Ganong’s Physiology Examination and

Board Review 1st Edition Kim E. Barrett

Visit to download the full and correct content document:
https://textbookfull.com/product/ganongs-physiology-examination-and-board-review-1
st-edition-kim-e-barrett/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...

Ganong’s Review of Medical Physiology Kim E. Barrett

https://textbookfull.com/product/ganongs-review-of-medical-
physiology-kim-e-barrett/

Ganong’s Review of Medical Physiology 26th Edition Kim

E. Barrett

https://textbookfull.com/product/ganongs-review-of-medical-
physiology-26th-edition-kim-e-barrett/

Ganong’s Review of Medical Physiology 25th Edition

Barrett

https://textbookfull.com/product/ganongs-review-of-medical-
physiology-25th-edition-barrett/

General Surgery Examination and Board Review Robert B.

Lim

https://textbookfull.com/product/general-surgery-examination-and-
board-review-robert-b-lim/
Pulmonary Disease Examination and Board Review 1st
Edition Ronaldo Collo Go

https://textbookfull.com/product/pulmonary-disease-examination-
and-board-review-1st-edition-ronaldo-collo-go/

Katzung & Trevor’s Pharmacology Examination and Board

Review Bertram G. Katzung

https://textbookfull.com/product/katzung-trevors-pharmacology-
examination-and-board-review-bertram-g-katzung/

Graber and Wilbur’s Family Medicine Examination and

Board Review Jason K. Wilbur

https://textbookfull.com/product/graber-and-wilburs-family-
medicine-examination-and-board-review-jason-k-wilbur/

Pediatrics Examination and Board Review (Oct 3,

2016)_(0071847685)_(McGraw Hill) 1st Edition Peterson

https://textbookfull.com/product/pediatrics-examination-and-
board-review-oct-3-2016_0071847685_mcgraw-hill-1st-edition-
peterson/

Guyton Hall Physiology Review Guyton Physiology 4th

Edition John E Hall Phd

https://textbookfull.com/product/guyton-hall-physiology-review-
guyton-physiology-4th-edition-john-e-hall-phd/
2
3
Copyright © 2018 by McGraw-Hill Education. All rights reserved. Except as permitted under
the United States Copyright Act of 1976, no part of this publication may be reproduced or
distributed in any form or by any means, or stored in a database or retrieval system, without
the prior written permission of the publisher.

ISBN: 978-0-07-183233-5
MHID: 0-07-183233-5.

The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-
183232-8, MHID: 0-07-183232-7.

eBook conversion by codeMantra

Version 1.0

All trademarks are trademarks of their respective owners. Rather than put a trademark symbol
after every occurrence of a trademarked name, we use names in an editorial fashion only, and
to the benefit of the trademark owner, with no intention of infringement of the trademark.
Where such designations appear in this book, they have been printed with initial caps.

McGraw-Hill Education eBooks are available at special quantity discounts to use as

premiums and sales promotions or for use in corporate training programs. To contact a
representative, please visit the Contact Us page at www.mhprofessional.com.

Notice

Medicine is an ever-changing science. As new research and clinical experience broaden our
knowledge, changes in treatment and drug therapy are required. The authors and the
publisher of this work have checked with sources believed to be reliable in their efforts to
provide information that is complete and generally in accord with the standards accepted at
the time of publication. However, in view of the possibility of human error or changes in
medical sciences, neither the authors nor the publisher nor any other party who has been
involved in the preparation or publication of this work warrants that the information
contained herein is in every respect accurate or complete, and they disclaim all responsibility
for any errors or omissions or for the results obtained from use of the information contained
in this work. Readers are encouraged to confirm the information contained herein with other
sources. For example and in particular, readers are advised to check the product information
sheet included in the package of each drug they plan to administer to be certain that the
information contained in this work is accurate and that changes have not been made in the
recommended dose or in the contraindications for administration. This recommendation is of
particular importance in connection with new or infrequently used drugs.

TERMS OF USE

This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in
and to the work. Use of this work is subject to these terms. Except as permitted under the
Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not
decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based
upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it
without McGraw-Hill Education’s prior consent. You may use the work for your own
noncommercial and personal use; any other use of the work is strictly prohibited. Your right

4
to use the work may be terminated if you fail to comply with these terms.

THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS

LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY,
ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM
USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED
THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY
DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT
LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A
PARTICULAR PURPOSE. McGraw-Hill Education and its licensors do not warrant or
guarantee that the functions contained in the work will meet your requirements or that its
operation will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors
shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of
cause, in the work or for any damages resulting therefrom. McGraw-Hill Education has no
responsibility for the content of any information accessed through the work. Under no
circumstances shall McGraw-Hill Education and/or its licensors be liable for any indirect,
incidental, special, punitive, consequential or similar damages that result from the use of or
inability to use the work, even if any of them has been advised of the possibility of such
damages. This limitation of liability shall apply to any claim or cause whatsoever whether
such claim or cause arises in contract, tort or otherwise.

5
Dedication
This volume is dedicated to William Francis (“Fran”) Ganong, renowned physiologist and
neuroendocrinologist. From the first edition in 1963, until the 22nd, he was the sole author of
Review of Medical Physiology. At the time of his death in 2007, it was one of the most widely
used physiology textbook in the world, and it retains an intensely loyal following. His
dedication to the volume was legendary, and he was well known for always carrying index
cards at his long-term institution, the University of California, San Francisco, where he was a
faculty member for almost 50 years and chaired the Department of Physiology from 1970 to
1987. The cards would be used to gather facts from colleagues and visiting speakers, and the
facts would be accumulated to inform the next edition of his text—remarkably, completed
without fail every 2 years. It is fitting that this new derivative of his life-long work will serve
to educate new generations of medical and other health professional students.

6
Contents

Preface

SECTION I
CELLULAR & MOLECULAR BASIS FOR MEDICAL
PHYSIOLOGY
1. General Principles & Energy Production in Medical Physiology

