 653 effects
endocrine, 603 Hypercapnia, 346 cellular signaling pathways, 625f
events, during ovarian and endometrial cycles, Hypercoagulable, 262 Hypothalamus, 161f, 183, 188, 189f, 287, 385,
701f Hyperemia, 265 450f, 501, 509, 602, 613, 614f, 626, 630
free/unbound hormone, 603 Hyperglycemia, 406. See also Diabetes mellitus anatomic and functional relationship, 614f
half-life, 603 Hypergonadotropic hypergonadism, 713 endocrine functions of, 615
interpretation of measurements, Hyperkalemia,38, 222, 463, 658, 665, 725 supraoptic/paraventricular nuclei, 459
610–611, 611t Hyperkalemic periodic paralysis (HyperKPP), 52 Hypothermia, 716, 731
intracrine, 603 Hypernatremia, 620 Hypothyroidism, 638
neural control, 610f Hyperopia, 136 primary hypothyroidism, 638–639
paracrine, 603 Hyperosmolarity, 722 secondary hypothyroidism, 639
precursor, 604 Hyperparathyroidism Hypotonia, 168, 175, 176
product, 625 primary, 488, 489 (see also Thyroid gland) Hypotonic encephalopathy, 30
receptor function, 611 secondary, 489, 651 Hypotonic muscle, 129
release Hyperphosphatemia, 489, 653 Hypotonic solutions, 28
patterns, 609f Hyperpnea, 388, 747 Hypoventilation, 366, 377, 382, 480
regulation of, 615–616 Hyperpolarization, 38 Hypovolemia, 484
sensitivity, 611f Hyperpolarization-activated current, 55 Hypovolemic shock, 301
specificity, 605 Hyperprolactinemia, 640, 693 Hypoxemia, 321, 379, 384
Hormone-sensitive lipase (HSL), 638, 675 Hyperreninemic hypoaldosteronism, 664 Hypoxia, 321, 346, 382, 391, 394, 730, 735
hPL. See Human placental lactogen (hPL) Hyperresonant, 329 altitude and acclimatization
H2 receptor antagonists, 510 Hypersensitivity, 111 altitude, acute effects, 736
5HT1 receptors, 551 Hypersomnolence, 187 cardiovascular system, 736
5HT3 receptors, 64, 551 Hypertension, 229, 282, 290, 292, 470, 640, 657, respiratory system, 736–738
Human body, 3f 664, 718 anemic hypoxia, 383
Human chorionic gonadotropin (hCG), 602, 625, Hyperthyroidism, 634, 638, 731, 732 classification of causes, 382t
688, 699, 703, 709 Graves’ disease, 639 effects of, 383
Human language, 195 primary, 732 histotoxic hypoxia, 383
Human placental lactogen (hPL), 626, 707f, TSH-secreting adenomas, 639 hypoperfusion hypoxia, 383
709, 711 Hypertonia, 169 hypoxic hypoxia, 382–383, 735
Human taste modalities Hypertonic (spastic) muscle, 129 Hypoxic hypoxia, 382, 735
bitter, 163 Hypertonic solutions, 28 diffusion impairment, 382–383
 INDEX 773

low alveolar PO2, 382 type B, 476, 476f Intrapleural pressure, 309, 314, 739
shunts, 383 Intercalated disks, 214 Intrapulmonary shunts, 355, 366
Hypoxic pulmonary vasoconstriction, 384, 736 Intercalated ducts, 523 Intrarenal chemical messengers, 405
chronic, 742 Intercellular adhesion molecules (ICAMs), 26 Intrinsic factor, 507, 513
Hysteresis, 319, 320 Intercostal muscles, 305 Intrinsic factor-cobalamin receptor (IFCR), 591
I Interdependence of alveolar units, 315 Intrinsic proteins, 16
IgA system, 537. See also Mucosal immune system Interferon therapy, 563 Intubated patient, 309
physiological functions, 537 Interleukins, 629, 646, 699, 700f, 719, 726f, Inulin, 418
secretion of IgA across, 535, 537f, 568, 569 731, 732f renal handling, 419f
structural aspects of IgA, 536–537 Intermediolateral column (IML), 177 Invasion of immune cell, 112
IGF receptor, 629 Internal anal sphincter, 554 Inverse stretch reflex, 129
Ileal brake, 502 Interstitial/alveolar edema, 382 Inward-going pacemaker current, 216
Ileal-fatty acid binding protein (I-FABP), 597 Interstitial cells of Cajal, 549 Inward rectifier, 17, 18
Ileocecal valve, 494, 554 Interstitial fibrosis, 382 Inward rectifier K channel (Kir), 17, 18f, 55
Ileum, 496 Interstitial fluid, 4, 28 Iodide channel, 635
Immune communication, 500 Interstitial hydrostatic pressure, 349 Iodine, uptake and organification, 634
Immune responses, alterations in, 725 Interstitium, 399, 477f, 479f, 487, 499, 603f, Ion movements
Impaired glucose tolerance, 631 663f, 664 factors controlling, 35–36
Implicit memory, 76 Intestinal calcium absorption, 644 receptors channels allowing, 102
Implicit/nondeclarative memory, 191 Intestinal flatus, composition, 540f Ionotropic ligand receptors, 20
Impotence, 631 Intestinal fluid transport Ions of importance, across muscle cell
Inactivation gate, 213 anatomical considerations membrane, 35t
Incontinence, 183, 754t, 755 innervation and regulatory cells, Ion transport pathways, 522f, 525f
Incretin, 501, 675 528–529 IP3 receptors, 101, 102f, 677f, 698
Infant respiratory distress syndrome, 321 intestinal surface area, amplification of, 528 IPSPs. See Inhibitory postsynaptic potentials
Inferior colliculi, 153 cellular basis (IPSPs)
Inferior olivary nuclei, 175 absorptive mechanisms, 531–532 Ischemia, 22, 63, 117, 248, 289, 302, 360, 372,
Inflammation, 112 secretory mechanisms, 532–533 630, 703
Inflammatory bowel diseases, 534, 538 endogenous regulators, 529t Ischemic heart disease, 711
Crohn’s disease, 534, 538 integration of influences, 530f Ischemic stroke, 63
ulcerative colitis, 534, 538 principles Islets of Langerhans, 518
Inhibin B, 685 electrolytes involved, 527–528 Isohydric principle, 376
Inhibitory G proteins, 216 role and significance, 527 Isohydric shift, 370
Inhibitory postsynaptic potentials (IPSPs), water and electrolyte transport, regulation Isomaltase, 585, 586
11, 67, 125 acute regulation, 530 Isometric contraction, 85, 86
Inhibitory spinal pathways, 287 chronic adaptation, 531 Iso-osmotic process, 423
Innocent murmurs, 300 regulatory strata, 529–530 Isopotential, 40
Inositol triphosphate (IP3) receptor (IP3R), 21 Intestinal lipolysis, mediators, 595t Isoproterenol, 346, 350
Inositol trisphosphate (IP3), 607 Intestinal microecology Isosmotic solution, 28
Inotropic, 220, 638 gas generation in intestine, 540 Isotonic contraction, 85, 86
Input–process–output structural framework, 10 intestinal microbiota, development, 538–539 Isotonic solution, 28
Inspiratory capacity (IC), 332 microbiota, physiological functions, 539–540 Ito cells, 562
Inspiratory neurons, 386 Intestinal motility
Inspiratory reserve volume (IRV), 332 basic principles J
Insulin, 394, 464, 587, 671, 715, 724 role and significance in colon, 553 Jaundice, 575
effects at target organs, 674 role and significance in small intestine, differential diagnosis, 578f
early effects, 674 552–553 J chain, 536
intermediate effects, 675 esophageal musculature, functional anatomy Jejunum, 496, 499, 500, 552, 554
long-term effects, 675 innervation, 544 J receptors, 390
effects on carbohydrate, fat, and protein muscle layers, 544 Juxtaglomerular (JG) apparatus, 403, 451
metabolism, 674 features of baroreceptor, 658
effects on hepatic glucose metabolism, 676f colonic motility, 555 components, 403f
glucose-induced stimulation of, 673 defecation, 556 extraglomerular mesangial cells, 403
physiologic effects of, 673 fed versus fasted patterns, 554–555 glomerular filtration rate (GFR), 403
receptor, 25, 674 mixing and segmentation, 555 granular cells, 403
substrates, 674 peristalsis, 555 juxtamedullary nephron, 403
regulation of release, 672, 673f functional anatomy macula densa cells, 403
resistance, 662, 678–680 enteric nervous system, 554 renin, 403
sensitivity, 755 muscle layers, 553 Juxtaglomerular cells, 401f, 403, 451
synthesis, 672 sphincters, 554
Insulin/glucagon ratios, 716 Intestinal pathogens, pathophysiological K
Insulin-like growth factor-1 (IGF-1), 627–629, 755 mechanisms, 540t KAch channels, 216
Insulin-like growth factor binding proteins Intestinal phase, 519 Kainate channels, 74
(IGFBPs), 629 Intestine organization, 493f Kallmann syndrome, 692
Insulinoma, 678 Intracellular fluid (ICF), 437 K channels, 18, 37, 55, 74, 102, 214, 673f
Insulin resistance, 662 Intracellular receptors, 606f Kernicterus, 575
Integrins, 26 Intraepithelial, 536 Ketoacidosis, 376, 379, 382, 394
Intensity, 118 Intraepithelial lymphocytes, 536 Ketogenesis, 674–676, 680
Intention tremor, 175 Intrafusal fibers, 126 enzymes involved in, 680t
Intercalated cells, 403, 466 Intralaminar nuclei, 108 in insulin deficiency, 679f
type A, 475, 476f Intralobular ducts, 523 Ketone bodies, 93, 394, 474, 676, 678, 679, 717
774 INDEX

