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Dedication to
William Francis Ganong

illiam Francis (“Fran”) Ganong was an outstanding scientist, educator,

W and writer. He was completely dedicated to the field of physiology and

medical education in general. Chairman of the Department of
Physiology at the University of California, San Francisco, for many years, he
received numerous teaching awards and loved working with medical students.
Over the course of 40 years and some 22 editions, he was the sole author of
the best selling Review of Medical Physiology, and a co-author of 5 editions of
Pathophysiology of Disease: An Introduction to Clinical Medicine. He was one
of the “deans” of the Lange group of authors who produced concise medical text
and review books that to this day remain extraordinarily popular in print and
now in digital formats. Dr. Ganong made a gigantic impact on the education of
countless medical students and clinicians.
A general physiologist par excellence and a neuroendocrine physiologist by
subspecialty, Fran developed and maintained a rare understanding of the entire
field of physiology. This allowed him to write each new edition (every 2 years!)
of the Review of Medical Physiology as a sole author, a feat remarked on and
admired whenever the book came up for discussion among physiologists. He
was an excellent writer and far ahead of his time with his objective of distilling a
complex subject into a concise presentation. Like his good friend, Dr. Jack
Lange, founder of the Lange series of books, Fran took great pride in the many
different translations of the Review of Medical Physiology and was always
delighted to receive a copy of the new edition in any language.
He was a model author, organized, dedicated, and enthusiastic. His book was
his pride and joy and like other best-selling authors, he would work on the next
edition seemingly every day, updating references, rewriting as needed, and
always ready and on time when the next edition was due to the publisher. He did
the same with his other book, Pathophysiology of Disease: An Introduction to
Clinical Medicine, a book that he worked on meticulously in the years following
his formal retirement and appointment as an emeritus professor at UCSF.
 Fran Ganong will always have a seat at the head table of the greats of the art
of medical science education and communication. He died on December 23,
2007. All of us who knew him and worked with him miss him greatly.
About the Authors

KIM E. BARRETT

Kim Barrett received her PhD in biological chemistry from University College
London in 1982. Following postdoctoral training at the National Institutes of
Health, she joined the faculty at the University of California, San Diego, School
of Medicine in 1985, rising to the rank of Professor of Medicine in 1996, and
was named Distinguished Professor of Medicine in 2015. From 2006 to 2016,
she also served the University as Dean of the Graduate Division. Her research
interests focus on the physiology and pathophysiology of the intestinal
epithelium, and how its function is altered by commensal, probiotic, and
pathogenic bacteria as well as in specific disease states, such as inflammatory
bowel diseases. She has published more than 250 articles, chapters, and reviews,
and has received several honors for her research accomplishments including the
Bowditch and Davenport Lectureships from the American Physiological Society
(APS), the Bayliss-Starling Lectureship from The Physiological Society of the
UK and Ireland, and the degree of Doctor of Medical Sciences, honoris causa,
from Queens University, Belfast. She has been very active in scholarly editing,
serving currently as the Editor-in-Chief of the Journal of Physiology. She is also
a dedicated and award-winning instructor of medical, pharmacy, and graduate
students, and has taught various topics in medical and systems physiology to
these groups for more than 30 years. Her efforts as a teacher and mentor were
recognized with the Bodil M. Schmidt- Nielson Distinguished Mentor and
Scientist Award from the APS in 2012, and she also served as the 86th APS
President from 2013 to 2014. Her teaching experiences led her to author a prior
volume (Gastrointestinal Physiology, McGraw-Hill, 2005; second edition
published in 2014) and she was honored to have been invited to take over the
helm of Ganong in 2007 for the 23rd and subsequent editions, including this one.

SUSAN M. BARMAN

Susan Barman received her PhD in physiology from Loyola University School
of Medicine in Maywood, Illinois. Afterward she went to Michigan State
University (MSU) where she is currently a Professor in the Department of
Pharmacology/Toxicology and the Neuroscience Program. She is also Chair of
the Institutional Animal Care and Use Committee and serves on the College of
Human Medicine (CHM) Curriculum Development Group for medical school
education. She has had a career-long interest in neural control of
cardiorespiratory function with an emphasis on the characterization and origin of
the naturally occurring discharges of sympathetic and phrenic nerves. She has
published about 150 research articles, invited review articles, and book chapters.
She was a recipient of a prestigious National Institutes of Health MERIT
(Method to Extend Research in Time) Award. She is also a recipient of an MSU
Outstanding University Woman Faculty Award, a CHM Distinguished Faculty
Award, a Distinguished Service Award from the Association of Chairs of
Departments of Physiology, and the Carl Ludwig Distinguished Lecture Award
from the Neural Control of Autonomic Regulation section of the American
Physiological Society (APS). She is also a Fellow of the APS and served as its
85th President. She has also served as a Councilor of APS and Chair of the
Women in Physiology and Section Advisory Committees of the APS. She is also
active in the Michigan Physiological Society, a chapter of the APS.
HEDDWEN L. BROOKS

Heddwen Brooks received her PhD from Imperial College, University of

London and is a Professor in the Departments of Physiology and Pharmacology
at the University of Arizona (UA). Dr. Brooks is a renal physiologist and is best
known for her development of microarray technology to address in vivo
signaling pathways involved in the hormonal regulation of renal function. Dr.
Brooks’ many awards include the American Physiological Society (APS) Lazaro
J. Mandel Young Investigator Award, which is for an individual demonstrating
outstanding promise in epithelial or renal physiology. In 2009, Dr. Brooks
received the APS Renal Young Investigator Award at the annual meeting of the
Federation of American Societies for Experimental Biology. Dr. Brooks served
as Chair of the APS Renal Section (2011–2014) and currently serves as
Associate Editor for the American Journal of Physiology-Regulatory, Integrative
and Comparative Physiology, and on the Editorial Board for the American
Journal of Physiology-Renal Physiology (since 2001). Dr. Brooks has served on
study sections of the National Institutes of Health, the American Heart
Association, and served as a member of the Nephrology Merit Review Board for
the Department of Veterans’ Affairs.

JASON X.-J. YUAN

Jason Yuan received his medical degree from Suzhou Medical College (Suzhou,
China) in 1983, his doctoral degree in cardiovascular physiology from Peking
Union Medical College (Beijing, China), and his postdoctoral training at the
University of Maryland at Baltimore. He joined the faculty at the University of
Maryland School of Medicine in 1993 and then moved to the University of
California, San Diego in 1999, rising to the rank of Professor in 2013. His
research interests center on pathogenic roles of membrane receptors and ion
channels in pulmonary vascular disease. He has published more than 300
articles, reviews, editorials and chapters, and has edited or co-edited nine books.
He has received several honors for his research accomplishments including the
Cournand and Comroe Young Investigator Award, the Established Investigator
Award and the Kenneth D. Bloch Memorial Lectureship from the American
Heart Association; the Guggenheim Fellowship Award from the John Simon
Guggenheim Memorial Foundation; the Estelle Grover Lectureship from the
American Thoracic Society; and the Robert M. Berne Memorial Lectureship
from The American Physiological Society. He is an elected Fellow of the
American Association for the Advancement of Science and an elected Member
of the American Society for Clinical Investigation and the Association of
American Physicians. He has served on many advisory committees including
Chair of the Respiratory Integrative Biology and Translational Research study
section of the National Institutes of Health and Chair of the Pulmonary
Circulation Assembly of the American Thoracic Society. He has also been very
active in scholarly editing serving currently as the Editor-in-Chief of the journal
Pulmonary Circulation and Associate Editor of the American Journal of
Physiology-Cell Physiology. He is a leading editor of the Textbook of Pulmonary
Vascular Disease (Springer, 2011).
Contents

Preface

SECTION I Cellular & Molecular Basis for Medical Physiology

1 General Principles & Energy Production in Medical Physiology

2 Overview of Cellular Physiology

3 Immunity, Infection, & Inflammation

4 Excitable Tissue: Nerve

5 Excitable Tissue: Muscle

6 Synaptic & Junctional Transmission

7 Neurotransmitters & Neuromodulators

SECTION II Central & Peripheral Neurophysiology

8 Somatosensory Neurotransmission: Touch, Pain, & Temperature

9 Smell & Taste

10 Vision
11 Hearing & Equilibrium

12 Reflex & Voluntary Control of Posture & Movement

13 Autonomic Nervous System

14 Electrical Activity of the Brain, Sleep–Wake States, & Circadian Rhythms

15 Learning, Memory, Language, & Speech

SECTION III Endocrine & Reproductive Physiology

16 Basic Concepts of Endocrine Regulation

17 Hypothalamic Regulation of Hormonal Functions

18 The Pituitary Gland

19 The Adrenal Medulla & Adrenal Cortex

20 The Thyroid Gland

21 Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of

Bone

22 Reproductive Development & Function of the Female Reproductive System

23 Function of the Male Reproductive System

24 Endocrine Functions of the Pancreas & Regulation of Carbohydrate

Metabolism

SECTION IV Gastrointestinal Physiology

25 Overview of Gastrointestinal Function & Regulation

26 Digestion & Absorption of Nutrients

27 Gastrointestinal Motility

28 Transport & Metabolic Functions of the Liver

SECTION V Cardiovascular Physiology

29 Origin of the Heartbeat & the Electrical Activity of the Heart

30 The Heart as a Pump

31 Blood as a Circulatory Fluid & the Dynamics of Blood & Lymph Flow

32 Cardiovascular Regulatory Mechanisms

33 Circulation Through Special Regions

SECTION VI Respiratory Physiology

34 Introduction to Pulmonary Structure & Mechanics

35 Gas Transport & pH

36 Regulation of Respiration

SECTION VII Renal Physiology

37 Renal Function & Micturition

38 Regulation of Extracellular Fluid Composition & Volume

39 Acidification of the Urine & Bicarbonate Excretion

Answers to Multiple Choice Questions

Index
Preface

It is difficult to believe that this preface signifies the fourth edition of Ganong’s
Review of Medical Physiology that our author group has overseen, and the 26th
edition overall of this important reference work aimed at medical and other
health professional students. As always, we have tried to maintain the highest
standards of excellence that were promulgated by the original author, Fran
Ganong, over the 46 years where he served, remarkably, as the sole author of the
textbook.
In this new edition, we have cast a fresh eye on the pedagogical approach
taken in each chapter and section, and have focused particularly on including
only material that is of the highest yield. We have thoroughly revised the
learning objectives for every chapter, reorganized and updated the text to ensure
that all objectives are clearly addressed in a logical order, aligned chapter
summaries so that the take-home messages quickly address each learning
objective in turn, and expanded the number of review questions so that readers
also have the ability to check their understanding and retention of every
objective covered. As a discipline evolves and new information emerges, there is
a tendency simply to concatenate these concepts such that chapter structure
degrades inevitably over time. With in-depth discussions amongst the author
team and significant “spring-cleaning,” we believe we have freshened and
simplified the volume while also making sure that important new developments
are incorporated. We are immensely thankful to Erica Wehrwein, PhD, Assistant
Professor of Physiology and an award-winning instructor at Michigan State
University, who took on the task of reviewing the book as a whole and providing
specific and detailed feedback to us on each chapter.
This new edition also welcomes a new member to the author team. We are
delighted to have been able to recruit Jason X.-J. Yuan, MD, PhD, Professor of
Medicine and Physiology as well as Chief of the Division of Translational and
Regenerative Medicine and Associate Vice President for Translational Health
Sciences at the University of Arizona, who has assumed responsibility for some
cell physiology and cardiovascular topics, as well as the respiratory physiology
section. We are particularly excited to have a physician-scientist on the team,
who can guide us overall to focus on material that is of most benefit to those
preparing for a career incorporating patient care. We are most grateful for the
past contributions of Scott Boitano, PhD, whose other obligations meant that he
could no longer serve as an author.
We continue to be gratified by the many colleagues and students who contact
us from all over the world to request clarification of material covered in the text,
or to point out errors or omissions. We are especially grateful to Rajan Pandit,
Lecturer in Physiology at Nepal Medical College, who has painstakingly offered
dozens of suggestions for revision over the years. His efforts, and those of the
many others whom we have not named, allow us to engage in a process of
continual improvement. While, as always, any errors that remain in the book
(inevitable in a complex project such as this) are the sole responsibility of the
authorship team, we greatly value critical input, and urge readers once again to
contact us with any suggestions or critiques. We thank you in advance both for
such feedback, and also for your support of this new edition.

