Vanders human physiology, the mechanisms of body function 9th ed e widmaier, h raff, k strang (mcgraw hill, 2003) 1

up-Chapter 1 Homeostasis: A Framework forHuman Physiology Thorough discussion of homeostasis Fluid composition across cell membranes Variability and time-averaged means Feedback at the o

Vander et al s Human Physiology:

9th Edition

Eric P Widmaier Hershel Raff

on the challenge of maintaining the strengths and reputation that have long been the

hallmark of Human Physiology: The Mechanisms of Body Function The fundamental

purpose of this textbook has remained undeniably the same: to present the principles and facts of human physiology in a format that is suitable for undergraduates regardless

of academic background or field of study Human Physiology, ninth edition, carries on

the tradition of clarity and accuracy, while refining and updating the content to meet the needs of today's instructors and students The ninth edition features a streamlined, clinically oriented focus to the study of human body systems Widmaier is considered

higher level than Human Physiology by Stuart Fox, due to its increased emphasis on the

mechanisms of body functions.

Human Physiology, Ninth

Edition

Companies, 2003

Assuming the authorship of a textbook with the

well-deserved reputation of Vander, Sherman, and Luciano’s

Human Physiology has been a privilege and an honor

for each of the new authors We have stayed true to the

overall mission of the textbook, which is to present the

topic of physiology in a sophisticated way that is

suit-able for any student of the science One of the strengths

of the Vander et al text has been its thoroughness and

clarity of presentation Although the text now reflects

our own writing style, we made it a priority to

con-tinue the tradition of presenting the material in each

chapter in an unambiguous, straightforward way, with

easy-to-follow illustrations and flow diagrams

The eighth edition of Human Physiology was

re-viewed extensively by colleagues across the United

States Many suggestions emerged that have enabled

us to improve even further the pedagogical value of

the textbook Long-time users of this textbook will

no-tice that certain chapters have been reorganized and,

in some cases, either expanded or condensed There

have also been a considerable number of new clinical

applications added to most chapters, without,

how-ever, having to resort to colored “boxes” scattered

throughout the text that distract the reader Many of

these new clinical features were incorporated into the

body of the text, while in other cases expanded

dis-cussions were added to the end-of-chapter sections in

a new feature called “Additional Clinical Examples.”

We feel that these additional clinical highlights will

grab the interest of students interested in any area of

health care, be it allied health, medicine or dentistry,

biomedical engineering, or any of the other related

health disciplines

Many features of this ninth edition will be familiar

to past users of the textbook For example, key terms

are featured in the text in boldface, while clinical terms

are in bold italics Key and clinical terms, with

pagi-nation, as well as succinct chapter summaries and

thought questions, are still included at the end of each

section and chapter The glossary, already among the

best of its kind, has been further expanded by over 400

terms Illustrations continue to make use of clear,

care-fully labelled diagrams and flowcharts However, the

new edition features something new in the inclusion of

photographs of individuals with clinical disorders

The goal of this revision has been to make an

ex-cellent textbook even better by presenting the material

in a sequence that is more geared to the typical sequence

of lectures offered in many human physiology courses.While we have retained the sophistication of the writ-ing style, we have also carefully gone over each sen-tence to improve the flow and readability of the text forthe modern student

“ the ninth edition appears poised to carry onthe excellence of its predecessors and shouldremain the most popular choice in the humanphysiology market.”

John J LepriUniversity of North Carolina-Greensboro

REVISION HIGHLIGHTS FOR NINTH EDITION

Consolidation of Homeostasis

A chief feature of the new edition is the consolidation

of the topic of homeostasis, which was previously splitbetween the opening chapter and Chapter 7 The textnow opens with an expanded, detailed chapter onhomeostasis and feedback This provides the studentwith a frame of reference, to enable him or her to ap-preciate the fact that homeostasis is the unifying prin-ciple of physiology This change also reflects the factthat many teachers of physiology begin their instruc-tion with a detailed discussion of homeostatic princi-ples

Streamlined Introductory Chapters

Former Chapter 2 has been retained and updated, whileformer Chapters 3 through 5 have been consolidatedinto a single chapter The material in Chapters 2 and 3

is presented in a logical pattern, beginning with cellchemistry and cell structure, proceeding to biochemicalcharacteristics of proteins, protein synthesis and degra-dation, and concluding with protein actions (includingenzymes) Some of the former material on the genetics

of the cell cycle and replication has been deleted, so thatthe focus of the introductory chapters is now directedmore toward protein structure and function and its re-lationship to physiology Streamlining this material hasalso allowed us to expand areas of particular interest inthe systems physiology chapters without extending thelength of the book

xxiPREFACE

Human Physiology, Ninth

Edition

Companies, 2003

“I like the idea of spending more time on organ

systems .consolidation of endocrine sections is a

good idea.”

James PorterBrigham Young University

New Endocrinology Chapter

A third major organizational change is the consolidation

of the presentations of thyroid function, endocrine

con-trol of growth, and the concon-trol of the stress response, from

their previous chapters throughout the text into a single

chapter on Endocrinology The hormones involved in

these processes are still referred to throughout the text in

the context of different organ systems, but the major

dis-cussions of thyroid hormone, growth hormone, and

cor-tisol are now presented as individual sections in Chapter

11 This change was made in response to numerous

re-quests from instructors to expand the endocrine unit and

make it more cohesive We have retained the

outstand-ing discussion of general principles of endocrinology as

the first section of the revised chapter

Improved Nervous System Coverage

The chapters on the nervous system, most notably, have

been updated to include new information on

neurotransmitter actions, learning and memory, and

sensory transduction, to name a few examples The

dis-cussion of electrical events in the cell has been expanded

and restructured For example, the Nernst equation and

its importance in understanding membrane potential

and ion flux has been moved from the appendices and

incorporated directly into the body of the text

Enhanced Clinical Coverage

Finally, dozens of new clinical features have been added

to the text, in order to better help the student put this

body of knowledge into a real-life context Some of these

are highlighted in the list that follows A list of clinical

terms used throughout the text has been included as a

separate index in Appendix F making it easy for the

reader to immediately locate where a particular

disor-der or disease is covered

“To me, the clinical examples are the strongest

point This makes the information more

relevant, and therefore, more learnable.”

James D HermanTexas A&M University

We believe the result of these changes is to make

a great book even better and more lecture-friendly, as

well as to draw the student deeper into the realm of

pathophysiology in addition to normal physiological

mechanisms

CHAPTER HIGHLIGHTS

The following is a list of some of the key changes, dates, and refinements that have been made to ninthedition chapters

up-Chapter 1 Homeostasis: A Framework forHuman Physiology

Thorough discussion of homeostasis Fluid composition across cell membranes Variability and time-averaged means Feedback at the organ and cellular levels Quantification of physiological variables

Chapter 2 Chemical Composition of the Body

Dehydration reactions Peptide/protein distinction Protein structures introduced ATP structure and importance

Chapter 3 Cell Structure and Protein Function

Condensed coverage of Chapters 3, 4, and 5 in eighth edition

Emphasis on protein biology Logical progression from cell chemistry through protein signaling mechanisms

Chapter 4 Movement of Molecules Across CellMembranes

Types of gated channels identified Details on transporter mechanisms Isotonic solutions to replace blood volume after injury

Chapter 5 Control of Cells by Chemical Messengers

Subunit structure and mechanism of G-proteins Genomic actions of cAMP

Calcium’s role in protein kinase C activation Eicosanoid structure and function

Chapter 6 Neuronal Signaling and the Structure of theNervous System

Revised discussion of the origin of resting and action potentials

Explanation of the Nernst equation and its importance

in understanding how ions move across neuronal membranes

Updated mechanisms of neurotransmitter release and actions Adrenergic subtypes and their actions

New Figures:

Myelin formation; Sodium and potassium channel function; Myelinization and saltatory conduction; Neurotransmitter storage and release; Brain surface and midline anatomy; Cellular organization of the cortex

New Clinical Material:

Mechanism of anesthetic action; Effects of diabetes on the nervous system

Chapter 7 Sensory Physiology

Recent discoveries related to sensory receptors Neural pathways of somatosensory system Phototransduction

New Figures:

Pathways of pain transmission; Phototransduction in Preface

xxii

Human Physiology, Ninth

Edition

Companies, 2003

photoreceptor; Neurotransmitter release in auditory

hair cell

New Clinical Material:

Genetics of color blindness; Genetic pedigree for red-green

color blindness; Loss of hearing and balance

Chapter 8 Consciousness, the Brain, and Behavior

Expansion of sleep/wake control mechanisms

New theories of memory function

Hemispheric dominance, including split-brain patients

New Figure:

Encoding and storing of memories

New Clinical Material:

Physiological changes associated with sleep; Manifestation

of unilateral visual neglect; Temporal lobe

dysfunction and formation of declarative memory;

Amygdala lobe dysfunction and emotions; Head

trauma and conscious state

Chapter 9 Muscle

Expanded description of cross-bridge cycle

Role of DHP and ryanodine receptors

Concentric versus eccentric muscle contractions

Tetanic muscle force

Oxygen debt

Latch state

New Figures:

Neuromuscular junction; Signaling at neuromuscular

junction; Muscle mechanics apparatus

New Clinical Material:

Paralytic agents in surgery; Nerve gas paralysis;

Botulinum toxin; Muscle cramps; Duchenne

muscular dystrophy; Myasthenia gravis

Chapter 10 Control of Body Movement

Expanded discussion of proprioception

New Clinical Material:

Embryonic stem cells and Parkinson’s disease; Cerebellar

function and autism; Clasp-knife phenomenon; Tetanus

Chapter 11 The Endocrine System

Membrane localization of certain receptors

Acute and delayed actions of hormones

Diffusion of steroid hormones

Effect of calcium on parathyroid hormone secretion

Thyroid anatomy; Thyroid hormone synthesis; Person with

goiter; Person with exophthalmia; Person with

Cushing’s syndrome; Person with acromegaly

New Clinical Material:

Androgen insensitivity syndrome; Autonomous

hormone-secreting tumors; Hypertrophy and goiter; Effects of

TH; Hyperthyroidism; Graves’ disease; Exophthalmos;

Hypothyroidism; Hashimoto’s disease; Myxedema;

Autoimmune thyroiditis; Treatment of thyroid

diseases; Effects of stress-induced cortisol production

on reproduction; Primary and secondary adrenal

insufficiency; Cushing’s syndrome; Treatment of

adrenal diseases; Laron dwarfism; Acromegaly and gigantism

Chapter 12 Cardiovascular Physiology

Updated information on pacemaker cells L-type calcium channels

Cushing’s phenomenon Reference table for ECG leads

New Figures:

Cardiac pacemaker cell action potential; Electron micrograph of brain capillary; Person with filariasis; Dye-contrast coronary angioplasty

New Clinical Material:

Angiostatin and blood vessel growth in cancer; Causes

of edema; Hypertrophic cardiomyopathy; Vasovagal syncope

“Content is appropriate level for my students, and

it is rigorous enough but not too rigorous.”

Charles NicollUniversity of California-Berkeley

Chapter 13 Respiratory Physiology

Law of Laplace Steep portion of oxygen dissociation curve

New Figures:

Law of Laplace; Sleep apnea

New Clinical Material:

Nitric oxide as treatment for persistent pulmonary hypertension; Acute respiratory distress syndrome; Sleep apnea

Chapter 14 The Kidneys and Regulation of Water andInorganic Ions

Effects of constriction and dilation of afferent and efferent arterioles; Dietary sources of vitamin D

New Figures:

Parathyroid glands; Arteriolar constriction and dilation in glomerulus; Hemodialysis

New Clinical Material:

Incontinence; Subtypes of diabetes insipidus; ACE inhibitors and angiotensin II receptor antagonists; Hyperaldosteronism; Hypercalcemia and hypocalcemia; Hyperparathyroidism; Humoral hypercalcemia of malignancy; Primary hypoparathyroidism; Pseudohypoparathyroidism

Chapter 15 The Digestion and Absorption of Food

Table on the functions of saliva Role of CNS in GI function Effect of pH on pepsin production Updated average daily intakes of carbohydrate, fat, and protein

New Figure:

Endoscopy

New Clinical Material:

Inflammatory bowel disease; Malabsorption; Pernicious anemia; Sjögren’s syndrome; Steatorrhea;

Lithotripsy

xxiii

Preface

Human Physiology, Ninth

Resistin and insulin resistance

Effect of temperature on rate of chemical reactions

New Clinical Material:

Familial hyperchlolesterolemia; Vitamin deficiency and

hyperthyroidism; Leptin resistance; Decreased leptin

during starvation; Hypothalamic disease; Brown

adipose tissue; Heat stroke and heat exhaustion

Chapter 17 Reproduction

Dihydrotestosterone; 5-alpha-reductase, and aromatase

New theories on initiation of parturition

New Figures:

Klinefelter’s syndrome; Congenital adrenal hyperplasia

New Clinical Material:

Male pattern baldness; Hypogonadism; Klinefelter’s

syndrome; Gynecomastia; Hyperprolactinemia;

Toxemia; Breech presentation; Contraception

methods; Amenorrhea; Cloning; Cryptorchidism;

Congenital adrenal hyperplasia; Virilization;

Ambiguous genitalia; Precocious puberty

Chapter 18 Defense Mechanisms of the Body

Cross-talk within immune system

Margination

Diapedesis

Types of antigens

Structure of immunoglobulins

New Clinical Material:

Karposi’s sarcoma; Systemic lupus erythematosus

ACKNOWLEDGMENTS

The authors are deeply indebted to the following

indi-viduals for their contributions to the ninth edition of

Human Physiology Their feedback on the eighth edition,

their critique of the revised text, or their participation

in a focus group provided invaluable assistance and

greatly improved the final product Any errors that may

remain are solely the responsibility of the authors

St Luke’s Medical Center

Lois Jane Heller

University of Minnesota, School of Medicine–Duluth

University of North Carolina–Greensboro

Charles Kingsley Levy

Boston University

Preface

xxiv

Human Physiology, Ninth

Mary Katherine K Lockwood

University of New Hampshire

Lansing Community College

We also wish to acknowledge the support and fessionalism of the McGraw-Hill Publishing team as-sociated with this text, particularly Publishers MartyLange and Colin Wheatley, Sponsoring Editor MichelleWatnick, Senior Developmental Editor Lynne Meyers,and Administrative Assistant Darlene Schueller Theauthors are extremely grateful for the expert and thor-ough assistance of our collaborator on this textbook,

pro-Dr Mary Erskine of Boston University Finally, warmthanks to Arthur Vander, Jim Sherman, and DorothyLuciano, for having the confidence to hand over thereigns of a wonderful textbook to a new team, and forproviding us with valuable advice along the way

Eric P WidmaierHershel RaffKevin T Strang

xxv

Preface

Human Physiology, Ninth

PHYSIOLOGY

The Scope of Human Physiology

How Is the Body Organized?