Kidney, 397–490 synaptic plasticity and, 192–193 hyperbilirubinemia, 578

anatomy, 399 habituation, 192 urinary elimination, 577–578
calyces, 399 sensitization, 192 bilirubin metabolism
cortex, 399 Left heart failure, 283 cellular heme metabolism, 575–576
functions, 397 Left ventricular failure, 226, 349, 390 hepatic transport mechanisms, 576
glucose handling by, 430f Left ventricular hypertrophy, 247, 282 hepatocyte conjugation, 576–577
Henle’s loop, 486 Length constant (λ), 40 role and significance, 575
hilum, 399 Length–tension relationship, 81, 88, 95, 95f blood vessels, bile ducts, and hepatocytes
influence of, 450f Lenticular nucleus, 171 arrangement, 561f
medulla, 399 Leptin, 501, 719–721, 750 cirrhosis, 620
pyramids, 399 Leptin receptor, 721 engineering considerations
stone, 435 Leukotrienes, 307, 323 biliary tract and gallbladder, 562
structural components, 399f Levator ani muscles, 556 blood supply, 560–561
urea handling, 434f Leydig cells, 683 hepatic parenchyma and sinusoids, 561–562
Kinesins, 66 LH. See Luteinizing hormone (LH) functions
Kinocilium, 150 Lidocaine, 53 lipid-soluble waste products, excretion, 560
Klinefelter syndrome, 692 Ligand, 16, 605f, 607, 647f, 660, 662f metabolism and detoxification, 559–560
Knee-jerk reflex, 12, 126 gated channels, 20, 607 protein metabolism and synthesis, 560
Kölliker-Fuse nucleus, 387 ionotropic ligand receptors, 20 gluconeogenesis, 559
Korotkoff sounds, 260 ligand-binding domain of, 706 glucose buffer function, 559
Krebs–Henseleit cycle, 578 metabotropic ligand receptors, 20 splanchnic circulation, 560f
Kupffer cells, 559, 561, 562, 575 osteoprotegerin, 646 Loading spindle, 127
Kyphoscoliosis, 319, 340, 382 Ligand-gated channels, 20 Local circuit interneurons, 121f
Kyphosis, 340 Limbic system, 108 Location of stimulus, 117
α-Limit dextrins, 584–586 Long-QT (LQT) syndrome, 52, 243
L Lipase, 507, 521, 594, 595, 629, 692 Long-term bed rest
Labyrinth. See Inner ear gastric and pancreatic, positional specificity, cardiovascular mechanisms involved, 298f
Labyrinth righting reflexes, 156 594f responses to cardiovascular system, 297–298
Lacrimal duct, 134 Lipases, 517 Long-term depression (LTD), 76, 193
Lacrimal gland, 134 Lipid assimilation Long-term memory, 76, 192f, 194
Lactase, 585, 586 epithelial events in Long-term potentiation (LTP), 76, 192–193
Lactated Ringer’s solution, 474 brush border events, 596–597 production of, 193f
Lactation, 617, 630, 651, 696, 703, 707f, 708, 709, 711 intracellular processing, 597 Loop diuretic, 442, 489
Lactic acid, 91, 474 lymphatic uptake of absorbed lipid, Loop of Henle. See Henle’s loop
production, 745 597–598 Loperamide, 530
Lactic acidosis, 382, 474 fat-soluble vitamins, absorption, 598 Loudness, 152
Lactic acid production, 745 intraluminal digestion Lou Gehrig’s disease, 86, 176
Lactoferrin, 523 bile acids/micelles, role of, 596 Low-density lipoprotein (LDL), 707
Lactose, 584, 586 gastric digestion, 594 Lower esophageal sphincter (LES), 495,
bush border digestion ad assimilation, 586f intestinal digestion, 594–596 508, 544
in dairy products, 591 intestinal handling of cholesterol, 597f Lower motor neurons, 168
Lactose intolerance, 591, 592 intestinal lipolysis, mediators of, 595t Low-pressure receptors, 289
Lactotrophs, 629 role of colipase, 595f Low-resistance electrical, 214
Lactulose, 580 principles Low vascular volume, responses to, 454f
Lambert–Eaton syndrome, 70 dietary and endogenous sources, 593–594 L-type (voltage-gated) calcium channels,
Lamina propria, 528 hydrophobic molecules, assimilation 94, 101
Laminar flow, 257, 322 barriers, 593 Luminal epithelial cell membrane, 619
Language role and significance, 593 Luminal/mucosal membrane, 29
disorders, 196 Lipids, 593 Luminal proteolysis
hemisphere concerned with, 195f bilayer, 1, 15, 596 gastric, 588
physiology of, 195 droplets, 2 intestinal, 588
hemisphere concerned with, 195f flip-flop, 16 Lung compliance, 318–321, 754
path taken by impulses, 196f lamellar phase, 596 Lung volumes, 331
and speech, 195 long-chain triglycerides, 593 measurement of, 332–333
Laplace’s law, 320 phosphatidylcholine, 594 body plethysmography, 334
Large intestine phospholipids, 593 helium-dilution technique, 334
anatomy, 496f rafts, 16 nitrogen-washout technique, 333
L-arginine, 265 Lipolysis, 692. See also Lipase pulmonary function tests, 333
Laron syndrome, 631 products of, 593 spirometry, 333
Latch state, 100, 101 Lipopolysaccharides, 731 and pulmonary vascular resistance,
Latent pacemaker, 214 Lithium treatment, 620 343–344
Lateral corticospinal tracts, 167 Lithocholic acid, 566 standard lung volumes, 331
Lateral geniculate bodies, 108, 139 Liver expiratory reserve volume (ERV), 332
Lateral inhibition, 117, 139, 161 ammonia metabolism, principles functional residual capacity (FRC), 332
Lateral olfactory stria, 159 extraintestinal production, 579 inspiratory capacity (IC), 332
Lateral sacs, 86 intestinal production, 578–579 inspiratory reserve volume (IRV), 332
Law of Laplace, 221, 232 role and significance, 578 residual volume (RV), 332
L-DOPA (levodopa), 173, 666 urea cycle, 579 tidal volume(VT), 331
Lead pipe rigidity, 173 urea disposition, 579–580 total lung capacity (TLC), 332
Lean body mass, 755 bilirubin homeostasis vital capacity (VC), 332
Learning, 191 bacterial metabolism, 577 Lusitropic effect, positive, 221
 INDEX 775

Luteinizing hormone (LH), 64, 602, 615, 623, 626, α-Melanocyte-stimulating hormone Mitral valve prolapse, 247
683, 686, 697–699, 702, 711, 726, 750 (α-MSH), 721 Mixed micelles, 565
Lymph, 4, 255, 350, 377, 496, 563 Melatonin, 188, 188f, 189, 615, 624 Mixed venous PO2, 737
Lymphatic system, 4, 255, 311, 350, 552 Membrane-bound hydrolases, 584 Mixed venous blood, 305
Lymphedema, 255, 262 Membrane capacitance, 34, 39 MLC kinase, 100
Lymphocytes, 536 Membrane conductance, 35 Modality, 117
Lymphoid tissues/MALT, 535 Membrane potentials, 10, 34 Modiolus, 149
Lysergic acid diethylamide (LSD), 64 changes in, 39, 44f Monge’s disease, 742
Lysosomal enzymes, 307 measurement, 34 Monitor peptide, 517, 519
Lysosomes, 2, 23, 311, 431, 608, 628, 646f, 703 Membrane proteins, 1, 17, 26, 66, 485, 590 Monoamine oxidase (MAO), 63, 64, 665
Membrane pumps, localization, 23t Monoamine transporters, 665
M Membrane receptors, 24 Monoiodinated tyrosine (MIT), 636
Macroglia, 105 enzyme-linked, 25 Monomer of glutamate receptor channels
Macrophages, 105, 307, 311, 350, 536, 703, G protein–coupled, 25 (gluR), 20
731, 732f Membrane resistance, 39–41 Monophasic action, 54
Macula densa cells, 406, 452 Membrane transport, 4, 521, 532, 568, 576 Monosodium glutamate (MSG), 163
Macula lutea, 134 active pathways, characteristics of, 528t Monosynaptic reflex, 125–126
Macular sparing, 142 protein, MRP2, 576 Morphine, 64, 120
Magnetic resonance image (MRI) scan, 112, 121, 631 Membranous labyrinth, 149 Mossy fibers, 175
Magnocellular cells, 141 Ménière disease, 156 Motilin, 499, 501, 551
Magnocellular neurons, 614f, 615–617, 619f Meningiomas, 161 Motility, 72, 491, 495, 502, 529
Magnocellular pathway, 141 Menopause, 301, 652, 711, 755 esophageal, 545–547
Main pancreatic duct, 518 Menstrual cycle, 99, 611f, 696, 697, 701f, 703, 706, gastric, 547–548
Major histocompatibility complex (MHC), 536 708, 713 intestinal, 552–556
Malabsorption, 496, 512, 521 Merkel cells, 115 Motoneuron, repetitive firing, 75f
Male reproductive system, 684f Messenger RNA (mRNA) Motor cortex, 169
Male sexual differentiation, 689f synthesis of proteins, 2 premotor cortex, 169
Malignant hyperthermia, 57 Metabolic acidosis, 377, 379, 382, 392, 481, 679, primary motor cortex, 169
Maltose, 584, 585f 725, 737, 749 supplementary motor cortex, 169
Maltotriose, 584, 585f, 586 causes, 379t Motor endplate, 68, 74, 85f, 86, 101,
Mamillary bodies, 193 renal response to, 482 128f, 544
Mammalian muscle spindle, 127f Metabolic alkalosis, 379, 481–483, 483f, 725 Motor homunculus, 169
Mammalian nerve fibers, 107, 109t causes, 379t Motor neurons, 9, 85
Mammalian target of rapamycin (mTOR), 675 Metabolic clearance rate, 417 areflexia, 168
Manubrium, 147 Metabolic functions of the liver, 559 axon, 10
Mass balance system, 729 Metabolic syndrome, 435, 719 dendrites of, 9
concept of, 5f Metabolic waste, excretion, 398 fasciculations, 168
Mast cells, 64 Metabotropic, 59 flaccid paralysis, 168
Maximum voluntary ventilation (MVV) test, 387 Metabotropic glutamate receptor hyporeflexia, 168
M cells, 141, 535 (mGluR4), 163 hypotonia, 168
Mean arterial blood pressure (MABP), 258, 297, Methemoglobin, 364, 368 in facial nuclei, 168
619f, 747, 749 Methemoglobinemia, 383 in hypoglossal nuclei, 168
Mean circulatory filling pressure, 276–277 Methimazole, 639 in trigeminal nuclei, 168
Mean electrical axis, 239f Metrorrhagia, 713 muscular atrophy, 168
Mean pulmonary artery pressure, 345f Micelles, 565, 567, 568, 594, 596, 598 spasticity, 168
Mean quantal content, 69, 70 Michaelis–Menten equation, 27 synapse, 10
Mechanical nociceptors, 115 Microbiota, 538 with myelinated axon, 107
Mechanoreceptors, 115, 289, 722 controlling factors, 538–539 α-Motor neurons, 171
afferents, 746 Microelectrode, 34 γ-Motor neurons (nerves), 45, 170
Mechanosensitive channels, 11, 18 Microglia, 105, 112 Motor unit, 68, 85, 89, 91, 385
Mechanosensory transduction, 43 Microtubules, 66 Mountain sickness, acute, 736
Medial and lateral descending brain stem Microvillous membrane, 584, 596 Mountain sickness, chronic, 742
pathways, 170f Midcollicular decerebration, 171 MRP2. See Multiple organic anion transporter
Medial geniculate bodies, 108, 153 Midline nuclei, 108 (MOAT)
Medial lemniscal system, 118 Mifepristone, 708 Mucins, 523
Medial lemniscus, 118 Migrating motor complex (MMC), 548, 551, 551f, Mucociliary escalator, 308
Median eminence, 613, 623 553, 554, 554f Mucosa-associated lymphoid tissues
Median nerve, 122 Milliosmoles, calculation of, 28 (MALT), 535
Median preoptic nucleus, 619 Mineralocorticoids, 626, 662 Mucosal immune system, 535
Medium-chain fatty acids, 596 diseases, 664 CD4 cell, 536
Medulla oblongata, 287 synthesis and release, 658–659 CD8 cell, 536
Medullary cardiovascular centers, 287 Miniature endplate potentials (MEPPs), 69 enteric antigens, immune response to, 537
Medullary collecting tubule, 406 Minute ventilation, 335 autoimmunity, 538
Medullary interstitial fluid, composition, 444 Minute volume, 335 immune responsiveness, 538
Medullary osmotic gradient, components of, 444 Miosis, 182 oral tolerance, 537–538
Medullary pyramids, 168 Mitochondria, 2, 15, 23, 64, 66, 68, 93, 509, 579, features, 535
Medullary raphe neurons, 183 580, 679f, 688f, 691 functional anatomy
Medullary respiratory center, 311, 385 Mitogen-activated protein kinase (MAPK), 674 adaptive immunity, cellular mediators, 536
Meissner’s corpuscles, 115 Mitral cells, 159 innate immunity, cellular mediators,
Melanocortin receptors (MCRs), 626 Mitral regurgitation, 247 535–536
Melanocyte-stimulating hormone, 626 Mitral stenosis, 246, 247, 349 lymphoid tissues, organization, 536
776 INDEX
Mucosal immune system (continued)
IgE, 536
IgG, 536
secretory IgA system
IgA, secretion, 537f
IgA, structural aspects, 536–537
physiological functions, 537
protective effects, mechanisms, 537
Mucus, 161, 307
Multidrug resistance protein 3 (MDR3), 568
Multidrug resistance (MDR) transporter, 24
Multiple organic anion transporter (MOAT),
568t, 569
Multiple sclerosis (MS), 53, 107, 112, 162
Multiple system atrophy (MSA), 183
Murmurs, 258
Muscarine, 60
Muscarinic receptors, 102, 179, 206, 510, 524
AChRs, 20, 60
Muscimol, 63
Muscle cell membrane, depolarization of, 6
Muscles contraction
changes in strength of, 80
period, 80
Muscles of respiration, 305
Muscle spindles, 45, 117, 125, 390
discharge, various conditions, 128f
function, 127–128
structure, 126–127
Muscle tone, 129–130
Muscle weakness, 723
Muscular atrophy, 168, 175
Muscular dystrophy, 85, 340
Muscularis mucosa, 493f, 494, 497f, 502, 553
Myasthenia gravis, 68, 70, 77, 86, 91, 382
Mydriasis, 182
Myelin, 68, 105, 106, 106f, 112
Myelination, 52
Myenteric plexus, 494
Myocardial contractility, 232
Myocardial infarction, 210, 282, 350, 360
Myocardial infarcts, 270
Myocardial ischemia, 272, 360
Myocardial oxygen consumption
determinants, 231–232
Myocytes, 93
Myoepithelial cells, 617
Myofibroblasts, 503, 523, 529
Myogenic response mechanism, 81, 265,
415, 547
Myoglobin (Mb), 90, 91, 93, 368, 369, 412, 575
Myometrium, 696f, 708
Myopia, 136, 138f
Myosin, 83
Myosin ATPase activity, 99
Myosin filament, 80, 83
Myosin light chain kinase (MLCK), 99,
100, 100f
Myosin light chain phosphatase, 99, 100, 100f
Myotonia, 57
N peritubular capillaries, 402, 405, 409, 426
Na–Ca antiporter, 486
Na/Ca exchanger (NCX), 24
Na/choline cotransporter, 61
Na–Cl symporter, 443
Na–glucose cotransporter (SGLT), 24
Na/glutamate cotransporter, 24
Na-GLUT antiporter, 27
Na-H antiporters (NHE3), 441, 455, 475
sodium–hydrogen exchanger, 531
Na–HCO3— symporters, 475 Nerve fiber, 107
Na+/K+-adenosine triphosphatase (ATPase), 662 mammalian, classification of, 109t
Na,K-ATPase, 531 relative susceptibility, 110t
Na,K-ATPase pumps, 425, 438, 455, 456, 465, 531 Nerve gases, 86
plasma membrane pumps, 464 Nerve growth factor (NGF), 111
Na–K–2Cl multiporter, 465, 479 Nervous system, 4, 45, 66, 623
Na–K–2Cl symporter (NKCC2), 442 types of glial cells in, 106f
Na/K pump, 37 Net filtration pressure (NFP), 412
cycle, 22f Net influx, 27
Named potentials, 10 Neuroblastomas, 161
Narcolepsy, 187 Neuroendocrine regulation, 715
Nasal hairs, 308 counterregulation to acute stress, 718
Nasal turbinates, 307 energy metabolism during fasted state, 716
Na/serotonin cotransporter, 24 fat, 716–717
Nasopharynx, 307 glucose, 716
Natriuretic peptides and hormones, 405, 457, 739 protein, 717–718
atrial natriuretic peptide (ANP), 457 energy metabolism during fed state, 715
brain natriuretic peptide (BNP), 457 fat, 716
Nausea, 551. See also Vomiting glucose, 715–716
NaV channels, 75 protein, 716
N-CAMs, 26 long-term energy balance and fat storage,
NE. See Norepinephrine (NE) maintenance of, 718–722
Near point of vision, 137 of stress response, 725
Nearsightedness. See Myopia chronic/severe stress, 726f
Necrotizing enterocolitis, 598 Neuroendocrine system, 609, 692
Negative base excess, 381 Neurofibrillary tangles, 194, 753, 755
Negative-feedback system, 12, 390 Neurogenic shock, 80, 301
Negative-pressure breathing, 313 Neurogenic tone, 267
Neocortex, 108, 161, 192f, 194, 195 Neurohormones, 615
Neomycin, 581 hypophysiotropic, 623
Neospinothalamic tract, 120 hypothalamic, 623
Neostigmine, 70 magnocellular neurons, 614f
Neosynephrine, 64 Neurohumoral regulation, 498
Nephrogenic, 620 Neurohypophysis, 613
Nephrogenic diabetes insipidus, 620 Neurokinin A, 503, 554
Nephron Neurological disorders
basic structure, 402f Bell’s palsy, 162
collecting ducts, 399 familial dysautonomia, 162
components, 400f multiple sclerosis, 162
juxtaglomerular apparatus, 403 primary amoeboid meningoencephalopathy, 162
extraglomerular mesangial cells, 403 vestibular schwannoma, 162
glomerular filtration rate (GFR), 403 Neurological examination, 120–121
granular cells, 403 Neuromuscular irritability, 647
juxtamedullary nephron, 403 Neuromuscular junction, 67f, 85–86, 85f
macula densa cells, 403 Neuromuscular synapse, 10
renin, 403 Neuromuscular system, 497
renal corpuscle, 399, 400, 401f enteric nervous system, 497
afferent arteriole, 400 Neuronal depolarization, 613
Bowman’s capsule, 400 Neurons, 9, 105–107
efferent arteriole, 400 types, in mammalian nervous system, 108
glomerulus (glomeruli), 400 Neuropeptides, 64, 717f
mesangial cell, 400 anorexigenic, 721
tubule, 400–403 hypothalamic, 615, 719
ascending thin limb, 400 produced by magnocellular neurons, 616
connecting tubule, 402 as potential prolactin-releasing factors, 629
descending thin limb, 400 from sensory terminals, 121f
distal convoluted tubule, 402 that function as hormones, 613
inner medullary collecting duct cells, 403 Neuropeptide Y, 721
intercalated cells, 403 Neurophysins, 616
loop of Henle, 400 Neurotensin (NT), 630
macula densa, 402 Neurotransmitters, 6, 60f, 63, 64, 75, 106, 179,
499, 500, 530, 610f, 673, 720
principal cells, 403 enteric, 503
proximal convoluted tubule, 400 intestinal epithelial transport regulated by, 529
proximal straight tubule, 400 VIP and nitric oxide as, 548
proximal tubule, 400 Neurotrophins, 110
thick ascending limb, 400 Neutrophil, 307
Nephrotic syndrome, 620 NHE3 sodium-hydrogen exchanger, 531
Nernst equilibrium potential, 36 Nicotine, 60
Nernst potential, 38, 39, 67, 74 Nicotinic acetylcholine receptor channels
generation of, 36–37 (nAChR), 20, 60
 INDEX 777