2. Overview of Cellular Physiology in Medical 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. Vision

10. Hearing & Equilibrium

11. Smell & Taste

7
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 Thyroid Gland

20. The Adrenal Medulla & Adrenal Cortex

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, & Nutritional Principles

8
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

Index

9
10
Preface

We have been gratified by the response we have received since taking over the helm of
Ganong’s Review of Medical Physiology with the 23rd edition, and now with two additional
editions under our belt. It has been our goal to reorganize and update this venerable resource,
while maintaining the features of the book that gave it such an important place in the
worldwide marketplace for physiology texts for the 22 editions produced by the extraordinary
Professor Fran Ganong. We have paid particular attention to overhauling the graphical
aspects of the volume to aid in consistency among chapters and to take advantage of its new
full-color format and have added new pedagogical features, such as clinical correlations and
therapeutic highlights. Throughout our endeavors to uphold Professor Ganong’s unique
perspective we have noticed that the book’s comprehensive nature reduces its utility as a tool
to review physiology content in preparation for Step 1 of the United States Medical Licensing
Exam (USMLE). We also felt that the current edition could be improved with supplemental
resources with which students can assess their own mastery of the content.
With these limitations in mind, we are pleased to present this companion title, Ganong’s
Medical Physiology Examination & Board Review. Our primary goal has been to streamline
the text of the “parent” volume for ease of review, retaining only the most high-yield
concepts and illustrations. We have specifically reworked the self-study questions from the
original book so that they are consistent with the “clinical vignette” format found in the
USMLE and have added many additional questions. In fact, this new book has more than 350
questions to test basic physiology knowledge in an applied context. Finally, every question
carries a comprehensive explanation of why the right answer is in fact correct and why the
distractors are wrong, further enhancing conceptual understanding of physiology rather than
simply reinforcing rote memorization. With these new features, this companion volume
represents a robust resource for USMLE preparation.
This new volume also introduces a change in the authorship team. While Professor
Heddwen Brooks will continue to contribute to the parent volume, other commitments
precluded her involvement in the current project. We are very fortunate to have been able to
recruit Professor Jane Reckelhoff to the author group. Janie is an acclaimed teacher of
medical and graduate students at the University of Mississippi Medical Center and brings a
wealth of experience in the areas of renal, cardiovascular, and gender-related physiology
research to our group. Janie’s involvement, furthermore, means that three past presidents of
the American Physiological Society are now included among the book’s authors—perhaps a
record for a physiology text.
We hope that a new generation of students will benefit from Ganong’s Medical
Physiology Examination & Board Review—either in conjunction with Ganong’s Review of
Medical Physiology, or as a standalone resource. We also hope that the late Professor Ganong
would have been pleased with this evolution of the text that became his life’s work.

11
12
 SECTION I CELLULAR & MOLECULAR BASIS FOR
MEDICAL PHYSIOLOGY

The detailed study of physiologic system structure and function has its foundations in
physical and chemical laws and the molecular and cellular makeup of each tissue and organ
system. This first section provides an overview of the basic building blocks that provide the
important framework for human physiology. It is important to note here that these initial
sections 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.
In the first part 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
building blocks, basic principles, and human physiology. These basic principles are followed
up with a discussion of the generic cell and its components.
In the second part of this introductory section, we take a cellular approach to lay
groundwork for 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 physiology 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 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 available. Students who are intrigued by the overview provided
in this first section are encouraged to visit such texts for a more thorough understanding of
these basic principles.

13
 CHAPTER

1
General Principles & Energy
Production in Medical Physiology

OBJECTIVES
After studying this chapter, you should be able to:

Define units used in measuring physiologic 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: nucleotides, amino
acids, carbohydrates, and fatty acids.
Understand higher-order structures of the basic building blocks: DNA, RNA,
proteins, and lipids.
Understand the basic contributions of the basic building blocks to cell structure,
function, and energy balance.

INTRODUCTION

In humans and other vertebrate animals, specialized cell groups form into organs and include
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. While 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 focuses on a review
of basic biophysical and biochemical principles and the introduction of the molecular
building blocks that contribute to cellular physiology.

14
 GENERAL PRINCIPLES

THE BODY AS ORGANIZED “SOLUTIONS”

The cells that make up the bodies of all, but the simplest multicellular animals are exposed to
extracellular fluid (ECF) enclosed within the integument of the animal. Cells take up O2
and nutrients from this fluid, and they discharge metabolic waste products into it. The
composition of ECF 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 plasma
and the cellular elements of the blood fill the vascular system, and together they constitute the
total blood volume. The interstitial fluid is that part of the ECF that is outside the vascular
and lymph systems, bathing the cells. About one-third of the total body water is
extracellular; the remaining two-thirds is intracellular (intracellular fluid). 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 this water is shown in
Figure 1–1A. Flow between these compartments is tightly regulated.

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.

WATER, ELECTROLYTES, & ACID/BASE

The water molecule (H2O) is an ideal solvent for physiologic reactions. H2O has a dipole

15
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 layperson’s terms, H2O is an excellent biologic 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).
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. 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 1–1). 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.

CLINICAL BOX 1–1

Acid–Base Disorders
Excesses of acid (acidosis) or base (alkalosis) exist when the blood 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. 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 root cause. Bicarbonate is typically used as a treatment for acute

16
 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.

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 physiologic
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 biologic 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 biologic
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: HA
H+ + A–. According to the laws of mass action, a relationship for the dissociation can be
defined mathematically as: Ka = [H+][A–]/[HA], where Ka is a constant, and the brackets
represent concentrations of the individual species. With some mathematical rearrangement,
this can be written in a more conventional form known as the Henderson-Hasselbalch
equation: pH = pKa + log [A–]/[HA], where pH is the –log of [H+] and pKa is the –log of the
above defined constant. 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 (eg, [A–] = [HA], pH = pKa). Similar
equations can be set up for weak bases. Important biologic buffers include carbonic acid,
phosphates, and proteins.

DIFFUSION & OSMOSIS

Diffusion is the process by which a gas or a substance in a solution expands, because of the
motion of its particles, to fill all the available volume. The particles (molecules or atoms) of a
substance dissolved in a solvent are in continuous random movement. 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, 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 is directly
proportional to the cross-sectional area across which diffusion is taking place and the
concentration or chemical gradient, and can be represented as Fick’s law of diffusion.
Thus

17
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. Diffusion is a major force affecting
the distribution of water and solutes in the body.
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 1–2). 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. 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.

FIGURE 1–2 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.

Osmotic pressure depends on the number rather than the type of particles in a solution. In
an ideal solution, osmotic pressure (P) is related to temperature and volume in the same way
as the pressure of a gas:

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 biologic solutions, the milliosmole (mOsm; 1/1000 of

18
1 Osm) is most 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. However, 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. 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 osmolality is expressed in milliosmoles
per liter (of water). Note that although a homogeneous solution contains osmotically active
particles that 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. The osmolality might be expected to be
higher than this, because the sum of all the cation and anion equivalents in plasma is over 300
mOsm/L. However, 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 nearly isosmotic; that is, they are in osmotic equilibrium. The term tonicity is used to
describe the osmolality of a solution of impermeable particles relative to plasma. Solutions
that have the same tonicity as plasma are said to be isotonic; hypertonic and hypotonic refer
to higher or lower tonicities as plasma, respectively. 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 across cell
membranes 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 can move across the plasma membrane, and
can be metabolized, so the net effect is that of infusing a hypotonic solution.

CLINICAL BOX 1–2

Plasma Osmolality & Disease

Unlike plant cells, which have rigid walls, animal cell membranes are flexible.