This edition is a revision of the original works of Dr. Francis Ganong.

 SECTION I
Cellular & Molecular Basis for
Medical Physiology

Study of physiological system structure and function, as well as

pathophysiological alterations, has its foundations in physical and chemical laws
and the molecular and cellular makeup of each tissue and organ system.
Ganong’s Review of Medical Physiology is structured into seven sections. This
first section provides an overview of the basic building blocks or bases that
provide the important framework for human physiology. It is important to note
here that the seven chapters in this initial section are not meant to provide an
exhaustive understanding of biophysics, biochemistry, or cellular and molecular
physiology; rather, they are to serve as a reminder of how the basic principles
from these disciplines contribute to medical physiology discussed in later
sections associated with physiological functions of organs and systems.

In the first two chapters of this section, the following basic building blocks are
introduced and discussed: electrolytes; carbohydrates, lipids, and fatty acids;
amino acids and proteins; and nucleic acids. Students are reminded of some of
the basic principles and building blocks of biophysics and biochemistry and how
they fit into the physiologic environment. Examples of direct clinical
applications are provided in the clinical boxes to help bridge the gap between
basic principles and human cell, tissue, and organ functions. These basic
principles are followed up with a discussion of the generic cell and its
components. It is important to realize the cell is the basic functional unit within
the body, and it is the collection and fine-tuned interactions among and between
these fundamental units that allow for proper tissue, organ, and organism
function.

In the third to seventh chapters of this introductory section, we take a cellular

approach to lay a groundwork of understanding groups of cells that interact with
many of the systems discussed in future chapters. The first group of cells
presented contribute to inflammatory reactions in the body. These individual
players, their coordinated behavior, and the net effects of the “open system” of
inflammation in the body are discussed in detail. The second group of cells
discussed are responsible for the excitatory responses in human physiological
function and include both neuronal and muscle cells. A fundamental
understanding of the inner workings of these cells, and how they are controlled
by their neighboring cells, helps the student to understand their eventual
integration into individual systems discussed in later sections.

This first section serves as an introduction, refresher, and quick source of

material to best understand organ functions and systems physiology presented in
the later sections. For detailed understanding of any of the chapters within this
section, several excellent and current textbooks that provide more in-depth
reviews of principles of biochemistry, biophysics, cell physiology, and muscle
and neuronal physiology are provided as resources at the end of each individual
chapter. Students are encouraged to visit these texts for a more thorough
understanding of these basic principles.
CHAPTER 1
General Principles & Energy Production in
Medical Physiology

OBJECTIVES

After studying this chapter, you should be able to:

Define functional units used in measuring physiological properties.

Define pH and buffering.
Understand electrolytes and define diffusion, osmosis, and tonicity.
Define and explain the significance of resting membrane potential.
Understand in general terms the basic building blocks of the cell (eg,
nucleotides, amino acids, carbohydrates, and fatty acids) to cell
metabolism, proliferation, and function.
Understand higher-order structures of the basic building blocks of the cell
(eg, DNA, RNA, proteins, and lipids) to cell replication, proliferation, and
signal transduction.
Understand the basic contributions of the basic building blocks of the cell to
its structure, function, and energy balance.

INTRODUCTION
In unicellular organisms, all vital processes occur in a single cell. As the
evolution of multicellular organisms progressed, various cell groups organized
into tissues, and organs have taken over particular functions. In humans and
other vertebrate animals, there are a number of specialized collections of cells
that consist in organ systems serving for different functions. For example, a
gastrointestinal system to digest and absorb food; a respiratory system to take up
O2 and eliminate CO2; a urinary system to remove wastes; a cardiovascular
system to distribute nutrients, O2, and the products of metabolism; a
reproductive system to perpetuate the species; and nervous and endocrine
systems to coordinate and integrate the functions of the other systems. This book
is concerned with the way these systems function and the way each contributes
to the functions of the body as a whole. This first chapter lays a foundation for
the discussion of these organ systems with a review of basic biophysical and
biochemical principles at the cellular level and the introduction of the molecular
building blocks that contribute to cell physiological function within these organ
systems.

GENERAL PRINCIPLES
THE BODY AS ORGANIZED “SOLUTIONS”
In the average young adult male, 18% of the body weight is protein and related
substances, 7% is mineral, and 15% is fat. The remaining 60% is water. The
distribution of the body water is shown in Figure 1–1A.

FIGURE 1–1 Organization of body fluids and electrolytes into

compartments. A) Body fluids can be divided into intracellular and
extracellular fluid compartments (ICF and ECF, respectively). Their contribution
to percentage body weight (based on a healthy young adult male; slight
variations exist with age and gender) emphasizes the dominance of fluid makeup
of the body. Transcellular fluids, which constitute a very small percentage of
total body fluids, are not shown. Arrows represent fluid movement between
compartments. B) Electrolytes and proteins are unequally distributed among the
body fluids. This uneven distribution is crucial to physiology. Prot−, protein,
which tends to have a negative charge at physiologic pH.

The cells that make up the bodies of all but the simplest multicellular animals,
both aquatic and terrestrial, exist in an “internal sea” of extracellular fluid
(ECF) enclosed within the integument of the animal. From this fluid, the cells
take up O2 and nutrients; into it, they discharge metabolic waste products. The
ECF is more dilute than present-day seawater, but its composition closely
resembles that of the primordial oceans in which, presumably, all life originated.
In animals with a closed vascular system, the ECF is divided into the
interstitial fluid, the circulating blood plasma, and the lymph fluid that
bridges these two domains. The interstitial fluid is the part of the ECF that is
outside the vascular and lymph systems, bathing the cells. The plasma and the
cellular elements of the blood, principally red blood cells, fill the vascular
system, and together they constitute the total blood volume. About one-third of
the total body water is extracellular; the remaining two-thirds is intracellular
(intracellular fluid). Inappropriate compartmentalization of the body fluids can
result in edema (Clinical Box 1–1).

CLINICAL BOX 1–1

Edema
Edema is the buildup of body fluids extracellularly or interstitially in tissues.
The increased fluid is related to an increased leak from the blood and/or
reduced removal by the lymph system. Edema is often observed in the feet,
ankles, and legs, but can happen in many areas of the body in response to
disease, including those of the heart, lung, liver, kidney, or thyroid.

THERAPEUTIC HIGHLIGHTS
The best treatment for edema includes reversing the underlying disorder. Thus,
proper diagnosis of the cause of edema is the primary first step in therapy. More
general treatments include restricting dietary sodium to minimize fluid retention
and using appropriate diuretic therapy.

The intracellular component of the body water accounts for about 40% of
body weight and the extracellular component for about 20%. Approximately
25% of the extracellular component is in the vascular system (plasma = 5% of
body weight) and 75% outside the blood vessels (interstitial fluid = 15% of body
weight). The total blood volume is about 8% of body weight. Flow between
these compartments is tightly regulated.

UNITS FOR MEASURING CONCENTRATION OF

SOLUTES
In considering the effects of various physiologically important substances and
the interactions among them, the number of molecules, electrical charges, or
particles of a substance per unit volume of a particular body fluid are often more
meaningful than simply the weight of the substance per unit volume. For this
reason, physiological concentrations are frequently expressed in moles,
equivalents, or osmoles.

Moles
A mole is the gram-molecular weight of a substance, that is, the molecular
weight (MW) of the substance in grams. Each mole (mol) consists of 6 × 1023
molecules. The millimole (mmol) is 1/1000 of a mole, and the micromole (µmol)
is 1/1,000,000 of a mole. Thus, 1 mol of NaCl = 23 g + 35.5 g = 58.5 g and 1
mmol = 58.5 mg. The mole is the standard unit for expressing the amount of
substances in the SI unit system.
The molecular weight of a substance is the ratio of the mass of one molecule
of the substance to the mass of one-twelfth the mass of an atom of carbon-12.
Because molecular weight is a ratio, it is dimensionless. The dalton (Da) is a unit
of mass equal to one-twelfth the mass of an atom of carbon-12. The kilodalton (1
kDa = 1000 Da) is a useful unit for expressing the molecular mass of proteins.
Thus, for example, one can speak of a 64-kDa protein or state that the molecular
mass of the protein is 64,000 Da. However, because molecular weight is a
dimensionless ratio, it is incorrect to say that the molecular weight of the protein
is 64 kDa.

Equivalents
The concept of electrical equivalence is important in physiology because many
of the solutes in the body are in the form of charged particles. One equivalent
(Eq) is 1 mol of an ionized substance divided by its valence. One mole of NaCl
dissociates into 1 Eq of Na+ and 1 Eq of Cl−. One equivalent of Na+ = 23 g, but
1 Eq of Ca2+ = 40 g ÷ 2 = 20 g. The milliequivalent (mEq) is 1/1000 of 1 Eq.
Electrical equivalence is not necessarily the same as chemical equivalence. A
gram equivalent is the weight of a substance that is chemically equivalent to 8.0
g of oxygen. The normality (N) of a solution is the number of gram equivalents
in 1 liter (L). A 1 N solution of hydrochloric acid (HCl) contains both H+ (1.0 g)
and Cl− (35.5 g) equivalents, = (1.0 g + 35.5 g)/L = 36.5 g/L.

WATER, ELECTROLYTES, & ACID/BASE

The water molecule (H2O) is an ideal solvent for physiological reactions. H2O
has a dipole moment where oxygen slightly pulls away electrons from the
hydrogen atoms and creates a charge separation that makes the molecule polar.
This allows water to dissolve a variety of charged atoms and molecules. It also
allows the H2O molecule to interact with other H2O molecules via hydrogen
bonding. The resulting hydrogen bond network in water allows for several key
properties relevant to physiology: (1) water has a high surface tension, (2) water
has a high heat of vaporization and heat capacity, and (3) water has a high
dielectric constant. In layman’s terms, H2O is an excellent biological fluid that
serves as a solute; it provides optimal heat transfer and conduction of current.
Electrolytes (eg, NaCl) are molecules that dissociate in water to their cation
(Na+) and anion (Cl−) equivalents. Because of the net charge on water
molecules, these electrolytes tend not to reassociate in water. There are many
important electrolytes in physiology, notably Na+, K+, Ca2+, Mg2+, Cl−, and
HCO3−. It is important to note that electrolytes and other charged compounds
(eg, proteins) are unevenly distributed in the body fluids (Figure 1–1B). These
separations play an important role in physiology, for example, in the
establishment of membrane potential and generation of action potential.
pH & BUFFERING
The maintenance of a stable hydrogen ion concentration ([H+]) in body fluids is
essential to life. The pH of a solution is defined as the logarithm to the base 10
of the reciprocal of the H+, that is, the negative logarithm of the [H+]. The pH of
water at 25°C, in which H+ and OH− ions are present in equal numbers, is 7.0
(Figure 1–2). For each pH unit less than 7.0, the [H+] is increased 10-fold; for
each pH unit above 7.0, it is decreased 10-fold. In the plasma of healthy
individuals, pH is slightly alkaline, maintained in the narrow range of 7.35–7.45
(Clinical Box 1–2). Conversely, gastric fluid pH can be quite acidic (on the
order of 3.0) and pancreatic secretions can be quite alkaline (on the order of 8.0).
Enzymatic activity and protein structure are frequently sensitive to pH; in any
given body or cellular compartment, pH is maintained to allow for maximal
enzyme/protein efficiency.