Nicotinic cholinergic receptor, 86 Olfactory cortex, 159–161 Osmotic pressure, 28, 254, 412
Nicotinic receptors, 86, 89, 503, 544 amygdala, 159 Ossicular conduction, 152
Niemann–Pick C1-like 1 (NPC1L1) gene anterior olfactory nucleus, 159 OST, bile acid transporter, 569
product, 596 entorhinal cortex, 159 Osteoblasts, 648f
Night blindness, 598 frontal cortex, 160 Osteoclast-differentiating factor (ODF), 646
Night terrors, 187 olfactory tubercle, 159 Osteoclasts, 648f
Night vision, 134 orbitofrontal cortex, 160 Osteocytes, 487, 648f
Nigrostriatal dopaminergic system, 171 piriform cortex, 159 Osteomalacia, 598, 650
Nitric oxide (NO), 75, 100, 265, 292, 346, 368, thalamus, 160 Osteonecrosis, 741
545, 692, 738 Olfactory discrimination, 161 Osteopenia, 755
Nitrogen narcosis, 741 Olfactory epithelium, 159, 160f Osteoporosis, 406, 487, 489, 638, 711, 750,
Nitrogen-washout technique, 333 Olfactory glomeruli, 159 753, 755
Nitroglycerin, 272 Olfactory nerve, 165 postmenopausal, 652, 713
Nitrous oxide, 350 Olfactory pathway, 161f prevention of, 652–653
N-methyl-d-aspartate (NMDA) receptors, 193 Olfactory receptors, 25 Osteosclerosis, 154
channel, 74, 76, 193 Olfactory sensory neurons, 159, 159f, 160f Otitis externa, 154
N1 nicotinic cholinergic receptors, 179 Oligoclonal bands, 112 Otitis media, 154
N2 nicotinic cholinergic receptors, 179 Oligodendrocytes, 105, 106f, 183 Otoconia, 150
Nociception, 116 Oligomenorrhea, 750 Otolithic organ (macula), 150
Nociceptive stimuli, 130 Oligospermia, 693 Otoliths, 150
Nociceptors, 45, 115, 118f, 119, 121f Olivocochlear bundle, 153 Ouabain, 22, 37
Nocturnal enuresis, 187 Omeprazole (Prilosec), 23 Oval window, 147
Nodes of Ranvier, 52, 106 On-center cell, 139 Ovarian cycle, 699
Nod2 molecule, 536 Oncotic pressure, 254, 412 Ovarian follicle, 695
Nonchloride anions, 468 in glomerular capillary plasma, 412–413 Ovarian hormones, 713
Nonessential amino acids, 560 of fluid in Bowman’s capsule, 412 overproduction and undersecretion, 713
Non-NMDA channels, 74 of interstitial fluid, 254 physiologic effects of, 705
Nonrespiratory acidosis, 379 of intracapillary fluid, 254 estrogen, 705–707
Nonsteroidal anti-inflammatory drugs (NSAIDs), Oogenesis, 699–701 placenta, 708–709
30, 116, 117, 435, 514 follicle growth and development, 702f progesterone, 707–708
Noradrenergic neurons, 179 and formation of dominant follicle, 699–701 synthesis, 697
Norepinephrine (NE), 56, 63, 178, 188, 189, 217, Open-angle glaucoma, 133 activin, 698
229, 268, 300, 346, 405, 665 Opiate drugs, 530 androgens, 697
receptors, 71 Opioid peptides, 120 estrogen, 697
Normal saline, 372 Optic chiasm, 141 follistatin, 698
NO synthase, 265 Optic disk, 134 inhibin, 698
NREM sleep, 186–190, 391 Optic neuritis, 112 progesterone, 697–698
Nuclear bag fiber Optic tract, 139 Ovulation, 701
dynamic and static, 126 Oral cavity, 495 corpus luteum, formation of, 703
Nuclear chain fiber, 126 Oral rehydration solutions, 529 follicle growth and development, 702f
Nuclear envelope, 3 Oral tolerance, 537–538 luteolysis, 703
Nucleases, 517 Organelles, 2, 3, 15, 23, 79, 95, 217 β-Oxidation of fatty acids, 678
Nucleation, 572 Organic anions, 431t Oxidative phosphorylation, 79, 80, 90, 91, 93,
Nucleolus, 3 Organic anion transporting polypeptide (OATP), 100, 383, 745
Nucleotide–gated cation channel, 163 569, 576 of glucose, 745
Nucleus, 3 Organic cations, 432t Oxidative stress, 176, 580
Nucleus ambiguus, 287, 386, 544 Organic cation transporter (OCT), 432 Oxygen
Nucleus basalis of Meynert, 193–194 Organic substances, renal handling of, 429 carrying capacity of hemoglobin, 364, 737
Nucleus of the tractus solitarius (NTS), 162, 386 organic anions, proximal secretion, 431–432 consumption, 269, 336, 746, 747
Nucleus para-ambigualis, 386 urate, 432 debt, 745
Nucleus parabrachialis medialis, 387 organic cations, proximal secretion, 432–433 delivery, 737
Nucleus retroambigualis, 386 passive reabsorption/secretion, pH inspired and alveolar partial pressures, 736
Nucleus retrofacialis, 544 dependence, 433 toxicity, 742
Nucleus tractus solitarius, 287, 509, 545 proximal reabsorption, 429 transport, factors affecting, 367–368
Nystagmus, 155 glucose, 430 Oxygen-carrying capacity, 364, 737
proteins and peptides, 430–431 Oxygen consumption, 269, 336, 746, 747
O urea, 433–435 Oxygen content of the mixed venous blood, 355
Obesity, 190, 292, 630, 718–719, 721 Organification, 634 Oxygen debt, 745
Obligatory water loss, 440 Organ of Corti, 149 Oxygen delivery, 737
Obstructive diseases, 326, 333 Organomegaly, 631 Oxygen extraction, 269
Obstructive sleep apnea (OSA), 187, 189, 329, 391 Organum vasculosum lamina terminalis, 619 Oxygen loading in lung, 365–366
Occipital lobe, 141 Orientation columns, 142 Oxygen toxicity, 742
Occlusion, 130 Ornithine, 430, 579f Oxyhemoglobin dissociation curve, 364–367,
Octreotide, 631 Oropharyngeal dysphagia, 556 737, 749
Ocular dominance columns, 142 Oropharynx, 307 Oxyntic glands, 508
Oculomotor nerves, 143, 178 Orthostatic/postural hypotension, 183, 298, 448, 620 Oxytocin, 64, 615
Odorant receptors, 159 Osmolarity, 28, 29, 208, 302, 441, 499, 620, 722, 725 physiologic effects of, 617
Off-center cell, 139 Osmoreceptor neurons, 619 release
Olfaction, 307 Osmoreceptors, 459 control of, 617
Olfactory bulbs, 159 Osmosis, 4, 27 physiologic effects and regulation of, 617f
basic neural circuits in, 160f Osmotic diuresis, 441, 468 synthesis and processing of, 616f
778 INDEX