19
 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 osmolality; however, these can be
overwhelmed under certain pathologies. Hyperosmolality can cause coma
(hyperosmolar coma). Because of the predominant role of the major solutes and the
deviation of plasma from an ideal solution, one can ordinarily approximate the plasma
osmolality within a few mOsm/L by using the following formula, in which the constants
convert the clinical units to millimoles of solute per liter:

Osmolarity (mOsm/L) = 2[Na+] (mEq/L) + 0.055[Glucose] (mg/dL) + 0.36[BUN]

(mg/dL)

BUN is the blood urea nitrogen. The formula is also useful in calling attention to
abnormally high concentrations of other solutes. An observed plasma osmolality
(measured by freezing-point depression) that greatly exceeds the value predicted by this
formula probably 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).

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 1–2).

NONIONIC DIFFUSION, DONNAN EFFECT & NERNST

POTENTIAL

Some weak acids and bases are quite soluble in cell membranes in the undissociated form,
whereas they cannot cross membranes in the 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.
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. The Gibbs–Donnan
equilibrium states that in the presence of a nondiffusible ion, the diffusible ions distribute
themselves so that at equilibrium their concentration ratios are equal. This 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 fluid, and because animal cells have
flexible walls, osmosis would make them swell and eventually rupture if it were not for Na,

20
K ATPase pumping ions back out of cells. Thus, normal cell volume and pressure depend on
Na, K ATPase. Second, because at equilibrium the distribution of permeant ions across the
membrane is asymmetric, an electrical difference exists across the membrane whose
magnitude can be determined by the Nernst equation (see further). Third, because there are
more proteins in plasma than in interstitial fluid, there is a Donnan effect on ion movement
across the capillary wall.
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:

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 be invoked to explain the distribution of Cl– across
the membrane.

TABLE 1–1 Concentration of some ions inside and outside mammalian spinal motor
neurons.

21
 A similar equilibrium potential can be calculated for K+ (EK; Table 1–1). In this case, the
concentration gradient is outward and the electrical gradient inward. In mammalian spinal
motor neurons EK is –90 mV. 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.
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 concentration of Na+ and
K+ remain constant because of selective permeability and because of 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).
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 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

22
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. The most important high-energy phosphate compound is adenosine triphosphate
(ATP). This ubiquitous molecule 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.
Another group of high-energy compounds are thioesters, the acyl derivatives of
mercaptans. Coenzyme A (CoA) is a widely distributed mercaptan-containing adenine,
ribose, pantothenic acid, and thioethanolamine. 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.”

BIOLOGIC 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. Biologic 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.
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 details). Ninety percent of the
O2 consumption in the basal state is mitochondrial, and 80% of this 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, 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 1–3). These
structures are bound to ribose or 2-deoxyribose to complete the nucleoside. When inorganic
phosphate is added to the nucleoside, a nucleotide is formed. Nucleosides and nucleotides
form the backbone for RNA and DNA, as well as a variety of coenzymes and regulatory
molecules of physiologic 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

23
catabolized. Minor amounts are excreted unchanged in the urine.

FIGURE 1–3 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.

TABLE 1–2 Purine- and pyrimidine-containing compounds.

DNA

DNA is found in the cell nuclei and in mitochondria. It is made up of two extremely long
nucleotide chains containing the bases adenine (typically abbreviated in sequence by the
letter “A”), guanine (G), thymine (T), and cytosine (C). The chains are bound together by
hydrogen bonding between the bases, with adenine bonding to thymine and guanine to
cytosine. This stable association forms a double-helical structure. The double helical structure
of DNA is compacted in the cell by association with histones, and further compacted into
chromosomes. A diploid human cell contains 46 chromosomes.
A fundamental unit of DNA, or a gene, can be defined as the sequence of DNA

24
nucleotides that contain the information for the production of an ordered amino acid sequence
for a single polypeptide chain. The protein encoded by a single gene may be subsequently
divided into several different physiologically active proteins. The basic structure of a typical
eukaryotic gene is shown in diagrammatic form in Figure 1–4. It is made up of a strand of
DNA that includes coding and noncoding regions. In eukaryotes the portions of the genes that
dictate the formation of proteins are usually broken into several segments (exons) separated
by segments that are not translated (introns). Near the transcription start site of the gene is a
promoter, which is the site at which RNA polymerase and its cofactors bind. It often
includes a thymidine–adenine–thymidine–adenine (TATA) sequence (TATA box), which
ensures that transcription starts at the proper point. Farther out in the 5′> or 3′> regions are
regulatory elements, which include enhancer and silencer sequences. Each gene can have
multiple regulatory sites. In a diploid cell each gene will have two alleles, or versions of that
gene. Each allele occupies the same position on the homologous chromosome. Individual
alleles can confer slightly different properties of the gene when fully transcribed. It is
interesting to note that changes in single nucleotides within or outside coding regions of a
gene (single nucleotide polymorphisms; SNPs) can have great consequences for gene
function.

FIGURE 1–4 Diagram of the components of a typical eukaryotic gene. The region that produces
introns and exons is flanked by noncoding regions. The 5′-flanking region contains stretches of DNA
that interact with proteins to facilitate or inhibit transcription. The 3′-flanking region contains the
poly(A) addition site. (Modified with permission from Murray RK et al: Harper’s Biochemistry, 28th
ed. New York, NY: McGraw-Hill; 2009.)

Gene mutations occur when the base sequence in the DNA is altered from its original
sequence. Alterations can be through insertions, deletions, or duplications. Such alterations
can affect protein structure and be passed on to daughter cells after cell division. The
collection of genes within the full expression of DNA from an organism is termed its
genome. An indication of the complexity of DNA in the human haploid genome (the total
genetic message) is its size; it is made up of 3 × 109 base pairs that can code for
approximately 30,000 genes. This genetic message is the blueprint for the heritable
characteristics of the cell and its descendants. The proteins formed from the DNA blueprint
include all the enzymes, and these in turn control the metabolism of the cell.
Each nucleated somatic cell in the body contains the full genetic message, yet there is
great differentiation and specialization in the functions of the various types of adult cells.
Only small parts of the message are normally transcribed. At the time of each somatic cell
division (mitosis), the two DNA chains separate, each serving as a template for the synthesis
of a new complementary chain. DNA polymerase catalyzes this reaction. One of the double
helices thus formed goes to one daughter cell and one goes to the other, so the amount of
DNA in each daughter cell is the same as that in the parent cell. The life cycle of the cell that

25
begins after mitosis is highly regulated and is termed the cell cycle (Figure 1–5). The G1 (or
Gap 1) phase represents a period of cell growth and divides the end of mitosis from the DNA
synthesis (or S) phase. Following DNA synthesis, the cell enters another period of cell
growth, the G2 (Gap 2) phase. The ending of G2 is marked by chromosome condensation and
the beginning of mitosis (M stage).