Cells: The Basic Units of Living Organisms

Tissues

Organs and Organ Systems

Body Fluid Compartments

Homeostasis: A Defining Feature of

Physiology

Variability and Time-Averaged Means

How Can Homeostasis Be Quantified?

General Characteristics ofHomeostatic Control Systems

Feedback Resetting of Set Points Feedforward Regulation

Components of Homeostatic ControlSystems

Reflexes Local Homeostatic Responses

Intercellular Chemical Messengers

Paracrine/Autocrine Agents

Processes Related to Homeostasis

Adaptation and Acclimatization Biological Rhythms Regulated Cell Death: Apoptosis Balance in the Homeostasis of Chemicals

Human Physiology, Ninth

Edition

Framework for Human Physiology

Companies, 2003

One cannot meaningfully analyze the complex activities

of the human body without a framework upon which

to build, a set of concepts to guide one’s thinking It is the

purpose of this chapter to provide such an orientation to the subject of human physiology.

ing of physiology is essential for the study and tice of medicine Indeed, many physiologists arethemselves actively engaged in research on the phys-iological bases of a wide range of diseases In this text,

prac-we will give many examples of pathophysiology to illustrate the basic physiology that underlies the disease

HOW IS THE BODY ORGANIZED?

Cells: The Basic Units of Living Organisms

The simplest structural units into which a complex ticellular organism can be divided and still retain the

mul-functions characteristic of life are called cells One of the

unifying generalizations of biology is that certain damental activities are common to almost all cells andrepresent the minimal requirements for maintaining cellintegrity and life Thus, for example, a human liver celland an amoeba are remarkably similar in their means

fun-of exchanging materials with their immediate ments, of obtaining energy from organic nutrients, ofsynthesizing complex molecules, of duplicating them-selves, and of detecting and responding to signals intheir immediate environment

environ-Each human organism begins as a single cell, a tilized egg, which divides to create two cells, each ofwhich divides in turn, resulting in four cells, and so on

fer-If cell multiplication were the only event occurring, theend result would be a spherical mass of identical cells.During development, however, each cell becomes spe-cialized for the performance of a particular function,such as producing force and movement (muscle cells)

or generating electric signals (nerve cells) The process

of transforming an unspecialized cell into a specialized

cell is known as cell differentiation, the study of which

is one of the most exciting areas in biology today Allcells in a person have the same genes; how then is oneunspecialized cell instructed to differentiate into a nervecell, another into a muscle cell, and so on? What are theexternal chemical signals that constitute these “instruc-tions, ” and how do they affect various cells differently?For the most part, the answers to these questions areunknown

In addition to differentiating, cells migrate to newlocations during development and form selective adhesions with other cells to produce multicellular2

THE SCOPE OF HUMAN

PHYSIOLOGY

Stated most simply and broadly, physiology is the

study of how living organisms work As applied to

hu-man beings, its scope is extremely broad At one end

of the spectrum, it includes the study of individual

molecules—for example, how a particular protein’s

shape and electrical properties allow it to function as

a channel for sodium ions to move into or out of a cell

At the other end, it is concerned with complex

processes that depend on the interplay of many widely

separated organs in the body—for example, how the

brain, heart, and several glands all work together to

cause the excretion of more sodium in the urine when

a person has eaten salty food

What makes physiologists unique among biologists

is that they are always interested in function and

inte-gration—how things work together at various levels of

organization and, most importantly, in the entire

or-ganism Thus, even when physiologists study parts of

organisms, all the way down to individual molecules,

the intention is ultimately to apply whatever

informa-tion is gained to the funcinforma-tion of the whole body As

the nineteenth-century physiologist Claude Bernard put

it: “After carrying out an analysis of phenomena, we

must always reconstruct our physiological

synthe-sis, so as to see the joint action of all the parts we have

isolated .”

In this regard, a very important point must be made

about the present status and future of physiology It is

easy for a student to gain the impression from a

text-book that almost everything is known about the

sub-ject, but nothing could be farther from the truth for

physiology Many areas of function are still only poorly

understood (for example, how the workings of the brain

produce the phenomena we associate with conscious

thought and memory)

Indeed, we can predict with certainty a

continu-ing explosion of new physiological information and

understanding One of the major reasons is related to

the recent landmark sequencing of the human

genome As the functions of all the proteins encoded

by the genome are uncovered, their application to the

functioning of the cells and organ systems discussed

in this text will provide an ever-sharper view of how

our bodies work

Finally, a word should be said about the

relation-ship between physiology and medicine Some disease

states can be viewed as physiology “gone wrong, ” or

pathophysiology, and for this reason an

understand-Human Physiology, Ninth

structures In this manner, the cells of the body are

arranged in various combinations to form a hierarchy

of organized structures Differentiated cells with

sim-ilar properties aggregate to form tissues (nerve tissue,

muscle tissue, and so on), which combine with other

types of tissues to form organs (the heart, lungs,

kid-neys, and so on), which are linked together to form

or-gan systems (Figure 1–1)

About 200 distinct kinds of cells can be identified in

the body in terms of differences in structure and

func-tion When cells are classified according to the broad

types of function they perform, however, four categories

emerge: (1) muscle cells, (2) nerve cells, (3) epithelial

cells, and (4) connective tissue cells In each of these

func-tional categories, there are several cell types that perform

variations of the specialized function For example, there

are three types of muscle cells—skeletal, cardiac, and

smooth—which differ from each other in shape, in the

mechanisms controlling their contractile activity, and in

their location in the various organs of the body

Muscle cells are specialized to generate the

me-chanical forces that produce movement They may be

attached to bones and produce movements of the limbs

or trunk They may be attached to skin, as for example,

the muscles producing facial expressions They may also

surround hollow cavities so that their contraction

ex-pels the contents of the cavity, as in the pumping of the

heart Muscle cells also surround many of the tubes in

the body—blood vessels, for example—and their

con-traction changes the diameter of these tubes

Nerve cells are specialized to initiate and conduct

electrical signals, often over long distances A signal may

initiate new electrical signals in other nerve cells, or it

may stimulate secretion by a gland cell or contraction

of a muscle cell Thus, nerve cells provide a major means

of controlling the activities of other cells The incredible

complexity of nerve-cell connections and activity

underlie such phenomena as consciousness and

per-ception

Epithelial cells are specialized for the selective

se-cretion and absorption of ions and organic molecules,

and for protection They are located mainly at the

sur-faces that (1) cover the body or individual organs or

(2) line the walls of various tubular and hollow

struc-tures within the body Epithelial cells, which rest on an

extracellular protein layer called the basement

mem-brane,form the boundaries between compartments and

function as selective barriers regulating the exchange of

molecules across them For example, the epithelial cells

at the surface of the skin form a barrier that prevents

most substances in the external environment—the

en-vironment surrounding the body—from entering the

body through the skin Epithelial cells are also found

in glands that form from the invagination of epithelial

surfaces

Fertilized egg

Cell division and growth

Cell differentiation

Specialized cell types

Tissues

Functional unit (e.g., nephron)

Organ (e.g., kidney)

Organ system (e.g., urinary system)

Total organism (human being)

Epithelial cell

tissue cell

Connective-Nerve cell

Muscle cell

Nephron

Ureter

Bladder Urethra Kidney

FIGURE 1 – 1

Levels of cellular organization.

Human Physiology, Ninth

ex-units often referred to as functional ex-units, each

per-forming the function of the organ For example, thekidneys’ functional units are termed nephrons (whichcontain the small tubes mentioned in the previous para-graph), and the total production of urine by the kidneys

is the sum of the amounts formed by the two millionindividual nephrons

Finally we have the organ system, a collection oforgans that together perform an overall function Forexample, the kidneys, the urinary bladder, the tubesleading from the kidneys to the bladder, and the tubeleading from the bladder to the exterior constitute theurinary system There are 10 organ systems in the body.Their components and functions are given in Table 1–1

To sum up, the human body can be viewed as acomplex society of differentiated cells structurally andfunctionally combined to carry out the functionsessential to the survival of the entire organism The in-dividual cells constitute the basic units of this society,and almost all of these cells individually exhibit the fun-damental activities common to all forms of life Indeed,many of the cells can be removed and maintained in

test tubes as free-living “organisms” (this is termed in

vitro, literally “in glass,” as opposed to in vivo, meaning

“within the body”)

There is a paradox in this analysis: How is it thatthe functions of the organ systems are essential to thesurvival of the body when each cell seems capable ofperforming its own fundamental activities? As de-scribed in the next section, the resolution of this para-dox is found in the isolation of most of the cells of thebody from the external environment and in the existence

of a reasonably stable internal environment (defined as

the fluid surrounding all cells)

BODY FLUID COMPARTMENTS

Water is present within and around the cells of the body,and within all the blood vessels Collectively, the fluidpresent in blood and in the spaces surrounding cells is

called extracellular fluid Of this, only about 20% is in the fluid portion of blood, the plasma, in which the var-

ious blood cells are suspended The remaining 80% ofthe extracellular fluid, which lies between cells, is

known as the interstitial fluid.

As the blood flows through the smallest of bloodvessels in all parts of the body, the plasma exchanges

CHAPTER ONE Homeostasis: A Framework for Human Physiology

4

Connective tissue cells, as their name implies,

con-nect, anchor, and support the structures of the body

Some connective tissue cells are found in the loose

meshwork of cells and fibers underlying most

epithe-lial layers; other types include fat-storing cells, bone

cells, and red blood cells and white blood cells

Tissues

Most specialized cells are associated with other cells of

a similar kind to form tissues Corresponding to the four

general categories of differentiated cells, there are four

general classes of tissues: (1) muscle tissue, (2) nerve

tissue, (3) epithelial tissue, and (4) connective tissue.

It should be noted that the term “tissue ” is used in

dif-ferent ways It is formally defined as an aggregate of a

single type of specialized cell However, it is also

com-monly used to denote the general cellular fabric of any

organ or structure, for example, kidney tissue or lung

tissue, each of which in fact usually contains all four

classes of tissue

The immediate environment that surrounds each

individual cell in the body is the extracellular fluid

Actually, this fluid is interspersed within a complex

extracellular matrix consisting of a mixture of protein

molecules (and, in some cases, minerals) specific for any

given tissue The matrix serves two general functions:

(1) It provides a scaffold for cellular attachments, and

(2) it transmits information to the cells, in the form of

chemical messengers, that helps regulate their activity,

migration, growth, and differentiation

The proteins of the extracellular matrix consist of

fibers —ropelike collagen fibers and rubberband-like

elastin fibers—and a mixture of nonfibrous proteins

that contain chains of complex sugars (carbohydrates)

In some ways, the extracellular matrix is analogous to

reinforced concrete The fibers of the matrix, particularly

collagen, which constitutes one-third of all bodily

pro-teins, are like the reinforcing iron mesh or rods in the

concrete, and the carbohydrate-containing protein

mol-ecules are the surrounding cement However, these

lat-ter molecules are not merely inert “packing malat-terial, ”

as in concrete, but function as adhesion/recognition

molecules between cells Thus, they are links in the

com-munication between extracellular messenger molecules

and cells

Organs and Organ Systems

Organs are composed of the four kinds of tissues

arranged in various proportions and patterns: sheets,

tubes, layers, bundles, strips, and so on For example,

the kidneys consist of (1) a series of small tubes, each

composed of a single layer of epithelial cells; (2) blood

vessels, whose walls contain varying quantities of

Human Physiology, Ninth

oxygen, nutrients, wastes, and other metabolic products

with the interstitial fluid Because of these exchanges,

concentrations of dissolved substances are virtually

identical in the plasma and interstitial fluid, except for

protein concentration With this major exception—

higher protein concentration in plasma than in

intersti-tial fluid—the entire extracellular fluid may be

consid-ered to have a homogeneous composition In contrast,

the composition of the extracellular fluid is very

differ-ent from that of the intracellular fluid, the fluid inside

the cells Maintaining differences in fluid composition

across the cell membrane is an important way in which

cells regulate their own activity For example,

intracel-lular fluid contains many different proteins that are

im-portant in regulating cellular events like growth and

metabolism

In essence, the fluids in the body are enclosed in

“compartments.” The volumes of the body fluid

com-partments are summarized in Figure 1–2 in terms of

water, since water is by far the major component of the

fluids Water accounts for about 60 percent of normalbody weight Two-thirds of this water (28 L in a normal70-kg person) is intracellular fluid The remaining one-third (14 L) is extracellular and as described above, 80percent of this extracellular fluid is interstitial fluid(11 L) and 20 percent (3 L) is plasma

Compartmentalization is an important general ciple in physiology Compartmentalization is achieved

prin-by barriers between the compartments The properties

of the barriers determine which substances can move tween contiguous compartments These movements inturn account for the differences in composition of the dif-ferent compartments In the case of the body fluid com-partments, the intracellular fluid is separated from theextracellular fluid by membranes that surround the cells.The properties of these membranes and how they ac-count for the profound differences between intracellularand extracellular fluid are described in Chapter 4 In con-trast, the two components of extracellular fluid—the in-terstitial fluid and the blood plasma—are separated by

be-TABLE 1–1 Organ Systems of the Body

SYSTEM MAJOR ORGANS OR TISSUES PRIMARY FUNCTIONS

Mouth, pharynx, esophagus, stomach, intestines, salivary glands, pancreas, liver, gallbladder Kidneys, ureters, bladder, urethra

Cartilage, bone, ligaments, tendons, joints, skeletal muscle

White blood cells, lymph vessels and nodes, spleen, thymus, and other lymphoid tissues

Brain, spinal cord, peripheral nerves and ganglia, special sense organs

All glands secreting hormones: Pancreas, testes, ovaries, hypothalamus, kidneys, pituitary, thyroid, parathyroid, adrenal, intestinal, thymus, heart, and pineal, and endocrine cells in other locations

Male: Testes, penis, and associated ducts and glands Female: Ovaries, fallopian tubes, uterus, vagina, mammary glands

Skin

Transport of blood throughout the body’s tissues

Exchange of carbon dioxide and oxygen; regulation of hydrogen ion concentration

Digestion and absorption of organic nutrients, salts, and water

Regulation of plasma composition through controlled excretion of salts, water, and organic wastes Support, protection, and movement of the body; production of blood cells

Defense against foreign invaders; return of extracellular fluid to blood; formation of white blood cells

Regulation and coordination of many activities in the body; detection of changes in the internal and external environments; states of consciousness;

learning; cognition Regulation and coordination of many activities in the body, including growth, metabolism, reproduction, blood pressure, electrolyte balance, and others

Production of sperm; transfer of sperm to female Production of eggs; provision of a nutritive environment for the developing embryo and fetus; nutrition of the infant

Protection against injury and dehydration; defense against foreign invaders; regulation of temperature

Human Physiology, Ninth

internal milieu that is a prerequisite for good health, a

concept later refined by the American physiologist

Walter Cannon, who coined the term homeostasis.