P Parasternal intercostal muscle, 315 luminal digestion, 589f

Pacemaker, 93. See also Cardiac pacemaker; Parasympathetic ganglia, 60, 71 transporters, 589–590
Gastric pacemaker Parasympathetic nerves, 286 peptide transporter 1 (PEPT1), 531, 589
potential, 55 Parasympathetic nervous system (PNS), 80, 101, Peptide YY, 502
Pacinian corpuscles, 44, 115 177, 180f, 523, 692 Percentage of inspired oxygen (FIO2), 355
Packed red blood cells, 372 Parasympathetic tone, 216 Percussion, 329
Pain Parasympathetic vasodilator nerves, 268 Periaqueductal gray matter (PAG), 120
inflammatory pain, 116 Parathyroid adenoma, 653 Pericardium, 203
neuropathic pain, 116 Parathyroid Ca2+-sensing receptor, 644f Periglomerular cells, 159
pathological/chronic pain, 116 Parathyroid gland hyperplasia, 653 Perilymph, 149
physiological/acute pain, 116 Parathyroid glands, 487, 489, 602f, 611, 643, Perineurium, 112
Pain transmission, modulation of, 120 644, 649, 653 Peripheral chemoreceptors, 392
Paleospinothalamic tract, 120 Parathyroid hormone (PTH), 487–489, 643 Peripheral edema, 742
Palpitations, 640, 667, 668, 678, 732, 736 cellular effects of, 645–646 Peripheral motor control system, 130f
Pancreas, 492 clinical evaluation of abnormalities in, 652t Peripheral nervous system, 66, 105–107, 601
acini, 518 hyperplasia of, 653 Peripheral neuropathy, 126
duct of Santorini, 518 hypocalcemia, 487 Peripheral peaking of pulse pressure, 258
islets of Langerhans, 518 mediated osteoclast differentiation, 647f Peripheral thermoreceptors, 730
main pancreatic duct (See Wirsung’s duct) mobilization of bone calcium, 646–647 Peripheral vascular system, 252
phases of secretion production, diseases of arterioles, 207
cephalic and gastric phases, 519 primary hyperparathyroidism, 653 blood vessels, control of, 207
intestinal phase, 519 pseudohypoparathyroidism, 653 capacitance vessels, 207
sphincter of Oddi, 518 secondary hyperparathyroidism, 653 capillaries, 207
structure, 518f release, regulation of, 643–644, 644f, 645t conduit vessels, 207
Pancreatic acinar cells, 518, 595 and renal calcium rabsorption, 645f structural characteristics, 206
receptors, 521f and renal inorganic phosphate (Pi) transmural distending pressure, 207
secretory products, 518t reabsorption, 646f Peripheral venous compartment, 275
zymogen granules, 518 target organs and physiologic effects, 644–645f Peripheral venous pool, 258
Pancreatic amylase, 587 Paraventricular nucleus, 183, 459, 614f, 615t, Peripheral venous pressure, 259, 262, 278,
Pancreatic hormones, 671, 672 617f, 626 288f, 299
diseases associated with, 678–680 Paresthesia, 122 influence on venous return, 279
Pancreatic insufficiency, 525, 584 Parietal cells, 494, 508 Peristalsis, 544–547, 555
Pancreatic juice, ionic composition, 520f ion transport proteins, 513f control of, 546f, 547f
Pancreatic polypeptide, 502, 671, 677, 678 receptors, schematic representation, 511f primary, 546f
Pancreatic proteases, activation avoiding ultrastructural appearance, 509f secondary, 546, 547f
mechanism, 589f Parietal glands, 508 Peritoneal cavity, 399, 563
Pancreatic secretion Parietal lobe, 169 Permeability, 4, 21, 26, 253
anatomic considerations Parkinsonism, 183 glomerular, 431
acinar cells, 518 Parkinson’s disease, 64, 172, 183 hydraulic, 412
ductular cells, 518 Parotid glands, 522, 523 ionic, 35
cellular basis Paroxysmal hypertension, 667 to K+, 37
acinar cells, 520–521 Paroxysmal nocturnal dyspnea, 283 passive, 524
ductular cells, 521 Partial pressure of alveolar oxygen, 754 to sodium ions, 48
pathophysiology, 521–522 Partial seizures, 185, 196 to water, 438, 443, 444, 459, 618
principles Parturition, 617 Permeable membrane, 26
pancreatic secretory products, 517–518 Parvocellular cells, 141 permeant/permeate substance, 26
role and significance, 517 Parvocellular neurons, 615 Pernicious anemia, 120
regulation Parvo (P) cells, 141 Peroxisome proliferator-activated receptor-γ
phases of, 519 Passive diffusion, 253 (PPAR-γ), 719
role of CCK, 519 Passive electrical properties, 39 Perturbation, 1, 6, 459
role of secretin, 519–520 long cylindrical cell, 39–41 of acid–base balance, 471
Pancreatitis, 525 small round cell, 39 in renal handling of potassium, 468–470
Paneth cells, 494 Passive transport, 26 Pertussis, 25
Pannexons, 22 Patent foramen ovale, 741 Peyer’s patches, 535, 536
Papillae, 162, 399 Pathologic anatomic shunts, 355 structure, 536f
circumvallate papillae, 162 Pathophysiology, 1 PGF2α, 346
foliate papillae, 162 Peak expiratory flow (PEF), 326, 384 Phalen’s sign, 122
fungiform papillae, 162 Pedicels, 411 Pharyngeal dilator muscles, 322
Para-aminohippurate (PAH), 418, 432 Pelvic nerves, 554 Pharyngeal dilator reflex, 390
Paracrine, 499 Penile meatus, 692 Pharynx, 544, 545
communication, 500 Pepsin, 507 movement of food, 546f
signaling, 6 secretion, regulation, 511f Phasic contractions, 548
Paradoxical potassium retention, 470 cephalic phase, 511 Phenobarbital, 63
Paradoxical reflex, 388 gastric phase, 512 Pheochromocytomas, 665, 667, 668
Parafollicular cells, 633 intestinal phase, 512 Phonation, 306
Parageusia, 163 Pepsinogen, 507 Phosphate, 643
Parallel fibers, 174 PEPT1, 531, 590 balance, 485–486
Paralytic ileus, 723 Peptic ulcer disease, 514 regulation, 485, 651
Paraplegia, 131 Peptides, 64, 504 renal phosphate handling, 489
Parasomnias, 187 disposition in intestinal epithelial cells, homeostasis, 651
Parasternal intercartilaginous muscles, 311 590f Phosphatidylcholine (PC), 15, 568, 594
 INDEX 779