FIGURE 1–5 Sequence of events during the cell cycle. (A) Immediately following mitosis (M) the
cell enters a gap phase (G1). At this point many cells will undergo cell arrest. G1 is followed by a DNA
synthesis phase (S) a second gap phase (G2) and back to mitosis. (B) Stages of mitosis are highlighted.

In germ cells, reductive division (meiosis) takes place during maturation. The net result is
that one of each pair of chromosomes ends up in each mature germ cell; consequently, each
mature germ cell contains half the amount of chromosomal material found in somatic cells.
Therefore, when a sperm unites with an ovum, the resulting zygote has the full complement
of DNA, half of which came from the father and half from the mother.

RNA

The strands of the DNA double helix not only replicate themselves but also serve as
templates by lining up complementary bases for the formation in the nucleus of RNA. RNA
differs from DNA in that it is single-stranded, has uracil in place of thymine, and its sugar
moiety is ribose rather than 2′>-deoxyribose. The production of RNA from DNA is called
transcription. Transcription can lead to several types of RNA including: messenger RNA
(mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), and other RNAs. Transcription
is catalyzed by various forms of RNA polymerase.

26
 Typical transcription of an mRNA includes several unique steps. When suitably activated,
transcription of the gene into a pre-mRNA starts at the cap site and ends about 20 bases
beyond the AATAAA sequence. The RNA transcript is capped in the nucleus by addition of
7-methylguanosine triphosphate to the 5′ end; this cap is necessary for proper binding to the
ribosome. A poly(A) tail of about 100 bases is added to the untranslated segment at the 3′-
end to help maintain the stability of the mRNA. The pre-mRNA formed by capping and
addition of the poly(A) tail is then processed by elimination of the introns, and once this
posttranscriptional modification is complete, the mature mRNA moves to the cytoplasm.
Posttranscriptional modification of the pre-mRNA is a regulated process where differential
splicing can occur to form more than one mRNA from a single pre-mRNA. The introns of
some genes are eliminated by spliceosomes, complex units that are made up of small RNAs
and proteins. Other introns are eliminated by self-splicing by the RNA they contain. Because
of introns and splicing, more than one mRNA can be formed from the same gene.
Most forms of RNA in the cell are involved in translation, or protein synthesis. A brief
outline of the transition from transcription to translation is shown in Figure 1–6. In the
cytoplasm, ribosomes provide a template for tRNA to deliver specific amino acids to a
growing polypeptide chain based on specific sequences in mRNA. The mRNA molecules are
smaller than the DNA molecules, and each represents a transcript of a small segment of the
DNA chain. For comparison, the molecules of tRNA contain only 70–80 nitrogenous bases,
compared with hundreds in mRNA and 3 billion in DNA. A newer class of RNA,
microRNAs, have recently been reported. MicroRNAs measure approximately 21–25-
nucleotides in length and have been shown to negatively regulate gene expression at the
posttranscriptional level. It is expected that roles for these small RNAs will continue to
expand as research into their function continues.

27
FIGURE 1–6 Diagrammatic outline of transcription to translation. In the nucleus, a messenger
RNA is produced from the DNA molecule. This messenger RNA is processed and moved to the cytosol
where it is presented to the ribosome. It is at the ribosome where charged tRNA match up with their
complementary codons of mRNA to position the amino acid for growth of the polypeptide chain. The
lines with multiple short projections in DNA and RNA represent individual bases. Small boxes labeled
A represent individual amino acids.

AMINO ACIDS & PROTEINS

AMINO ACIDS
28
Amino acids that form the basic building blocks for proteins are identified in Table 1–3.
These amino acids are often referred to by their corresponding three-letter, or single-letter
abbreviations. Various other important amino acids such as ornithine, 5-hydroxytryptophan,
L-dopa, taurine, and thyroxine (T4) occur in the body but are not found in proteins. In higher
animals, the L isomers of the amino acids are the only naturally occurring forms in proteins.
The amino acids are acidic, neutral, or basic, depending on the relative proportions of free
acidic (–COOH) or basic (–NH2) groups in the molecule. Some of the amino acids are
nutritionally essential amino acids; that is, they must be obtained in the diet, because they
cannot be made in the body. Arginine and histidine must be provided through diet during
times of rapid growth or recovery from illness and are termed conditionally essential. All
others are nonessential amino acids in the sense that they can be synthesized in vivo in
amounts sufficient to meet metabolic needs.

TABLE 1–3 Amino acids found in proteins.