In its simplest form, homeostasis may be defined

as a state of reasonably stable balance between the iological variables such as those just described Thissimple definition cannot give a complete appreciation

phys-of what homeostasis truly entails, however There ably is no such thing as a physiological variable that isconstant over long periods of time In fact, some vari-ables undergo fairly dramatic swings around an aver-age value during the course of a day, yet may still beconsidered “in balance.” That is because homeostasis is

prob-a dynprob-amic process, not prob-a stprob-atic one Consider the swings

in blood glucose levels over the course of a day After ameal, blood glucose levels may nearly double Clearly,such a large rise above baseline cannot be consideredparticularly stable What is important, though, is thatonce glucose increases, compensatory mechanismsquickly restore glucose levels toward baseline In thecase of glucose, the endocrine system is primarily re-sponsible for this quick adjustment, but in other exam-ples, a wide variety of control systems may be initiated

In later chapters, we will see how nearly every organ

CHAPTER ONE Homeostasis: A Framework for Human Physiology

6

the cellular wall of the smallest blood vessels, the

capil-laries How this barrier normally keeps 80 percent of the

extracellular fluid in the interstitial compartment and

re-stricts proteins mainly to the plasma is described in

Chapter 12

HOMEOSTASIS: A DEFINING

FEATURE OF PHYSIOLOGY

From the earliest days of physiology—at least as early

as the time of Aristotle—physicians recognized that

good health was somehow associated with a “balance”

among the multiple life-giving forces (“humours”) in

the body It would take millennia, however, for

scien-tists to determine just what it was that was being

bal-anced, and how this balance was achieved The advent

of modern tools of science, including the ordinary

microscope, led to the discovery that living tissue is

composed of trillions of small cells, each of which is

packaged in such a way as to permit movement of

cer-tain substances, but not others, across the cell

mem-brane Over the course of the nineteenth and twentieth

centuries, it became clear that most cells are in contact

with the interstitial fluid The interstitial fluid, in turn,

was found to be in a state of flux, with chemicals, gases,

and water traversing it in two directions back and forth

between the cell interiors and the blood in nearby

ves-sels called capillaries (Figure 1–2)

It was further determined by careful observation

that most of the common physiological variables found

Total body water (TBW) Volume = 42 L, 60% body weight

Extracellular fluid (ECF) (Internal environment) Volume = 14 L, 1/3 TBW

Intracellular fluid Volume = 28 L, 2/3 TBW

Interstitial fluid Volume = 11 L 80% of ECF

Plasma Volume = 3 L 20% of ECF

FIGURE 1 – 2

Fluid compartments of the body Volumes are for an average 70-kg (154-lb) person The bidirectional arrows indicate that fluid can move between any two adjacent compartments TBW ⫽ total body water; ECF ⫽ extracellular fluid.

Human Physiology, Ninth

and tissue of the human body contributes to

homeo-stasis, sometimes in multiple ways, and usually in

con-cert with each other

Thus, homeostasis does not imply that a given

physiological function is rigidly constant with respect

to time, but that it is relatively constant, and when

dis-turbed (up or down) from the normal range, it is

re-stored to baseline

Variability and Time-Averaged Means

What do we mean when we say that something remains

“relatively” constant? This depends on just what is

be-ing monitored If the circulatbe-ing arterial oxygen level of

a healthy person breathing air at sea level is measured,

it does not change much over the course of time, even

if the person exercises Such a system is said to be tightly

controlled and to demonstrate very little variability or

scatter around an average value Blood glucose levels,

as we have seen, may vary considerably over the course

of a day Yet, if a time-averaged mean glucose level was

determined in the same person on many consecutive

days, it would be much more predictable over days or

even years than random, individual measurements of

glucose over the course of a single day In other words,

there may be considerable variation in glucose values

over short time periods, but less when they are

aver-aged over long periods of time Homeostasis must be

described differently, therefore, for each variable

It is also important to realize that a person may be

homeostatic for one variable, but not homeostatic for

another For example, as long as the concentration of

sodium in the blood remains within a few percent of

the normal range, sodium homeostasis is established

But a person in sodium homeostasis may suffer from

other disturbances, such as abnormally high carbon

dioxide levels in the blood, a condition that could be

fa-tal Just one nonhomeostatic variable, among the many

that can be described, can have life-threatening

conse-quences Typically, though, if one system becomes

dra-matically out of balance, other systems in the body

be-come nonhomeostatic as a consequence In general, if

all the major organ systems are operating in a

homeo-static manner, a person is in good health Certain kinds

of disease, in fact, can be defined as the loss of

homeo-stasis in one or more systems in the body To elaborate

on our definition of physiology, therefore, when

homeo-stasis is maintained, we refer to physiology; when it is

not, we refer to pathophysiology

How Can Homeostasis Be Quantified?

How are time-averaged means determined, and what

conditions must be met in order to ascertain whether or

not a person is homeostatic for a given variable? To

ob-tain this information, we must observe the person

enough times to define the normal baseline values forthat variable In practice, this is not always possible,since it is usually a loss of homeostasis that brings aperson to the doctor’s office for an examination Instead,

we rely on values obtained from large populations ofhealthy subjects, distributed according to age, sex,weight, and other characteristics

To interpret the meaning of, say, a person’s bodytemperature, we must first know not only what the nor-mal body temperature should be, but how it normallyvaries over the course of a day For example, body tem-perature is typically affected by activity, eating, and time

of day If we didn’t know this, we could draw erroneousconclusions by comparing a body temperature readingtaken after a meal in the late afternoon with a “stan-dard” value obtained from healthy subjects beforebreakfast Even in a tightly controlled setting that elim-inates the confounding factors of activity and eating,both of which raise body temperature, there is an un-derlying, daily cycle in body temperature that is inde-pendent of other factors (see the section on circadianrhythms at the end of this chapter) Thus, it is crucial totake into account all of these factors when assessingwhether or not a person’s body temperature is homeo-static

Body temperature is not the only physiological able that fluctuates each day with a cyclical periodicity.Such rhythms are widespread in nature, and in the hu-man body they are seen in the concentrations of circu-

vari-lating hormones (a type of chemical messenger secreted

into the blood), in sleep-wake cycles, and in theexpression of certain cellular proteins, to give a few ex-amples As a consequence, measurements of a particu-lar variable are usually obtained at a single time of dayconsistently from person to person In some diseasestates, however, this may not be sufficient In certaintypes of hormonal diseases, for example, the plasmaconcentration of the hormone may be normal at onetime of the daily cycle, but higher than normal at othertimes Thus, if the hormone in the blood was measured

at only one time of day, the disorder might be missed.One way to avoid this problem is to obtain repeatedmeasurements of the hormone over a 24-hour period.Ideally, repeated blood measurements could be drawn

to provide as complete a profile as possible of theminute-to-minute changes in circulating hormone lev-els Because this is usually not practical, a simplermethod is to obtain a 24-hour cumulative urine sample.Metabolites of many hormones appear in the urine aspart of the daily process of clearing excess hormonefrom the blood The more hormone in the blood, themore it or its metabolites appear in the urine A 24-hourmeasurement will provide information on the inte-grated, or summed, amount of hormone produced dur-ing that day and night This, then, is a time-averaged

Human Physiology, Ninth

mean It tells nothing of the countless small (and

some-times large) fluctuations in circulating hormone

concentration that occurred during that time It does,

however, reveal whether or not abnormally low or high

total amounts of hormone were produced.

GENERAL CHARACTERISTICS

OF HOMEOSTATIC

CONTROL SYSTEMS

The activities of cells, tissues, and organs must be

reg-ulated and integrated with each other in such a way that

any change in the extracellular fluid initiates a reaction

to correct the change Homeostasis, then, denotes the

relatively stable conditions of the internal environment

that result from these compensating regulatory

re-sponses performed by homeostatic control systems.

Consider again the regulation of body temperature

Our subject is a resting, lightly clad man in a room

hav-ing a temperature of 20°C and moderate humidity His

internal body temperature is 37°C, and he is losing heat

to the external environment because it is at a lower

tem-perature However, the chemical reactions occurring

within the cells of his body are producing heat at a rate

equal to the rate of heat loss Under these conditions, the

body undergoes no net gain or loss of heat, and the body

temperature remains constant The system is said to be

in a steady state, defined as a system in which a

partic-ular variable (temperature, in this case) is not changing

but energy (in this case, heat) must be added

continu-ously to maintain this variable constant (Steady state

differs from equilibrium, in which a particular variable

is not changing but no input of energy is required to

maintain the constancy.) The steady-state temperature in

our example is known as the set point (also termed the

operating point) of the thermoregulatory system

This example illustrates a crucial generalization

about homeostasis: Stability of an internal

environmen-tal variable is achieved by the balancing of inputs and

outputs In this case, the variable (body temperature)

re-mains constant because metabolic heat production

(in-put) equals heat loss from the body (out(in-put)

Now we lower the temperature of the room rapidly,

say to 5°C, and keep it there This immediately increases

the loss of heat from our subject’s warm skin, upsetting

the dynamic balance between heat gain and loss The

body temperature therefore starts to fall Very rapidly,

however, a variety of homeostatic responses occur to

limit the fall These are summarized in Figure 1–3 The

reader is urged to study Figure 1–3 and its legend carefully

because the figure is typical of those used throughout the

remainder of the book to illustrate homeostatic systems, and

the legend emphasizes several conventions common to such

figures.

Constriction

of skin blood vessels

Curling up Shivering

Return of body temperature toward original value

Begin

Room temperature

Heat loss from body

Body temperature Heat loss from body

Heat production (Body's responses)

FIGURE 1 – 3

The homeostatic control system maintains a relatively constant body temperature when room temperature decreases This flow diagram is typical of those used throughout the remainder of this book to illustrate homeostatic systems, and several conventions should be noted The “begin” sign indicates where

to start The arrows next to each term within the boxes denote increases or decreases The arrows connecting any two boxes in the figure denote cause and effect; that is, an arrow can be read

as “causes” or “leads to.” (For example, decreased room temperature “leads to” increased heat loss from the body.) In general, one should add the words “tends to” in thinking about these cause-and-effect relationships For example, decreased room temperature tends to cause an increase in heat loss from the body, and curling up tends to cause a decrease in heat loss from the body Qualifying the relationship in this way is necessary because variables like heat production and heat loss are under the influence of many factors, some of which oppose each other.

Human Physiology, Ninth

The first homeostatic response is that blood vessels

to the skin become narrowed (“constricted”), reducing

the amount of warm blood flowing through the skin

and thus reducing heat loss to the environment At a

room temperature of 5°C, however, blood vessel

con-striction cannot completely eliminate the extra heat loss

from the skin Our subject curls up in order to reduce

the surface area of the skin available for heat loss This

helps a bit, but excessive heat loss still continues, and

body temperature keeps falling, although at a slower

rate He has a strong desire to put on more clothing—

“voluntary” behavioral responses are often crucial

events in homeostasis—but no clothing is available

Clearly, then, if excessive heat loss (output) cannot be

prevented, the only way of restoring the balance

be-tween heat input and output is to increase input, and

this is precisely what occurs He begins to shiver, and

the chemical reactions responsible for the skeletal

mus-cular contractions that constitute shivering produce

large quantities of heat

Feedback

The thermoregulatory system just described is an

ex-ample of a negative feedback system, in which an

in-crease or dein-crease in the variable being regulated brings

about responses that tend to move the variable in the

direction opposite (“negative” to) the direction of the

original change Thus, in our example, the decrease in

body temperature led to responses that tended to

in-crease the body temperature—that is, move it toward its

original value

“Feedback,” a term borrowed from engineering, is

a fundamental feature of homeostasis It can occur at

multiple levels of organization, and it can be either

negative or positive, the former being by far the more

common

Without feedback, oscillations like some of those

described in this chapter would be much greater; i.e.,

the variability in a given system would increase

Feedback also prevents the compensatory responses

to a loss of homeostasis from continuing unabated

For example, one major compensatory response that

is common to a loss of homeostasis in many variables

is a rise in the blood level of a hormone called

corti-sol (which is made in the adrenal glands) The effects

of cortisol are widespread, encompassing metabolic,

cardiovascular, respiratory, renal, and immune

activ-ities These actions tend to restore homeostasis (e.g.,

help restore blood glucose levels if glucose should fall

below normal) Although vital and often life-saving,

too much cortisol can be dangerous Prolonged

ex-posure to cortisol may produce a variety of problems;

in the previous example, too much cortisol would

cause blood glucose levels to rise higher than the

nor-mal range Thus, it is crucial that once cortisol hasdone its job, it is removed from the circulation andreturned to normal levels This is accomplished by

the process of negative feedback inhibition In this case,

cortisol inhibits the production of those blood-bornesignals that stimulated the production of cortisol inthe first place Details of the mechanisms and char-acteristics of negative feedback within different sys-tems will be addressed in later chapters For now, it

is important to recognize that negative feedback is avital part of the checks and balances on most physi-ological variables

Negative feedback may occur at the organ, cellular,

or molecular level, and it is not unique to hormonalpathways For instance, many enzymatic processes areregulated by feedback properties, shown in schematicform in Figure 1–4 In this example, the product formedfrom a substrate by an enzyme (a protein that facilitateschemical reactions) negatively feeds back to inhibit fur-ther action of the enzyme This may occur by severalprocesses, such as chemical modification of the enzyme

by the product of the reaction The production of ergy within cells is a good example of a chemical processthat is regulated by feedback When energy is needed

en-by a cell, sugar molecules (glucose) are converted into

a stored form of chemical energy called adenosinetriphosphate (ATP) The ATP that accumulates in thecell inhibits the activity of some of the enzymes involved

Human Physiology, Ninth

in-to deprive the infectious organisms of the iron they quire to replicate Several controlled studies haveshown that iron replacement can make the illnessmuch worse Clearly it is crucial to distinguish be-tween those deviations of homeostatically controlledvariables that are truly part of a disease and those that,through resetting, are part of the body’s defensesagainst the disease

re-The examples of fever and plasma iron tion may have left the impression that set points arereset only in response to external stimuli, such as thepresence of bacteria, but this is not the case Indeed, asalluded to previously and described in more detail inthe text that follows, the set points for many regulatedvariables change on a rhythmical basis every day; forexample, the set point for body temperature is higherduring the day than at night

concentra-Although the resetting of a set point is adaptive insome cases, in others it simply reflects the clashing de-mands of different regulatory systems This brings us

to one more generalization: It is not possible for thing to be held relatively constant by homeostatic con-trol systems In our example, body temperature waskept relatively constant, but only because large changes

every-in skevery-in blood flow and skeletal muscle contraction werebrought about by the homeostatic control system.Moreover, because so many properties of the internalenvironment are closely interrelated, it is often possible

to keep one property relatively constant only by ing others farther from their usual set point This is what

mov-we meant by “clashing demands.”