Phosphatidylethanolamine (PE), 15 PNS. See Parasympathetic nervous system (PNS) cardiac, 228, 230
Phosphatidylinositol (PIP2), 15, 16, 101 Podocytes, 411 muscle, 88, 95
Phosphatidylinositol bisphosphate, 607 Poiseuille equation, 203, 258, 322 shifts, 96
Phosphatidylserine (PS), 15, 16 Poiseuille’s law, 203, 258, 322 venous return, 747
Phosphodiesterase (PDE), 607, 638, 675, 692 Polio or Poliomyelitis, 66, 340 ventricular, 226
Phospholamban, 57, 94, 221 Polycythemia, 742 effect of changes, 228
Phospholipase (PLCβ), 25 Polydipsia, 448, 678 larger, 228
Phospholipase A2, 595 Polymeric immunoglobulin receptor (pIgR), 536 Premature ventricular contractions
Phospholipase C (PLC), 21, 101, 607, 658 Polymodal nociceptors, 116 (PVCs), 243
Phospholipids, 593 Polyphagia, 678 Preoptic neurons, 188
bilayer, organization of, 2 Polysomnogram (PSG), 189 Presbycusis, 154
translocators, 15, 16 Polysynaptic reflexes, 125, 130 Presbyopia, 137
Phosphosphingolipid, 15 Polyuria, 620, 678 Pressure, 5
Photoreceptors, 43, 115 Pons, 387 transmural, 5
mechanism, 138–139 Pontine respiratory groups, 387 Pressure natriuresis, 455
current flow in visual receptors, effect of Pores of Kohn, 310 Pressure–volume curve, 318
light on, 138 Portal circulation, 492 Presynaptic cell, 9
photosensitive compounds, 139 Portal hypertension, 563, 580 Presynaptic inhibition, 75
phototransduction in rods and cones, 139f Portal triads, 561 Presynaptic neuron, 59
potentials, ionic basis of, 138 Portal vein, 560 Presynaptic processes, 60, 72
Photosensitive compounds Position agnosia, 121 Presynaptic terminals, 106
opsin and retinal, 139 Positive end-expiratory pressure (PEEP), 321, 348 Prevertebral/collateral ganglia, 178
rhodopsin, 139 Positive feedback system, 7, 12 Primary active transport, 27
scotopsin, 139 Positive-pressure ventilation or breathing, Primary adrenal insufficiency, 664. See also
Phrenic nerves, 315 313, 620 Adrenal gland
Physiological stresses, 738, 739 Positive-pressure ventilation with positive Primary amoeboid meningoencephalopathy, 162
cardiovascular responses to, 286 end-expiratory pressure, 336 Primary colors, 142
Physiologic dead space, 335 Positive-pressure ventilators, 321 Primary/essential hypertension, 292
Physiologic reserves, 750 Positron emission tomography (PET), 191 Primary hyperaldosteronism, 664
Physiologic shunt, 355 Posterior pituitary gland, 268, 448, 459, 613 Primary hyperparathyroidism, 489
Physostigmine, 70, 77 anatomic and functional relationship, 614 Primary hyperthyroidism, 732
Picrotoxin, 63 hormones of, 616–617, 618t Primary metabolic acidosis, 394. See also
Pigment epithelium, 134 synthesis and processing of, 616f Metabolic alkalosis
Pigment stones, 572 Postganglionic fibers, nerves, or neurons, 71, Primary somatosensory area, 169
Pillar cells, 149 177, 286 Primary spontaneous pneumothorax, 330
Pilocarpine, 524 Postmenopausal osteoporosis, 652 Primary uncompensated disorder, 481
Pineal gland, 188f, 189, 615 Postobstructive polyuria, 644 Primary visual cortex, 141
Pinealocytes, 189 Postsynaptic cell, 10, 59 Principal cells, 403, 443, 466
Pineal sand, 189 Postsynaptic inhibition, 128 potassium secretion, 466f
Pituitary, 623 Postsynaptic potential (PSP), 11, 59 Procedural memory, 76
adenoma, 144, 630 Postsynaptic processes, 66–67 Processivity, 66
and hypothalamus, anatomic and functional Post-tetanic potentiation, 71, 192 Procolipase, 595
relationship, 614f Posttraumatic diabetes insipidus, 620 Progesterone, 378, 697, 709
insufficiency, 630 Posture, 167 antiestrogen actions, 708
tumor, 144 Potassium balance, regulation metabolic fate of, 705f
Pituitary adenoma, 144, 630 intracellular and extracellular compartments, physiologic actions, 630f, 707–708
Pituitary adenylate cyclase activating peptide 463–464 receptor–mediated effects, 707–708
(PACAP), 503 hormonal regulation of, 724 receptors, 707
Pituitary insufficiency, 630 renal potassium handling, 464–466 Programmed cell death, 493. See Apoptosis
Pituitary tumors, 142 distal nephron secretion and regulation, Prolactin, 615, 623, 711
Placenta, 299, 625 466–468 family, 624
structure and physiologic function, 708 perturbations in, 468–470 physiologic effects of, 630, 630f
Planum temporale, 195 Potassium channel (KACh), 56 prolactin release, regulation of, 629–630
Plaques, 272 Potassium equilibrium potential, 212 Prolactinomas, 630, 631, 692
Plasma calcium concentration, physiological Potassium excretion, 731 Prolonged QT intervals, 243
responses, 488f Potassium retention, paradoxical, 470 Proopiomelanocortin (POMC), 624, 626
Plasma creatinine, 419 Potassium transport, 466f processing, 627f
steady-state relation, 420f Potential, membrane, 34 Proopiomelanocortin-derived hormones
Plasma norepinephrine, 183 Potentiation, 7 adrenocorticotropic hormone, 626
Plasma osmolality, 755 P1 receptors, 21 β−endorphin, 626
Plasma potassium, 467 Precocious puberty, 692, 713 melanocyte-stimulating hormone, 626
Plasma transcobalamin II (TC II), 591 Prednisone, 53, 77, 662, 732 Prophospholipase A2, 518
Plasma volume, 749 Preganglionic fibers or nerves, 71, 286 Propranolol, 273
Plateau phase, 55 Pregnancy, 299, 696 Proprioception, 117, 126
Platelet-activating factor, 307 and lacatation, 709 Proprioceptors, 9, 11, 156, 387, 748
Platelet aggregation, 208, 272 fetoplacental unit hormone synthesis, 710f Proptosis, 639, 733
Pleural effusion, 282 hormonal control of milk secretion, 711 Propylthiouracil, 639
P loop, 17 mammary gland development, 710–711 Prosopagnosia, 196
Plug formation, 208 parturition, hormonal control of, 709–710 Prostacyclin, 346
Pneumonia, 176, 360, 556, 756 tests, 709 Prostaglandin 15-dehydrogenase, 708
Pneumothorax, 321, 329, 330, 349, 360 Preload, 87 Prostaglandin E2, 117, 307
780 INDEX

Prostaglandins, 117, 307, 529, 533, 708, 732 lung volume and, 343–344 5HT3 receptors, 551
synthesis of, 617 passive influences on, 346t in muscle, tendons, skin, and viscera, 390
Prostaglandins G2 and H2, 307 recruitment and distention, 344–345 potential, 43
Prostate, 683 Pulmonary vascular smooth muscle pulmonary vascular, 390
Prostatic hyperplasia, 687 control of, 345–346 regulating activity of intracellular proteins,
Proteases, 517 Pulmonary wedge pressure, 282 607
Protein kinase A, 25, 57, 94, 97, 100, 231, 607, Pulse oximetry, 750 Receptor tyrosine kinases (RTK), 25
618, 675 Pumps, 16, 22–23 Reciprocal innervation, 128
Protein kinase C, 101–102, 607 Pupillary light reflex, 143 Recompression, 741
Protein kinase G, 100, 103 Purinergic channels, 102 Recruitment, spatial and temporal, 89
Protein/peptide hormones, 602 Purinergic (P2) receptors, 21, 179, 456 Rectoanal inhibitory reflex, 554
synthesis, 603f Purines, 64, 435 Rectum
Protein assimilation Purkinje cells, 174 553f
basic principles, 587–590 Purkinje fibers, 54, 214, 216 Rectus abdominis, 311, 556
barriers to water-soluble macromolecules, Purkinje system, 236 Red blood cell production, regulation, 398
584 PVR. See Pulmonary vascular resistance (PVR) 5α-Reductase inhibitors, 687
brush border hydrolysis, 588–589 P wave, 216, 224 Referred pain, 120
luminal proteolysis, 588 P2X receptors (P2XRs), 21 Reflection coefficient, 28, 349
oligopeptides/amino acids, uptake P2X ATP receptors, 64 Reflex arc, 125, 126f, 131, 499
mechanisms, 589–590 P2X4 receptors, 45 Reflexes, 1. See also Respiratory reflexes
regulation, 590 P2X3 receptor channels, 45 cardiovascular, 288
role and significance, 583 Pyelogram, 447 chemoreceptor, 289
vs. carbohydrate assimilation, 587–588 Pylorus, 494, 508, 548 hyperactive stretch, 169
digestion and absorption, 583 Pyramidal cells, 108, 159 intrinsic, 549, 550
Proteinuria, 427 Pyramids, 399 inverse stretch, 128, 129
Protein zero (P0), 106 Pyrogens, 731, 732f local, 545
Prothrombin, 209 from receptors in heart & lungs, 289
Proton pump, 512 Q respiratory, 388–390, 389t
inhibitor, 514 QRS complex, 216, 238–239 vagovagal, 510, 519, 546, 549, 550
Protoplasmic astrocytes, 105 Quadriplegia, 131 Reflux, 495
Proximal convoluted tubule, 405 Quanta disease, 547
Proximal stump, 112 of ACh, 69 Refraction, 136, 137f
Proximal tubule, 405, 423, 429, 737 Quisqualate channel, 74 Refractory fiber, 89
Pseudohypoparathyroidism, 653 Refractory period
Psilocin, 64 R absolute/relative, 51
Psilocybin, 64 Rabies, 66 Regulatory hypothalamic factor, 625
Psychogenic polydipsia, 448 Radiation, 730 Regulatory systems, 529
PTH. See Parathyroid hormone (PTH) Radioactive iodine uptake test, 733 Reissner’s membrane, 149
PTH-related protein (PTHrP), 489, 645 Raloxifene, 652 REM sleep, 186–188
Ptosis, 91 Raphe magnus nucleus, 120 Renal acid–base processing, 471–484
P-type E1–E2 pumps, 23 Raphe nucleus, 287 Renal angiogram, 461
P-type pumps, 22 Rapid eye movement (REM) sleep, 185 Renal artery, 399, 409, 414
Puberty, 189, 629, 690, 707, 711 Rapidly adapting pulmonary stretch angioplasty, 462
Puborectalis muscle, 556 receptors, 390 blockage, 462
Pudendal nerves, 554 Rapidly adapting (phasic) receptors, 118 obstruction in, 419
Pulmonary blood flow, 341, 355 Rapture of deep, 741 pressure, 415, 455
interaction of gravity and extravascular Rarefaction, 292, 754 stenosis, 453, 462
pressure, 347–348 RAS. See Renin-angiotensin systems (RAS) Renal artery stenosis, 453, 462
positive endexpiratory pressure (PEEP), 348 Rathke’s pouch, 623 Renal blood flow (RBF), 409–410, 449
regional distribution, 346–347 RBF. See Renal blood flow (RBF) afferent arterioles, 409
zones of lung, 347f R-binding protein, 591 arcuate arteries, 409
Pulmonary capillary blood volume, 360 Reaction time, 127, 130 autoregulation, 415–416, 415f
Pulmonary capillary hydrostatic pressure, 349 Reactive/post-occlusion hyperemia, 265 cortical radial arteries, 409
Pulmonary circulation, 342 Rebound phenomenon, 175 efferent arterioles, 409
nonrespiratory functions, 350 Receptive field, 43, 117 kidneys
Pulmonary edema, 30, 247, 283, 348–349, 360 Receptive relaxation process, 495, 549 flow, resistance, and blood pressure,
conditions leading to, 349–350 Receptor, 24 410–411
Pulmonary emboli, 336 Receptor activator of nuclear factor-κβ ligand peritubular capillaries, 409
Pulmonary embolism, 262, 307, 360, 361 (RANKL), 646 vasa recta, 410
Pulmonary embolus, 354, 360 Receptor desensitization, 667 Renal clearance, 417, 418
Pulmonary function tests, 333 Receptor downregulation, 608 Renal compensatory mechanisms, 380
Pulmonary resistance, 322 Receptor kinase, 606f Renal failure, 482, 580
Pulmonary sarcoidosis, 322 Receptor-linked kinase receptors, 606f, 607 chronic, 406, 489
Pulmonary stretch receptors, 388, 390 Receptor-mediated endocytosis, 30 Renal function curves, 292
Pulmonary surfactant, 307, 321 Receptor potential, 161 Renal insufficiency, 630, 664, 722
Pulmonary tissue resistance, 322 Receptor protein tyrosine kinases, 607 Renal-MAP set point, 290
Pulmonary vascular congestion, 351 Receptors, 1, 59, 390, 524, 551. See also Cell Renal microcirculation, 410f
Pulmonary vascular resistance (PVR), 300, membrane receptors Renal plasma flow (RPF), 414, 754
342–343, 748 in airways and lungs, 390 Renal processes. See also Nephron
active influences on, 346t cardiovascular, 390 catabolism, 403
distribution of, 343 5HT1 receptors, 551 chloride reabsorption, 439
 INDEX 781

