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" The values reported for the extracellular compartment are also applicable to plasma. b Calculated by assuming a daily urinary output of 2 liters.

c Amount excreted in a 24-hr interval by a normal man consuming an average mixed diet.

Renal blood vessel

Renal medulla (pyramid)

Renal column

Renal cortex

Renal papillae

Arcuate artery

Renal

Renal artery

Ureter

lar artery

Calyx

Renal capsule

Renal blood vessel

Renal medulla (pyramid)

Renal column

Renal

Renal artery

Ureter

Calyx

Renal cortex

Renal papillae

Arcuate artery lar artery

Renal capsule

FIGURE 15-1 Cross section of a human kidney.

Bowman's capsule

Glomerulus

Bowman's capsule

Glomerulus

Afferent arteriole

Efferent arteriole Interlobular artery Interlobular vein

Arctiate artery Arcuate vein

FIGURE 15-2 Schematic diagram of a nephron with its associated vascular system.

Afferent arteriole

Efferent arteriole Interlobular artery Interlobular vein

Arctiate artery Arcuate vein

FIGURE 15-2 Schematic diagram of a nephron with its associated vascular system.

the loop of Henle as well as the arborized network of capillaries.

An important distinction to note is that the far distal region of each renal tubule is anatomically connected to the afferent arteriole of its own glomerulus. The point of attachment of each distal tubule to its glomerulus is the macula densa; the cells of the macula densa interact with the juxtaglomerular cells. Thus, this anatomical specialization allows for physiological, metabolic, and hormonal communication to occur between the distal tubule (containing the exiting urine) and the afferent arteriole (containing the entering blood, which will be filtered).

The distal convoluted tubule empties into a branch of the collecting ducts that ultimately leads to a main collecting duct, in turn connecting to a network of renal papillae coursing through the renal pyramids to the renal pelvis.

4. Physiological Processes

The kidney is the principal organ responsible for the homeostasis of a wide spectrum of electrolytes, as well as the conservation of body water. The kidney carries out its homeostatic actions sequentially by selective glomerular filtration (mediated by a high blood pressure in the glomerulus), tubular secretion, and tubular reabsorption; these are all processes that collectively regulate the concentration of the metabolic end products, osmotic pressure, ionic composition, and

Distal tubule

Macula densa of distal tubule

Efferent arteriole

Distal tubule

Macula densa of distal tubule

Efferent arteriole

FIGURE 15-3 Cross section of a renal corpuscle. The upper part shows the vascular pole with afferent and efferent arterioles and the macula densa. Note the juxtaglomerular cells in the wall of the afferent arteriole. Podocytes cover the glomerular capillaries. Their nuclei protrude on the cell surface. Podocyte processes can be seen. The cells of the parietal layer of Bowman's capsule are shown. The lower part of the drawing shows the urinary pole and the proximal convoluted tubule. Modified from Junquiera, L. C. and Carneiro, J. (1983). "Basic Histology," 4th ed., p. 400. Lange Medical Publications, Los Altos, CA.

FIGURE 15-3 Cross section of a renal corpuscle. The upper part shows the vascular pole with afferent and efferent arterioles and the macula densa. Note the juxtaglomerular cells in the wall of the afferent arteriole. Podocytes cover the glomerular capillaries. Their nuclei protrude on the cell surface. Podocyte processes can be seen. The cells of the parietal layer of Bowman's capsule are shown. The lower part of the drawing shows the urinary pole and the proximal convoluted tubule. Modified from Junquiera, L. C. and Carneiro, J. (1983). "Basic Histology," 4th ed., p. 400. Lange Medical Publications, Los Altos, CA.

volume of the internal environment. Figure 15-4 is a schematic diagram of a typical kidney nephron, indicating the sites of reabsorption of the various ionic substances. The key to the achievement of homeostasis is the process of countercurrent distribution. Counter-

current distribution occurs as a consequence of the anatomical organization of the nephron and is supported by the processes of passive diffusion, tubular reabsorption, and tubular secretion. Both of the latter processes utilize energy-dependent active transport mechanisms. The end result of these activities is the formation of the residual urine containing bodily wastes (both ionic, organic, and nitrogenous); however, in the process of forming the urine from the glomerular filtrate, the tubule has returned many essential nutrients and electrolytes to the blood. A comparison of the extracellular concentrations to urine concentrations of major urine constituents is presented in Table 15-2.