FIGURE 1–2 Proton concentration and pH. Relative proton (H+)

concentrations for solutions on a pH scale are shown.

Molecules that act as H+ donors in solution are considered acids, while those
that tend to remove H+ from solutions are considered bases. Strong acids (eg,
HCl) or bases (eg, NaOH) dissociate completely in water and thus can most
change the [H+] in solution. In physiological compounds, most acids or bases are
considered “weak,” that is, they contribute or remove relatively few H+ from
solution. Body pH is stabilized by the buffering capacity of the body fluids. A
buffer is a substance that has the ability to bind or release H+ in solution, thus
keeping the pH of the solution relatively constant despite the addition of
considerable quantities of acid or base. Of course there are a number of buffers
at work in biological fluids at any given time. All buffer pairs in a homogenous
solution are in equilibrium with the same [H+]; this is known as the isohydric
principle. One outcome of this principle is that by assaying a single buffer
system, we can understand a great deal about all of the biological buffers in that
system.
When acids are placed into solution, there is dissociation of some of the
component acid (HA) into its proton (H+) and free acid (A−). This is frequently
written as an equation:

According to the laws of mass action, a relationship for the dissociation can
be defined mathematically as:

CLINICAL BOX 1–2

Acid–Base Balance and Disorders

Excesses of acid (acidosis) or base (alkalosis) exist when the blood or blood
plasma is outside the normal pH range (7.35–7.45). Such changes impair the
delivery of O2 to and removal of CO2 from tissues. There are a variety of
conditions and diseases that can interfere with pH control in the body and
cause blood pH to fall outside of healthy limits. Acid–base disorders that
result from respiration to alter CO2 concentration are called respiratory
acidosis and respiratory alkalosis. Respiratory acidosis is often caused by
respiratory failure or ventilator failure, while respiratory alkalosis is caused
by alveolar hyperventilation and often found in patients with chronic liver
disease. Nonrespiratory disorders that affect HCO3− concentration are
referred to as metabolic acidosis and metabolic alkalosis. Metabolic acidosis
or alkalosis can be caused by electrolyte disturbances, severe vomiting or
diarrhea, ingestion of certain drugs and toxins, kidney disease, and diseases
that affect normal metabolism (eg, diabetes).
 THERAPEUTIC HIGHLIGHTS
Proper treatments for acid–base disorders are dependent on correctly
identifying the underlying causal process(es). This is especially true when
mixed disorders are encountered. Treatment of respiratory acidosis should be
initially targeted at restoring ventilation, whereas treatment for respiratory
alkalosis is focused on the reversal of the primary causes (eg, alveolar
hyperventilation associated with head injury and anxiety, hypoxemia due to
peripheral chemoreceptor stimulation, pulmonary embolism, and edema).
Bicarbonate (via intravenous injection) is typically used as a treatment for acute
metabolic acidosis. An adequate amount of a chloride salt can restore acid–base
balance to normal over a matter of days for patients with a chloride-responsive
metabolic alkalosis whereas chloride-resistant metabolic alkalosis requires
treatment of the underlying disease.

where Ka is a constant, and the brackets represent concentrations of the

individual species (elements). In layman’s terms, the product of the proton
concentration ([H+]) and the free acid concentration ([A−]) divided by the bound
acid concentration ([HA]) is a defined constant (K). This can be rearranged to
read:

If the logarithm of each side is taken:

Both sides can be multiplied by –1 to yield:

This can be written in a more conventional form known as the Henderson-

Hasselbalch equation:

This relatively simple equation is quite powerful. One thing that can be
discerned right away is that the buffering capacity of a particular weak acid is
best when the pKa of that acid is equal to the pH of the solution, or when:

Similar equations can be set up for weak bases. An important buffer in the
body is carbonic acid (H2CO3). Carbonic acid is a weak acid, and thus is only
partly dissociated into H+ and HCO3−:

If H+ is added to a solution of carbonic acid, the equilibrium shifts to the left

and most of the added H+ is removed from solution. If OH− is added, H+ and OH
− combine, taking H+ out of solution. However, the decrease is countered by

more dissociation of H2CO3, and the decline in H+ concentration is minimized.

A unique feature of HCO3− is the linkage between its buffering ability and the
ability for the lungs to remove CO2 from the body. Other important biological
buffers include phosphates and proteins.

DIFFUSION
The particles (molecules or atoms) of a substance dissolved in a solvent are in
continuous random movement. Diffusion is the process by which a gas or a
substance in a solution expands or moves from a region to another, because of
the motion of its particles, to fill all the available volume. A given particle is
equally likely to move into or out of an area in which it is present in high
concentration. However, because there are more particles in the area of high
concentration, the total number of particles moving to areas of lower
concentration is greater; that is, there is a net flux of solute particles from areas
of high concentration to areas of low concentration. The time required for
equilibrium by diffusion is proportional to the square of the diffusion distance.
The magnitude of the diffusing tendency from one region to another separated
by a boundary (eg, cell membrane, blood-gas barrier) is directly proportional to
the cross-sectional area across which diffusion is taking place and the
concentration gradient, or chemical gradient, which is the difference in
concentration of the diffusing substance divided by the thickness of the boundary
(Fick’s law of diffusion). Thus,
where J is the net rate of diffusion, D is the diffusion coefficient, A is the area,
and Δc/Δx is the concentration gradient. The minus sign indicates the direction
of diffusion. When considering movement of molecules from a higher to a lower
concentration, Δc/Δx is negative, so multiplying by –DA gives a positive value.
The permeabilities of the boundaries across which diffusion occurs in the body
vary, but diffusion is still a major force affecting the distribution of water and
solutes.

OSMOSIS
When a substance is dissolved in water, the concentration of water molecules in
the solution is less than that in pure water, because the addition of solute to water
results in a solution that occupies a greater volume than does the water alone. If
the solution is placed on one side of a membrane that is permeable to water but
not to the solute, and an equal volume of water is placed on the other, water
molecules diffuse down their concentration (chemical) gradient into the solution
(Figure 1–3). This process—the diffusion of solvent molecules into a region in
which there is a higher concentration of a solute to which the membrane is
impermeable—is called osmosis. It is an important factor in physiological
processes. The tendency for movement of solvent molecules to a region of
greater solute concentration can be prevented by applying pressure to the more
concentrated solution. The pressure necessary to prevent solvent migration is the
osmotic pressure of the solution.
Osmotic pressure—like vapor pressure lowering, freezing-point depression,
and boiling-point elevation—depends on the number rather than the type of
particles in a solution; that is, it is a fundamental colligative property of
solutions. In an ideal solution, osmotic pressure (P) is related to temperature and
volume in the same way as the pressure of a gas:
FIGURE 1–3 Diagrammatic representation of osmosis. Water molecules are
represented by small open circles, and solute molecules by large solid circles. In
the diagram on the left, water is placed on one side of a membrane permeable to
water but not to solute, and an equal volume of a solution of the solute is placed
on the other. Water molecules move down their concentration (chemical)
gradient into the solution, and, as shown in the diagram on the right, the volume
of the solution increases. As indicated by the arrow on the right, the osmotic
pressure is the pressure that would have to be applied to prevent the movement
of the water molecules.

where n is the number of particles, R is the gas constant, T is the absolute

temperature, and V is the volume. If T is held constant, it is clear that the
osmotic pressure is proportional to the number of particles in solution per unit
volume of solution. For this reason, the concentration of osmotically active
particles is usually expressed in osmoles. One osmole (Osm) equals the gram-
molecular weight of a substance divided by the number of freely moving
particles that each molecule liberates in solution. For biological solutions, the
milliosmole (mOsm; 1/1000 of 1 Osm) is more commonly used.
If a solute is a nonionizing compound such as glucose, the osmotic pressure is
a function of the number of glucose molecules present. If the solute ionizes and
forms an ideal solution, each ion is an osmotically active particle. For example,
NaCl would dissociate into Na+ and Cl− ions, so that each mole in solution
would supply 2 Osm. One mole of Na2SO4 would dissociate into Na+, Na+, and
SO42− supplying 3 Osm. However, the body fluids are not ideal solutions, and
although the dissociation of strong electrolytes is complete, the number of
particles free to exert an osmotic effect is reduced owing to interactions between
the ions. Thus, it is actually the effective concentration (activity) in the body
fluids rather than the number of equivalents of an electrolyte in solution that
determines its osmotic capacity. This is why, for example, 1 mmol of NaCl per
liter in the body fluids contributes somewhat less than 2 mOsm of osmotically
active particles per liter. The more concentrated the solution, the greater the
deviation from an ideal solution.
The osmolal concentration of a substance in a fluid is measured by the degree
to which it depresses the freezing point, with 1 mol of an ideal solution
depressing the freezing point by 1.86°C. The number of milliosmoles per liter in
a solution equals the freezing point depression divided by 0.00186. The
osmolarity is the number of osmoles per liter of solution (eg, plasma), whereas
the osmolality is the number of osmoles per kilogram of solvent. Therefore,
osmolarity is affected by the volume of the various solutes in the solution and
the temperature, while the osmolality is not. Osmotically active substances in the
body are dissolved in water, and the density of water is 1, so osmolal
concentrations can be expressed as osmoles per liter (Osm/L) of water. In this
book, osmolal (rather than osmolar) concentrations are considered, and
osmolality is expressed in milliosmoles per liter (of water).
Note that although a homogeneous solution contains osmotically active
particles and can be said to have an osmotic pressure, it can exert an osmotic
pressure only when it is in contact with another solution across a membrane
permeable to the solvent but not to the solute.