excretion, 403 assessment of, 325–329 (see also Flow- responses to light, 140f
filtration, 403 volume curves) horizontal cells, 134
average values, 405t distribution of, 322 optic nerve, 134
individual tubular segments increased, clinical consequences of, 329 processing of visual information in, 139
collecting duct system, 443–444 lung volume and, 323 projection, on primary visual cortex, 141f
distal convoluted tubule, 443 alveolar pressure, 314 rod and cone density, 136f
Henle’s loop, 442–443 dynamic compression of airways, 324–325 rods, 134
proximal tubule, 440–442 functions visual receptors in, 134–135
metabolism by tubules, 405 acid–base balance, 306 Retraction, 316
for sodium, chloride, and water, 437 filtration and removal of inspired particles, Retrograde amnesia, 192
fundamental elements, 404f by airways, 309 Retrograde giant contraction, 552
glomerular filtration, 404 gas exchange, 305, 306f Retrograde transport, 110
reabsorption, 403 handling of bioactive materials, 307 Retropulsion, 550, 551
average values, 405t phonation, 306 Reversal potential, 67
tubular reabsorption, 404 pulmonary defense mechanisms, 306–307 Reverse T3 (rT3), 637
regional function, overview of, 405–406 pulmonary metabolism, 307 Rhodopsin, 44f
renal function, regulation, 405 removal of material, from alveolar Rho kinase pathway, 100
secretion, 403 surface, 311 Rhythmicity, 240–241
tubular secretion, 404–405 hypoxia of altitude, 736–737 Ribosomes, 2, 603f
sodium reabsorption, 438–439 intrapleural pressure, 314 Rickets, 598, 650
synthesis, of secreted substances, 403 mechanical interaction Right atrial pressure (RAP), 747
urinary concentration between lung and chest wall, 314, 314f, Right axis deviation, 742
urea, 445–447 321–322, 338 Right heart failure, 284
vasa recta, 445 medullary respiratory center, 311 Right ventricular failure, 742
water reabsorption, 439–440 muscles of, 311, 315 Right ventricular hypertrophy, 738
Renal tubular acidosis, 427 bronchial smooth muscle, control of, Rods of Corti, 149
Renin, 658 322–323 ROMK potassium channels, 466
secretion, control, 453f expiratory muscles, 317 activity, 467f
Renin–angiotensin–aldosterone system, inspiratory muscles, 315–316 Rostral ventrolateral medulla, 183, 287
658, 722 normal tidal breath, events involved in, 317t Rough endoplasmic reticulum (RER), 2, 60,
aldosterone release, regulation, 661f volume, pressure, and airflow changes 66, 597
Renin-angiotensin system, 406, 451–453, 482 during, 318f Round window, 149
ACE inhibitors, 453 pressure, flow, and resistance, relationship Rubrospinal tracts, 167
angiotensin II receptor blockers (ARB), 453 among, 322 Ruffini corpuscles, 115
components of, 452f pressure-volume relationships in, 318 Rugae, 508
Renovascular hypertension, 462 alveolar interdependence, 321 Ryanodine receptors (RyR), 21, 80, 86, 86f,
Renshaw cell, 130 clinical evaluation of compliance, 319 94, 101
Reserpine, 64 compliance of lung and, 318–319
Reserve, 95 elastic recoil, 319–321 S
Residual volume (RV), 325, 332 pulmonary surfactant, 321 Saccades, 143
Resistance, 5 structure, 307 Saccules, 134, 147, 150, 151f, 154
Resistance vessels, 207 airways, 307–309 Safety factor, 53, 350, 366
Resistance work of breathing, 737 alveolar–capillary unit, 309–310 Saliva
Resonator, 152 alveolar septum, 310f constituents, 523
Respiratory acidosis, 377, 378, 481 human lung parenchyma, 309f ionic composition, 524f
causes, 378t pulmonary capillary, 310f Salivary amylase, 523, 584
Respiratory alkalosis, 378–379, 481, 736 transpulmonary pressure, 314 Salivary glands, 492, 495, 523
causes, 379t ventilatory response to exercise, 747–749, 748t salivatory center, 523
Respiratory compensatory mechanisms, 380 work of breathing, 329 salivatory nuclei, 523
Respiratory control system, 385 Respiratory zone, 308 salivary gland anatomy
organization of, 386f Resting membrane potential, 34, 80, 102, acinar cells, 523
response to 212, 214 ductular cells, 523
carbon dioxide, 390–392 of hair cells, 150 salivary secretion
hydrogen ions, 392–393 hyperpolarization, 216 acinar cells, 524
hypoxia, 394 Resting potential, 10, 34, 37–38 ductular cells, 524
spontaneous rhythmicity, 386–388 generation, 35 neural regulation, 523–524
Respiratory gases Kir channels supporting, 38 role and significance, 522
partial pressures of, 336–337 Restrictive disease, 326, 333, 340 salivary secretory products, 522–523
Respiratory pump, 299, 302 Reticular activating system, 110, 188 Salivary secretory products, 522–523
Respiratory rate, 329, 330, 339, 340, 350, 360, 372, Reticular formation, 110, 386 Salivatory center, 523
385, 388, 394, 427 Reticular lamina, 149 Salivatory nuclei, 523
Respiratory reflexes, 388, 389t Reticuloendothelial system, 575 Salmonella, 534
cardiovascular receptors, 390 Reticulospinal tracts, 167, 170 Salt appetite, 461
j receptors, 390 Retina, 134 Saltatory conduction, 52, 106
pulmonary stretch receptors, 388, 390 amacrine cells, 134 Salt restriction, 293
receptors bipolar cells, 134 SA node, 289
in airways, 390 cones, 134 Sarcoidosis, 319, 322, 329, 360, 382
in muscle, tendons, skin, and viscera, 390 extrafoveal portion, neural components of, Sarcolemma (SL), 79, 85, 100
Respiratory rhythm generator, 387 135f sarcoplasmic reticulum (SR) interaction, 93
Respiratory system, 305–396 ganglion cells, 134 Sarcomeres, 83
airway resistance, 322 projections from right hemiretina of, 141f pattern of striation, 84f
782 INDEX

Sarcopenia, 753 Sensory receptors, 115, 125 central sleep apnea, 187
Sarcoplasmic reticulum (SR), 79, 86, 101, 217, 231 cutaneous mechanoreceptors, 115 hypersomnolence, 187
Scalae, 149 nociceptors and thermoreceptors, 115–117 narcolepsy, 187
Scala media, 149 sensory receptors in skeletal muscles & joints, night terrors, 187
Scala tympani, 149 115–117 nocturnal enuresis, 187
Scala vestibuli, 149 Sensory systems, 4 parasomnias, 187
Scalene muscles, 311, 315 code elementary attributes of, 116f, 117 somnambulism, 187
Scanning speech, 175 improving discrimination, 139 stages, 186–187
Scar formation, 112 Sensory transduction, 43 distribution of, 187
S cells, 519 Sensory unit, 117 K complexes, 186
Schaffer collateral LTP, 193 Sepsis, 618 PET scans during REM sleep, 187
Schizophrenia, 64, 195 Septal ischemia, 222 pontogeniculooccipital (PGO)
Schwann cells, 105, 106, 107f, 112 SERCA pump, 23 spikes, 187
Scleroderma, 360 Serosal/peritubular membrane, 29 slow-wave sleep, 186
Scoliosis, 340 Serotonin (5-HT), 63, 116, 188, 307, 503 theta rhythm, 186
Scuba, 740 receptors, 20 Sleep–wake cycle, 187–188
Secondary active transport, 27 Sertoli cells, 683, 684 circadian rhythms and, 187–189
Secondary hyperparathyroidism, 651 Set point, 6, 731 and melatonin, 189
Secondary hypoaldosteronism, 664 Set point for temperature regulation, 289 Slit diaphragms, 411
Secondary hypothyroidism, 639 Severe sweating, coordinated response to, 461f Slowly adapting (tonic) receptors, 118
Secondary peristalsis, 546 Sex hormone–binding globulin (SHBG), 686 Slow-wave sleep, 186, 624
Secondary respiratory alkalosis, 394 Sex hormone synthesis, 626 SL voltage-gated calcium channels, 80
Secondary spontaneous pneumothorax, 330 SGLT-1, 531 Small intestine, 496
Secondary transporter, 23 Shallow water blackout, 740 chloride secretion, 532f
Secondary tympanic membrane, 149 Shear stress, 257 electroneutral NaCl absorption, 532f
Second-degree heart block, 242 Sheehan syndrome, 630 epithelial layers, morphology of, 493f
Secretin, 499, 501, 519, 568 Shivering thermogenesis, 730 ion transport mechanisms, 528ft
function, 520f Shock, 80, 379, 618, 665 jejunum and ileum, 496
Secretory component, 537 Shock lung syndrome, 321 role, 552
Secretory diarrheal disease, 530f Short bowel syndrome, 598 Small skeletal muscles
Secretory granules, 2 Shortening stapedius, 147
Secretory immunoglobulin (IgA) maximum velocity of, 88 tensor tympani, 147
molecules, 535 Short stature, 631 Smooth muscle, 79–81, 99–103
Segmental propulsion, 555 Short-term memory, 76, 192, 196 contraction, 99–100
Segmentation, 555 Shunt equation, 355 influences on, 102f
Selectins, 26 Shunt flow, 355 energy, for contraction and relaxation, 100
Selective estrogen receptor modulators Shunt fraction, 355 multiunit versus unitary, 100–101
(SERMs), 652 Shuntlike states, 355 smooth muscle cell types, comparison of, 100
Selective serotonin reuptake inhibitors, 64 Shunts, 383 stimulation, methods of, 101–103
Self-contained underwater breathing apparatus Shy–Drager syndrome, 183 vascular versus visceral, 100–101
(Scuba), 740 Sickle cell disease, 350, 364 Smooth pursuit movements, 144
Semen, 684 Sildenafil, 692 SNAP-25, 65
Semicircular canals, 147 Silicosis, 329 SNARE proteins, 65
Seminal fluid, 684 Simple cells, 142 Sneeze, 390
Seminiferous tubules, 683 Simple diffusion, 26 S-nitrosohemoglobin (SNO-Hb), 368
Senescence, 690 Sinoatrial (SA) node, 54, 93, 212, 228, 236 SNS. See Sympathetic nervous system (SNS)
Senile dementia, 194–195 Sinusoidal endothelium, 561, 562 Sodium
Sense organ, 115 Sinusoids, 560–563, 569 excretion, regulation
Sensitization, 541 Sitosterolemia, 596 and angiotensin II, 454–455
Sensors, 9, 12 ABCG5 transporters, 596 and autoregulation, 456–457
central thermoreceptors, 730 ABCG8 transporters, 596 and ECF volume, 453–454
peripheral thermoreceptors, 730 Skeletal muscle, 79–81, 83–91 glomerular filtration rate, 453
Sensory adaptation, 45 cell, 9 important variables, 458f
fast and slow, 45f excitation–contraction coupling, 86 long-term control, 455–456
Sensory coding, 117–118 fiber (cell) types, comparison of, 90 natriuretic peptides, 457–458
Sensory endings glycogenolysis, 715 pressure natriuresis and diuresis, 455
primary (group I) ending, 126 neuromuscular junction, 85–86 renin–angiotensin systems, 451–453
secondary (group II) endings, 126 pattern of sarcomeres, 83–84 summary, 458
Sensory fibers, 110 pump, 269, 297, 747 vascular resistance, renal
numerical classification for, 110t regulation of control of, 451
Sensory generator potential, 10, 43 contraction in skeletal muscle, 89–90 intake and loss, normal routes, 438t
all-or-none, 10 contraction-length-tension, 88–89 reabsorption, 731
encoded, 43 sarcomere within, 84 collecting duct system, 438
graded, 10 types of contractions, 86–88 comparison with water reabsorption, 439t
Sensory hair cells, 44 voluntary, 80, 85 distal convoluted tubule, 438
Sensory homunculus, 120 Skeletal muscle pump, 269, 297, 747 Henle’s loop, 438
Sensory information Sleep Na,K-ATPase pumps, 438
from peripheral receptors to cerebral and arousal, neurochemical mechanisms pathways for, 440f
cortex, 119f promoting, 188 proximal tubule, 438
Sensory neuron, 9, 12f, 108, 111, 117, 119f, 149, disorders, 187 summary of mechanisms, 441t
159, 160, 162, 502f cataplexy, 187 transport pathways, 442f, 443f
 INDEX 783