The generalizations we have given about static control systems are summarized in Table 1–2.One additional point is that, as is illustrated by the reg-

homeo-ulation of body temperature, multiple systems often control a single parameter The adaptive value of such

redundancy is that it provides much greater tuning and also permits regulation to occur even whenone of the systems is not functioning properly because

fine-of disease

Feedforward RegulationAnother type of regulatory process often used in con-junction with negative feedback systems is feedfor-ward Let us give an example of feedforward and thendefine it The temperature-sensitive nerve cells that

CHAPTER ONE Homeostasis: A Framework for Human Physiology

10

in the chemical conversion of glucose to ATP Thus, as

ATP levels increase within a cell, further production of

ATP is slowed down Conversely, when ATP levels drop

within a cell, negative feedback is released and more

glucose is consumed to make new ATP

Not all forms of feedback are negative, however

In some cases, positive feedback may actually

accel-erate a process, leading to an “explosive” system At

first glance, this would appear to be counter to the

principle of homeostasis, since a positive feedback

loop has no obvious means of stopping Not

surpris-ingly, therefore, positive feedback is less common in

nature than negative feedback Nonetheless, there are

examples in physiology where positive feedback is

very important For example, when a brain cell is

stimulated, pore-like channels on the surface of the

cell are opened These channels permit the entry of

extracellular sodium ions into the cell interior When

sodium ions enter a cell, they carry their positive

charges with them Positive charges inside brain cells

cause the opening of more sodium channels (by a

mechanism to be described in Chapter 6) This leads

to more sodium influx, more channel openings, and

so on (positive feedback) The result is a brain cell

with altered electrical properties due to the change in

the concentration of charged sodium ions across its

surface For this process to stop and be reversed,

en-ergy must be used by the cell to restore the sodium

ions to their original concentrations inside and

out-side the cell

Resetting of Set Points

As we have seen, perturbations in the external

envi-ronment can displace a variable from its preexisting

set point In addition, the set points for many

regu-lated variables can be physiologically altered or reset.

That is, the values that the homeostatic control systems

are “trying” to keep relatively constant can be altered

A common example is fever, the increase in body

tem-perature that occurs in response to infection and that

is somewhat analogous to raising the setting of your

house’s thermostat The homeostatic control systems

regulating body temperature are still functioning

dur-ing a fever, but they maintain the temperature at a

higher value This regulated rise in body temperature

is adaptive for fighting the infection In fact, this is why

a fever is often preceded by chills and shivering The

set point for body temperature has been reset to a

higher value, and the body responds by generating

heat by shivering

The fact that set points can be reset adaptively, as

in the case of fever, raises important challenges for

medicine, as another example illustrates Plasma iron

Human Physiology, Ninth

trigger negative feedback regulation of body

temper-ature when body tempertemper-ature begins to fall are located

inside the body In addition, there are

temperature-sensitive nerve cells in the skin, and these cells, in effect,

monitor outside temperature When outside

tempera-ture falls, as in our example, these nerve cells

imme-diately detect the change and relay this information to

the brain, which then sends out signals to the blood

vessels and muscles, resulting in heat conservation and

increased heat production In this manner,

compensa-tory thermoregulacompensa-tory responses are activated before

the colder outside temperature can cause the internal

body temperature to fall Thus, feedforward

regula-tion anticipates changes in a regulated variable such

as internal body temperature, improves the speed of

the body’s homeostatic responses, and minimizes

fluc-tuations in the level of the variable being regulated—

that is, it reduces the amount of deviation from the set

point

In our example, feedforward control utilizes a set

of “external environmental” detectors It is likely,

how-ever, that many examples of feedforward control are the

result of a different phenomenon—learning The first

times they occur, early in life, perturbations in the

ex-ternal environment probably cause relatively large

changes in regulated internal environmental factors,

and in responding to these changes the central nervous

system learns to anticipate them and resist them more

effectively A familiar form of this is the increased heartrate that occurs just before an athletic competitionbegins

COMPONENTS OF HOMEOSTATIC CONTROL SYSTEMS

ReflexesThe thermoregulatory system we used as an example

in the previous section, and many of the body’s otherhomeostatic control systems, belong to the general cat-egory of stimulus-response sequences known as re-flexes Although in some reflexes we are aware of thestimulus and/or the response, many reflexes regulatingthe internal environment occur without any consciousawareness

In the most narrow sense of the word, a reflex is a

specific involuntary, unpremeditated, unlearned in” response to a particular stimulus Examples of suchreflexes include pulling one’s hand away from a hotobject or shutting one’s eyes as an object rapidly ap-proaches the face There are also many responses, how-ever, that appear to be automatic and stereotyped butare actually the result of learning and practice Forexample, an experienced driver performs many com-plicated acts in operating a car To the driver thesemotions are, in large part, automatic, stereotyped, andunpremeditated, but they occur only because a greatdeal of conscious effort was spent learning them We

“built-term such reflexes learned, or acquired In general, most

reflexes, no matter how basic they may appear to be,are subject to alteration by learning; that is, there is of-ten no clear distinction between a basic reflex and onewith a learned component

The pathway mediating a reflex is known as the flex arc,and its components are shown in Figure 1–5

re-A stimulus is defined as a detectable change in the

internal or external environment, such as a change intemperature, plasma potassium concentration, or blood

pressure A receptor detects the environmental change.

A stimulus acts upon a receptor to produce a signal that

is relayed to an integrating center The pathway

trav-eled by the signal between the receptor and the

inte-grating center is known as the afferent pathway (the

general term “afferent” means “to carry to,” in this case,

to the integrating center)

An integrating center often receives signals frommany receptors, some of which may respond to quitedifferent types of stimuli Thus, the output of an inte-grating center reflects the net effect of the total afferentinput; that is, it represents an integration of numerousbits of information

1 Stability of an internal environmental variable is achieved by

balancing inputs and outputs It is not the absolute

magnitudes of the inputs and outputs that matter but the

balance between them.

2 In negative feedback systems, a change in the variable being

regulated brings about responses that tend to move the

variable in the direction opposite the original change—that

is, back toward the initial value (set point).

3 Homeostatic control systems cannot maintain complete

constancy of any given feature of the internal environment.

Therefore, any regulated variable will have a more-or-less

narrow range of normal values depending on the external

environmental conditions.

4 The set point of some variables regulated by homeostatic

control systems can be reset—that is, physiologically raised

or lowered.

5 It is not always possible for everything to be maintained

relatively constant by homeostatic control systems in

response to an environmental challenge There is a hierarchy

of importance, such that the constancy of certain variables

may be altered markedly to maintain others at relatively

constant levels.

TABLE 1–2 Some Important Generalizations

About Homeostatic Control Systems

Human Physiology, Ninth

component is known as an effector The information

go-ing from an integratgo-ing center to an effector is like acommand directing the effector to alter its activity Thepathway along which this information travels is known

as the efferent pathway (the general term “efferent”

means “to carry away from,” in this case, away fromthe integrating center)

Thus far we have described the reflex arc as the quence of events linking a stimulus to a response If theresponse produced by the effector causes a decrease inthe magnitude of the stimulus that triggered the se-quence of events, then the reflex leads to negative feed-back and we have a typical homeostatic control system.Not all reflexes are associated with such feedback Forexample, the smell of food stimulates the secretion of ahormone by the stomach, but this hormone does noteliminate the smell of food (the stimulus)

se-To illustrate the components of a negative feedbackhomeostatic reflex arc, let us use Figure 1–6 to applythese terms to thermoregulation The temperature re-ceptors are the endings of certain nerve cells in variousparts of the body They generate electrical signals in thenerve cells at a rate determined by the temperature

CHAPTER ONE Homeostasis: A Framework for Human Physiology

Effector

Efferent pathway

FIGURE 1 – 5

General components of a reflex arc that functions as a negative

feedback control system The response of the system has the

effect of counteracting or eliminating the stimulus This

phenomenon of negative feedback is emphasized by the minus

sign in the dashed feedback loop.

Begin

INTEGRATING CENTER

Body temperature

Constriction Signaling rate

skin blood vessels Temperature-sensitive

Human Physiology, Ninth

These electrical signals are conducted by the nerve

fibers—the afferent pathway—to a specific part of the

brain—the integrating center for temperature

regula-tion The integrating center, in turn, sends signals out

along those nerve cells that cause skeletal muscles and

the muscles in skin blood vessels to contract The nerve

fibers to the muscles are the efferent pathway, and the

muscles are the effectors The dashed arrow and the 䊞

indicate the negative feedback nature of the reflex

Almost all body cells can act as effectors in

homeo-static reflexes There are, however, two specialized

classes of tissues—muscle and gland—that are the

ma-jor effectors of biological control systems In the case of

glands, for example, the effector may be a hormone

se-creted into the blood

Traditionally, the term “reflex” was restricted to

sit-uations in which the receptors, afferent pathway,

inte-grating center, and efferent pathway were all parts of

the nervous system, as in the thermoregulatory reflex

Present usage is not so restrictive, however, and

recog-nizes that the principles are essentially the same when

a blood-borne chemical messenger, rather than a nerve

fiber, serves as the efferent pathway, or when a

hormone-secreting gland (termed an endocrine gland)

serves as the integrating center Thus, in the

ther-moregulation example, the integrating center in the

brain not only sends signals by way of nerve fibers, as

shown in Figure 1–6, but also causes the release of a

hormone that travels via the blood to many cells, where

it increases the amount of heat produced by these cells

This hormone therefore also serves as an efferent

path-way in thermoregulatory reflexes

Accordingly, in our use of the term “reflex,” we

in-clude hormones as reflex components Moreover,

depending on the specific nature of the reflex, the

inte-grating center may reside either in the nervous system

or in an endocrine gland In addition, an endocrine

gland may act as both receptor and integrating center

in a reflex; for example, the endocrine gland cells that

secrete the hormone insulin, which lowers plasma

glu-cose concentration, themselves detect changes in the

plasma glucose concentration

In conclusion, many reflexes function in a

homeo-static manner to keep a physical or chemical variable of

the body relatively constant One can analyze any such

system by answering the questions listed in Table 1–3

Local Homeostatic Responses

In addition to reflexes, another group of biological

re-sponses is of great importance for homeostasis We shall

call them local homeostatic responses They are

initi-ated by a change in the external or internal environment

(that is, a stimulus), and they induce an alteration of cell

activity with the net effect of counteracting the

stimu-lus Like a reflex, therefore, a local response is the result

of a sequence of events proceeding from a stimulus.Unlike a reflex, however, the entire sequence occurs only

in the area of the stimulus For example, damage to anarea of skin causes cells in the damaged area to releasecertain chemicals that help the local defense against fur-ther injury and promote tissue repair The significance

of local responses is that they provide individual areas

of the body with mechanisms for local self-regulation

INTERCELLULAR CHEMICAL MESSENGERS

Essential to reflexes and local homeostatic responses,and therefore to homeostasis, is the ability of cells tocommunicate with one another In the majority of cases,

this communication between cells—intercellular

com-munication—is performed by chemical messengers.There are three categories of such messengers: hor-mones, neurotransmitters, and paracrine agents (Fig-ure 1–7)

A hormone functions as a chemical messenger thatenables the hormone-secreting cell to communicate with

cells acted upon by the hormone—its target cells—with

the blood acting as the delivery system Most nerve cellscommunicate with each other or with effector cells by

means of chemical messengers called ters.Thus, one nerve cell alters the activity of another

neurotransmit-by releasing from its ending a neurotransmitter that fuses through the extracellular fluid separating the twonerve cells and acts upon the second cell Similarly, neu-rotransmitters released from nerve cells into the extra-cellular fluid in the immediate vicinity of effector cellsconstitute the controlling input to the effector cells

dif-1 What is the variable (for example, plasma potassium concentration, body temperature, blood pressure) that is maintained relatively constant in the face of changing conditions?

2 Where are the receptors that detect changes in the state of this variable?

3 Where is the integrating center to which these receptors send information and from which information is sent out to the effectors, and what is the nature of these afferent and efferent pathways?

4 What are the effectors, and how do they alter their activities

so as to maintain the regulated variable near the set point

of the system?