OSMOLAL CONCENTRATION OF PLASMA:

TONICITY
The freezing point of normal human plasma averages −0.54°C, which
corresponds to an osmolal concentration in plasma of 290 mOsm/L. This is
equivalent to an osmotic pressure against pure water of 7.3 atmospheres (atm).
The osmolality might be expected to be higher than 290 mOsm/L, because the
sum of all the cation and anion equivalents in plasma is over 300 mOsm/L. It is
not this high because plasma is not an ideal solution and ionic interactions
reduce the number of particles free to exert an osmotic effect. Except when there
has been insufficient time after a sudden change in composition for equilibrium
to occur, all fluid compartments of the body are in (or nearly in) osmotic
equilibrium. The term tonicity is used to describe the osmolality of a solution
relative to plasma. Solutions that have the same osmolality as plasma are said to
be isotonic; those with greater osmolality are hypertonic; and those with lesser
osmolality are hypotonic. All solutions that are initially isosmotic with plasma
(ie, that have the same actual osmotic pressure or freezing-point depression as
plasma) would remain isotonic if it were not for the fact that some solutes
diffuse into cells and others are metabolized. Thus, a 0.9% saline solution
remains isotonic because there is no net movement of the osmotically active
particles in the solution into cells and the particles are not metabolized. On the
other hand, a 5% glucose solution is isotonic when initially infused
intravenously, but glucose is metabolized, so the net effect is that of infusing a
hypotonic solution.
It is important to note the relative contributions of the various plasma
components to the total osmolal concentration of plasma. All but about 20 of the
290 mOsm in each liter of normal plasma are contributed by Na+ and its
accompanying anions, principally Cl− and HCO3−. Other cations and anions
make a relatively small contribution. Although the concentration of the plasma
proteins is large when expressed in grams per liter, they normally contribute less
than 2 mOsm/L because of their very high molecular weights. The major
nonelectrolytes of plasma are glucose and urea, which in the steady state are in
equilibrium with cells. Their contributions to osmolality are normally about 5
mOsm/L each but can become quite large in hyperglycemia or uremia. The total
plasma osmolality is important in assessing dehydration, overhydration, and
other fluid and electrolyte abnormalities (Clinical Box 1–3).

NONIONIC DIFFUSION
Some weak acids and bases are quite soluble in cell membranes in the
undissociated form, whereas they cannot cross membranes in the charged (ie,
dissociated) form. Consequently, if molecules of the undissociated substance
diffuse from one side of the membrane to the other and then dissociate, there is
appreciable net movement of the undissociated substance from one side of the
membrane to the other. This phenomenon is called nonionic diffusion.

DONNAN EFFECT
When an ion on one side of a membrane cannot diffuse through the membrane,
the distribution of other ions to which the membrane is permeable is affected in a
predictable way. For example, the negative charge of a nondiffusible anion
hinders diffusion of the diffusible cations and favors diffusion of the diffusible
anions. Consider the situation shown in Figure 1–4, in which the membrane (M)
between compartment X and compartment Y is impermeable to charged proteins
(Prot−) but freely permeable to K+ and Cl−.

FIGURE 1–4 Equilibrium across a cell membrane. Diagram showing two

compartments (X and Y) separated by the membrane (M). Charged K+ and Cl−
are distributed in both compartments, while charged protein (prot−) is only in X
compartment.

CLINICAL BOX 1–3

Plasma Osmolarity & Disease

Unlike plant cells, which have rigid walls, animal cell membranes are
flexible. Therefore, animal cells swell when exposed to extracellular
hypotonicity and shrink when exposed to extracellular hypertonicity. Cells
contain ion channels and pumps that can be activated to offset moderate
changes in osmolarity; however, these can be overwhelmed under certain
pathological conditions. Hyperosmolality can cause coma (hyperosmolar
coma), a prolonged state of deep unconsciousness. Because of the
predominant role of the major solutes and the deviation of plasma from an
ideal solution, one can ordinarily approximate the plasma osmolarity within a
few mOsm/L by using the following formula, in which the constants convert
the clinical units to millimoles of solute per liter:
 BUN is the blood urea nitrogen. The formula is also useful in calling
attention to abnormally high concentrations of other solutes. An observed
plasma osmolarity (measured by freezing-point depression) that greatly
exceeds the value predicted by this formula indicates the presence of a
foreign substance such as ethanol, mannitol (sometimes injected to shrink
swollen cells osmotically), or poisons such as ethylene glycol (component of
antifreeze) or methanol (alternative automotive fuel).

Assume that the concentrations of the anions (eg, Cl−) and of the cations (eg,
K+) on the two sides are initially equal. Cl− diffuses down its concentration
gradient from Y to X, and some K+ moves with the negatively charged Cl−
because of its opposite charge. Therefore,

Furthermore,

that is, more osmotically active particles are on side X (or compartment X) than
on side Y (or compartment Y).
Donnan and Gibbs showed that in the presence of a nondiffusible ion, the
diffusible ions distribute themselves so that at equilibrium their concentration
ratios are equal:

Cross-multiplying,

This is the Gibbs–Donnan equation. It holds for any pair of cations and anions
of the same valence.
The Donnan effect on the distribution of ions has three effects in the body
introduced here and discussed below. First, because of charged proteins (Prot−)
in cells, there are more osmotically active particles in cells than in interstitial or
intercellular fluid, and because animal cells have flexible walls, osmosis would
make them swell and eventually rupture if it were not for the sodium-potassium
adenosine triphosphatase (Na, K ATPase) pumping ions back out of cells. Thus,
normal cell volume and pressure largely depend on Na, K ATPase, also known
as the Na+/K+ pump. Second, because at equilibrium the distribution of permeant
ions across the membrane (m, in the example shown in Figure 1–4) is
asymmetric, an electrical difference exists across the membrane whose
magnitude can be determined by the Nernst equation (see below). In the
example used here (Figure 1–4), side X will be negative relative to side Y. The
charges line up along the membrane, with the concentration gradient for Cl−
exactly balanced by the oppositely directed electrical gradient, and the same
holds true for K+. Third, because there are more proteins in plasma than in
interstitial fluid, there is a Donnan effect on ion movement across the capillary
wall.

FORCES ACTING ON IONS

The forces acting across the cell membrane on each ion can be analyzed
mathematically. Chloride ions (Cl−) are present in higher concentration in the
ECF than in the cell interior, and they tend to diffuse along this concentration
gradient into the cell. The interior of the cell is negative relative to the exterior,
and chloride ions are pushed out of the cell along this electrical gradient. An
equilibrium is reached between Cl− influx and Cl− efflux. The membrane
potential at which this equilibrium exists is the equilibrium potential. Its
magnitude can be calculated from the Nernst equation, as follows:

where
ECl = equilibrium potential for Cl−
R = gas constant
T = absolute temperature
F = the Faraday number (number of coulombs per mole of charge)
ZCl = valence of Cl− (–1)
[Clo−] = Cl− concentration outside the cell
[Cli−] = Cl− concentration inside the cell
 Converting from the natural log to the base 10 log and replacing some of the
constants with numeric values holding temperature at 37°C, the equation
becomes:

Note that in converting to the simplified expression the concentration ratio is

reversed because the –1 valence of Cl− has been removed from the expression.
The equilibrium potential for Cl− (ECl) in the mammalian spinal neuron,
calculated from the standard values listed in Table 1–1, is −70 mV, a value
identical to the typical measured resting membrane potential of −70 mV.
Therefore, no forces other than those represented by the chemical and electrical
gradients need to be invoked to explain the distribution of Cl− across the
membrane.
A similar equilibrium potential can be calculated for K+ (EK; again, at 37°C):

where
EK = equilibrium potential for K+
ZK = valence of K+ (+1)
[Ko+] = K+ concentration outside the cell
[Ki+] = K+ concentration inside the cells R, T, and F as above

In this case, the concentration gradient is outward and the electrical gradient
inward. In mammalian spinal motor neurons, EK is −90 mV (Table 1–1).
Because the resting membrane potential is −70 mV, there is somewhat more K+
in the neurons that can be accounted for by the electrical and chemical gradients.
TABLE 1–1 Concentration of some ions inside and outside mammalian spinal motor neurons.
 The situation for Na+ in the mammalian spinal motor neuron is quite different
from that for K+ or Cl−. The direction of the chemical gradient for Na+ is inward,
to the area where it is in lesser concentration, and the electrical gradient is in the
same direction. ENa is +60 mV (Table 1–1). Because neither EK nor ENa is equal
to the membrane potential, one would expect the cell to gradually gain Na+ and
lose K+ if only passive electrical and chemical forces were acting across the
membrane. However, the intracellular concentrations of Na+ and K+ remain
constant because of selective permeability of the membrane to different ions
(Na+, K+) and the action of the Na, K ATPase that actively transports Na+ out of
the cell and K+ into the cell (against their respective electrochemical gradients).

ESTABLISHMENT OF THE MEMBRANE

POTENTIAL
The distribution of ions across the cell membrane and the nature of this
membrane provide the explanation for the membrane potential. The
concentration gradient for K+ facilitates its movement out of the cell via K+
channels, but its electrical gradient is in the opposite (inward) direction.
Consequently, an equilibrium is reached in which the tendency of K+ to move
out of the cell is balanced by its tendency to move into the cell, and at that
equilibrium there is a slight excess of cations on the outside and anions on the
inside. This condition is maintained by Na, K ATPase, which uses the energy of
ATP to pump K+ back into the cell and keeps the intracellular concentration of
Na+ low. Because the Na, K ATPase moves three Na+ out of the cell for every
two K+ moved in, it also contributes to the membrane potential, and thus is
termed an electrogenic pump. It should be emphasized that the number of ions
responsible for the membrane potential is a minute fraction of the total number
present and that the total concentrations of positive and negative ions are equal
everywhere except along the membrane.

ENERGY PRODUCTION
ENERGY TRANSFER
Energy used in cellular processes and cell function is primarily stored in bonds
between phosphoric acid residues and certain organic compounds. Because the
energy of bond formation in some of these phosphates is particularly high,
relatively large amounts of energy (10–12 kcal/mol) are released when the bond
is hydrolyzed. Compounds containing such bonds are called high-energy
phosphate compounds. Not all organic phosphates are of the high-energy type.
Many, like glucose 6-phosphate, are low-energy phosphates that on hydrolysis
liberate 2–3 kcal/mol. Some of the intermediates formed in carbohydrate
metabolism are high-energy phosphates, but the most important energy-rich
phosphate compound is adenosine triphosphate (ATP). This ubiquitous
molecule, ATP (Figure 1–5), is the energy storehouse of the body. On hydrolysis
to adenosine diphosphate (ADP), it liberates energy directly to such processes as
muscle contraction, active transport, and the synthesis of many chemical
compounds. Loss of another phosphate to form adenosine monophosphate
(AMP) releases more energy.
FIGURE 1–5 Energy-rich adenosine derivatives. Adenosine triphosphate is
broken down into its backbone purine base and sugar (at right) as well as its
high-energy phosphate derivatives (across bottom). (Reproduced with
permission from Murray RK, et al: Harper’s Biochemistry, 28th ed. New York,
NY: McGraw-Hill; 2009.)

Another group of energy-rich, or high-energy, compounds are the thioesters,

the acyl derivatives of mercaptans. Coenzyme A (CoA) is a widely distributed
mercaptan-containing adenine, ribose, pantothenic acid, and thioethanolamine
(Figure 1–6). Reduced CoA (usually abbreviated HS-CoA) reacts with acyl
groups (R–CO–) to form R–CO–S–CoA derivatives. A prime example is the
reaction of HS-CoA with acetic acid to form acetylcoenzyme A (acetyl-CoA), a
compound of pivotal importance in intermediary metabolism. Because acetyl-
CoA has a much higher energy content than acetic acid, it combines readily with
substances in reactions that would otherwise require outside energy. Acetyl-CoA
is therefore often called “active acetate.” From the point of view of energetics,
formation of 1 mol of any acyl-CoA compound is equivalent to the formation of
1 mol of ATP.
FIGURE 1–6 Coenzyme A (CoA) and its derivatives. Left: Formula of
reduced coenzyme A (HS-CoA) with its components highlighted. Right:
Formula for reaction of CoA with biologically important compounds to form
thioesters. R, remainder of molecule.