29
Another random document with
no related content on Scribd:
Abraham.—“But in that country there are many hills; which shall I
ascend?”
The voice of God.—“A mountain on which shall rest my Glory; there
shall it be told thee further what thou must do.”
Abraham prepared to fulfil the command of God, but he dreaded the
separation between Sarah and her son. If he took Isaac away
secretly, then he feared that, in the excess of her distress, she would
do herself harm. At last he decided on this course; he went to
Sarah’s tent, and he said to her, “My dearest, prepare this day a little
banquet, that in our old days we may rejoice our hearts.”
Sarah answered, “Wherefore this day, my husband? Are you about
to lose anything this day?”
Abraham said, “Think, my wife, Sarah! how good God has been to
us; therefore it behoves us to thank Him all the days of our life.”
Sarah did as Abraham had commanded.
As they sat and ate, Abraham said, “Thou knowest well, dear wife,
that I knew the One true God from the time that I was three years
old. Isaac is older, and it behoves him to know more of the law of
God. Therefore I design to take him with me to Shem and Eber, our
ancestors, who live not far from here, that they may instruct him.
Hast thou anything to object to this, Sarah?”
She answered, “No; do that which is pleasing in thine eyes; only let
not Isaac be away too long, for thou knowest how precious the sight
of him is to me.”
Then Sarah put her arms round her son, and kissed him, and they
parted with many tears; and she exhorted Abraham to have great
care of the youth, that the journey might not be too great for him.
Next morning, very early, Abraham rose, and he saddled the ass
himself, though he had many slaves, for he was eager to be gone,
and to go where the Lord called him. This was the ass, born of the
she-ass created by God on the eve of the sixth day, upon which
Moses afterwards rode when he went to Egypt;[327] it is the ass which
spake to Balaam, and it is the ass of which the prophet Zechariah
has spoken, that on it Messiah shall ride.[328]
This ass was of a hundred colours.[329]
Sarah clothed Isaac in the garment that Abimelech had given her,
and placed a jewel-studded fillet about his head. She provided the
travellers with food for their journey, and accompanied them with her
maids, till Abraham bade them return. Then she clasped Isaac once
more to her breast, and said with tears, “God be gracious to thee, my
son; how know I that I shall see thee again?”
Abraham had two to accompany him, Eliezer and Ishmael; he had
cut fig and palm wood and made a faggot. On the way this discourse
took place between Eliezer and Ishmael.
Ishmael said, “I perceive clearly that my father is about to offer Isaac
as a whole burnt offering; therefore I, his eldest son, will inherit his
possessions.”
But Eliezer said, “That is false: I am his trusty servant! Did not thy
father drive thee away from home? He will leave all to me.”
Whilst they thus spake, there came a voice from heaven, “O ye fools!
neither of you knows the truth.”
Abraham in the meantime walked forward. Then came Satan to him
in the form of an old man bowed upon a staff, and said to him,
“Whither goest thou?”
He answered, “I go to offer up my prayers.”
“Wherefore this knife, and fuel, and fire?” asked Satan.
“I take them in case we have to spend much time on the mountain,
that we may bake bread and slay beasts.”
“Old man, thou deceivest me,” said Satan. “Was I not by when a
voice bade thee slay thy son, thine only son; and now, what art thou
about to do? Thinkest thou that thou shalt have another son, now
that thou art a hundred years old? Art thou then about to cut down
with thine own hands the main pillar of thy tent, the staff on which
thou mayest lean in thine old age? Knowest thou not the proverb,
‘He who destroys his own goods, how shall he get more?’ That was
not the voice of God, it was the voice of the Tempter, and thou didst
listen to it. Dost thou think that God, who promised to make of thee a
great nation, and to bless all generations through Isaac, would thus
persuade thee to make void His own promises?”
Abraham answered, “No, it was not the Tempter who spake, it was
the voice of God; therefore I will not hearken to thy words, but walk
on still in mine uprightness.”
“But if God were to ask of thee some further sacrifice, wouldst thou
grant it?”
“Of a truth would I,” answered Abraham.
“Thy piety is folly,” said Satan impatiently. “To-morrow God will
punish thee for this murder thou art about to commit, since thou wilt
shed the blood of thine own son.”
But when Satan saw that Abraham was not to be moved from his
purpose, then he took the form of a blooming youth, and joined
himself to Isaac, and asked him the object of his journey.
Isaac replied that he was going to receive instruction in the law of the
Most High.
“Art thou going to receive this instruction living or dead?” asked
Satan, scornfully.
Isaac.—“Can a man receive instruction after he is dead?”
Satan.—“O thou son of a mother much to be pitied, knowest thou not
that thy father is leading thee to death?”
Isaac.—“Nevertheless I shall follow him.”
Satan.—“Then all the tears and prayers of thy mother, beseeching
Heaven to grant her a son, end in this! All the pains and grief in
childbearing! All the afflictions she laid on Hagar and Ishmael! All the
care she has taken of thy youth! All the love she has expended upon
thee! All these things for nothing!”
Isaac.—“As my father wills.”
Satan.—“Then the inheritance passes to Ishmael. How he will glory
in being the first-born, and his mother Hagar will despise Sarah, and
maybe will drive her out!”
Isaac.—“I obey the command of my father and the will of God, be
they what they may.”
But these words were not without some effect on Isaac. With piteous
voice he urged his father to suspend or delay what he had
undertaken. But Abraham exhorted his son not to listen or give
credence to the words he had heard, for they were the temptations
of Satan, to draw him from the path of obedience and the fear of
God.
They went a little further and came to a broad stream. Abraham,
Isaac, and their followers sought to wade it; the water at first reached
their knees, but when they were in the middle, it rose to their necks.
Abraham, who knew well the spot, and that there was neither brook
nor river there by nature, recognized this as a deception of Satan, to
divert them from the right way. He told Isaac that this was his
opinion, and raising his eyes to heaven he prayed: “Thou, O Lord,
didst declare to me Thy will, that I should take Isaac my son and
offer him to Thee in pledge of my obedience. I did not hesitate, I did
not refuse, and now the water overwhelms us and we sink; how then
can I perform that which Thou badest me do?”
The Lord answered, “Fear not, through thee shall My Name be
known.”
Then the stream vanished away, and they stood upon dry land.
But now Satan made another attempt to turn Abraham from his
purpose. He drew him aside and said, “The object of thy journey has
failed. I caught a whisper in heaven, and it was this—God will
prepare a lamb for the sacrifice, and not thy son.”
Abraham answered, “Even if thy words be true, it matters not; for this
is the penalty of liars, that when they speak the truth they are not
believed.”
Abraham journeyed on the rest of that day, without seeing his
appointed place. Next day he retraced his steps, but could find no
signs of the place. The Almighty had so ordered it, that men might
not say Abraham was hasty and acted precipitately, but might see
that he had leisure and time for reflection on what he was about to
do.
On the morning of the third day,[330] they reached the height of
Zophim, and thence Abraham saw a beautiful mountain-land, and on
the top of one of the mountains was a fiery pillar, which reached from
earth to heaven,—it was the Glory of the Lord appearing in the
cloud.
When Abraham asked Isaac if he beheld this sight, he answered that
he did so; but when he asked his other companions, they replied that
they saw nothing save the brown hills and purple valleys. Some say
they answered that one hill was to them like every other hill.
From this, Abraham concluded that God was well pleased with Isaac