B. Cardiovascular System

1. Heart

The heart, although weighing less than 450 g, is a remarkable organ. Its continuous beating provides the driving force to ensure the delivery of oxygen, nutrients, hormones, and other regulatory molecules to every cell in the body, as well as effecting the continuous removal of metabolic waste products. Over an average lifetime, the heart pumps approximately 300 million liters (—80 million gallons) of blood. The dynamic range of the heart pumping capacity is also impressive; cardiac output can range from a low of 5 to an upper limit of 35 liters of blood per minute. The heart is also the source of an important hormone, atrial natriuretic hormone (ANF), which is involved with the regulation of blood pressure.

Figure 15-5 presents a cross-sectional view of the heart. The human heart is divided longitudinally into right and left halves, each of which consists of two chambers, the atrium and the ventricle. The function of the heart is to pump the blood into the arterial system that has been delivered to the heart from the venous system. The right side of the heart receives from the venae cavae the oxygen-depleted blood from the peripheral tissues; this is then pumped into the pulmonary artery for circulation to the lungs. The left side of the heart receives the oxygen-enriched blood back from the lungs via the pulmonary veins; this blood is then pumped into the aorta for disbursement to all of the peripheral tissues.

The pressure necessary for these tasks is created by the strong contractions of the various musculatures of the heart. However, the force and rate of these heart contractions, as well as the volume of blood that may exit the heart with each heartbeat, are determined via a complex set of physiological and hormonal signals

figure 15-4 Schematic diagram of a kidney nephron illustrating the process of counter-current exchange. The numbers indicate the gradients in osmolarity that result as a consequence of simple diffusion and transport or exchange. The filtrate, as it enters the loop of Henle, becomes further concentrated by diffusion of water into the hypotome interstitium. In the ascending limb of the loop of Henle, Na+ is actively transported out of the filtrate (thereby diluting it) into the interstitium, where it is concentrated. The osmolarity of the interstitial fluid can increase from 300 to 1100 mOsm/kg Hg2 as the papilla is approached. Then, as the distal tubule passes back past the glomerulus, additional Na+ may be reabsorbed in exchange for H+ or K+ ions; eventually water is reabsorbed in the distal tubule and collecting duct. Also indicated are the sites of reabsorption of various constituents. Aldosterone and antidiuretic hormone act principally on the collecting duct. Modified from Pitts, R. F. (1974). "Physiology of the Kidney and Body Fluids," 3rd ed., p. 134. Year Book Medical Publishers, Inc., Chicago.

figure 15-4 Schematic diagram of a kidney nephron illustrating the process of counter-current exchange. The numbers indicate the gradients in osmolarity that result as a consequence of simple diffusion and transport or exchange. The filtrate, as it enters the loop of Henle, becomes further concentrated by diffusion of water into the hypotome interstitium. In the ascending limb of the loop of Henle, Na+ is actively transported out of the filtrate (thereby diluting it) into the interstitium, where it is concentrated. The osmolarity of the interstitial fluid can increase from 300 to 1100 mOsm/kg Hg2 as the papilla is approached. Then, as the distal tubule passes back past the glomerulus, additional Na+ may be reabsorbed in exchange for H+ or K+ ions; eventually water is reabsorbed in the distal tubule and collecting duct. Also indicated are the sites of reabsorption of various constituents. Aldosterone and antidiuretic hormone act principally on the collecting duct. Modified from Pitts, R. F. (1974). "Physiology of the Kidney and Body Fluids," 3rd ed., p. 134. Year Book Medical Publishers, Inc., Chicago.

operative in the circulatory system. A detailed discussion of these topics is beyond the scope of this text.

2. Cardiovascular System

The circulatory system or cardiovascular system comprises the heart and blood vessels, or the body's "plumbing system;" see Figure 15-6A. The heart is the pumping organ that ejects blood into the arterial network; the blood is then returned to the heart via the venous system. The capillaries represent microscopic vesicles that interconnect between the small arteries (arterioles) and small veins (venules); see Figure 15-6B. The walls of the capillaries are only one endothelial cell in thickness. Tiny openings, or fenestrations, facilitate the delivery and exchange between the circulating blood in the capillary and the interstitial fluid that surrounds and bathes the neighboring cells.

figure 15-5 Interior view of the human heart. The arrows indicate the direction of blood flow. [Modified with permission from Figure 20-6, of Solomon, E. P., Schmidt, R. R., and Adragna, P. J. (1990). "Human Anatomy and Physiology," p. 676. Saunders College Publishing, Philadelphia, PA.