BIOLOGICAL OXIDATIONS
Oxidation is the combination of a substance with O2, or loss of hydrogen, or
loss of electrons. The corresponding reverse processes are called reduction.
Biological oxidations are catalyzed by specific enzymes. Cofactors (simple ions)
or coenzymes (organic, nonprotein substances) are accessory substances that
usually act as carriers for products of the reaction. Unlike the enzymes, the
coenzymes may catalyze a variety of reactions.
A number of coenzymes serve as hydrogen acceptors. One common form of
biological oxidation is removal of hydrogen from an R–OH group, forming
R=O. In such dehydrogenation reactions, nicotinamide adenine dinucleotide
(NAD+) and dihydronicotinamide adenine dinucleotide phosphate (NADP+) pick
up hydrogen, forming dihydronicotinamide adenine dinucleotide (NADH) and
dihydronicotinamide adenine dinucleotide phosphate (NADPH) (Figure 1–7).
The hydrogen is then transferred to the flavoprotein–cytochrome system,
reoxidizing the NAD+ and NADP+. Flavin adenine dinucleotide (FAD) is formed
when riboflavin is phosphorylated, forming flavin mononucleotide (FMN). FMN
then combines with AMP, forming the dinucleotide. FAD can accept hydrogens
in a similar fashion, forming its hydro (FADH) and dihydro (FADH2)
derivatives.

FIGURE 1–7 Structures of molecules important in oxidation–reduction

reactions to produce energy. Top: Formula of the oxidized form of
nicotinamide adenine dinucleotide (NAD+). Nicotinamide adenine dinucleotide
phosphate (NADP+) has an additional phosphate group at the location marked by
the asterisk. Bottom: Reaction by which NAD+ and NADP+ become reduced to
form NADH and NADPH. R, remainder of molecule; R′, hydrogen donor.

The flavoprotein–cytochrome system is a chain of enzymes that transfers

hydrogen to oxygen, forming water. This process occurs in the mitochondria.
Each enzyme in the chain is reduced and then reoxidized as the hydrogen is
passed down the line. Each of the enzymes is a protein with an attached
nonprotein prosthetic group. The final enzyme in the chain is cytochrome c
oxidase, which transfers hydrogens to O2, forming H2O. It contains two atoms of
Fe and three of Cu and has 13 subunits.
The principal process by which ATP is formed in the body is oxidative
phosphorylation. This process harnesses the energy from a proton gradient
across the mitochondrial membrane to produce the high-energy bond of ATP
(see Figure 2–4 for more detail). Ninety percent of the O2 consumption, the
amount of oxygen used by the body per minute, in the basal state is in
mitochondria, and 80% of the mitochondrial O2 consumption is coupled to ATP
synthesis.
ATP is utilized throughout the cell, with the bulk used in a handful of
processes: approximately 27% is used for protein synthesis, 24% by Na, K
ATPase to help set membrane potential, 9% by gluconeogenesis, 6% by Ca2+
ATPase to maintain a low cytosolic Ca2+ concentration, 5% by myosin ATPase,
and 3% by ureagenesis.

MOLECULAR BUILDING BLOCKS

NUCLEOSIDES, NUCLEOTIDES, & NUCLEIC
ACIDS
Nucleosides contain a sugar linked to a nitrogen-containing base. The
physiologically important bases, purines and pyrimidines, have ring structures
(Figure 1–8). These structures are bound to a sugar, either ribose or 2-
deoxyribose, to complete the nucleoside. When inorganic phosphate is added to
the nucleoside, a nucleotide is formed (Figure 1–9). Nucleosides and
nucleotides form the backbone for RNA and DNA, as well as a variety of
coenzymes and regulatory molecules of physiological importance (eg, NAD+,
NADP+, and ATP) (Table 1–2). Nucleic acids in the diet are digested and their
constituent purines and pyrimidines absorbed, but most of the purines and
pyrimidines are synthesized from amino acids, principally in the liver. The
nucleotides and RNA and DNA are then synthesized. RNA is in dynamic
equilibrium with the amino acid pool, but DNA, once formed, is metabolically
stable throughout life. The purines and pyrimidines released by the breakdown
of nucleotides may be reused or catabolized. Minor amounts are excreted
unchanged in the urine.
FIGURE 1–8 Principal physiologically important purines and pyrimidines.
Purine and pyrimidine structures are shown next to representative molecules
from each group. Oxypurines and oxypyrimidines may form enol derivatives
(hydroxypurines and hydroxypyrimidines) by migration of hydrogen to the
oxygen substituents.

FIGURE 1–9 Synthesis and breakdown of uric acid. Adenosine is converted

to hypoxanthine, which is then converted to xanthine, and xanthine is converted
to uric acid. The latter two reactions are both catalyzed by xanthine oxidase.
Guanosine is converted directly to xanthine, while 5-PRPP and glutamine can be
converted to uric acid.
TABLE 1–2 Purine- and pyrimidine-containing compounds.