as a victim. Then he said to Eliezer and Ishmael:
“Tarry ye here with the ass, for you are not worthy to behold the
Shekinah nearer. But I and the youth will go on, so many only shall
go.”
Now, as he said these words, it suddenly came to his mind that God
had promised him a great people descended from Isaac, so many as
the stars for multitude, and with prophetic voice he said, “If the Lord
will, so many as go on, so many shall return.”
Then Abraham laid the wood of the sacrifice on his son Isaac, and
took the fire and the knife in his hand; and they went on both
together, Abraham joyous, and Isaac without fear or thought.
But after they had gone some way, Isaac turned to his father and
said, “Father, whither are we going alone?”
Abraham.—“My son, we go to offer a sacrifice.”
Isaac.—“But art thou a priest to execute this undertaking?”
Abraham.—“Shem, the High Priest, will prepare the victim.”
A great fear fell upon Isaac when he saw that they had no animal
with them to offer, and he said, “Here are the fire and the wood, but
where is a lamb for the whole offering?”
Abraham.—“The lamb which is to be offered is foreknown to the
Almighty. He will provide the lamb; and if none other is here, then
must thou be the offering, my son.”
Isaac was silent, for the fear of death came over him. But presently
he recovered himself and said, “If God chooses me, I place my soul
in His hands.”
Abraham.—“My son! Is there any blemish in thee within? For the
offering must be without blemish of any sort.”
Isaac.—“My father! There is none. I swear by God and by thy life,
that in my heart there is not the least resistance to the Divine will. My
limbs do not tremble, and there is no quaking at my heart. With
gladness do I say, The Lord be praised, who has chosen me for a
whole sacrifice.”[331]
Abraham.—“O my son, with many a wish wast thou brought into this
world. Since thou hast been in it, every care has been lavished on
thee. I hoped to have had thee to follow me and make a great nation.
But now I must, myself, offer thee. Wondrous was thy coming into
this world, and wondrous will be thy going out of it![332] Not by
sickness, not by war, but as a sacrifice. I had designed thee to be my
comfort and stay in old age; now God himself must take thy
place.”[333]
Isaac.—“It were unworthy of thee were I to think to withstand the
decree of God, and of thee. Had the decision been thine alone, I
would have obeyed.”
When they reached the top of Moriah, God said to Abraham,—
“This is the place where once Adam, when driven out of Paradise,
built an altar to My name. Here also Cain and Abel offered their
sacrifice. Then came the Flood, and when it was passed away, Noah
offered victims to Me here. When the people were scattered from the
tower at Babel, then this altar was overthrown. Now it is for thee,
friend of God, to set it up again!”
Abraham built the altar, and Isaac brought him the stones. But,
according to some authors, this was not so. Abraham hid his son in a
cave, lest Satan should take advantage of the opportunity, with a
stone or clod of earth, to blemish him.
And when all was ready and the wood laid in order, then Isaac said
to his father, “Bind me hand and foot, lest in the fear of death I start
and thou wound me, and so I be blemished. Fold thy garments
together, and gird thy loins, and bare thine arm, and strike me with
the knife and then burn me to ashes, and lay up my ashes in a
coffer, and let this coffer be preserved as a memorial of me in thy
house, before my mother; and when thou passest by it, bid her
remember me. But remind her not of it near a well, or on the edge of
a precipice, lest she cast herself down in her grief.”[334]
And he continued, “When thou returnest home, how wilt thou
console my mother?”
Abraham answered, “Well I know that He who comforted us before
thou earnest, will comfort us after thou art gone from us.”[335]
Abraham now stood over his son, who was bound with his hands to
his feet, upon the wood laid in order; and the eyes of Abraham
rested on the eyes of his son. But Isaac looked up into heaven, and
saw the angel hosts crowded about God’s throne. Abraham saw not
this, and he lifted the knife; but he trembled and the knife fell from his
hand, and he cried aloud, “O my son! Would that another offering
were found instead of thee! But my help cometh only from the Lord
who hath made heaven and earth!”
Then he gathered up his resolution, and took the knife and held it
once more to strike; and Isaac’s spirit left him, and he swooned
away.
But the angels of God, who stood round about His throne,
announced to the Most High all that took place, and they cried and
wept, and even the fiery seraphim exclaimed, “Woe! He slays his
son.” And the tears of the angels fell upon the face of Isaac, and
made him ever after sad of countenance.
Then God said, “Behold, and see how great is the faith of My servant
Abraham, how on earth a man can hallow My great name, and
devote his best and dearest to My service; see that, ye, who at the
creation exclaimed, What is man, that thou art mindful of him, and
the son of man, that thou so regardest him?”
Then He ordered Michael to fly swiftly, and stay the hand of
Abraham.
And the archangel, when he came near, cried aloud, “Abraham!
Abraham! what doest thou?”
Abraham looked in the direction of the voice, in doubt, and said,
“Here am I.”
Then said the angel, “Lay not thine hand upon the lad, neither do
thou anything unto him.”
And Abraham said, “Who art thou?”
Michael told him who he was. Then said Abraham, “The Most High
appeared to me in a vision, and bade me take my son as a whole
offering to the place which He should say, and I may take no
command from a servant of God, against that which God Himself
hath laid upon me.”
Then heaven opened, and he saw the glory of God, and God said to
him, “Touch not the lad to do him harm, for now I know that thou
fearest God, seeing thou hast not withheld thy son, thine only son,
from Me.”
And Abraham said, “How is this, O Lord! that Thou changest Thy
purpose, and sayest one day, Do this, and the next, Do it not?”
And the Lord answered, and said, “I said not unto thee, Slay the lad
as a burnt offering, but I said, Take thy son to the place that I shall
tell thee, as a whole burnt offering. This hast thou done; thou hast
fulfilled My command, I exact no more of thee. I change not My
purpose, but I did suffer thee to misunderstand the purport of My
command, and to think that I exacted more of thee; and this I did to
prove thee. And now, by Myself have I sworn; for because thou hast
done this thing, and hast not withheld thy son, thine only son; that in
blessing I will bless thee, and in multiplying I will multiply thy seed as
the stars of the heavens, and as the sand which is upon the sea-
shore; and thy seed shall possess the gate of his enemies.”
Then Isaac revived, and Abraham cut his cords, and he stood up
and said, “Praised be the Eternal One, who quickeneth those that be
dead.”
And Abraham turned to the Shekinah and said, “Lord! how shall I
depart hence without having offered to Thee a sacrifice?” The Lord
answered, “Lift thine eyes, and thou shalt see a beast for sacrifice
behind thee.”
In the thicket of the wood was that ram which God created at dusk
on the sixth day, that it might serve this purpose. An angel had
brought it out of Paradise, where it had lived since its creation, and
had fed under the shadow of the Tree of Life, and had drunk of the
River that there flows. And when the ram was brought into this earth,
all the earth was filled with the fragrance from its fleece, on which
hung the odours of the flowers on which it had lain in Paradise.
But by Satan’s fraud, the animal was frightened and strayed away,
and Abraham tracked it by its foot-prints. Then Satan decoyed the
beast behind some bushes and entangled its horns in the thicket;
and Abraham would have passed by, and not seen it, but the ram
caught him by his cloak. So Abraham slew it, and offered it in
sacrifice, and sprinkled with its blood the altar he had made.
Now the Last Trumpets that shall sound, the one to call the just, the
other the unjust, are made of the horns of this wondrous ram.
 11. THE DEATH OF SARAH.