Sodium-bicarbonate cotransporter (NBC), 521 rectoanal inhibitory reflex, 554 zona glomerulosa, 656
Sodium channels upper esophageal sphincter, 544 zona reticularis, 656
inactivated, 48 Sphingolipids, 15 Steroidogenesis. See Sex hormone synthesis
repolarized, 48 Sphingomyelin, 15 Steroidogenic acute regulatory (STAR)
Sodium-coupled cotransporters Sphygmomanometry, 297 protein, 656
SVCT1/SVCT2, 590 Spina bifida, 340 Steroid receptor superfamily, 607
Sodium-coupled nutrient absorption, 531f Spinal cord, 105, 385 Stethoscope, 226
Sodium-dependent glucose symporter lateral spinothalamic tract, 119 Stimulatory G proteins, 217
(SGLUT), 430 Spinal cord injury (SCI), 131 Stimulus-secretion reflex, 629
Sodium/glucose cotransporter Spinal integration, 131 Stomach, 495, 547
SGLT-1 transporter, 531, 586, 587 Spinal motor neurons, 167 antrum, 548
Sodium–hydrogen exchanger (NHE-1), 513 Spinal nerves, 107 cardia, 495, 548
Sodium–iodide (Na+/I-) symporter, 635 Spinal shock, 131 corpus, 548
Sodium/potassium/2 chloride cotransporter Spinal ventral roots, 125 functional regions, 495f, 548f
(NKCC1), 532 Spindle sensitivity, 129 antrum, 508
Sodium–proton antiporter (NHE3), 426 Spinocerebellum, 174 cardia, 508
Sodium reabsorption, 731 Spinoreticular pathway, 119 fundus, 508
Sodium taurocholate cotransporting polypeptide Spinothalamic tract, 115 gastric glands, 508
(NTCP), 569 Spiny stellate cells, 109 gastric pits, 508
Soluble N-ethylmaleimide-sensitive factor Spiral ganglion, 149 gastrin, 508
attachment protein (SNAP)-receptor Splanchnic circulation lower esophageal sphincter, 508
proteins, 65 schematic anatomy, 497f oxyntic glands, 508
Soma, 72 Splanchnic nerve, 548 rugae, 508
Somatic sensory areas Spleen, 560f, 575, 740 fundus, 548
somatic sensory area I (SI), 118 Stagnant hypoxia, 383 gastric glands, 495
somatic sensory area II (SII), 118 Staircase phenomenon, 94 intrinsic and vagovagal reflexes, 550f
Somatomedins, 629 Standard 12-lead electrocardiogram, 240 phasic and tonic contractions, 548
Somatomotor, 183, 290 Standard lung capacities, 331 pylorus, 548
peripheral organization and transmitters Standard lung volumes, 331 receptive relaxation, 495
released by, 178f Starch, 584 Stones. See also Gallstone disease; Kidney, stone
Somatosensory pathways, 118 Starling equation, 348 formation, 485
dorsal column pathway, 118–119 Starling forces, 426 Storage-operated channels (SOC), 102
dorsal horn, 118 Starling hypothesis, 254 Strabismus, 137
Somatostatin (SST), 503, 509, 627, 676, 677 Starling’s law of heart, 205, 277 Stratified squamous epithelium, 493
Somatotopic organization, 169 Stasis, 360 Strenuous exercise
Somnambulism, 187 Static compliance, 319 blood flow in skeletal muscle, 271
Sound Static response, 126 cardiac output, 227, 270, 359
amplitude, 152 Steady state, 37 diffusion limitation of oxygen transfer
bels, 152 Steatorrhea, 512 during, 359
decibel scale, 152 Stellate cells, 175, 561 lactic acidosis associated with, 474
frequency, 152 Stenosis, 272, 462 left ventricular output, distribution of, 747f
pitch, 152 aortic, 246, 248 oxygen consumption rate, 270
Sound localization, 153–154 mitral, 246f, 247, 349 Stretch receptors, 386, 388
Space constant, 40 renal artery, 453, 462 Stretch reflex, 12, 125–126
Space of Disse, 562, 576 Stents, 273, 750 pathways responsible for, 128f
Spasticity, 110, 129, 131, 168, 171, 173 Stercobilinogens, 577 Striatum, 171
Spatial and temporal facilitation, 130 Stercobilins, 577 Stricture, 556
Spatial recruitment, 89, 90 Stereocilia, 150 Stroke, 130
Spatial summation, 73 Stereognosis, 121 Stroke volume (SV), 95, 228, 258
Specificity, 24, 576, 605 Sternocleidomastoid, 311 influences on, 228
of CCK and gastrin, 501 Steroid hormone receptors, 24 cardiac muscle contractility, 229–230
of cholesterol esterase, 595 and mineralocorticoid specificity, 662f cardiac output, 230f
and high affinity, for hormones, 605 Steroid hormones, 602 Starling’s law, 228
of pepsins, 588 alterations in synthesis, 659f ventricular afterload, 228–229
positional, of lipases, 594f androgens, 655 Strong acid, 375
Specific sensory relay nuclei, 108 cholesterol esterase, 656 Structural interdependence of alveoli, 321
Sperm, 683 corticosterone, 656 Strychnine, 63
and accessory organs for production, 684t cortisol, 656 ST segment depression, 750
Spermatogenesis, 690–691 cytochrome P450 sidechain cleavage (SCC) Subfornical organ, 619
key events in, 691f enzyme, 656 Sublingual gland, 523
and functional importance, 691t DHEA and DHEA sulfate (DHEAS), 656 Submandibular gland, 523
regulation of, 691 glucocorticoids, 655 Submucosal gland cells, 307
Spermatogonia, 683 mineralocorticoids, 655 Substance P, 116, 265, 503, 545
Spermatozoa, 683 receptors and mineralocorticoid Substantia gelatinosa, 118
Spermiation, 690 specificity, 662f Sucrase, 585
Sphincter of Oddi, 494, 518, 562 steroidogenic acute regulatory (StAR) Sucrase-isomaltase, 586
Sphincters, 494, 554 protein, 656 Sucrose, 584, 586
external anal sphincter, 554 synthesis and metabolism, key bush border digestion ad assimilation, 586f
ileocecal valve, 554 enzymes, 658t Sulfonyl urea receptor, 673
internal anal sphincter, 554 target organ cellular effects, 660–661 Sulfur-containing amino acids, 473
lower esophageal sphincter (LES), 495, 508, 544 zona fasciculata, 656 Summation, 89
784 INDEX

Suppression scotoma, 137 Taste cells iodine metabolism in thyroid follicular cell,
Suprachiasmatic nucleus, 188, 615, 623 type I, II, and III, 162 regulation, 635–636
Supraventricular abnormalities, 240–241 Taste modalities, 162 key features of, 636t
Supraventricular arrhythmias, 242f Taste pathways, 161–162, 164f parafollicular cells, 633
Supraventricular tachycardia, 232, 241, 242 Tau protein, 194, 755 regulation and function, 636t
Surface mucous cells, 509 T-cells, 535 thyroglobulin, 633
Surface tension, 319 receptor, 536 thyroid hormone, 731, 732
Sustaining collateral, 111 Tectospinal tracts, 167, 170f Thyroid hormone, 731, 732
SVR. See Systemic vascular resistance (SVR) Temperature-regulating mechanisms, 731f biologic effects, 637–638
Swallowing center, 544 Temporal bone, 149 diseases of, 638
Sweat glands, 730 Temporal lobe, 191, 195, 196 hyperthyroidism, 639
Sylvian fissure, 118, 119, 195 Temporal recruitment, 89 hypothyroidism, 638–639
Sympathetically mediated vasoconstriction, 738 Temporal summation, 39, 73 inotropic and chronotropic effects of, 638
Sympathetic celiac plexus, 405 Tension, 86–88 iodine metabolism, 639–640
Sympathetic chain, 178 developed tension, 88 metabolism, 637, 637f
Sympathetic ganglia, 71 passive tension, 88 organ-specific effects, 638
Sympathetic nerves, 286 total tension, 88 release, regulation, 636
Sympathetic nervous system (SNS), 80, 94, 101, Tension pneumothorax, 330 synthesis, 634–635, 636f
177, 180f, 268, 524, 745 Terminal buttons/boutons, 106 transport and tissue delivery, 637
Sympathetic paravertebral ganglion, 178 Testosterone, 683 Thyroid hyperplasia, 634
Sympathetic preganglionic and postganglionic biosynthesis and metabolism, 688f Thyroiditis, 634, 639
fibers, 179f diseases of, 692–693 chronic, 640
Sympathetic tone, 216 receptor-mediated effects of, 687f Thyroid peroxidase, 636
Sympathetic vasoconstrictor nerves, 267 specific actions of, 689t Thyroid-stimulating hormone (TSH), 615, 623,
Sympathomimetic effects, 638 Tetanic contractions, 89 633, 634, 640, 732
Synapse, 6, 10, 40, 59, 62, 67, 71, 73, 74, 119, 126, Tetanus, 66, 89 Thyroid-stimulating immunoglobulins (TSI), 639
178, 188, 497, 571 toxin, 63 Thyroid storm, 731, 733. See Hyperthyroidism
Synaptic cleft, 11, 59, 68 Tetany, 52, 653 Thyrotoxicosis, 732
Synaptic currents Tetraiodothyronine (T4), 602, 634 thyroid storm, 733
integration, 73–74 Tetrodotoxin (TTX), 53 Thyrotropin releasing hormone (TRH),
Synaptic knobs, 106 Thalamic fasciculus, 171 625, 633
Synaptic plasticity, 192 Thalamic reticular nucleus, 108 Thyrotropin-secreting tumors, 630
Synaptic release, 64–66 Thalamostriatal pathway, 171 Thyroxine, 732
Synaptic transmission Thalamus, 107, 108, 111, 119, 154, 160, 161f, 164f, Thyroxine-binding globulin, 707
depression, 70, 71f 167, 171, 173 Tidal volume (VT), 329, 331
facilitation, 70–71, 71f Thermal nociceptors, 115 Tight junctions, 6, 29
posttetanic potentiation (PTP) of, 71f Thermoreceptors, 115 Time constant, 39
Synaptic vesicle docking, 60f cold and warm receptors, 115 Tinel’s sign, 122
Synaptotagmin, 66 Thermoregulation, 715 Tinnitus, 156
Syncope, 210, 289, 290 Thermostatic set point, 6 Tip links, 150
Syncytium, 93, 205 Thermostat signals, 6 Tissue plasminogen activator (tPA), 209
Syndrome of inappropriate ADH secretion, 620 Theta rhythm, 186 Tissue pressure hypothesis, 266
Synovial fluid, 4 Thiazide diuretics, 443 Titin, 85
Systemic anaphylaxis, 541 Thiazolidinedione drugs, 719 Titratable acidity, 480
Systemic and pulmonary circulations Third degree (total) AV nodal heart block, 221 Toll-like receptors, 536
differences in pressure, 343 Third-degree heart block, 242 Tonic–clonic seizure, 185
Systemic cardiovascular circuit, 276f Thoracic duct, 597–598 Tonic contractions, 548
Systemic hypertension, 292 Thoracoabdominal pump, 299, 747 Tonicity, 28
Systemic vascular resistance (SVR), 258, 343, 638, Threshold, 47 Tonsils, 308
739, 747 Thrombi, 272 Total body water, 200, 755
Systole, 56, 204, 221, 224, 225, 229, 247, Thrombin, 209 Total cholesterol, 707
269, 270 Thromboembolus, 361 Total CO2, 377
Systolic compression, 269 Thrombolytic drugs, 361 Total lung capacity (TLC), 322, 332, 750
Systolic heart failure, 245, 282, 283f Thrombophlebitis, 262 Total peripheral resistance (TPR), 232, 258, 264,
Thrombosis, 360 285, 292, 299, 302, 343, 450, 451, 453, 460
T Thromboxane, 208, 346 Toxic nodules, 635
Tachycardia, 232, 241, 242f, 243f, 301, 350, 361, Thymectomy, 77 Tracheobronchial tree, 307
640, 667 Thyroglobulin, 633, 634 Transcapillary fluid movement, 254–255
Tachykinins, 503 Thyroid autoimmune disease, 634 Transcapillary solute diffusion, 253–254
neurokinin A, 503 Thyroid-binding globulin (TBG), 637 pathways, 253f
substance P, 503 Thyroidectomy, 733 Transcellular processes, 425
Tachyphylaxis, 667 Thyroid gland Transcortin, 658, 707
Tachypnea, 350, 361, 372, 427 calcitonin, 633 Transcytosis, 30
Tactile acuity, 117 colloid, 633 Transducers, 43, 115
Tactile agnosia, 121 euthyroid, 638 Transducin, 44f, 45, 139, 139f
Taenia coli, 553 follicular (epithelial) cells, 633 Transepithelial transport mechanisms, 527
Taste buds, 161–163 functional anatomy Transient ischemic attack (TIA), 210
basal cells, 161 thyroid follicle, 633 Transient receptor potential (TRP), 45
dark cells, 162 hypothalamic–pituitary–thyroid axis, Transient shrinking, 29
intermediate cells, 162 evaluation, 640 Transitional zone, 308
light cells, 162 iodide concentration, mechanism, 635f Transmembrane protein, 2f, 194, 607
 INDEX 785