TABLE 1–3 Questions to Be Asked About Any

Homeostatic Reflex

Human Physiology, Ninth

Edition

Framework for Human Physiology

Companies, 2003

acts upon the very cell that secreted it Such messengers

are termed autocrine agents (Figure 1–7) Frequently a

messenger may serve both paracrine and autocrinefunctions simultaneously—that is, molecules of themessenger released by a cell may act locally on adjacentcells as well as on the same cell that released themessenger

One of the most exciting developments in ogy today is the identification of a growing number ofparacrine/autocrine agents and the extremely diverseeffects they exert Their structures span the gamut from

physiol-a simple gphysiol-as (nitric oxide) to fphysiol-atty physiol-acid derivphysiol-atives (theeicosanoids, Chapter 5) to peptides and amino acid de-rivatives They tend to be secreted by multiple cell types

in many tissues and organs According to their tures and functions, they can be gathered into families;for example, one such family constitutes the “growthfactors,” encompassing more than 50 distinct molecules,each of which is highly effective in stimulating certaincells to divide and/or differentiate

struc-CHAPTER ONE Homeostasis: A Framework for Human Physiology

14

Chemical messengers participate not only in

re-flexes but also in local responses Chemical messengers

involved in local communication between cells are

known as paracrine agents.

Paracrine/Autocrine Agents

Paracrine agents are synthesized by cells and released,

once given the appropriate stimulus, into the

extracel-lular fluid They then diffuse to neighboring cells, some

of which are their target cells (Note that, given this

broad definition, neurotransmitters theoretically could

be classified as a subgroup of paracrine agents, but by

convention they are not.) Paracrine agents are generally

inactivated rapidly by locally existing enzymes so that

they do not enter the bloodstream in large quantities

There is one category of local chemical messengers

that are not intercellular messengers—that is, they do

not communicate between cells Rather, the chemical is

secreted by a cell into the extracellular fluid and then

Target cell

Hormone-secreting gland cell

Nerve impulse

Blood vessel

Blood vessel

Local cell Local cell

Paracrine agent Autocrine agent

Target cell

Target cell

Neuron or effector cell

FIGURE 1 – 7

Categories of chemical messengers (a) Reflexes Note that chemical messengers that are secreted by nerve cells and act on adjacent nerve cells or effector cells are termed neurotransmitters, whereas those that enter the blood and act on distant effector cells

(synonymous with target cells) are classified as hormones (also termed neurohormones) (b) Local homeostatic responses With the

exception of autocrine agents, all messengers act between cells—that is, intercellularly.

Human Physiology, Ninth

Stimuli for the release of paracrine/autocrine

agents are also extremely varied, including not only

lo-cal chemilo-cal changes (for example, in the concentration

of oxygen), but neurotransmitters and hormones as

well In these two latter cases, the paracrine/autocrine

agent often serves to oppose the effects induced locally

by the neurotransmitter or hormone For example, the

neurotransmitter norepinephrine strongly constricts

blood vessels in the kidneys, but it simultaneously

causes certain kidney cells to secrete paracrine agents

that cause the same vessels to dilate This provides a

lo-cal negative feedback, in which the paracrine agents

keep the action of norepinephrine from becoming too

intense This, then, is an example of homeostasis

oc-curring at a highly localized level

A point of great importance must be emphasized

here to avoid later confusion: A nerve cell, endocrine

gland cell, and other cell type may all secrete the same

chemical messenger Thus, a particular messenger may

sometimes function as a neurotransmitter, as a

hor-mone, or as a paracrine/autocrine agent

All types of intercellular communication described

so far in this section involve secretion of a chemical

mes-senger into the extracellular fluid However, there are

two important types of chemical communication

between cells that do not require such secretion In the

first type, which occurs via gap junctions (Chapter 3),

chemicals move from one cell to an adjacent cell

with-out ever entering the extracellular fluid In the second

type, the chemical messenger is not actually released

from the cell producing it but rather is located in the

plasma membrane of that cell; when the cell encounters

another cell type capable of responding to the message,

the two cells link up via the membrane-bound

messen-ger This type of signaling (sometimes termed

“jux-tacrine”) is of particular importance in the growth and

differentiation of tissues as well as in the functioning of

cells that protect the body against microbes and other

foreign agents (Chapter 18)

PROCESSES RELATED

TO HOMEOSTASIS

A variety of seemingly unrelated processes, such as

biological rhythms and aging, have important

implica-tions for homeostasis and are discussed here to

em-phasize this point

Adaptation and Acclimatization

The term adaptation denotes a characteristic that favors

survival in specific environments Homeostatic control

systems are inherited biological adaptations An

indi-vidual’s ability to respond to a particular

environmen-tal stress is not fixed, however, but can be enhanced,

with no change in genetic endowment, by prolongedexposure to that stress This type of adaptation—theimproved functioning of an already existing homeo-

static system—is known as acclimatization.

Let us take sweating in response to heat exposure

as an example and perform a simple experiment Onday 1 we expose a person for 30 min to a high temper-ature and ask her to do a standardized exercise test.Body temperature rises, and sweating begins after a cer-tain period of time The sweating provides a mechanismfor increasing heat loss from the body and thus tends

to minimize the rise in body temperature in a hot ronment The volume of sweat produced under theseconditions is measured Then, for a week, our subjectenters the heat chamber for 1 or 2 h per day and exer-cises On day 8, her body temperature and sweating rateare again measured during the same exercise test per-formed on day 1; the striking finding is that the subjectbegins to sweat earlier and much more profusely thanshe did on day 1 Accordingly, her body temperaturedoes not rise to nearly the same degree The subject hasbecome acclimatized to the heat; that is, she has under-gone an adaptive change induced by repeated exposure

envi-to the heat and is now better able envi-to respond envi-to heat posure

ex-The precise anatomical and physiological changesthat bring about increased capacity to withstand changeduring acclimatization are highly varied Typically, theyinvolve an increase in the number, size, or sensitivity ofone or more of the cell types in the homeostatic controlsystem that mediate the basic response

Acclimatizations are usually completely reversible.Thus, if the daily exposures to heat are discontinued,the sweating rate of our subject will revert to the preac-climatized value within a relatively short time If an ac-climatization is induced very early in life, however, at

the critical period for development of a structure or response, it is termed a developmental acclimatization

and may be irreversible For example, the barrel-shapedchests of natives of the Andes Mountains represent not

a genetic difference between them and their lowlandcompatriots but rather an irreversible acclimatizationinduced during the first few years of their lives by theirexposure to the low-oxygen environment of high alti-tude The altered chest size remains even though the in-dividual moves to a lowland environment later in lifeand stays there Lowland persons who have sufferedoxygen deprivation from heart or lung disease duringtheir early years show precisely the same chest shape.Biological Rhythms

As noted earlier, a striking characteristic of many bodyfunctions is the rhythmical changes they manifest The

most common type is the circadian rhythm, which

cycles approximately once every 24 h Waking and

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potassium in our food during the day, not at night when

we are asleep Therefore, the total amount of potassium

in the body fluctuates less than if the rhythm did notexist

A crucial point concerning most body rhythms is

that they are internally driven Environmental factors do

not drive the rhythm but rather provide the timing cues

important for entrainment (that is, setting of the actual

hours) of the rhythm A classic experiment will clarifythis distinction

Subjects were put in experimental chambers thatcompletely isolated them from their usual external en-vironment, including knowledge of the time of day Forthe first few days, they were exposed to a 24 h rest-activity cycle in which the room lights were turned onand off at the same time each day Under these condi-tions, their sleep-wake cycles were 24 h long Then, allenvironmental time cues were eliminated, and the sub-jects were allowed to control the lights themselves.Immediately, their sleep-wake patterns began to change

On the average, bedtime began about 30 min later each

day and so did wake-up time Thus a sleep-wake cycle

persisted in the complete absence of environmental

cues, and such a rhythm is called a free-running rhythm.In this case it was approximately 25 h ratherthan 24 This indicates that cues are required to entrain

a circadian rhythm to 24 h

One more point should be mentioned: By alteringthe duration of the light-dark cycles, sleep-wake cyclescan be entrained to any value between 23 and 27 h, butshorter or longer durations cannot be entrained; instead,the rhythm continues to free-run Because of this, peo-ple whose work causes them to adopt sleep-wake cy-cles longer than 27 h are never able to make the properadjustments and achieve stable rhythms

The light-dark cycle is the most important mental time cue in our lives but not the only one Othersinclude external environmental temperature, meal tim-ing, and many social cues Thus, if several people wereundergoing the experiment just described in isolationfrom each other, their free-runs would be somewhat dif-ferent, but if they were all in the same room, social cueswould entrain all of them to the same rhythm

environ-Environmental time cues also function to shift rhythms—in other words, to reset the internalclock Thus if one jets west or east to a different timezone, the sleep-wake cycle and other circadian rhythmsslowly shift to the new light-dark cycle These shifts taketime, however, and the disparity between external timeand internal time is one of the causes of the symptoms

phase-of jet lag—disruption phase-of sleep, gastrointestinal

distur-bances, decreased vigilance and attention span, and ageneral feeling of malaise

Similar symptoms occur in workers on permanent

or rotating night shifts These people generally do not

CHAPTER ONE Homeostasis: A Framework for Human Physiology

16

sleeping, body temperature, hormone concentrations

in the blood, the excretion of ions into the urine, and

many other functions undergo circadian variation

(Figure 1–8)

What have biological rhythms to do with

ho-meostasis? They add an “anticipatory” component to

homeostatic control systems, in effect a feedforward

sys-tem operating without detectors The negative-feedback

homeostatic responses we described earlier in this

chap-ter are corrective responses, in that they are initiated afchap-ter

the steady state of the individual has been perturbed

In contrast, biological rhythms enable homeostatic

mechanisms to be utilized immediately and

automati-cally by activating them at times when a challenge is

likely to occur but before it actually does occur For

ex-ample, there is a rhythm in the urinary excretion of

potassium such that excretion is high during the day

and low at night This makes sense since we ingest

Circadian time (hours)

Circadian rhythms of several physiological variables in a human

subject with room lights on (open bars at top) for 16 h and off

(black bars at top) for 8 h As is usual in dealing with rhythms,

we have used a 24-h clock in which both 0 and 24 designate

midnight and 12 designates noon.

Human Physiology, Ninth

adapt to these schedules even after several years

be-cause they are exposed to the usual outdoor light-dark

cycle (normal indoor lighting is too dim to function as

a good entrainer) In recent experiments, night-shift

workers were exposed to extremely bright indoor

lighting while they worked and 8 h of total darkness

during the day when they slept This schedule produced

total adaptation to the night-shift work within 5 days

What is the neural basis of body rhythms? In the

part of the brain called the hypothalamus is a specific

collection of nerve cells (the suprachiasmatic nucleus)

that function as the principal pacemaker (time clock)

for circadian rhythms How it “keeps time”

independ-ent of any external environmindepend-ental cues is not really

understood, but it appears to involve the rhythmical

turning on and off of critical genes in the pacemaker

cells

The pacemaker receives input from the eyes and

many other parts of the nervous system, and these

in-puts mediate the entrainment effects exerted by the

ex-ternal environment In turn, the pacemaker sends out

neural signals to other parts of the brain, which then

in-fluence the various body systems, activating some and

inhibiting others One output of the pacemaker is to

the pineal gland, a gland within the brain that secretes

the hormone melatonin These neural signals from the

pacemaker cause the pineal to secrete melatonin during

darkness but not to secrete it during daylight It has been

hypothesized, therefore, that melatonin may act as an

important “middleman” to influence other organs

ei-ther directly or by altering the activity of the parts of

the brain that control these organs Studies to determine

whether the administration of melatonin at specific

times can reduce the symptoms of jet lag remain

in-conclusive

It should not be surprising that rhythms have

ef-fects on the body’s resistance to various stresses and

re-sponses to different drugs Also, certain diseases have

characteristic rhythms For example, heart attacks are

almost twice as common in the first hours after waking,

and asthma often flares at night Insights about these

rhythms have already been incorporated into therapy;

for example, once-a-day timed-release pills for asthma

are taken at night and deliver a high dose of

medica-tion between midnight and 6 A.M

Regulated Cell Death: Apoptosis

It is obvious that the proliferation and differentiation of

cells are important for the development and

mainte-nance of homeostasis in multicellular organisms Only

recently, however, have physiologists come to

appre-ciate the contribution of another characteristic shared

by virtually all cells—the ability to self-destruct by

activation of an intrinsic “cell suicide” program This

type of cell death, termed apoptosis, plays important

roles in the sculpting of a developing organism and

in the elimination of undesirable cells (for example,cells that have become cancerous), but it is particu-larly crucial for regulating the number of cells in a tis-sue or organ Thus, the control of cell number withineach cell lineage is normally determined by a balancebetween cell proliferation and cell death, both ofwhich are regulated processes For example, whiteblood cells called neutrophils are programmed to die

by apoptosis 24 hours after they are produced in thebone marrow

Apoptosis occurs by controlled autodigestion of thecell contents Within a cell, enzymes are activated thatbreak down the cell nucleus and its DNA, as well asother cell organelles Importantly, the plasma mem-brane is maintained as the cell dies so that the cell con-tents are not dispersed Instead the apoptotic cell sendsout chemical messengers that attract neighboringphagocytic cells (cells that “eat” matter or other cells),which engulf and digest the dying or dead cell In thisway the leakage of breakdown products, many of whichare toxic, is prevented Apoptosis is, therefore, very dif-ferent from the death of a cell due to injury In that case

(termed necrosis) the plasma membrane is disrupted,

and the cell swells and releases its cytoplasmic material,inducing an inflammatory response, as described inChapter 18

The fact that virtually all normal cells contain theenzymes capable of carrying out apoptosis means thatthese enzymes must normally remain inactive if the cell

is to survive In most tissues this inactivity is maintained

by the constant supply to the cell of a large number ofchemical “survival signals” provided by neighboringcells, hormones, and the extracellular matrix In otherwords, most cells are programmed to commit suicide ifsurvival signals are not received from the internal en-vironment For example, prostate gland cells undergoapoptosis when the influence on them of testosterone,the male sex hormone, is removed In addition, thereare other chemical signals, some exogenous to theorganism (for example, certain viruses and bacterial tox-ins) and some endogenous (for example, certain mes-sengers released by nerve cells and white blood cells)that can inhibit or override survival signals and inducethe cell to undergo apoptosis

It is very likely that abnormal inhibition of priate apoptosis may contribute to diseases, like cancer,characterized by excessive numbers of cells At the otherend of the spectrum, too high a rate of apoptosis prob-ably contributes to degenerative diseases, such as that

appro-of bone in the disease called osteoporosis The hope is

that therapies designed to enhance or decrease sis, depending on the situation, would ameliorate thesediseases

apopto-Human Physiology, Ninth

mol-It should be recognized that not every pathway

of this generalized schema is applicable to every stance For example, mineral electrolytes such assodium cannot be synthesized, do not normally enterthrough the lungs, and cannot be removed by me-tabolism

sub-The orientation of Figure 1–9 illustrates two portant generalizations concerning the balance concept:(1) During any period of time, total-body balance de-pends upon the relative rates of net gain and net loss tothe body; and (2) the pool concentration depends notonly upon the total amount of the substance in the body,

im-but also upon exchanges of the substance within the

body

For any chemical, three states of total-body balanceare possible: (1) Loss exceeds gain, so that the totalamount of the substance in the body is decreasing, and

the person is said to be in negative balance; (2) gain

ex-ceeds loss, so that the total amount of the substance inthe body is increasing, and the person is said to be in

positive balance;and (3) gain equals loss, and the

per-son is in stable balance.