3. Regulation of Blood Pressure

Table 15-4 classifies normal and hypertensive blood pressures. The principal determinants of mean arterial blood pressure are the volume of cardiac output (stroke volume and heart rate), systemic blood flow, and resistance to blood flow in the various perfused organs. These functions are regulated by a variety of hormones, neurotransmitters, and local paracrine factors, as well as by the health and vigor of the heart.

III. HOMEOSTASIS OF FLUID, ELECTROLYTES, AND BLOOD PRESSURE

A. Introduction

Hormones are intimately involved in the regulation of both cardiovascular and renal functions. The maintenance of salt homeostasis, circulatory volume, and blood pressure requires the integrated actions of the renin-angiotensin-aldosterone system, the adrenergic nervous system, vasopressin, atrial natriuretic hormone, kinins, endothelins, prostaglandins, and the nitric oxide system.

Some of these hormones can affect heart rate and contractility directly or effect vasoconstriction or vasodilation of the arteries and veins. In addition, the growth factor properties of hormones are able to influence cardiovascular development and muscular hyperplasia or hypertrophy, as well as being involved with pathological changes that can be associated with atherosclerosis, cardiac hypertrophy, and heart failure. These hormone systems are also capable of mediating important biological effects in the kidney.

The volume of the extracellular fluid (ECF) is governed by its Na+ concentration. The Na+ concentration of the ECF is determined by regulating the extent of excretion of Na+ in the urine, which is mediated by aldosterone and ANF. The principal, although not exclusive, factors governing the excretion of Na+ are the steroid hormone aldosterone and the glomerular filtration rate. The glomerular filtration of the kidney can be markedly increased by the actions of ANP, thus increasing the extraction of blood Na+. Also, ANP acts on the smooth muscle present in large arteries and vascular beds to effect relaxation and, thus, achieve a reduction in blood pressure. The function of aldosterone is to directly stimulate the absorption of Na+ by the renal tubules; this has the consequence of increas ing the extracellular fluid volume. Thus, in the renin-angiotensin system, the rate of secretion of aldosterone by the adrenal cortex is ultimately regulated by the extracellular fluid volume.

As discussed in Chapter 10, bilateral adrenalectomy is fatal; this results from the absence of aldosterone, which, in turn, leads to an increased loss of Na+ in the urine, a concomitant retention of K+ in the extracellular fluid, and loss of water from both the extracellular and intracellular compartments. If this process continues, death inevitably follows.

B. Renin-Angiotensin II

Renin is an enzyme of 347 amino acids of molecular mass «42 kDa. Renin may be isolated from both kidney and mouse submaxillary glands. The original isolation of the pure protein required a 3 million-fold purification; the primary sequence of human renin has been deduced through cloning and sequence analysis of cDNA prepared from human kidney mRNA. Renin as an enzyme belongs to the class of aspartyl proteinases.

Renin is biosynthesized as a preprorenin consisting of 406 amino acids. The prepro form is converted to prorenin by the removal of 20 amino acids. Then the mature renin is generated by specific cleavage of a 43-amino-acid pro sequence by a prorenin processing enzyme (PPE). The PPE has been highly purified, but not fully characterized. On the basis of both immuno-histochemical and biochemical studies, the suggestion has been made that PPE is identical to the protease cathepsin B; both PPE and cathepsin antibodies stained proximal renal tubules as well as renal juxtaglomerular cells. Approximately 50% of the prorenin in the juxtaglomerular cells is constitutively secreted continuously without proteolytic processing, while the other 50% of the prorenin is sorted to secretory granules, where it is proteolytically processed and stored as renin. The release of this renin is regulated by cAMP. Renin in the circulatory system is variably glycosylated and circulates as 4-5 isoenzymes.

Human renin has, at the amino acid level, 63% homology with mouse submaxillary gland renin and 34% homology with human pepsinogen (see Chapter 8). In renin the aspartyl residues at positions 38 and 226 are believed to be important for catalytic activity. The X-ray crystallographic structure of human renin has been determined to 2.5 A. The general shape of renin is bilobal with a long deep cleft that contains the aspartyl 38 and 226 residues.

