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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).
Another Random Scribd Document
with Unrelated Content
 LIV

T
HAT word—purity, rang like a gong in Anthony's thoughts:
Eliza had emphasized it, questioning him. The term became
inexplicably merged with Eliza into one shining whole—Eliza,
purity; purity, Eliza. A swift impression of massed, white flowers
swept before him, leaving a delicate and trailing fragrance. He had a
vision of purity as something concrete, something which, like a
priceless and fragile vase, he guarded in his hands. It had been a
charge from her, a trust that he must keep unspotted, inviolable,
that she would require—but she was gone, she was dead.
“... through the valley of the shadow,” the other cried.
She had left him; he stood alone, guarding a meaningless thing,
useless as the money in his pocket.
A man with bare, corded arms and an apron, broke roughly
through the circle; and with a hand on Anthony's back, a hand on
the back of his opponent, urged them toward the door. “You'll have
to take this outside,” he pronounced, “you're blocking the bar.”
An arm linked within Anthony's, and swung him aside.
“Unavoidably detained by merest 'quaintance,” Thomas Meredith
explained with ponderous exactitude. Unobserved, they found a
place at the table they had occupied earlier in the evening. The
latter ordered a fresh bottle, but was persuaded by Anthony to
surrender the check which accompanied it.
A sudden hatred for the money that had come too late possessed
him: if he had had the whole forty-seven thousand dollars there he
would have torn it up, trampled upon it, flung it to the noisome
corners of the saloon. It seemed to have become his for the express
purpose of mocking at his sorrow, his loss. His hatred spread to
include that purity, that virtue, which he had conceived of as
something material, an actual possession.... That, at any rate, he
might trample under foot, destroy, when and as it pleased him. Eliza
was gone and all that was left was valueless. It had been, all
unconsciously, dedicated to her; and now he desired to cast it into
the mold that held her.
He fingered with a new care the sum in his pocket, an admirably
comprehensive plan had occurred to him—he would bury them both,
the money and purity, beneath the same indignity. Tom Meredith, he
was certain, could direct his purpose to its fulfillment. Nor was he
mistaken. The conversation almost immediately swung to the
subject of girls, girls gracious, prodigal of their charms. They would
sally forth presently and “see the town.” Tom loudly asseverated his
knowledge of all the inmates of all the complacent quarters under
the gas light. Before a cab was summoned Anthony stumbled
mysteriously to the bar, returning with a square, paper-wrapped
parcel.
“Port wine,” he ejaculated, “must have it... for a good time.”
 LV