Clearly a stable balance can be upset by a change

in the amount being gained or lost in any single way in the schema; for example, severe negative waterbalance can be caused by increased sweating.Conversely, stable balance can be restored by homeo-static control of water intake and output

path-Let us take sodium balance as another example Thecontrol systems for sodium balance have as their targetsthe kidneys, and the systems operate by inducing thekidneys to excrete into the urine an amount of sodiumapproximately equal to the amount ingested daily Inthis example, we assume for simplicity that all sodium

CHAPTER ONE Homeostasis: A Framework for Human Physiology

18

Balance in the Homeostasis of

Chemicals

Many homeostatic systems are concerned with the

bal-ance between the addition to and removal from the

body of a chemical substance Figure 1–9 is a

general-ized schema of the possible pathways involved in such

balance The pool occupies a position of central

impor-tance in the balance sheet It is the body’s readily

avail-able quantity of the substance and is often identical to

the amount present in the extracellular fluid The pool

receives substances from and contributes them to all the

pathways

The pathways on the left of the figure are sources

of net gain to the body A substance may enter the body

through the gastrointestinal (GI) tract or the lungs

Alternatively, a substance may be synthesized within

the body from other materials

The pathways on the right of the figure are causes

of net loss from the body A substance may be lost in

the urine, feces, expired air, or menstrual fluid, as well

as from the surface of the body as skin, hair, nails, sweat,

and tears The substance may also be chemically altered

and thus removed by metabolism

The central portion of the figure illustrates the

dis-tribution of the substance within the body The

sub-stance may be taken from the pool and accumulated

in storage depots (for example, the accumulation of fat

in adipose tissue) Conversely, it may leave the storage

depots to reenter the pool Finally, the substance may

be incorporated reversibly into some other molecular

structure, such as fatty acids into membranes or iodine

into thyroxine Incorporation is reversible in that the

substance is liberated again whenever the more

com-plex structure is broken down This pathway is

distin-guished from storage in that the incorporation of the

Metabolism

POOL

Storage depots

Reversible incorporation into other molecules

FIGURE 1 – 9

Balance diagram for a chemical substance.

Human Physiology, Ninth

loss from the body occurs via the urine (although some

is also lost in perspiration) Now imagine a person with

a daily intake and excretion of 7 g of sodium—a

mod-erate intake for most Americans—and a stable amount

of sodium in her body (Figure 1–10) On day 2 of our

experiment, the subject changes her diet so that her daily

sodium consumption rises to 15 g—a large but

com-monly observed intake—and remains there indefinitely.

On this same day, the kidneys excrete into the urine

somewhat more than 7 g of sodium, but not all the

in-gested 15 g The result is that some excess sodium is

re-tained in the body on that day—that is, the person is in

positive sodium balance The kidneys do somewhat

better on day 3, but it is probably not until day 4 or 5

that they are excreting 15 g From this time on, output

from the body once again equals input, and sodium

bal-ance is once again stable (The delay of several days

be-fore stability is reached is quite typical for the kidneys’

handling of sodium, but should not be assumed to

apply to other homeostatic responses, most of which are

much more rapid.)

But, and this is an important point, although again

in stable balance, the woman has perhaps 2 percent

more sodium in her body than was the case when she

was in stable balance ingesting 7 g It is this 2 percent

extra body sodium that constitutes the continuous error

signal to the control systems driving the kidneys to

ex-crete 15 g/day rather than 7 g/day [Recall the

gener-alization (Table 1–2, no 3) that homeostatic control

sys-tems cannot maintain complete constancy of the internal

environment in the face of continued change in the

per-turbing event since some change in the regulated

vari-able (body sodium content in our example) must

per-sist to serve as a signal to maintain the compensating

responses.] An increase of 2 percent does not seem large,but it has been hypothesized that this small gain might

facilitate the development of high blood pressure

(hy-pertension) in some people

In summary, homeostasis is a complex, dynamicprocess that regulates the adaptive responses of thebody to changes in the external and internal environ-ments To work properly, homeostatic systems require

a sensor to detect the environmental change, and ameans to produce a compensatory response Since com-pensatory responses require either muscle activity, be-havioral changes, or synthesis of chemical messengerssuch as hormones, homeostasis is only achieved by theexpenditure of energy The fuel sources that provide thisenergy, and the chemical reactions that convert the fuelsources to energy, are described in the following twochapters

15 0

1 2

FIGURE 1 – 10

Effects of a continued change in the amount of sodium ingested

on sodium excretion and total-body sodium balance Stable

sodium balance is reattained by day 4 but with some gain of

total-body sodium.

S U M M A R Y

The Scope of Human Physiology

I Physiology is the study of how living organismswork Physiologists are unique among biologists inthat they are always interested in function

II Disease states are physiology “gone wrong”

(pathophysiology)

How Is the Body Organized?

I Cells are the simplest structural units into which acomplex multicellular organism can be divided andstill retain the functions characteristic of life

II Cell differentiation results in the formation of fourcategories of specialized cells

a Muscle cells generate the mechanical activitiesthat produce force and movement

b Nerve cells initiate and conduct electrical signals

c Epithelial cells selectively secrete and absorb ionsand organic molecules

d Connective tissue cells connect, anchor, andsupport the structures of the body

III Specialized cells associate with similar cells to formtissues: muscle tissue, nerve tissue, epithelial tissue,and connective tissue

IV Organs are composed of the four kinds of tissuesarranged in various proportions and patterns; manyorgans contain multiple small, similar functional units

V An organ system is a collection of organs thattogether perform an overall function

Body Fluid Compartments

I The body fluids are enclosed in compartments

a The extracellular fluid is composed of theinterstitial fluid (the fluid between cells) and theblood plasma Of the extracellular fluid, 80 percent

is interstitial fluid, and 20 percent is plasma

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Processes Related to Homeostasis

I Acclimatization is an improved ability to respond to

an environmental stress

a The improvement is induced by prolongedexposure to the stress with no change in geneticendowment

b If acclimatization occurs early in life, it may be irreversible and is known as a developmentalacclimatization

II Biological rhythms provide a feedforwardcomponent to homeostatic control systems

a The rhythms are internally driven by brainpacemakers, but are entrained by environmentalcues, such as light, which also serve to phase-shift(reset) the rhythms when necessary

b In the absence of cues, rhythms free-run

III Apoptosis, regulated cell death, plays an importantrole in homeostasis by helping to regulate cellnumbers and eliminating undesirable cells

IV The balance of substances in the body is achieved by

a matching of inputs and outputs Total body balance

of a substance may be negative, positive, or stable

CHAPTER ONE Homeostasis: A Framework for Human Physiology

20

b Interstitial fluid and plasma have essentially the

same composition except that plasma contains a

much higher concentration of protein

c Extracellular fluid differs markedly in composition

from the fluid inside cells—the intracellular fluid

d Approximately one-third of body water is in the

extracellular compartment, and two-thirds is

intracellular

II The differing compositions of the compartments

reflect the activities of the barriers separating them

Homeostasis: A Defining Feature of Physiology

I The body’s internal environment is the extracellular

fluid surrounding cells

II The function of organ systems is to maintain the

internal environment relatively constant—homeostasis

III Numerous variables within the body must be

maintained homeostatically When homeostasis is

lost for one variable, it may trigger a series of

changes in other variables

General Characteristics of Homeostatic Control Systems

I Homeostasis denotes the stable conditions of the

internal environment that result from the operation

of compensatory homeostatic control systems

a In a negative feedback control system, a change in

the variable being regulated brings about

responses that tend to push the variable in the

direction opposite to the original change

Negative feedback minimizes changes from the

set point of the system, leading to stability

b In a positive feedback system, an initial

disturbance in the system sets off a train of events

that increases the disturbance even further

c Homeostatic control systems minimize changes in

the internal environment but cannot maintain

complete constancy

d Feedforward regulation anticipates changes in a

regulated variable, improves the speed of the

body’s homeostatic responses, and minimizes

fluctuations in the level of the variable being

regulated

Components of Homeostatic Control Systems

I The components of a reflex arc are receptor, afferent

pathway, integrating center, efferent pathway, and

effector The pathways may be neural or hormonal

II Local homeostatic responses are also

stimulus-response sequences, but they occur

only in the area of the stimulus, neither nerves nor

hormones being involved

Intercellular Chemical Messengers

I Intercellular communication is essential to reflexes

and local responses and is achieved by

neurotransmitters, hormones, and paracrine agents

Less common is intercellular communication through

either gap junctions or cell-bound messengers

K EY T E R M S

acclimatization 15acquired reflex 11adaptation 15afferent pathway 11apoptosis 17autocrine agent 14basement membrane 3cell 2

cell differentiation 2circadian rhythm 15collagen fiber 4connective tissue 4connective tissue cell 4critical period 15developmentalacclimatization 15effector 12

efferent pathway 12elastin fiber 4endocrine gland 13entrainment 16epithelial cell 3epithelial tissue 4equilibrium 8external environment 3extracellular fluid 4extracellular matrix 4feedforward 11fiber 4free-running rhythm 16

functional unit 4homeostasis 6homeostatic controlsystem 8hormone 7integrating center 11internal environment 4interstitial fluid 4intracellular fluid 5learned reflex 11local homeostaticresponse 13melatonin 17muscle cell 3muscle tissue 4necrosis 17negative balance 18negative feedback 9neurotransmitter 13nerve cell 3nerve tissue 4organ 3organ system 3pacemaker 17paracrine agent 14pathophysiology 2phase-shift 16physiology 2pineal gland 17plasma 4

Human Physiology, Ninth

8 Contrast feedforward and negative feedback

9 List the components of a reflex arc

10 What is the basic difference between a localhomeostatic response and a reflex?

11 List the general categories of intercellularmessengers

12 Describe two types of intercellular communicationthat do not depend on extracellular chemicalmessengers

13 Describe the conditions under which acclimatizationoccurs In what period of life might an

acclimatization be irreversible? Are acclimatizationspassed on to a person’s offspring?

14 Under what conditions do circadian rhythms becomefree-running?

15 How do phase shifts occur?

16 What are the important environmental cues forentrainment of body rhythms?

17 Draw a figure illustrating the balance concept inhomeostasis

18 What are the three possible states of total-bodybalance of any chemical?

T H O U G H T Q U E S T I O N S

(Answers are given in Appendix A.)

1 Eskimos have a remarkable ability to work in thecold without gloves and not suffer decreased skinblood flow Does this prove that there is a geneticdifference between Eskimos and other people withregard to this characteristic?

2 Explain how an imbalance in any given physiologicalvariable might produce a change in one or moreother variables

C L I N I C A L T E R M S

hypertension 19

R E V I E W Q U E S T I O N S

1 Describe the levels of cellular organization and state

the four types of specialized cells and tissues

2 List the 10 organ systems of the body and give

one-sentence descriptions of their functions

3 Contrast the two categories of functions performed

by every cell

4 Name two fluids that constitute the extracellular

fluid What are their relative proportions in the body,

and how do they differ from each other in

composition?

5 State the relative volumes of water in the body-fluid

compartments

6 Describe five important generalizations about

homeostatic control systems

7 Contrast negative feedback systems and positive

Human Physiology, Ninth

Solutions

Molecular Solubility Concentration Hydrogen Ions and Acidity

Classes of Organic Molecules

Carbohydrates Lipids Proteins Nucleic Acids ATP

Human Physiology, Ninth

Edition

Atoms and molecules are the chemical units of cell

structure and function In this chapter we describe the

distinguishing characteristics of the major chemicals in the

human body The specific roles of these substances will

be discussed in subsequent chapters This chapter is, in essence, an expanded glossary of chemical terms and structures, and like a glossary, it should be consulted as needed.

upon assigning the carbon atom a mass of 12 On thisscale, a hydrogen atom has an atomic weight of ap-proximately 1, indicating that it has one-twelfth themass of a carbon atom; a magnesium atom, with anatomic weight of 24, has twice the mass of a carbonatom