Transmembrane solute transport, mechanisms, Type II alveolar epithelial cells, 307 Vascular smooth muscle, 263–264
424f Tyrosine hydroxylase (TH), 63, 665 Vascular tone, 264
Transmitter–receptor interaction, 69–70 Tyrosine kinases, 629 Vasculature, 206–207, 257, 267, 336, 404, 445,
Transmitters, 10–11, 59 Tyrosine-tyrosine, 502 451, 563, 619
Transmural distending pressure, 207 blood vessels, control of, 207
Transmural pressure gradient, 265, 314, 343 U Vas deferens, 683
Transport across cell membranes, 26 UDP glucuronyl transferase (UGT), 576 Vasoactive intestinal polypeptide (VIP), 64, 265,
active, 27 Ulcerative, 538 501, 503, 521, 529, 547, 630
facilitated, 27 Ulcerative colitis, 534 Vasopressin, 64, 268, 302
passive, 26–27 Unacclimatized person, 736 Vasovagal syncope, 210, 289
Transport across epithelial cells, 29–30 Uncal herniation, 171 Venoconstriction, 268
Transporters, 16, 23, 424 Uncompensated respiratory alkalosis, 361, 384 Venous admixture, 355
types of, 24f Unidirectional efflux, 27 Venous capacitance, 747
Transport mechanisms Unidirectional influx, 27 Venous function curve, 278
classification, 426 Uniporters (UT family) transports, 434 Venous return, 277, 747f
Transpulmonary pressure, 314, 318, 338–339 Unloading oxygen, at tissues, 366 Venous tone
Transthyretin, 637 Upper endoscopy, 556 control of, 268–269
Transverse tubules, 11 Upper esophageal sphincter, 544 Ventilation–perfusion mismatch, 355
Traumatic pneumothorax, 330 Upper motor neuron lesion, 130 Ventilation-perfusion ratio, 748
Traveler’s diarrhea, 534 Upper motor neurons, 168 matching, 737
Trefoil factors, 507 Urate, 432–433 mismatching, 754
Tremor, 171, 173 Urea, 433–435, 445–447 Ventilation–perfusion ratio line, 355
Tremor at rest, 173 Urea cycle, 578, 579, 580f. See also Krebs- Ventilation-perfusion ratio matching, 737
Treppe, 94 Henseleit cycle Ventilation-perfusion relationships and ratios,
T1R3 family, 163 Urea disposition, 579–580 353–356
T2R family, 163 Ureases, 579 alveolar–arterial oxygen difference, 355–356
Triiodothyronine (T3), 602f, 634, 733 Uremia, 434, 653 increased, causes of, 356t
Trochlear nerves, 143 Ureter, 399f, 400, 403, 414, 435, 444, 447 mismatched, testing for, 355
Tropic hormones, 623 Urethra, 399f, 684 physiologic dead space, 355
Tropomyosin, 83 Uric acid, 208, 398, 405, 432, 435 physiologic shunts, 355
Troponin, 80, 83, 94 Urinary system shunt equation, 355
TnC, 83 anatomy, 399 regional differences in lung, 356–357
TnI, 83 in female, 399f distribution, 357f
TnT, 83 Urobilinogens, 539, 577 ventilation–perfusion ratios, 353–355
Trousseau’s sign, 648 Urobilins, 577 high and low, consequences of, 353–355
Trypsin, 517, 588 Urolithiasis, 653 Ventral anterior/lateral nuclei, 108
Trypsin inhibitors, 517 Ursodeoxycholic acid, 566 Ventral cochlear nuclei, 153
Trypsinogen, 517, 588 Uterine contractility, 708 Ventral posterior lateral (VPL), 108
Tryptophan hydroxylase, 64 Utricle, 147, 149f, 150, 154, 155f nucleus, 118
T score, 652 Ventral posteromedial, 108
TSH receptor, 733 V nucleus, 162
t-SNARE syntaxin, 65 Vagal communication, 503 Ventral respiratory groups (VRG), 386
T-tubule, 86, 94 Vagovagal reflexes, 510, 529 Ventricular abnormalities, 242–244
T-type calcium channels, 55 Vagus nerves, 60, 162, 178, 216, 323, 390, 503, 509, Ventricular arrhythmias, 243f
D-Tubocurare, 70 545, 547, 552f Ventricular depolarization, 238, 239
Tubular maximum (Tm), 418, 426 Valsalva maneuver, 299 and generation of QRS complex, 239f
Tubular osmolality, 447f Valve abnormalities, common, 246 Ventricular fibrillation, 243
Tubular potassium transport, 465t Vanilloid receptor, 45 Ventricular gallop rhythm, 226
Tubular transport mechanisms VR1 for, 45 Ventricular repolarization, 239
limits on rate Vanillylmandelic acid (VMA), 665 and T wave, 239f
Tm and gradient-limited systems, 426–427 Variable obstructions, 326 Ventricular systole, 225
paracellular route, 424 Varicocele, 692 Ventricular tachycardia, 243
proximal tubule reabsorption, 423–426 Vasa recta, 409, 445 Ventrolateral spinothalamic tract, 119–120
transcellular and paracellular reabsorption, 424f Vascular bed, 753 Verapamil, 273
transcellular route, 424 stiffening (see Arteriosclerosis) Vermis, 174, 175
Tubuloglomerular feedback, 456 Vascular control Vertigo, 156, 552
Tubulovesicles, 509, 512 mechanisms, 269 Vesicles, 10, 60
Tufted cells, 159 in specific organs, 269 Vestibular movements, 144
Tumor necrosis factor, 731 cerebral blood flow, 271–272 Vestibular schwannoma, 162
Turbulent flow, 257, 322 coronary blood flow, 269–270 Vestibular system, 154
T wave, 215f, 216, 226, 236, 237, 239, 241, 242, skeletal muscle blood flow, 270–271 Deiters’ nucleus, 154
248, 360 Vascular function, basic, 255 vestibular apparatus, 154
Twitch, 88 arteries and veins, elastic properties, 259 vestibular nuclei, 154
Two-point discrimination test, 117 blood flow velocities, peripheral, 256–258 Vestibulo-ocular reflex, 155
Tympanic membrane, 147 blood volumes, peripheral, 258 Vestibulospinal tracts, 167
Tympanic reflex, 152 and flow in networks of vessels, 255–256 Vibratory sensibility, 120
Type A intercalated cells, 475 resistance, 255–256 Vibrio cholerae, 533
Type B intercalated cells, 476 vascular resistances, peripheral, 258 Vibrissae, 308
Type 1 diabetes mellitus, 394, 587 Vascular pressure Villus structures, 493
Type 2 diabetes mellitus, 292, 406 effect of gravity on, 296f VIP. See Vasoactive intestinal polypeptide (VIP)
Type I alveolar cells, 310 responses to changes in body position, 296–297 Virilization, 657
786 INDEX

Visceral senses, 159 Voltage clamping, 49–51 plasma volume pathway, 457f
Visual acuity, 134 circuit for squid giant axon, 49 thirst and salt appetite, 460–461
Visual agnosia, 121 Voltage-dependent Ca2+ channels, 673 gain and loss, normal routes, 439t
Visual evoked potential test, 112 Voltage-dependent K channels (KV), 49 insensible loss, 439
Visual field exam, 144 topology of monomer, 19f obligatory water loss, 440
Visual pathways, 139–141, 140f Voltage-dependent Na (NaV) channels, 19, 48 reabsorption, 439–440
optic pathways, effect of lesions in, 142 Voltage-gated channels, 213, 485 pathways for, 440f
macular sparing, 142 Voltage-sensitive Ca2+ channels (CaV), 19 Water-soluble vitamins, 429
primary visual cortex, 141–142 Voltage-sensitive channels, 11 assimilation, 590–591
Vital capacity (VC), 325, 332, 334 voltage-sensitive Ca2+ channels (CaV), 11, 19 vitamin B12 (cobalamin), 591
Vitamin A, 139 voltage-sensitive Na channels (NaV), 11, 19 vitamin C, 590
Vitamin B12, 507 role of, 47–49 digestion and absorption, 583
Vitamin D toxicity, 650 Voltage-sensitive Na channels (NaV), 11, 19 Weak acid, 375
Vitamins, 590 role of, 47–49 Weber and Schwabach tests, 154
homeostasis, 590 Voluntary movement, 167, 168f, 169 Wernicke’s area, 195
vitamin A, retinoic acid, 594 Voluntary muscle, 80, 85 White rami communicans, 178
vitamin B12, 507, 591 Vomiting, 156, 279, 379, 394, 474, 489, Willebrand factor, 208
deficiencies, 120 551–552, 563 Wirsung’s duct, 518
gastrointestinal absorption, 591f neural pathways, 552f Withdrawal reflex, 116
vitamin C, 590 (See also Ascorbic acid) v-SNARE synaptobrevin, 65 Wolff-Chaikoff effect, 636
vitamin D, 486, 643 V-type H+ pump, 23, 60 Working memory, 192–194
abnormal levels, 650 Work of breathing, 329, 748
active form, 398 W
analogs, 653 Wallerian degeneration, 66, 111 X
calciferol, 594 Warfarin, 262 Xenobiotics, 560
cellular effects of, 650 Wasting syndrome, 718
1,25-(OH)2D; calcitriol, 487 Water Z
insufficiency, 755 balance concept, regulation, 397–398 Zones of the lung, 346–348
metabolism and physiologic effects at, 649f diuresis, 444 Zone-specific, adrenal steroid hormone synthetic
production, regulation, 398 excretion, regulation, 458 pathway, 657f
synthesis and activation, 649–650 ADH secretion, baroreceptor control, Z score, 652
vitamin E, tocopherol, 594 459–460 Zymogen granules, 518
vitamin K, 594 ADH secretion, osmoreceptor control, 459
Vmax, 88, 96, 96f goals, 449
Voltage-activated L-type CaV channels, 54 mechanism, 459f, 460f