Sarah,—who, as we have seen, accompanied Abraham and Isaac

part of the way to Moriah,—on her return to the tent, found an old
man awaiting her. It was Satan.
He greeted her with profound respect, and asked after her husband
and son.
She answered that they had gone forth on a journey.
“Whither have they gone?” asked Satan.
“My lord has gone to visit the school of Shem and Eber, our
grandsires, there to leave my son Isaac to be instructed in the law of
God.”
“Alas! alas!” exclaimed the Apostate Angel; “thou art greatly
deceived.”
Sarah was alarmed; and she asked wherefore he spake thus.
“Know then,” said Satan, “that Abraham has gone forth with Isaac to
sacrifice him, upon a mountain, to the Most High.”
When she heard this, Sarah laid her head on the bosom of a slave,
and fainted. When she came to herself she hurried with her maidens
to the school of Shem and Eber, and inquired after her husband and
son, but they had neither seen nor heard anything of them. So Sarah
was convinced that what had been told her was true, and there was
no spirit left in her.
Now when Satan knew that Abraham was bringing back his son, and
that God had accepted the will for the deed, he was moved with envy
and spite, and he could not rest to think of the joy that this would
cause; so he went hastily to Sarah, and she was weeping in her tent,
and sorely cast down and broken in spirit. Then he said suddenly to
her, “Thy son liveth and is returning. God hath spared him!”
And she rose up and uttered a cry, and fell, and was dead; for the joy
had killed her.
Abraham and Isaac in the meantime had returned from Moriah, and
they sought Sarah at Beer-sheba, but she was not there; therefore
they went to Hebron, and there they found her corpse. Isaac fell
weeping upon the face of his mother, and he cried, “Mother, mother!
why hast thou forsaken me? why hast thou gone away?”
Abraham wept aloud, and all the dwellers in Hebron wept and
lamented over Sarah, and ceased from their labours, that they might
mourn with Abraham and Isaac. Sarah’s age was one hundred and
seven-and-twenty years, and she was as fair to look upon when she
died as in the bloom of her youth.
And as Abraham was bowed over the body of his wife, he heard the
laugh of the Angel of Death, and his words, “Wherefore weepest
thou? Thou bearest the blame of her death. Hadst thou not taken her
son from her, she would have been alive now.”
Abraham sought a place where to bury her; and he went to the
Hittites and asked them to suffer him to buy for his possession a
parcel of land, where he might bury one dead body. But they said,
“Nay, we will give thee land;” but he would not. So they said,
“Choose now a place where thou wouldst have thy sepulchre, and
we will entreat the owner for thee.”
Then Abraham said, “I desire the double cave of Ephron the son of
Zohar. If it be your mind that I should bury my dead out of my sight,
hear me, and entreat for me to Ephron the son of Zohar, that he may
give me the cave of Machpelah, which he hath; for as much money
as is worth he shall give it me, for a possession of a burying-place
amongst you.”
And this was the reason why Abraham desired that cave. When he
had gone after the calf, to slay it for the three angels that came to
him before the destruction of Sodom, the calf had fled from him, and
he had pursued it into this cave; and on entering it, he found that it
was roomy, and in the inner recesses he saw the bodies of Adam
and Eve laid out with burning tapers around them, and the air was
fragrant with incense.
The Hittites elected Emor their chief that he might deal with
Abraham, for it did not become a chief and prince, like Abraham, to
deal with an inferior; and Emor said in the audience of the people of
the land, “My Lord, hear me; the field give I thee, and the cave that is
therein, I give it thee; in the presence of the sons of my people give I
it thee; bury thy dead.”
But this he said with craft, for he sought to take an advantage of
Abraham.[336]
Then Ephron said, “Put thine own price upon the land;” but this
Abraham would not do.
Then Ephron said to Abraham, “My lord, hearken unto me; the land
is worth four hundred shekels of silver; what is that betwixt me and
thee? bury therefore thy dead.”
Now the land was not worth half that sum, but Emor said in his heart,
“Abraham can afford to pay it, and he is in haste to bury his dead out
of his sight.”
Nevertheless, Abraham paid him in the sight of all his people. And
the transfer of the land and cave was signed by Amigal, son of
Abischna the Hittite; Elichoran, son of Essunass, the Hivite; Abdon,
son of Ahirah, the Gomorrhite; and Akdil, son of Abdis, the Sidonian.
Machpelah (double cave) was so called, because, say some, it
contained two chambers; or, say others, because Abraham paid
double its value; or, say others, because it became doubly holy; but
others again observe, with the highest probability, because Adam’s
body had to be doubled up to get it into the cave.
Because the Hittites dealt honourably, and sought to procure a place
for Abraham, where he might lay Sarah, their name is written ten
times in the Holy Scriptures.
They took also an oath of Abraham, that he and his seed should
never attack their city Jebus with violence; and they wrote his
promise on brazen pillars, and set them up in the market-place of
Jebus. Therefore, when the Israelites conquered Canaan, they left
the Jebusites unmolested.[337] But when David sought to take the
stronghold of Jebus,[338] its inhabitants said to him, “Thou canst not
storm our city, because of the covenant of Abraham, which is
engraven on these pillars of brass.”
David removed these brazen pillars, for they were in time honoured
as idols; therefore the inhabitants of Jebus were hated of David’s
soul;[339] but he did not break the covenant of Abraham, for he
obtained the city of Jebus, not by force of arms, but by purchase.[340]
Sarah was buried with the utmost honour; Shem (Melchizedek), his
grandson Eber, Abimelech, Aner, Eshcol and Mamre, together with
all the great men of the land, followed the bier. Abraham caused a
great mourning throughout the country to be made for seven days.
After that, Abraham returned to Beer-sheba, and Isaac went to be
instructed in the law by Melchizedek. A year after, died Abimelech,
king of Gerar, and Abraham attended his funeral. Soon after, also,
died Nahor, Abraham’s brother.
 12. THE MARRIAGE OF ISAAC.