24

ATOMS

The units of matter that form all chemical substances

are called atoms The smallest atom, hydrogen, is

ap-proximately 2.7 billionths of an inch in diameter Each

type of atom—carbon, hydrogen, oxygen, and so on—

is called a chemical element A one- or two-letter

sym-bol is used as a shorthand identification for each

ele-ment Although slightly more than 100 elements exist

in the universe, only 24 (Table 2–1) are known to be

es-sential for the structure and function of the human body

The chemical properties of atoms can be described

in terms of three subatomic particles—protons,

neu-trons, and electrons The protons and neutrons are

con-fined to a very small volume at the center of an atom,

the atomic nucleus, whereas the electrons revolve in

or-bits at various distances from the nucleus This

minia-ture solar-system model of an atom is an

oversimp-lification, but it is sufficient to provide a conceptual

framework for understanding the chemical and

physi-cal interactions of atoms

Each of the subatomic particles has a different

elec-tric charge: Protons have one unit of positive charge,

electrons have one unit of negative charge, and neutrons

are electrically neutral (Table 2–2) Since the protons are

located in the atomic nucleus, the nucleus has a net

pos-itive charge equal to the number of protons it contains

The entire atom has no net electric charge, however,

because the number of negatively charged electrons

or-biting the nucleus is equal to the number of positively

charged protons in the nucleus

Atomic Number

Each chemical element contains a specific number of

protons, and it is this number that distinguishes one

type of atom from another This number is known as

the atomic number For example, hydrogen, the

sim-plest atom, has an atomic number of 1, corresponding

to its single proton; calcium has an atomic number of

20, corresponding to its 20 protons Since an atom is

elec-trically neutral, the atomic number is also equal to the

number of electrons in the atom

Atomic Weight

Atoms have very little mass A single hydrogen atom,

for example, has a mass of only 1.67⫻ 10⫺24g The

atomic weight scale indicates an atom’s mass

rela-tive to the mass of other atoms This scale is based

Trace Elements: Less Than 0.01% of Total Atoms

Human Physiology, Ninth

Edition

www.mhhe.com/widmaier9 25

Since the atomic weight scale is a ratio of atomic

masses, it has no units The unit of atomic mass is known

as a dalton One dalton (d) equals one-twelfth the mass

of a carbon atom Thus, carbon has an atomic weight of

12, and a carbon atom has an atomic mass of 12 daltons

Although the number of neutrons in the nucleus

of an atom is often equal to the number of protons,

many chemical elements can exist in multiple forms,

called isotopes, which differ in the number of

neu-trons they contain For example, the most abundant

form of the carbon atom, 12C, contains 6 protons and

6 neutrons, and thus has an atomic number of 6

Protons and neutrons are approximately equal in

mass; therefore, 12C has an atomic weight of 12 The

radioactive carbon isotope 14C contains 6 protons and

8 neutrons, giving it an atomic number of 6 but an

atomic weight of 14

One gram atomic mass of a chemical element is

the amount of the element in grams that is equal to

the numerical value of its atomic weight Thus, 12 g

of carbon (assuming it is all 12C) is 1 gram atomic mass

of carbon One gram atomic mass of any element contains

the same number of atoms For example, 1 g of

hydro-gen contains 6⫻ 1023 atoms, and 12 g of carbon,

whose atoms have 12 times the mass of a hydrogen

atom, also has 6⫻ 1023 atoms (the so-called

Avogadro’s number)

Atomic Composition of the Body

Just four of the body’s essential elements (Table 2–1)—

hydrogen, oxygen, carbon, and nitrogen—account for

over 99 percent of the atoms in the body

The seven essential mineral elements are the most

abundant substances dissolved in the extracellular and

intracellular fluids Most of the body’s calcium and

phosphorus atoms, however, make up the solid matrix

of bone tissue

The 13 essential trace elements are present in

ex-tremely small quantities, but they are nonetheless

es-sential for normal growth and function For example,iron plays a critical role in the transport of oxygen bythe blood

Many other elements, in addition to the 24 listed inTable 2–1, can be detected in the body These elementsenter in the foods we eat and the air we breathe but arenot essential for normal body function and may eveninterfere with normal body chemistry For example,ingested arsenic has poisonous effects

MOLECULES

Two or more atoms bonded together make up a cule. For example, a molecule of water contains twohydrogen atoms and one oxygen atom, which can berepresented by H2O The atomic composition of glucose,

mole-a sugmole-ar, is C6H12O6, indicating that the molecule tains 6 carbon atoms, 12 hydrogen atoms, and 6 oxygenatoms Such formulas, however, do not indicate how theatoms are linked together in the molecule

con-Covalent Chemical BondsThe atoms in molecules are held together by chemicalbonds, which are formed when electrons are trans-ferred from one atom to another or are shared betweentwo atoms The strongest chemical bond between two

atoms, a covalent bond, is formed when one

elec-tron in the outer elecelec-tron orbit of each atom is sharedbetween the two atoms (Figure 2–1) The atoms in mostmolecules found in the body are linked by covalentbonds

The atoms of some elements can form more thanone covalent bond and thus become linked simultane-ously to two or more other atoms Each type of atomforms a characteristic number of covalent bonds, whichdepends on the number of electrons in its outermostorbit The number of chemical bonds formed by the fourmost abundant atoms in the body are hydrogen, one;oxygen, two; nitrogen, three; and carbon, four Whenthe structure of a molecule is diagramed, each covalentbond is represented by a line indicating a pair of sharedelectrons The covalent bonds of the four elements justmentioned can be represented as

A molecule of water H2O can be diagramed as

TO ELECTRON ELECTRIC LOCATION

PARTICLE MASS CHARGE IN ATOM

Human Physiology, Ninth

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Molecules are not rigid, inflexible structures Withincertain limits, the shape of a molecule can be changedwithout breaking the covalent bonds linking its atomstogether A covalent bond is like an axle around whichthe joined atoms can rotate As illustrated in Figure 2–3,

a sequence of six carbon atoms can assume a number

of shapes as a result of rotations around various lent bonds As we shall see, the three-dimensional,flexible shape of molecules is one of the major factorsgoverning molecular interactions

cova-IONS

A single atom is electrically neutral since it containsequal numbers of negative electrons and positive pro-tons If, however, an atom gains or loses one or more

CHAPTER TWO Chemical Composition of the Body

26

electrons from each atom Carbon dioxide (CO2)

contains two double bonds:

OPCPO

Note that in this molecule the carbon atom still forms

four covalent bonds and each oxygen atom only two

Molecular Shape

When atoms are linked together, molecules with various

shapes can be formed Although we draw diagrammatic

structures of molecules on flat sheets of paper, molecules

are actually three-dimensional When more than one

co-valent bond is formed with a given atom, the bonds are

distributed around the atom in a pattern that may or

may not be symmetrical (Figure 2–2)

Neutrons Protons Electrons Carbon

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electrons, it acquires a net electric charge and becomes

an ion For example, when a sodium atom (Na), which

has 11 electrons, loses one electron, it becomes a

sodium ion (Na⫹) with a net positive charge; it still has

11 protons, but it now has only 10 electrons On the

other hand, a chlorine atom (Cl), which has 17

elec-trons, can gain an electron and become a chloride ion

(Cl⫺) with a net negative charge—it now has 18

elec-trons but only 17 protons Some atoms can gain or lose

more than one electron to become ions with two or

even three units of net electric charge (for example,

cal-cium Ca2⫹)

Hydrogen atoms and most mineral and trace

ele-ment atoms readily form ions Table 2–3 lists the ionic

forms of some of these elements Ions that have a net

positive charge are called cations, while those that have

a net negative charge are called anions Because of their

ability to conduct electricity when dissolved in water,

the ionic forms of the seven mineral elements are

col-lectively referred to as electrolytes.

The process of ion formation, known as ionization,can occur in single atoms or in atoms that are covalentlylinked in molecules Within molecules two commonlyencountered groups of atoms that undergo ionization

are the carboxyl group (OCOOH) and the amino group

(ONH2) The shorthand formula when indicating only

a portion of a molecule can be written as ROCOOH or

RONH2, where R signifies the remaining portion of themolecule The carboxyl group ionizes when the oxygenlinked to the hydrogen captures the hydrogen’s onlyelectron to form a carboxyl ion (ROCOO⫺) and releases

H

H H

H

H H

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The ionization of each of these groups can be reversed,

as indicated by the double arrows; the ionized carboxylgroup can combine with a hydrogen ion to form an un-ionized carboxyl group, and the ionized amino groupcan lose a hydrogen ion and become an un-ionizedamino group

FREE RADICALS

The electrons that revolve around the nucleus of anatom occupy regions known as orbitals, each of whichcan be occupied by one or more pairs of electrons, de-pending on the distance of the orbital from the nucleus

An atom is most stable when each orbital is occupied

by its full complement of electrons An atom containing

a single (unpaired) electron in its outermost orbital isknown as a free radical, as are molecules containingsuch atoms Free radicals can react with other atoms,thereby filling the unpaired orbital

Free radicals are diagramed with a dot next to theatomic symbol Examples of biologically important freeradicals are superoxide anion, O2ⴢ⫺; hydroxyl radical,

OHⴢ ; and nitric oxide, NO ⴢ Note that a free radicalconfiguration can occur in either an ionized (charged)

or an un-ionized atom A number of free radicals playimportant roles in the normal and abnormal function-ing of the body

POLAR MOLECULES

As we have seen, when the electrons of two atoms teract, the two atoms may share the electrons equally,forming a covalent bond that is electrically neutral.Alternatively, one of the atoms may completely capture

in-an electron from the other, forming two ions Betweenthese two extremes are bonds in which the electrons arenot shared equally between the two atoms, but insteadreside closer to one atom of the pair This atom thus ac-quires a slight negative charge, while the other atom,having partly lost an electron, becomes slightly positive

Such bonds are known as polar covalent bonds (or,

sim-ply, polar bonds) since the atoms at each end of the bond

28

TABLE 2–3 Most Frequently Encountered lonic Forms of Elements

C C

C C

C C

C

C C C

C C C

C C C

C

C C

C C

C C C

C C

C C C C C C

C C

C C

FIGURE 2 – 3

Changes in molecular shape occur as portions of a molecule

rotate around different carbon-to-carbon bonds, transforming

this molecule’s shape, for example, from a relatively straight

chain into a ring.

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have an opposite electric charge For example, the bond

between hydrogen and oxygen in a hydroxyl group

(OOH) is a polar covalent bond in which the oxygen is

slightly negative and the hydrogen slightly positive:

(⫺) (⫹)

(Polar bonds will be diagramed with parentheses

around the charges, as above.) The electric charge

asso-ciated with the ends of a polar bond is considerably less

than the charge on a fully ionized atom For example,

the oxygen in the polarized hydroxyl group has only

about 13 percent of the negative charge associated with

the oxygen in an ionized carboxyl group, ROCOO⫺

Polar bonds do not have a net electric charge, as do ions,

since they contain equal amounts of negative and

pos-itive charge

Atoms of oxygen and nitrogen, which have a

rela-tively strong attraction for electrons, form polar bonds

with hydrogen atoms In contrast, bonds between

car-bon and hydrogen atoms and between two carcar-bon

atoms are electrically neutral (Table 2–4)

Different regions of a single molecule may contain

nonpolar bonds, polar bonds, and ionized groups.Molecules containing significant numbers of polar

bonds or ionized groups are known as polar molecules,

whereas molecules composed predominantly of

electri-cally neutral bonds are known as nonpolar molecules.

As we shall see, the physical characteristics of these twoclasses of molecules, especially their solubility in water,are quite different

Hydrogen BondsThe electrical attraction between the hydrogen atom in

a polar bond in one molecule and an oxygen or gen atom in a polar bond of another molecule—orwithin the same molecule if the bonds are sufficiently

nitro-separated from each other—forms a hydrogen bond.

This type of bond is very weak, having only about 4 cent of the strength of the polar bonds linking the hy-drogen and oxygen within a single water molecule (H2O).Hydrogen bonds are represented in diagrams by dashed

per-or dotted lines to distinguish them from covalent bonds(Figure 2–4) Hydrogen bonds between and within mol-ecules play an important role in molecular interactionsand in determining the shape of large molecules

TABLE 2–4 Examples of Nonpolar and Polar Bonds, and Ionized Chemical Groups

Carbon-hydrogen bond

Nonpolar Bonds

Carbon-carbon bond

RXOXH(⫺) (⫹) Hydroxyl group (ROOH)

Nitrogen-hydrogen bond

Carboxyl group (ROCOO ⫺ )

Phosphate group (ROPO 4 ⫺ ) P

O

OⴚO

N H

C C

C H

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Reactions of this type are known as hydrolytic reactions,

or hydrolysis Many large molecules in the body are

broken down into smaller molecular units by lysis, usually with the assistance of a class of moleculescalled enzymes

hydro-SOLUTIONS

Substances dissolved in a liquid are known as solutes, and the liquid in which they are dissolved is the solvent Solutes dissolve in a solvent to form a solution Water

is the most abundant solvent in the body, accountingfor 60 percent of the total body weight A majority ofthe chemical reactions that occur in the body involvemolecules that are dissolved in water, either in theintracellular or extracellular fluid However, not allmolecules dissolve in water

Molecular Solubility

In order to dissolve in water, a substance must be trically attracted to water molecules For example, tablesalt (NaCl) is a solid crystalline substance because of thestrong electrical attraction between positive sodiumions and negative chloride ions This strong attractionbetween two oppositely charged ions is known as an

elec-ionic bond.When a crystal of sodium chloride is placed

in water, the polar water molecules are attracted to thecharged sodium and chloride ions (Figure 2–5) The ionsbecome surrounded by clusters of water molecules, al-lowing the sodium and chloride ions to separate fromthe salt crystal and enter the water—that is, to dissolve.Molecules having a number of polar bonds and/orionized groups will dissolve in water Such molecules

are said to be hydrophilic, or “water-loving.” Thus, the

presence in a molecule of ionized groups, such as boxyl and amino groups, or of polar groups, such ashydroxyl groups, promotes solubility in water Incontrast, molecules composed predominantly of carbonand hydrogen are insoluble in water since their elec-trically neutral covalent bonds are not attracted to

car-water molecules These molecules are hydrophobic, or

“water-fearing.”

When hydrophobic molecules are mixed withwater, two phases are formed, as occurs when oil ismixed with water The strong attraction between polarmolecules “squeezes” the nonpolar molecules out of thewater phase Such a separation is never 100 percentcomplete, however, and very small amounts of nonpo-lar solutes remain dissolved in the water phase.Molecules that have a polar or ionized region at oneend and a nonpolar region at the opposite end are called

amphipathic—consisting of two parts When mixedwith water, amphipathic molecules form clusters, withtheir polar (hydrophilic) regions at the surface of thecluster where they are attracted to the surrounding wa-ter molecules The nonpolar (hydrophobic) ends are

CHAPTER TWO Chemical Composition of the Body

30

Water

Hydrogen is the most common atom in the body, and

water is the most common molecule Out of every 100

molecules, 99 are water The covalent bonds linking the

two hydrogen atoms to the oxygen atom in a water

mol-ecule are polar Therefore, the oxygen in water has a

slight negative charge, and each hydrogen has a slight

positive charge The positively polarized regions near

the hydrogen atoms of one water molecule are

electri-cally attracted to the negatively polarized regions of the

oxygen atoms in adjacent water molecules by hydrogen

bonds (Figure 2–4)

At body temperature, water exists as a liquid

be-cause the weak hydrogen bonds between water

mole-cules are continuously being formed and broken If the

temperature is increased, the hydrogen bonds are

bro-ken more readily, and molecules of water escape into

the gaseous state; however, if the temperature is

low-ered, hydrogen bonds are broken less frequently so

that larger and larger clusters of water molecules are

formed until at 0⬚C water freezes into a continuous

crystalline matrix—ice

Water molecules take part in many chemical

reac-tions of the general type:

R1OR2⫹ HOOOH n R1OOH ⫹ HOR2

In this reaction, the covalent bond between R1and R2

and the one between a hydrogen atom and oxygen in

water are broken, and the hydroxyl group and

hydro-gen atom are transferred to R and R, respectively

O – –

+ +

H

H

O –

H

H

O –

+

FIGURE 2 – 4

Five water molecules Note that polarized covalent bonds link

the hydrogen and oxygen atoms within each molecule and that

hydrogen bonds occur between adjacent molecules Hydrogen

bonds are represented in diagrams by dashed or dotted lines,

and covalent bonds by solid lines.