Changes in the secretion of renin by the renal juxtaglomerular cells can occur in response to changes in renal arterial pressure, via sympathetic nervous system signals and also via changes in the status of a number of hormones (see Table 15-5). The secretion of renin is governed at the level of the renal glomerulus by both long and short feedback loops. The dominant negative long feedback loop, which diminishes renin secretion, involves increased renal arterial pressure, which is sensed by stretch receptors present in the glomerular afferent arteriolar wall so as to result in a reduction in renin release and, ultimately, a diminution in aldosterone production. A negative short feedback loop is mediated by angiotensin II, which directly inhibits renin release.

C. Angiotensins I and II

The natural substrate for renin is the plasma protein a2-globulin, which is termed angiotensinogen. Angio-tensinogen is a glycoprotein of 57 kDa that is synthesized and secreted into the bloodstream by the liver. The biosynthesis of angiotensinogen is increased by glucocorticoids, estrogens, and some oral contraceptives. The details of the conversion of angiotensinogen into angiotensin I (a decapeptide) and angiotensin II (an octapeptide) are summarized in Figure 15-7. In the circulatory system, renin hydrolyzes the Leu-Leu bond of angiotensinogen at residues 10 and 11 to generate the biologically inactive decapeptide angiotensin I. Angiotensin I is then converted by a converting enzyme (molecular mass ~ 200 kDa) that removes the carboxyl-terminal His-Leu dipeptide to yield the octapeptide hormone angiotensin II.

Angiotensin-converting enzyme (ACE) is a zinc-containing protein. Its most important actions are (a) to convert angiotensin I —> II and (b) to inactivate bradykinin (a very potent vasodilator). The principal site of conversion of angiotensin I to II is in the vascular epithelium of the lung; however, ACE activity is also present in the kidney, vascular epithelium, heart, brain, and testis. A potent orally active synthetic inhibitor of the converting enzyme is the drug captopril or Z-(D-3-mercapto-3-methylpropanoyl)-2-proline. The converting enzyme is also called kininase II because of its action on bradykinin (see Figure 15-16). Angiotensin III, a nonapeptide, is produced by the action of an N-terminal peptidase on angiotensin I. Table 15-6 summarizes the biological actions of the angiotensins. Angiotensin II is the most potent vasoconstrictive agent known. All of the components of the renin-angiotensin system necessary to produce angiotensin II are also present in the brain, where the latter substance may function as a neurotransmitter.

The two principal biological actions of angiotensin II are (a) to stimulate the production of aldosterone in the adrenal zona glomerulosa and (b) to function as a highly potent vasoconstrictor in the circulatory system,

Capillaries

Veins from head and upper extremities

Arteries to head and upper extremities

Superior vena cava

Pulmonary artery

Pulmonary veins

Lung

Right atrium Right ventricle

Capillaries

Veins from head and upper extremities

Right atrium Right ventricle

Arteries to head and upper extremities

Aorta

Left atrium

Veins from abdomen and lower extremities

Capillaries

FIGURE 15-6 Diagram of the human circulatory system. (A) Illustration of the pulmonary and systemic circulatory sysems. The pulmonary circulation includes the pulmonary arteries, capillaries, and veins. The systemic circulation includes all of the other arteries, capillaries, and veins of the body. (B) Diagram of a capillary bed. Precapillary sphincters are relaxed, thus permitting the flow of blood through the capillary network. A greatly magnified portion of capillary wall is shown in the inset at the upper left of B. Modified with permission from Figure 16-4 of Chaffee, E. E. and Lytle, I. M. (1980). "Basic Physiology and Anatomy," 4th ed., p. 336. J. B. Lippincott Co., Philadelphia, PA.

Aorta

Left atrium

Inferior vena cava Hepatic vein Liver

Portal vein

Veins from abdomen and lower extremities

Left ventricle

Arteries to abdomen and lower extremities

Spleen

Stomach Pancreas

Intestine

Capillaries

FIGURE 15-6 Diagram of the human circulatory system. (A) Illustration of the pulmonary and systemic circulatory sysems. The pulmonary circulation includes the pulmonary arteries, capillaries, and veins. The systemic circulation includes all of the other arteries, capillaries, and veins of the body. (B) Diagram of a capillary bed. Precapillary sphincters are relaxed, thus permitting the flow of blood through the capillary network. A greatly magnified portion of capillary wall is shown in the inset at the upper left of B. Modified with permission from Figure 16-4 of Chaffee, E. E. and Lytle, I. M. (1980). "Basic Physiology and Anatomy," 4th ed., p. 336. J. B. Lippincott Co., Philadelphia, PA.

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