The pyrimidines are catabolized to the β-amino acids, β-alanine, and β-

aminoisobutyrate. These amino acids have their amino group on β-carbon, rather
than the α-carbon typical to physiologically active amino acids. Because β-
aminoisobutyrate is a product of thymine degradation, it can serve as a measure
of DNA turnover. The β-amino acids are further degraded to CO2 and NH3.
Uric acid is formed by the breakdown of purines and by direct synthesis from
5-phosphoribosyl pyrophosphate (5-PRPP) and glutamine (Figure 1–9). In
humans, uric acid is excreted in the urine, but in other mammals, uric acid is
further oxidized to allantoin before excretion. The normal blood uric acid level
in humans is approximately 4 mg/dL (0.24 mmol/L). In the kidney, uric acid is
filtered, reabsorbed, and secreted. Normally, 98% of the filtered uric acid is
reabsorbed and the remaining 2% makes up approximately 20% of the amount
excreted. The remaining 80% comes from the tubular secretion. The uric acid
excretion on a purine-free diet is about 0.5 g/24 h and on a regular diet about 1
g/24 h. Excess uric acid in the blood or urine is a characteristic of gout (Clinical
Box 1–4).
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frowning behind, looks, from across the firth, absolutely like a
tasteful little haunt of the capricious spirit of romance.
Well, between this road on the lowland side of the firth, and the
water’s-edge, and before it winds off round by the romantic seat of
Sir Michael Shaw Stewart, farther up, there stand, or stood, two or
three small fishing cottages which, from the hills nearly over them,
looked just like white shells, of a large size, dropped fancifully down
upon the green common between the hills and the road. In these
cottages, it was observed, the fishermen had numerous families,
who, while young, assisted them in their healthful employment; and
that the girls, of which there were a number, were so wild in their
contented seclusion, that if any passenger on the road stopped to
observe them, as they sat in groups on the green mending their
father’s nets, they would take alarm, and rise and run off like fawns,
and hide among the rocks by the sea, or trip back into the cottages.
Now it happened, once on a time, that a great event took place to one
of the cottager’s daughters, which, for a long period, deranged and
almost destroyed the happy equality in which they had hitherto lived;
and becoming the theme of discourse and inquiry concerning things
beyond the sphere of the fisher people and all their neighbours as far
as Gourock, introduced among them no small degree of ambition
and discontent.
There was one of the fishermen, a remarkably decent, well
disposed Highlandman, from the opposite shore of Argyleshire,
named Martin M‘Leod, and he had two daughters, the youngest of
which, as was no uncommon case, turned out to be remarkably and
even delicately beautiful.
But nobody ever saw or thought anything about the beauty of
Catherine M‘Leod, except it might be some of the growing young
men in the neighbouring cottages, several of whom began, at times,
to look at her with a sort of wonder, and seemed to feel a degree of
awe in her company; while her family took an involuntary pride in
her beyond all the others; and her eldest sister somehow imitated her
in every thing, and continually quoted her talk, and trumpeted about
among the neighbours what was said and done by “my sister Kate.”
Things continued in this way as Kate grew to womankind; and she
was the liveliest little body about the place, and used to sing so
divertingly at the house-end, as she busied herself about her father’s
fishing gear, and ran up and down “among the brekans on the brae,”
behind the cottages, or took her wanderings off all the way to the
Clough lighthouse at the point. I say things continued in this way
until a gentleman, who, it turned out, was all the way from London,
came to lodge in Greenock, or Gourock, or Inverkip, or somewhere
not very far distant; and, being a gentleman, and, of course, at liberty
to do every sort of out-of-the-way thing that he pleased, he got a
manner of coming down and wandering about among the cottages,
and asking questions concerning whatever he chose of the fishermen;
and then it was not long until he got his eyes upon Kate.
“The gentleman,” as her sister used to tell afterwards, “was
perfectly ill, and smitten at once about our Kate. He was not able,”
she said, “to take the least rest, but was down constantly about us for
weeks; and then he got to talking to and walking with Kate, she
linking her arm in his beneath the hill, just as it had been Sir Michael
Stewart and my lady; and then such presents as he used to bring for
her, bought in the grand shop of Bailie Macnicol, at Greenock;
gowns, and shawls, and veils, and fine chip hats, never speaking of
ribbons, and lace edging, and mob caps—perfectly beautiful.”
The whole of the fishermen’s daughters became mad with envy of
poor Kate, and admiration of her new dress, which some said was
mostly bought by her father after all, who wanted to have his
daughter made a lady of; and now nothing was heard in the hamlet
but murmurings and discontented complaints; every girl looking at
herself in the little cracked glass that her father used to shave by, to
see if she were pretty, and wishing and longing, not only for a lover of
her own, but even for a gentleman. So, as matters grew serious, and
the gentleman was fairly in love, old Martin M‘Leod, who looked
sharply after Kate, behoved to have sundry conversations with the
gentleman about her; and masters being appointed to teach her right
things, which the fisher folks never heard of, but which were to turn
her into a lady, Kate and the gentleman, after a time, were actually
married in Greenock new church, and set off for London.
During all this time, there were various opinions among the fisher
people, how that Kate never was particularly in love with the
gentleman; and some even said that she was in love with somebody
else (for pretty maidens must always be in love), or, at least, that
some of the youths of the neighbourhood were in love with her; but
then the old folks said, that love was only for gentle people who could
afford to pay for it; and that when a gentleman was pleased to fall in
love, no one had a right to say him nay, or pretend to set up against
him. Some of the young women, to be sure, ventured to contest this
doctrine, and cited various cases from the authority of printed
ballads bought at the Greenock fair, at a halfpenny each; and also
from the traditionary literature of Argyleshire, which was couched in
the mellifluous numbers of the Gaelic language; but, however this
might be, the fame of Catherine M‘Leod’s happy marriage and great
fortune was noised abroad exceedingly, among the fisher people
throughout these coasts, as well as about Gourock and all the parts
adjacent.
As to the gentleman, it was found out that his name was Mr
Pounteney, and that little Kate M‘Leod was now Mrs Pounteney, and
a great London lady, but what quality of a gentleman Mr Pounteney
really was, was a matter of much controversy and discussion. Some
said that he was a great gentleman, and others thought that, from
various symptoms, he was not a very great gentleman; some went so
far as to say he was a lord or a prince, while others maintained that
he was only a simple esquire.
Nothing, therefore, could be talked of wherever Flora M‘Leod
went, but about “my sister Kate;” and she was quite in request
everywhere, because she could talk of the romantic history and
happy fortune of her lucky sister. Mrs Pounteney’s house in London,
therefore, Mrs Pounteney’s grand husband, and Mrs Pounteney’s
coach, excited the admiration and the discontent of all the
fishermen’s daughters, for many miles round this romantic seacoast,
and these quiet cottages under the hills, where the simple people live
upon their fish, and did not know that they were happy. Many a long
summer’s day, as the girls sat working their nets on a knoll towards
the sea, the sun that shone warm upon their indolent limbs on the
grass, and the breeze that blew from the firth, or swept round from
the flowery woods of Ardgowan, seemed less grateful and delicious,
from their discontented imaginings about the fortune of Mrs
Pounteney; and many a sweet and wholesome supper of fresh boiled
fish was made to lose its former relish, or was even embittered by
obtrusive discourse about the fine wines and the gilded grandeur of
“my sister Kate.” Even the fisher lads in the neighbourhood—fine
fearless youths—found a total alteration in their sweethearts; their
discourse was not relished, their persons were almost despised; and
there was now no happiness found for a fisherman’s daughter, but
what was at least to approach to the state of grandeur and felicity so
fortunately obtained by “my sister Kate.”
The minds of Kate’s family were so carried by her great fortune,
that vague wishes and discontented repinings followed their constant
meditations upon her lucky lot. Flora had found herself above
marrying a fisherman; and a young fellow called Bryce Cameron,
who had long waited for her, and whose brother, Allan, was once a
sweetheart of Kate’s herself, being long ago discarded; and she, not
perceiving any chances of a gentleman making his appearance to
take Bryce’s place, became melancholy and thoughtful; she began to
fear that she was to have nobody, and her thoughts ran constantly
after London and Mrs Pounteney. With these anxious wishes, vague
hopes began to mix of some lucky turn to her own fortune, if she
were only in the way of getting to be a lady; and at length she formed
the high wish, and even the adventurous resolve, of going all the way
to London, just to get one peep at her sister’s happiness.
When this ambition seized Flora M‘Leod, she let the old people
have no rest, nor did she spare any exertion to get the means of
making her proposed pilgrimage to London. In the course of a
fortnight from its first serious suggestion, she, with a gold guinea in
her pocket, and two one-pound notes of the Greenock Bank, besides
other coins and valuables, and even a little old-fashioned Highland
brooch, with which the quondam lover of her sister, Allan Cameron,
had the temerity to intrust to her, to be specially returned into the
hand of the great lady when she should see her, besides a hundred
other charges and remembrances from the neighbours, she set off
one dewy morning in summer, carrying her shoes and stockings in
her hand, to make her way to London, to get a sight of everything
great, and particularly of her happy sister Kate.
Many a weary mile did Flora M‘Leod walk, and ride, and sail,
through unknown places, and in what she called foreign parts; for
strange things and people met her eye, and long dull regions of
country passed her like a rapid vision, as she was wheeled towards
the great capital, and proper centre of England. After travelling to a
distance that was to her perfectly amazing, she was set down in
London, and inquired her way, in the best English she could
command, into one of those long brick streets, of dark and dull
gentility, to which she was directed; and after much trouble and
some expense, at length found the door of her sister’s house. She
stood awhile considering, on the steps of the mansion, and felt a sort
of fear of lifting the big iron knocker that seemed to grin down upon
her; for she was not in the habit of knocking at great folk’s doors, and
almost trembled lest somebody from within would frown her into
nothing, even by their high and lofty looks.
And yet she thought the house was not so dreadfully grand after
all;—not at all such as she had imagined, for she had passed houses
much bigger and grander than this great gentleman’s; it was not even
the largest in its own street, and looked dull and dingy, and shut up
with blinds and rails, having a sort of melancholy appearance.
But she must not linger, but see what was inside. She lifted up the
iron knocker, and as it fell the very clang of it, and its echo inside,
smote upon her heart with a sensation of strange apprehension. A
powdered man opened it, and stared at her with an inquisitive and
impertinent look, then saucily asked what she wanted. Flora
courtesied low to the servant from perfect terror, saying she wanted
to see Mrs Pounteney.
“And what can you want with Mrs Pounteney, young woman, I