Human Physiology, Ninth

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oriented toward the interior of the cluster (Figure 2–6)

Such an arrangement provides the maximal interaction

between water molecules and the polar ends of the

am-phipathic molecules Nonpolar molecules can dissolve

in the central nonpolar regions of these clusters and thus

exist in aqueous solutions in far higher amounts than

would otherwise be possible based on their low bility in water As we shall see, the orientation ofamphipathic molecules plays an important role in thestructure of cell membranes and in both the absorption

solu-of nonpolar molecules from the gastrointestinal tractand their transport in the blood

+ – +

– +

+ – +

+

+ – +

+ – +

+ – + +

– +

+ – +

FIGURE 2 – 5

The ability of water to dissolve sodium chloride crystals depends upon the electrical attraction between the polar water molecules and the charged sodium and chloride ions For simplicity, the oxygen atoms of water are shown with a single negative sign, but in reality the electrons from both bonded hydrogens are in close proximity to oxygen.

Water molecule (polar)

Amphipathic molecule Nonpolar region Polar region

+ +

+ +

+

+

+ +

+

+ +

+ + –

+ + –

+ + –

+ + – + + –

+

+ + – +

+ –

+ + –

+ + –

FIGURE 2 – 6

In water, amphipathic molecules aggregate into spherical clusters Their polar regions form hydrogen bonds with water molecules at the surface of the cluster, while the nonpolar regions cluster together away from water.

Human Physiology, Ninth

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Hydrogen Ions and Acidity

As mentioned earlier, a hydrogen atom has a singleproton in its nucleus orbited by a single electron A hy-drogen ion (H⫹), formed by the loss of the electron, isthus a single free proton Hydrogen ions are formedwhen the proton of a hydrogen atom in a molecule isreleased, leaving behind its electron Molecules thatrelease protons (hydrogen ions) in solution are called

acids,for example:

Conversely, any substance that can accept a

hydro-gen ion (proton) is termed a base In the reactions

shown, bicarbonate and lactate are bases since they cancombine with hydrogen ions (note the double arrows inthe two reactions) It is important to distinguish be-tween the un-ionized acid and ionized base forms ofthese molecules Also, note that separate terms are usedfor the acid forms, lactic acid and carbonic acid, and thebases derived from the acids, lactate and bicarbonate

By combining with hydrogen ions, bases lower thehydrogen ion concentration of a solution

When hydrochloric acid is dissolved in water, 100percent of its atoms separate to form hydrogen andchloride ions, and these ions do not recombine in so-lution (note the one-way arrow in the preceding dia-gram) In the case of lactic acid, however, only a frac-tion of the lactic acid molecules in solution releasehydrogen ions at any instant Therefore, if a 1 mol/Lsolution of hydrochloric acid is compared with a

1 mol/L solution of lactic acid, the hydrogen ion centration will be lower in the lactic acid solution than

con-in the hydrochloric acid solution Hydrochloric acidand other acids that are 100 percent ionized in solu-

tion are known as strong acids, whereas carbonic and

lactic acids and other acids that do not completely

ionize in solution are weak acids The same

princi-ples apply to bases

It must be understood that the hydrogen ion centration of a solution refers only to the hydrogen ionsthat are free in solution and not to those that may bebound, for example, to amino groups (RONH3 ⫹) The

con-acidityof a solution refers to the free (unbound)

hydro-gen ion concentration in the solution; the higher the

lactate

⫹ CH3 COH

HCOOH

lactic acid

CH3 COH

Solute concentration is defined as the amount of the

solute present in a unit volume of solution One

mea-sure of the amount of a substance is its mass given in

grams The unit of volume in the metric system is a liter

(L) (One liter equals 1.06 quarts See Appendix C for

metric and English units.) Smaller units commonly used

in physiology are the deciliter (0.1 liter), the milliliter

(ml, or 0.001 liter) and the microliter (␮l, or 0.001 ml)

The concentration of a solute in a solution can then be

expressed as the number of grams of the substance

pres-ent in one liter of solution (g/L)

A comparison of the concentrations of two

differ-ent substances on the basis of the number of grams per

liter of solution does not directly indicate how many

molecules of each substance are present For example, 10

g of compound X, whose molecules are heavier than

those of compound Y, will contain fewer molecules than

10 g of compound Y Concentrations in units of grams

per liter are most often used when the chemical

struc-ture of the solute is unknown When the strucstruc-ture of

a molecule is known, concentrations are usually

ex-pressed as moles per liter, which provides a unit of

con-centration based upon the number of solute molecules

in solution, as described next

The molecular weight of a molecule is equal to the

sum of the atomic weights of all the atoms in the

molecule For example, glucose (C6H12O6) has a

molec-ular weight of 180 (6⫻ 12 ⫹ 12 ⫻ 1 ⫹ 6 ⫻ 16 ⫽ 180)

One mole (abbreviated mol) of a compound is the

amount of the compound in grams equal to its

molec-ular weight A solution containing 180 g of glucose

(1 mol) in 1 L of solution is a 1 molar solution of

glu-cose (1 mol/L) If 90 g of gluglu-cose were dissolved in

enough water to produce 1 L of solution, the solution

would have a concentration of 0.5 mol/L Just as 1 gram

atomic mass of any element contains the same number

of atoms, 1 mol (1 gram molecular mass) of any

mole-cule will contain the same number of molemole-cules—6⫻

1023(Avogadro’s number) Thus, a 1 mol/L solution of

glucose contains the same number of solute molecules

per liter as a 1 mol/L solution of urea or any other

substance

The concentrations of solutes dissolved in the body

fluids are much less than 1 mol/L Many have

concen-trations in the range of millimoles per liter (1 mmol/L⫽

0.001 mol/L), while others are present in even smaller

concentrations—micromoles per liter (1 ␮mol/L ⫽

0.000001 mol/L) or nanomoles per liter (1 nmol/L⫽

0.000000001 mol/L) By convention, the liter (L) term is

sometimes dropped when referring to concentrations

Thus, a 1 mmol/L solution is often written as 1 mM

(the capital “M” stands for “molar,” and is defined as

mol/L)

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hydrogen ion concentration, the greater the acidity The

hydrogen ion concentration is often expressed in terms

of the pH of a solution, which is defined as the

nega-tive logarithm to the base 10 of the hydrogen ion

concentration The brackets around the symbol for the

hydrogen ion in the following formula indicate

con-centration:

pH⫽ ⫺log [H⫹]

Thus, a solution with a hydrogen ion concentration

of 10⫺7mol/L has a pH of 7, whereas a more acidic

solution with a higher H⫹ concentration of 10⫺6

mol/L has a lower pH of 6 Note that as the acidity

increases, the pH decreases; a change in pH from 7 to

6 represents a tenfold increase in the hydrogen ion

concentration

Pure water, due to the ionization of some of the

molecules into H⫹and OH⫺, has a hydrogen ion

con-centration of 10⫺7 mol/L (pH⫽ 7.0) and is termed a

neutral solution Alkaline solutionshave a lower

hy-drogen ion concentration (a pH higher than 7.0), while

those with a higher hydrogen ion concentration (a pH

lower than 7.0) are acidic solutions The extracellular

fluid of the body has a hydrogen ion concentration of

about 4⫻ 10⫺8

mol/L (pH⫽ 7.4), with a normal range

of about pH 7.35 to 7.45, and is thus slightly alkaline

Most intracellular fluids have a slightly higher

hydro-gen ion concentration (pH 7.0 to 7.2) than extracellular

fluids

As we saw earlier, the ionization of carboxyl and

amino groups involves the release and uptake,

respec-tively, of hydrogen ions These groups behave as weak

acids and bases Changes in the acidity of solutions

con-taining molecules with carboxyl and amino groups

al-ter the net electric charge on these molecules by

shift-ing the ionization reaction to the right or left

ROCOO⫺⫹ H⫹34 ROCOOH

For example, if the acidity of a solution containing

lac-tate is increased by adding hydrochloric acid, the

con-centration of lactic acid will increase and that of lactate

will decrease

If the electric charge on a molecule is altered, its

interaction with other molecules or with other regions

within the same molecule is altered, and thus its

func-tional characteristics are altered In the extracellular

fluid, hydrogen ion concentrations beyond the

ten-fold pH range of 7.8 to 6.8 are incompatible with life

if maintained for more than a brief period of time

Even small changes in the hydrogen ion

concentra-tion can produce large changes in molecular

interac-tions For example, many enzymes in the body

oper-ate efficiently within very narrow ranges of pH.Should pH vary from the normal homeostatic rangedue to disease, these enzymes would have reducedactivities, creating an even worse pathological sit-uation

CLASSES OF ORGANIC MOLECULES

Because most naturally occurring carbon-containingmolecules are found in living organisms, the study ofthese compounds became known as organic chemistry.(Inorganic chemistry is the study of noncarbon-containing molecules.) However, the chemistry of liv-

ing organisms, biochemistry, now forms only a portion

of the broad field of organic chemistry

One of the properties of the carbon atom that makeslife possible is its ability to form four covalent bondswith other atoms, in particular with other carbon atoms.Since carbon atoms can also combine with hydrogen,oxygen, nitrogen, and sulfur atoms, a vast number ofcompounds can be formed with relatively few chemi-cal elements Some of these molecules are extremely

large (macromolecules), being composed of thousands

of atoms Such large molecules are formed by linkingtogether hundreds of smaller molecules (subunits) and

are thus known as polymers (many small parts) The

structure of macromolecules depends upon the ture of the subunits, the number of subunits linkedtogether, and the three-dimensional way in which thesubunits are linked

struc-Most of the organic molecules in the body can beclassified into one of four groups: carbohydrates, lipids,proteins, and nucleic acids (Table 2–5)

CarbohydratesAlthough carbohydrates account for only about 1 per-cent of the body weight, they play a central role inthe chemical reactions that provide cells with energy.Carbohydrates are composed of carbon, hydrogen, andoxygen atoms in the proportions represented by the

general formula Cn(H2O)n, where n is any whole

num-ber It is from this formula that the class of molecules

gets its name, carbohydrate—water-containing

(hy-drated) carbon atoms Linked to most of the carbonatoms in a carbohydrate are a hydrogen atom and a hy-droxyl group:

It is the presence of numerous hydroxyl groups thatmakes carbohydrates readily soluble in water

OH

H C

Human Physiology, Ninth

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respectively Larger carbohydrates can be formed

by linking a number of monosaccharides together.Carbohydrates composed of two monosaccharides are

known as disaccharides Sucrose, or table sugar (Figure

2–9), is composed of two monosaccharides, glucose andfructose The linking together of most monosaccharidesinvolves the removal of a hydroxyl group from onemonosaccharide and a hydrogen atom from the other,giving rise to a molecule of water and linking the twosugars together through an oxygen atom Conversely,hydrolysis of the disaccharide breaks this linkage byadding back the water and thus uncoupling the twomonosaccharides Additional disaccharides frequentlyencountered are maltose (glucose-glucose), formed dur-ing the digestion of large carbohydrates in the intestinaltract, and lactose (glucose-galactose), present in milk.When many monosaccharides are linked together

to form polymers, the molecules are known as saccharides Starch, found in plant cells, and glycogen

poly-(Figure 2–10), present in animal cells and often called

CHAPTER TWO Chemical Composition of the Body

34

Most carbohydrates taste sweet, and it is among the

carbohydrates that we find the substances known as

sugars The simplest sugars are the monosaccharides

(single-sweet), the most abundant of which is glucose,

a six-carbon molecule (C6H12O6) often called “blood

sugar” because it is the major monosaccharide found in

the blood

There are two ways of representing the linkage

be-tween the atoms of a monosaccharide, as illustrated in

Figure 2–7 The first is the conventional way of drawing

the structure of organic molecules, but the second gives

a better representation of their three-dimensional shape

Five carbon atoms and an oxygen atom form a ring that

lies in an essentially flat plane The hydrogen and

hy-droxyl groups on each carbon lie above and below the

plane of this ring If one of the hydroxyl groups below

the ring is shifted to a position above the ring, as shown

in Figure 2–8, a different monosaccharide is produced

Most monosaccharides in the body contain five or

six carbon atoms and are called pentoses and hexoses,

TABLE 2–5 Major Categories of Organic Molecules in the Body

PERCENT

OF BODY CATEGORY WEIGHT PREDOMINANT ATOMS SUBCLASS SUBUNITS

Carbohydrates 1 C, H, O Monosaccharides

(sugars) Polysaccharides Monosaccharides Lipids 15 C, H Triglycerides 3 fatty acids ⫹ glycerol

Phospholipids 2 fatty acids ⫹ glycerol ⫹ phosphate ⫹ small

charged nitrogen molecule Steroids

Proteins 17 C, H, O, N Peptides and polypeptides Amino acids

Nucleic acids 2 C, H, O, N DNA Nucleotides containing the bases adenine,

cytosine, guanine, thymine, the sugar deoxyribose, and phosphate RNA Nucleotides containing the bases adenine,

cytosine, guanine, uracil, the sugar ribose, and phosphate

C H

H H

OH H

C

HO

OH C H

Glucose

C

Glucose Galactose OH

OH

CH 2 OH

C

OH H

C OH

C H

H OH

H

OH C H

CH2OH

C

OH H

C OH

C H

H H

OH C H

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OH C

C H 2 OH C

C OH

C O

+

CH2OH

C

OH H

C OH

C H

H OH

C H

H OH

H

OH C H

H 2 O O

+ +

C OH

C

C H

C OH

C

C H

H OH

C OH

C

C H

H OH

O H

C O

C

C H H OH H

Many molecules of glucose linked end-to-end and at branch points form the branched-chain polysaccharide glycogen, shown in

diagrammatic form in (a) The four red subunits in (b) correspond to the four glucose subunits in (a).