A
SEEMINGLY interminable ride followed, they rattled over rough
stones, rolled with a clacking tire over asphalt. A smell
unnamable, fulsome, corrupt, hung in Anthony's nostrils; the
driver objurgated his horse in a desperate whisper; Tom's head fell
from side to side on his breast. The mists surged about Anthony,
veiling, obscuring all but the sullen purpose compressing his heart,
throbbing in his brain.
There was a halt, a rocking pavement and unctuous tones. Then a
hall, a room, and the tinny racket of a piano, feminine voices that, at
the same time, were hoarsely sexless, empty, like harsh echoes flung
from a rocky void. A form in red silk took possession of Anthony's
hand, sat by his side; a hot breath, a whisper, flattened against his
ear. At times he could distinguish Tom's accents; he seemed to be
arguing masterfully, but a shrill, voluble stream kept pace with him,
silenced him in the end.
Anthony strove against great, inimical forces to maintain his sanity
of action, ensure his purpose: he sat with a grim, haggard face as
rigid as wood, as tense as metal. The cloudy darkness swept over
him, impenetrable, appalling; through it he seemed to drop for
miles, for years, for centuries; it lightened, and he found himself
clutching the sides of his chair, shuddering over the space which, he
had felt, gaped beneath him.
In moments of respite he saw, gliding through the heated glare,
gaily-clad forms; they danced; yet for all the dancing, for all the
colors, they were more sinister than merry, they were incomparably
more grievous than gay. A tray of beer glasses was held before him,
but he waved it aside. “Champagne,” he muttered. The husky voices
commended him; a bare arm crept around his neck, soft, stifling;
the red silk form was like a blot of blood on the gloom; it spread
over his arm like a tide of blood welling from his torn heart.
 He thought at intervals, when the piano was silent, that he could
distinguish the sound of low, continuous sobbing; and the futility of
grief afforded a contemptuous amusement. “It's fierce,” a shrill voice
pronounced. “They ought to have took her somewhere else; this is a
decent place.” A second hotly silenced this declaration. In the jumble
of talk which followed he heard the title “captain” pronounced
authoritatively, conclusively imposing an abrupt lull. Men entered.
With an effort which taxed his every resource of concentration he
saw that there were two; he distinguished two tones—one
deliberate, coldly arrogant, the other explosive, iterating noisy
assertions. Peering through the film before his eyes, Anthony saw
that the first, insignificant in stature, exactly and fashionably
dressed, had a countenance flat and dark, like a Chinaman's; the
other was a fleshy young man in an electric blue suit, his neck
swelling in a crimson fold above his collar, who gesticulated with a
fat, white hand.
Anthony felt the attention of the room centered upon himself, he
heard disconnected periods; “... to the eyes. Good fellow... threw
friend out—one of them lawyer jags, too dam' smart.” A voice
flowed, thick and gummy like molasses, from the redness at his side,
“He's my fellow; ain't you, Raymond?”
A wave of deathly sickness swept up from the shuddering void and
enveloped him. He summoned his dissipated faculties, formed his
cold lips in readiness to pronounce fateful words, when he was
diverted by the sharp impact of a shutting door, he heard with
preternatural clearness a bolt slip in its channel. The young man in
the blue suit had disappeared. Again the sobbing, low and distinct,
rose and fell upon his hearing.
There was a general stir in the room; the form beside him rose;
and he was lunging to his feet when, in the act of moving, he
became immovable; he stood bent, with his hands extended,
listening; he turned his head slowly, he turned his dull, straining
gaze from side to side. Then he straightened up as though he had
been opened by a spring.
“Who—who called?” he demanded. “Who called me—Anthony?”
 In the short, startled silence which followed the room grew
suddenly clear before him, the mist dissolved before a garish flood
of gaslight that fell upon a grotesque circle of women in shapeless,
bright apparel; he saw haggard, youthful countenances on which
streaks of paint burned like flames; he saw eyes shining and dead
like glass marbles; mouths drawn and twisted as though by torture.
He saw the fragile, fashionably dressed youth with the flat face. No
one of them could have called him in the clear tone that had swept
like a silver stream through the miasma of his consciousness.
Again he heard it. “Anthony!” Its echo ran from his brain in thrills
of wonder, of response, to the tips of his fingers. “Anthony!” Oh,
God! he knew now, beyond all question, all doubt, that it was the
voice of Eliza. But Eliza was dead. It was an inexplicable, a cunning
and merciless jest, at the expense of his love, his longing....
“Anthony!” it came from above, from within.
A double, sliding door filled the middle of the wall, and, starting
forward, he fumbled with its small, brass handles. A sudden,
subdued commotion of curses, commands, arose behind him; hands
dragged at his shoulders; an arm as thin and hard as steel wire
closed about his throat. He broke its strangling hold, brushed the
others aside. The door was bolted. Yes, it came from beyond; and
from within came the sobbing that had hovered continuously at the
back of his perception.
He shook the door viciously; then, disregarding the hands tearing
at him from the rear, burst it open with his shoulder. He staggered
in, looking wildly about.... It had, after all, been only a freak of his
disordered mind, an hallucination of his pain. The room was empty
but for the young man in electric blue, now with his coat over the
back of a chair, and a girl with a torn waist, where her thin, white
shoulder showed dark, regular prints, and a tangle of hair across her
immature face.
The man in shirt sleeves rose from the couch, on which he had
been sitting, with a stream of sudden, surprised oaths. The girl who
stood gazing with distended eyes at Anthony turned and flashed
through the broken door. “Stop her!” was urgently cried; “the hall
door—” Anthony heard a chair fall in the room beyond, shrill cries
that sank, muffled in a further space.
The two men faced him in the silent room: the larger, with an
empurpled visage, bloodshot eyes, shook with enraged concern; the
other was as motionless as a piece of furniture, in his wooden
countenance his gaze glittered like a snake's, glittered as icily as the
diamond that sparkled in his crimson tie folded exactly beneath an
immaculate collar. Only, at intervals, his fingers twitched like jointed
and animated straws.
An excited voice cried from the distance: “She's gone! Alice's face
is tore open... out the door like a devil, and up the street in her
petticoat.”
The man with the flushed face wilted. “This is as bad as hell,” he
whimpered. “It will come out, sure. You—” he particularized Anthony
with a corroding epithet. “The captain is in it deep... this will do for
him, we'll all go up—”
“Why?” the other demanded. He indicated Anthony with his left
hand, while the other stole into his pocket. “He brought her here...
you heard the girl and broke into the room; there was a fight—a
fight.” He drew nearer to Anthony by a step.
 LVI

A
NTHONY gazed above their heads. There, again, clear and
sweet, his name shaped like a bell-note. The familiar scent of
a springtide of lilacs swept about him; the placid murmur of
water slipping between sodded banks, tumbling over a fall; the
querulous hunting cry of owls hovered in his hearing, singing in the
undertone of that pronouncement of his name out of the magic
region of his joy.
“No good,” a voice buzzed, indistinct, immaterial. “Who'll shut this
—? who'll get the girl?”
“The girl can't reach us alone....”
An intolerable scarlet hurt stabbed at Anthony out of a pungent,
whitish cloud. There was a fretful report. A flat, dark face without
expression, without the blink of an eyelid, a twitch of the mouth,
loomed before him and then shot up into darkness. The hurt
multiplied a thousand fold, it poured through him like molten metal,
lay in a flashing pool upon his heart, filled his brain. He opened his
lips for a protest, put out his hands appealingly. But he uttered no
sound, his arms sank, grew stiff... the light faded from his eyes....
imponderable silence. Frigid night....
Far off he heard her calling him, imperative, confident, glad. Her
crystal tones descended into the abyss whose black and eternal
walls towered above him. He must rise and bear to her that gift like
a precious and fragile vase which he held unbroken in his hands. An
ineffable fragrance deepened about him from the massed blooms
rosy in the glow where she waited, drawing him up to her out of the
chaotic wash beyond the worlds where the vapors of corrupted
matter sank and sank in slow coils, falling endlessly, forever.

THE END
*** END OF THE PROJECT GUTENBERG EBOOK THE LAY ANTHONY:
A ROMANCE ***

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