should like to know?” said the fellow; for Flora neither looked like a
milliner’s woman nor any other sort of useful person likely to be
wanted by a lady.
Flora had laid various pretty plans in her own mind, about taking
her sister by surprise, and seeing how she would look at her before
she spoke, and so forth; at least she had resolved not to affront her
by making herself known as her sister before the servants; but the
man looked at her with such suspicion, and spoke so insolently, that
she absolutely began to fear, from the interrogations of this fellow,
that she would be refused admittance to her own sister, and was
forced to explain and reveal herself before the outer door was fully
opened to her. At length she was conducted, on tiptoe, along a
passage, and then upstairs, until she was placed in a little back
dressing-room. The servant then went into the drawing-room, where
sat two ladies at opposite sides of the apartment, there to announce
Flora’s message.
 On a sofa, near the window, sat a neat youthful figure, extremely
elegantly formed, but petite, with a face that need not be described,
further than that the features were small and pretty, and that, as a
whole, it was rich in the nameless expression of simple beauty. Her
dress could not have been plainer, to be of silk of the best sort; but
the languid discontent, if not melancholy, with which the female, yet
quite in youth, gazed towards the window, or bent over a little silk
netting with which she carelessly employed herself, seemed to any
observer strange and unnatural at her time of life. At a table near the
fire was seated a woman, almost the perfect contrast to this
interesting figure, in the person of Mr Pounteney’s eldest sister, a
hard-faced, business-like person, who, with pen and ink before her,
seemed busy among a parcel of household accounts, and the
characteristic accompaniment of a bunch of keys occasionally
rattling at her elbow.
The servant approached, as if fearful of being noticed by “the old
one,” as he was accustomed to call Miss Pounteney, and in a half
whisper intimated to the little figure that a female wanted to see her.
“Eh! what!—what is it you say, John?” cried the lady among the
papers, noticing this manœuvre of the servant.
“Nothing, Madam; it is a person that wants my lady.”
“Your lady, sirrah; it must be me!—Eh! what!”
“No, Madam; she wants to see Mrs Pounteney particularly.”
“Ah, John!” said the little lady on the sofa; “just refer her to Miss
Pounteney. There is nobody can want me.”
“Wants to see Mrs Pounteney particularly!” resumed the sister-in-
law: “how dare you bring in such a message, sirrah? Mrs Pounteney
particularly, indeed! Who is she, sirrah! Who comes here with such a
message while I am in the house?”
“You must be mistaken, John,” said the little lady sighing, who was
once the lively Kate M‘Leod of the fishing cottage in Scotland; “just
let Miss Pounteney speak to her, you need not come to me.”
“No, madam,” said the servant, addressing Miss Pounteney, the
natural pertness of his situation now returning to overcome his
dread of “the old one.” “This young person wants to see my mistress
directly, and I have put her into her dressing-room; pray, ma’am,
go,” he added, respectfully, to the listless Kate.
 “Do you come here to give your orders, sirrah?” exclaimed Miss
Pounteney, rising like a fury, and kicking the footstool half way
across the room, “and to put strange people of your own accord into
any dressing-room in this house! and to talk of your mistress, and
wanting to speak to her directly, and privately, while I am here! I
wonder what sister Becky would say, or Mr Pounteney, if he were at
home!”
“Who is it, John? Do just bring her here, and put an end to this!”
said Kate, imploringly, to the man.
“Madam,” said John at last to his trembling mistress, “it is your
sister!”
“Who, John?” cried Kate, starting to her feet; “my sister Flora—my
own sister, from Clyde side! Speak, John, are you sure?”
“Yes, Madam, your sister from Scotland.”
“Oh, where is she, where is she? Let me go!”
“No, no; you must be mistaken, John,” said the lady with the keys,
stepping forward to interrupt the anxious Kate. “John, this is all a
mistake,” she added, smoothly; “Mrs Pounteney has no sister! John,
you may leave the room;” and she gave a determined look to the
other sister, who stood astonished.
The moment the servant left the room, Miss Pounteney came
forward, and stood in renewed rage over the fragile, melancholy
Kate, and burst out with “What is this, Kate? Is it really possible,
after what you know of my mind, and all our minds, that you have
dared to bring your poor relations into my brother’s house? That it is
not enough that we are to have the disgrace of your mean
connections, but we are to have your sisters and brothers to no end
coming into the very house, and sending up their beggarly names
and designations by the very servants! Kate, I must not permit this. I
will not—I shall not;” and she stamped with rage.
“Oh, Miss Pounteney,” said Kate, with clasped hands, “will you not
let me go and see my sister? Will you just let me go and weep on the
neck of my poor Flora? I will go to a private place—I will go to
another house, if you please; I will do anything when I return to you,
if I ever return, for I care not if I never come into this unhappy house
more!” and, uttering this, almost with a shriek, she burst past the two
women, and ran through the rooms to seek her sister.
 Meantime, Flora had sat so long waiting, without seeing her sister,
that she began to feel intense anxiety; and, fancying her little Kate
wished to forget her, because she was poor, had worked herself up
into a resolution of assumed coldness, when she heard a hurried
step, and the door was instantly opened. Kate paused for a moment
after her entrance, and stood gazing upon the companion of her
youth, with a look of such passionate joy, that Flora’s intended
coldness was entirely subdued; and the two sisters rushed into each
other’s arms in all the ecstacy of sisterly love.
“Oh, Flora, Flora! my dear happy Flora!” cried Kate, when she
could get words, after the first burst of weeping; “have you really
come all the way to London to see me?—poor me!” and her tears and
sobs were again like to choke her. “Kate—my dear little Kate!” said
Flora, “this is not the way I expected to find you. Do not greet so
dreadfully; surely you are not happy, Kate?”
“But you are happy,” said Kate, weeping. “And how is my good
Highland father, and mother, and my brother Daniel? Ah! I think,
Flora, your clothes have the very smell of the seashore, and of the
bark of the nets, and of the heather hills of Argyleshire. Alas the
happy days you remind me of, Flora!”
“And so, Kate, you are not so very happy, after all,” said Flora,
looking incredulously in her face; “and you are so thin, and pale, and
your eyes are so red; and yet you have such a grand house, Kate! Tell
me if you are really not happy.”
“I have no house, Flora,” said Kate, after a little, “and, I may say,
no husband. They are both completely ruled by his two vixen sisters,
who kept house for him before he married me, and still have the
entire ascendancy over him. My husband, too, is not naturally good
tempered; yet he once loved me, and I might enjoy some little
happiness in this new life, if he had the feeling, or the spirit, to treat
me as his wife, and free himself and the house from the dominion of
his sisters, especially the eldest. But I believe he is rather
disappointed in his ambitious career, and in the hopes he
entertained of matches for his sisters, and he is somewhat sour and
unhappy; and I have to bear it all, for he is afraid of these women;
and I, the youngest in the family, and the only one who has a chance
of being good tempered, am, on account of my low origin, forced to
bear the spleen of all in this unhappy house.”
 “But, Kate, surely your husband would not behave so bad as to cast
up to you that your father was a fisherman, when he took you from
the bonnie seaside himself, and when he thought himself once so
happy to get you?”
“Alas! he does indeed!—too often—too often—when he is crossed
abroad, and when his sisters set him on; and it so humbles me, Flora,
when I am sitting at his table, that I cannot lift my head; and I am so
sad, and so heart-broken among them all!”
“Bless me! and can people be really so miserable,” said Flora,
simply, “who have plenty of money, and silk dresses to wear every
day they rise?”
“It is little you know, my happy Flora, of artificial life here in
London,” said Kate, mournfully. “As for dress, I cannot even order
one but as my sister-in-law chooses; and as for happiness, I have left
it behind me on the beautiful banks of the Clyde. O that I were there
again!”
“Poor little Kate!” said Flora, wistfully looking again in her sister’s
face; “and is that the end of all your grand marriage, that has set a’
the lasses crazy, from the Fairlie Roads to Gourock Point? I think I’ll
gang back and marry Bryce Cameron after a’.”
“Is Allan Cameron married yet?” said Kate, sadly. “When did you
see blithe and bonnie Allan Cameron?—Alas the day!”
“He gave me this brooch to return to you, Kate,” said Flora, taking
the brooch out of her bosom. “I wish he had not gien it to me for you,
for you’re vexed enough already.”
“Ah! well you may say I am vexed enough,” said she, weeping and
contemplating the brooch. “Tell Allan Cameron that I am sensible I
did not use him well—that my vain heart was lifted up; but I have
suffered for it; many a sad and sleepless night I have lain in my bed,
and thought of the delightful days I spent near my father’s happy
cottage in Scotland, and about you, and about Allan. Alas! just tell
him not to think more of me; for I am a sad and sorry married
woman, out of my own sphere, and afraid to speak to my own people,
panting my heart out and dying by inches, like the pretty silver fish
that floundered on the hard stones, after my father had taken them
out of their own clear water.”
 “God help you, Kate!” said Flora, rising; “you will break my heart
with grief about you. Let me out of this miserable house! Let me
leave you and all your grandeur, since I cannot help you; and I will
pray for you, my poor Kate, every night at my bedside, when I get
back to the bonnie shore of Argyleshire.”
Sad was the parting of the two weeping sisters, and many a kiss of
fraternal affection embittered, yet sweetened, the hour; and anxious
was Flora M‘Leod to turn her back upon the great city of London,
and to journey northwards to her own home in Scotland.
It was a little before sundown, on a Saturday evening, shortly after
this, that a buzz of steam let off at the Mid Quay of Greenock,
indicated that a steamboat had come in; and it proved to be from the
fair seaport of Liverpool, having on board Flora M‘Leod, just down
from London. The boat as it passed had been watched by the
cottagers where she lived up the Firth; and several of them, their
day’s work being over, set out towards the Clough to see if there was
any chance of meeting Flora.
Many were the congratulations, and more the inquiries, when they
met Flora, lumbering homewards with her bundle and her umbrella,
weary and looking anxiously out for her own sweet cottage by Clyde
side. “Ah, Flora! is this you!” cried the whole at once; “and are you
really here again! And how is your sister, and all the great people in
London? And, indeed, it is very good of you not to look the least
proud, after coming from such a grand place!”
With such congratulations was Flora welcomed again among the
light-hearted fisher people in the West of Scotland. But it was
observed that her tone was now quite altered, and her own humble
contentment had completely returned. In short, to bring our story to
a close, she was shortly after married to Bryce Cameron, and various
other marriages soon followed; for she gave such an account of what
she had seen with her eyes, that a complete revolution took place in
the sentiments of the whole young people of the neighbourhood.
It was observed in the hamlet that the unhappy Mrs Pounteney
was never named after this by any but with a melancholy shake of the
head; the ambition of the girls to get gentlemen seemed quite
extinguished, and Flora in time began to nurse children of her own in
humble and pious contentment.—The Dominie’s Legacy.
 WAT THE PROPHET.