After the death of Sarah, say some, Abraham had a daughter named
Bakila, by Hagar, who returned to him now that her enemy was
dead; but, according to others, the great blessing of Abraham
consisted in this, that he had no daughters. Ishmael abandoned his
disorderly ways, and loved and respected his brother.
Isaac mourned his mother three years. When this time was elapsed,
Abraham called to him his faithful servant Eliezer, and said to him, “I
am old, and I know not the day of my death; therefore must I no
longer delay the marriage of my son Isaac. Lay thine hand upon my
thigh, and swear to me by God Almighty to fulfil my commission. Do
not take for my son a wife of the daughters of the Canaanites, but go
to Haran, to the place whence I came, and bring thence a wife for my
son Isaac.” And he added the proverb, “When you have wheat of
your own, do not sow your field with your neighbour’s corn.”
Eliezer asked, “But how, if a woman of that place will not accompany
me hither?”
But Abraham said, “Fear not; go, and the Lord be with thee.”
So the servant of Abraham went with ten camels, and he reached
Haran in three hours, for the earth fled under the feet of his camels,
and Michael, the angel, protected him on his way.
When he reached Haran, he besought the Lord to give him a sign,
by which he might know the maiden who was to be the wife of Isaac.
“Let it come to pass, that the damsel to whom I shall say, Let down
thy pitcher, I pray thee, that I may drink; and she shall say, Drink,
and I will give thy camels drink also; let the same be she that Thou
hast appointed for Thy servant Isaac.”
And there were many damsels by the fountain. And the servant said
to them, “Let down the pitcher that I may drink.” But they all said,
“We may not tarry, for we must take the water home.”
Then came Rebekah the daughter of Bethuel, son of Milcah, the wife
of Nahor, Abraham’s brother, out to the well, and she chid the
maidens for their churlishness; and lo! the water in the well leaped to
the margin, and she let down her pitcher and offered it to the man,
and said, “Drink; and I will give thy camels drink also.” Then Eliezer
leaped from his camel, and he brought forth his gifts, and he gave
her a nose ring with a jewel of half a shekel weight, and bracelets of
ten shekels weight. And he asked if he might lodge in her house one
night.
She answered, “Not one night only, but many.”
Now Rebekah’s brother, Laban, so called from the paleness of his
face,—or, say some, from the cowardice of his breast, which made
him pale,—coveted the man’s gold, and resolved to kill him.
Therefore he put poison in the bowl of meat which was offered him.
But the bowl was changed by accident, and it fell to the portion of
Bethuel, and he ate, and died that same night.
And Laban would have fallen upon Eliezer with his own hand, but
that he saw him lead the two camels at once over the brook, and he
knew thereby that he was stronger than he.
After the engagement had been drawn up, as is written in the first
book of Moses,[341] Eliezer urged for a speedy departure. Mother and
brother consented, but on the following day they asked that, besides
the seven days of mourning for Bethuel, they should tarry a year, or
at least ten months, according to the usual custom. But Rebekah
opposed them, and said that she would go at once.
It was noon when Eliezer and his retinue, together with Rebekah and
her nurse Deborah, left Haran, and in three hours they were at
Hebron.
At the self-same time Isaac was abroad in the fields, returning from
the school of Seth, lamenting over his mother, and saying his
evening prayer. Rebekah saw him with his hands outspread, and his
angel walking behind him, and she said, “Who is that with a shining
countenance, with another walking behind him?”
At the same moment she knew who it was, and with prophetic vision
she saw that she would become the mother of Esau, and she
trembled and fell from the camel.
Isaac took Rebekah to wife and led her into the tent of Sarah, and
the door was once more open, and the perpetual lamp was again
kindled, and it seemed to Isaac as if all the happiness that had gone
with Sarah, had returned with Rebekah, so he was comforted for his
mother.
Eliezer was rewarded for his faithful service, for Abraham gave him
his freedom, and he was taken into Paradise without having tasted of
death.
 13. THE DEATH OF ABRAHAM.

Abraham, after the death of Sarah, had brought back Hagar, and she
was called Keturah, which signifies “the Bond-woman,” and this she
was called because she had ever regarded herself as bound to
Abraham, though he had cast her away. But others say that Keturah
was not Hagar, but was a daughter of one of Abraham’s slaves. She
bare him six sons,[342] all strong, and men of clear understandings.
According to Mussulman traditions, she was the daughter of Jokdan,
and was a Canaanitish woman.
Abraham said to the Most High, in gratitude of heart, “Thou didst
promise me one son, Isaac, and thou hast given me many!”
All his substance he gave to Isaac; but some say he gave him a
double portion only, and the rest he made over to his other sons.
And to Isaac only he gave the right to be buried in the cave of
Machpelah, and along with that, his blessing. But others say that he
did not give his blessing to Isaac, lest it should cause jealousy to
spring up between him and his brothers. He said, “I am a mortal
man; to-day here, and to-morrow in the grave; I have done all I can
do for my children, and now I will depart when it pleases my
heavenly Father.”
He sent the sons of Keturah away, that they might not dwell near
Isaac, lest his greatness should swallow them up; and he built them
a city of iron, with walls of iron. But the walls were so high that the
light of the sun could not penetrate the streets, therefore he set in
them diamonds and pearls to illumine the iron city.
Epher, a grandson of Abraham and Keturah,[343] went with an army
into Libya and conquered it, and founded there a kingdom, and the
land he called after his own name, Africa.
Abraham was alive when Rebekah, after twenty years of barrenness,
bare to Isaac his sons, Esau and Jacob; and he saw them grow up
before him till their fifteenth year, and he died on the day that Esau
sold his birthright.
The days of his life had been 175 years; he reached not the age of
180, to which Isaac attained, because God shortened his life by five
years, lest he should know the evil deeds of Esau.
The Angel of Death did not smite him, but God kissed him, and he
died by that kiss; and because the sword of the angel touched him
not, but his soul parted to the kiss of God, his body saw no
corruption.
This is the Mussulman story of his death. The Angel of Death, when
bidden to take the soul of the prophet, hesitated about doing so
without his consent. So he took upon him the form of a very old man,
and came to Abraham’s door. The patriarch invited him in and gave
him to eat, but he noted with surprise the great infirmity of the old
man, how his limbs tottered, how dull was his sight, and how
incapable he was of feeding himself, for his hands shook, and how
little he could eat, for his teeth were gone. And he asked him how old
he was. Then the angel answered, “I am aged 202.” Now Abraham
was then 200 years old. So he said, “What! in two years shall I be as
feeble and helpless as this? O Lord, suffer me to depart; now send
the Angel of Death to me, to remove my soul.” Then the angel took
him,[344] having first watched till he was on his knees in prayer.[345]
Isaac and Ishmael buried him in the double cave by the side of
Sarah; and he was followed to his grave by all the inhabitants of
Canaan, and Shem and Eber went before the bier. And all the people
wailed and said, “Woe to the vessel when the pilot is gone! woe to
the pilgrims when their guide is lost!”
A whole year was Abraham lamented by the inhabitants of the land;
men, and women, and young children joined in bewailing him.
Never was there a man like Abraham in perfect righteousness,
serving God, and walking in His way from the earliest youth to the
day of his death.
Abraham was the first, say the Mussulmans, whose beard became
white. He asked God when it became so, “What is this?” The Lord
replied, “It is a token of gentleness, my son.”
 XXV.
MELCHIZEDEK.

We have seen that, according to Jewish traditions, Melchizedek is

Shem, the son of Noah, whom God consecrated to be a priest for
ever, and who set up a kingdom on Salem.[346]
It is also said that, before he died, Lamech ordered his son, Noah, to
transport the body of Adam to the centre of the earth. Now the centre
or navel of the earth is Salem, afterwards called Jerusalem.
Lamech also bade Noah confide to one of his children the custody of
the body of Adam, obliging him to remain all his life in the service of
God, and in the practice of celibacy, never to shed blood, and to offer
to God only the sacrifice of bread and wine.
Noah chose, according to some, Shem; according to others,
Melchizedek, the son of Shem. He did not suffer him to wear other
garments than the skins of beasts; nor to shave his head nor cut his
nails, nor to build a house.
A Christian tradition is that Adam was buried on Golgotha, and that
when Christ died, His blood flowed down upon the head of Adam,
and cleansed him of his sin.
Dom Calmet, in one of his dissertations, gives various curious
opinions which have been entertained on the subject of Melchizedek:
some affirmed that he was identical with the patriarch Enoch, who
came from the Terrestrial Paradise to confer with Abraham; and
others, that the Magi who adored the infant Christ were Enoch,
Melchizedek, and Elias.