By James Hogg, “The Ettrick Shepherd.”

About sixty years ago[4] there departed this life an old man, who,
for sixty years previous to that, was known only by the name of Wat
the Prophet. I am even uncertain what his real surname was, though
he was familiarly known to the most of my relatives of that day, and I
was intimately acquainted with his nephew and heir, whose name
was Paterson,—yet I hardly think that was the prophet’s surname,
but that the man I knew was a maternal nephew. So far, I am
shortcoming at the very outset of my tale, for in truth I never heard
him distinguished by any other name than Wat the Prophet.[5]
4. This interesting account of a very extraordinary character was contributed
to the Edinburgh Literary Journal in 1829.
5. The old prophet’s surname was Laidlaw, being of a race that has produced
more singular characters than any of our country.
He must have been a very singular person in every respect. In his
youth he was so much more clever and acute than his fellows, that he
was viewed as a sort of phenomenon, or rather “a kind of being that
had mair airt than his ain.” It was no matter what Wat tried, for
either at mental or manual exertion he excelled; and his gifts were so
miscellaneous, that it was no wonder his most intimate
acquaintances rather stood in awe of him. At the sports of the field,
at the exposition of any part of Scripture, at prayer, and at
mathematics, he was altogether unequalled. By this, I mean in the
sphere of his acquaintance in the circle in which he moved, for he
was the son of a respectable farmer who had a small property. In the
last-mentioned art his comprehension is said to have been truly
wonderful. He seemed to have an intuitive knowledge of the science
of figures from beginning to end, and needed but a glance at the rules
to outgo his masters.
But this was not all. In all the labours of the field his progress was
equally unaccountable. He could with perfect ease have mown as
much hay as two of the best men, sown as much, reaped as much,
shorn as many sheep, and smeared as many, and with a little extra
exertion could have equalled the efforts of three ordinary men at any
time. As for ploughing, or any work with horses, he would never put
a hand to it, for he then said he had not the power of the labour
himself. However unaccountable all this may be, it is no fabrication;
I have myself heard several men tell, who were wont to shear and
smear sheep with him, when he was a much older man than they,
that even though he would have been engaged in some fervent
demonstration, in spite of all they could do, “he was aye popping off
twa sheep, or maybe three, for their ane.”
I could multiply anecdotes of this kind without number, but these
were mere atoms of the prophet’s character—a sort of excrescences,
which were nevertheless in keeping with the rest, being matchless of
their kind. He was intended by his parents for the Church—that is
the Church of the Covenant, to which they belonged. I know not if
Wat had consented thereto, but his education tended that way.
However, as he said himself, he was born for a higher destiny, which
was to reveal the future will of God to mankind for ever and ever. I
have been told that he committed many of his prophecies to writing;
and I believe it, for he was a scholar, and a man of rather
supernatural abilities; but I have never been able to find any of them.
I have often heard fragments of them, but they were recited by
ignorant country people, who, never having understood them
themselves, could not make them comprehensible to others. But the
history of his call to the prophecy I have so often heard, that I think I
can state the particulars, although a little confused in my recollection
of them.
This event occurred about this time one hundred years ago, on an
evening in spring, as Wat was going down a wild glen, which I know
full well. “I was in a contemplative mood,” he said (for he told it to
any that asked him), “and was meditating on the mysteries of
redemption, and doubting, grievously doubting, the merits of an
atonement by blood; when, to my astonishment in such a place, there
was one spoke to me close behind, saying, in the Greek language, ‘Is
it indeed so? Is thy faith no better rooted?’
“I looked behind me, but, perceiving no one, my hair stood all on
end, for I thought it was a voice from heaven; and, after gazing into
the firmament, and all around me, I said fearfully, in the same
language, ‘Who art thou that speakest?’ And the voice answered me
again, ‘I am one who laid down my life, witnessing for the glorious
salvation which thou art about to deny; turn, and behold me!’
“And I turned about, for the voice seemed still behind me, turn as I
would, and at length I perceived dimly the figure of an old man, of
singular aspect and dimensions, close by me. His form was
exceedingly large and broad, and his face shone with benignity; his
beard hung down to his girdle, and he had sandals on his feet, which
covered his ankles. His right arm and his breast were bare, but he
had a crimson mantle over his right shoulder, part of which covered
his head, and came round his waist. Having never seen such a figure
or dress, or countenance before, I took him for an angel, sent from
above to rebuke me; so I fell at his feet to worship him, or rather to
entreat forgiveness for a sin which I had not power to withstand. But
he answered me in these words: ‘Rise up, and bow not to me, for I
am thy fellow-servant, and a messenger from Him whom thou hast
in thy heart denied. Thou shalt worship the Lord thy God, and Him
only shalt thou serve. Come, I am commissioned to take thee into the
presence of thy Maker and Redeemer.’
“And I said, ‘Sir, how speakest thou in this wise? God is in heaven,
and we are upon the earth; and it is not given to mortal man to scale
the heavenly regions, or come into the presence of the Almighty.’
And he said, ‘Have thy learning and thy knowledge carried thee no
higher than this? Knowest thou not that God is present in this wild
glen, the same as in the palaces of light and glory—that His presence
surrounds us at this moment—and that He sees all our actions, hears
our words, and knows the inmost thoughts of our hearts?’
“And I said, ‘Yes, I know it.’
“‘Then, are you ready and willing at this moment,’ said he, ‘to step
into His presence, and avow the sentiments which you have of late
been cherishing?’
 “And I said, ‘I would rather have time to think the matter over
again.’
“‘Alack! poor man!’ said he, ‘so you have never been considering
that you have all this while been in His immediate presence, and
have even been uttering thy blasphemous sentiments aloud to His
face, when there was none to hear but He and thyself.’
“And I said, ‘Sir, a man cannot force his belief.’
“And he said, ‘Thou sayest truly; but I will endeavour to convince
thee.’”
Here a long colloquy ensued about the external and internal
evidences of the Christian religion, which took Wat nearly half a day
to relate; but he still maintained his point. He asked his visitant twice
who he was, but he declined telling him, saying he wanted his reason
convinced, and not to take his word for anything.
Their conversation ended by this mysterious sage leading Wat
away by a path which he did not know, which was all covered with a
cloud of exceeding brightness. At length they came to a house like a
common pavilion, which they entered, but all was solemn silence,
and they heard nobody moving in it, and Wat asked his guide where
they were now.
“This is the place where heavenly gifts are distributed to
humanity,” said the reverend apostle; “but they are now no more
required, being of no repute. No one asks for them, nor will they
accept of them when offered, for worldly wisdom is all in all with the
men of this age. Their preaching is a mere farce—an ostentatious
parade, to show off great and shining qualifications, one-third of the
professors not believing one word of what they assert. The gift of
prophecy is denied and laughed at; and all revelation made to man
by dreams or visions utterly disclaimed, as if the Almighty’s power of
communicating with his creatures were not only shortened, but cut
off for ever. This fountain of inspiration, once so crowded, is now,
you see, a dreary solitude.”
“It was, in truth, a dismal-looking place, for in every chamber, as
we passed along, there were benches and seats of judgment, but none
to occupy them; the green grass was peeping through the seams of
the flooring and chinks of the wall, and never was there a more
appalling picture of desolation.
 “At length, in the very innermost chamber, we came to three men
sitting in a row, the middle one elevated above the others; but they
were all sleeping at their posts, and looked as if they had slept there
for a thousand years, for their garments were mouldy, and their faces
ghastly and withered.
“I did not know what to do or say, for I looked at my guide, and he
seemed overcome with sorrow; but thinking it was ill-manners for an
intruder not to speak, I said, ‘Sirs, I think you are drowsily inclined?’
but none of them moved. At length my guide said, in a loud voice,
‘Awake, ye servants of the Most High! Or is your sleep to be
everlasting?’
“On that they all opened their eyes at once, and stared at me, but
their eyes were like the eyes of dead men, and no one of them moved
a muscle, save the middlemost, who pointed with pale haggard hand
to three small books, or scrolls, that lay on the bench before them.
“Then my guide said, ‘Put forth thine hand and choose one from
these. They are all divine gifts, and in these latter days rarely granted
to any of the human race.’ One was red as blood, the other pale, and
the third green; the latter was farthest from me, and my guide said,
‘Ponder well before you make your choice. It is a sacred mystery, and
from the choice you make, your destiny is fixed through time and
eternity.’ I then stretched out my hand, and took the one farthest
from me, and he said, ‘It is the will of the Lord; so let it be! That
which you have chosen is the gift of the spirit of prophecy. From
henceforth you must live a life of sufferance and tribulation, but your
life shall be given you for a proof, in order that you may reveal to
mankind all that is to befall them in the latter days.’ And I opened
the book, and it was all written in mystic characters, which I could
not decipher nor comprehend; and he said, ‘Put up the book in thy
bosom, and preserve it as thou wouldst do the heart within thy
breast; for as long as thou keepest that book, shall thy natural life
remain, and the spirit of God remain with thee, and whatsoever thou
sayest in the spirit, shall come to pass. But beware that thou deceive
not thyself; for, if thou endeavour to pass off studied speeches, and
words of the flesh for those of the spirit, woe be unto thee! It had
been better for thee that thou never hadst been born. Put up the
book; thou canst not understand it now, but it shall be given thee to
understand it, for it is an oracle of the most high God, and its words
and signs fail not. Go thy ways, and return to the house of thy fathers
and thy kinsfolk.’
“And I said, ‘Sir, I know not where to go, for I cannot tell by what
path you brought me hither.’ And he took me by the hand, and led
me out by a back-door of the pavilion; and we entered a great valley,
which was all in utter darkness, and I could perceive through the
gloom that many people were passing the same way with ourselves;
and I said, ‘Sir, this is dreadful! What place is this?’ And he said,
‘This is the Valley of the Shadow of Death. Many of those you see will
grope on here for ever, and never get over, for they know not whether
they go, or what is before them. But seest thou nothing beside?’
“And I said, ‘I see a bright and shining light beyond, whose rays
reach even to this place.’—‘That,’ said he, ‘is the light of the
everlasting Gospel; and to those to whom it is given to perceive that
beacon of divine love, the passage over this valley is easy. I have
shown it to you; but if you keep that intrusted to your care, you shall
never enter this valley again, but live and reveal the will of God to
man till mortality shall no more remain. You shall renew your age
like the eagles, and be refreshed with the dews of renovation from
the presence of the Lord. Sleep on now, and take your rest, for I must
leave you again in this world of sin and sorrow. Be you strong, and
overcome it, for men will hold you up to reproach and ridicule, and
speak all manner of evil of you; but see that you join them not in
their voluptuousness and iniquity, and the Lord be with you!’”
There is no doubt that this is a confused account of the prophet’s
sublime vision, it being from second hands that I had it; and, for one
thing, I know that one-half of his relation is not contained in it. For
the consequences I can avouch. From that time forth he announced
his mission, and began prophesying to such families as he was sent
to. But I forgot to mention a very extraordinary fact, that this vision
of his actually lasted nine days and nine nights, and at the end of that
time he found himself on the very individual spot in the glen where
the voice first spoke to him, and so much were his looks changed,
that, when he went in, none of the family knew him.
He mixed no more with the men of the world, but wandered about
in wilds and solitudes, and when in the spirit, he prophesied with a
sublimity and grandeur never equalled. He had plenty of money, and
some property to boot, which his father left him; but these he never
regarded, but held on his course of severe abstemiousness, often
subsisting on bread and water, and sometimes for days on water
alone, from some motive known only to himself. He had a small
black pony on which he rode many years, and which he kept always
plump and fat. This little animal waited upon him in all his fastings
and prayings with unwearied patience and affection. There is a well,
situated on the south side of a burn, called the Earny Cleuch, on the
very boundary between the shires of Dumfries and Selkirk. It is
situated in a most sequestered and lonely place, and is called to this
day the Prophet’s Well, from the many pilgrimages that he made to
it; for it had been revealed to him in one of his visions that this water
had some divine virtue, partaking of the nature of the Water of Life.
At one time he lay beside this well for nine days and nights, the pony
feeding beside him all that time, and though there is little doubt that
he had some food with him, no body knew of any that he had; and it
was believed that he fasted all that time, or at least subsisted, on the
water of that divine well.
Some men with whom he was familiar—for indeed he was
respected and liked by everybody, the whole tenor of his life having
been so inoffensive;—some of his friends, I say, tried to reason him
into a belief of his mortality, and that he would taste of death like
other men; but that he treated as altogether chimerical, and not
worth answering; when he did answer, it was by assuring them, that
as long as he kept his mystic scroll, and could drink of his well, his
body was proof against all the thousand shafts of death. His
unearthly monitor appeared to him very frequently, and revealed
many secrets to him, and at length disclosed to him that he was
Stephen, the first martyr for the Gospel of Christ. Our prophet, in
the course of time, grew so familiar with him, that he called him by
the friendly name of Auld Steenie, and told his friends when he had
seen him, and part of what he had told him, but never the whole.
When not in his visionary and prophetic moods, he sometimes
indulged in a little relaxation, such as draught-playing and fishing;
but in these, like other things, he quite excelled all compeers. He was
particularly noted for killing salmon, by throwing the spear at a great
distance. He gave all his fish away to poor people, or such as he
favoured that were nearest to him at the time; so that, either for his
prophetic gifts, or natural bounty, the prophet was always a welcome
guest, whether to poor or rich.
He prophesied for the space of forty years, foretelling many things
that came to pass in his lifetime, and many which have come to pass
since his death. I have heard of a parable of his, to which I can do no
justice, of a certain woman who had four sons, three of whom were
legitimate, and the other not. The latter being rather uncultivated in
his manners, and not so well educated as his brethren, his mother
took for him ample possessions at a great distance from the rest of
the family. The young blade succeeded in his farming speculations
amazingly, and was grateful to his parent, and friendly with his
brethren in all their interchanges of visits. But when the mother
perceived his success, she sent and demanded a tenth from him of all
he possessed. This rather astounded the young man, and he
hesitated about compliance in parting with so much, at any rate. But
the parent insisted on her right to demand that or any sum which she
chose, and the teind she would have. The lad, not wishing to break
with his parent and benefactor, bade her say no more about it, and
he would give her the full value of that she demanded as of his own
accord; but she would have it in no other way than as her own proper
right. On this the headstrong and powerful knave took the law on his
mother; won, and ruined her; so that she and her three remaining
sons were reduced to beggary. Wat then continued—“And now it is to
yourselves I speak this, ye children of my people, for this evil is nigh
you, even at your doors. There are some here who will not see it, but
there are seven here who will see the end of it, and then they shall
know that there has been a prophet among them.”
It having been in a private family where this prophecy was
delivered, they looked always forward with fear for some contention
breaking out among them. But after the American war and its
consequences, the whole of Wat’s parable was attributed thereto, and
the good people relieved from the horrors of their impending and
ruinous lawsuit.
One day he was prophesying about the judgment, when a young
gentleman said to him, “O, sir, I wish you could tell us when the
judgment will be.” “Alas! my man,” returned he, “that is what I
cannot do; for of that day and of that hour knoweth no man; no, not
the angels which are in heaven, but the Almighty Father alone. But
there will be many judgments before the great and general one. In
seven years there will be a judgment on Scotland. In seven times
seven there will be a great and heavy judgment on all the nations of
Europe; and in other seven times seven there will be a greater one on
all the nations of the world; but whether or not that is to be the last
judgment, God only knoweth.”
These are dangerous and difficult sayings of our prophet. I wonder
what the Rev. Edward Irving would say about them, or if they
approach in any degree to his calculations. Not knowing the year
when this prophecy was delivered, it is impossible to reason on its
fulfilment, but it is evident that both the first eras must be overpast.
He always predicted ruin on the cause of Prince Charles Stuart, even
when the whole country was ringing with applauses of his bravery
and conquests. Our prophet detested the politics of that house, and
announced ruin and desolation not only on the whole house, but on
all who supported it. The only prophecy which I have yet seen in
writing relates to that brave but unfortunate adventurer, and is
contained in a letter to a Mrs Johnston, Moffat, dated October 1st,
1745, which must have been very shortly after the battle of
Prestonpans. After some religious consolation, he says, “As for that
man, Charles Stuart, let no spirit be cast down because of him, for he
is only a meteor predicting a sudden storm, which is destined to
quench his baleful light for ever. He is a broken pot; a vessel wherein
God hath no pleasure. His boasting shall be turned into dread, and
his pride of heart into astonishment. Terror shall make him afraid on
every side; he shall look on his right hand, and there shall be none to
know him; and on his left hand, and lo! destruction shall be ready at
his side—even the first-born of death shall open his jaws to devour
him. His confidence shall pass away for ever, even until the king of
terrors arrive and scatter brimstone upon his habitation. His roots
shall be dried up beneath, and the foliage of his boughs stripped off
above, until his remembrance shall perish from the face of the earth.
He shall be thrown into the deep waters, and the billows of God’s
wrath shall pass over him. He shall fly to the mountains, but they
shall not hide him; and to the islands, but they shall cast him out.
Then shall he be driven from light into darkness, and chased out of
the land.
 “Knowest thou not this of old time, that the triumph of the wicked
is of short duration, and the joy of the hypocrite but for a moment?
Though his excellency mount up into the heavens, and his pride
reach the stars, yet shall he perish for ever, like a shadow that
passeth away and is no more. They who have seen him in the pride of
his might shall say, Where is he? Where now is the man that made
the nations to tremble? Is he indeed passed away as a dream, and
chased away as a vision of the night? Yea, the Lord, who sent him as
a scourge on the wicked of the land, shall ordain the hand of the
wicked to scourge him till his flesh and his soul shall depart, and his
name be blotted out of the world. Therefore, my friend in the Lord,
let none despond because of this man, but lay these things up in thy
heart, and ponder on them, and when they are fulfilled, then shalt
thou believe that the Lord sent me.”
From the tenor of this prophecy, it would appear that he has
borrowed largely from some of the most sublime passages of
Scripture, which could not fail of giving a tincture of sublimity to
many of his sayings, so much admired by the country people. It
strikes me there are some of these expressions literally from the
Book of Job; but, notwithstanding, it must be acknowledged that
some parts of it are peculiarly applicable to the after-fate of Charles
Edward.
When old age began to steal on him, and his beloved friends to
drop out of the world, one after another, he became extremely heavy-
hearted at being obliged to continue for ever in the flesh. He never
had any trouble; but he felt a great change take place in his
constitution, which he did not expect, and it was then he became
greatly concerned at being obliged to bear a body of fading flesh
about until the end of time, often saying, that the flesh of man was
never made to be immortal. In this dejected state he continued about
two years, often entreating the Lord to resume that which He had
given him, and leave him to the mercy of his Redeemer, like other
men. Accordingly, his heavenly monitor appeared to him once more,
and demanded the scroll of the spirit of prophecy, which was
delivered up to him at the well in the wilderness; and then, with a
holy admonition, he left him for ever on earth. Wat lived three years
after this, cheerful and happy, and died in peace, old, and full of
days, leaving a good worldly substance behind him.