H

kinase. The rise in cAMP concentration produced by ACTH might account for its effect on the enzyme.

Trophic Action on Adrenal Cortical Cell Size. ACTH maintains the size of the two inner zones of the adrenal cortex, presumably by stimulating the synthesis of structural elements of the cells, however, it does not affect the size of the cells of the zona glomerulosa. The trophic effect of ACTH is clearly evident in states of ACTH deficiency or excess. In hypophysectomized or ACTH-deficient individuals, the cells of the two inner zones atrophy. Chronic stimulation of these cells with ACTH causes them to hypertrophy. The mechanisms involved in this trophic action of ACTH are unclear.

ACTH and Aldosterone Production. The cells of the zona glomerulosa have ACTH receptors, which are coupled to adenylyl cyclase. In these cells, cAMP increases in response to ACTH, resulting in some increase in aldos-terone secretion. However, angiotensin II is the important physiological regulator of aldosterone secretion, not ACTH. Other factors, such as an increase in serum potassium, can also stimulate aldosterone secretion, but normally, they play only a secondary role.

Formation of Angiotensin II. Angiotensin II is a short peptide consisting of eight amino acid residues. It is formed in the bloodstream by the proteolysis of the a2-globulin angiotensinogen, which is secreted by the liver. The formation of angiotensin II occurs in two stages (Fig. 34.8). Angiotensinogen is first cleaved at its N-ter-minal end by the circulating protease renin, releasing the inactive decapeptide angiotensin I. Renin is produced and secreted by granular (juxtaglomerular) cells in the kidneys (see Chapter 23). A dipeptide is then removed from the C-terminal end of angiotensin I, producing angiotensin II. This cleavage is performed by the protease angiotensin-converting enzyme present on the endothelial cells lining the vasculature. This step usually occurs as angiotensin I molecules traverse the pulmonary circulation. The rate-limiting factor for the formation of angiotensin II is the renin concentration of the blood.

Cleavage of the N-terminal aspartate from angiotensin II results in the formation of angiotensin III, which circulates at a concentration of 20% that of angiotensin II. Angiotensin III is as potent a stimulator of aldosterone secretion as angiotensin II.

Action of Angiotensin II on Aldosterone Secretion. Angiotensin II stimulates aldosterone synthesis by promoting the rate-limiting step in steroidogenesis (i.e., the movement of cholesterol into the inner mitochondrial membrane and its conversion to pregnenolone). The primary mechanism is shown in Figure 34.9.

The stimulation of aldosterone synthesis is initiated when angiotensin II binds to its receptors on the plasma membranes of zona glomerulosa cells. The signal generated by the interaction of angiotensin II with its receptors is transmitted to phospholipase C (PLC) by a G protein, and the enzyme becomes activated. The PLC then hydrolyzes phosphatidylinositol 4,5 bisphosphate (PIP2) in the plasma membrane, producing the intracellular second messengers inositol trisphosphate (IP3) and diacylglycerol (DAG). The IP3 mobilizes calcium, which is bound to intracellular structures, increasing the calcium concentration in the cytosol. This increase in intracellular calcium and DAG activates protein kinase C (PKC). The rise in intracellular calcium also activates calmodulin-dependent protein kinase (CMK). These enzymes phosphorylate proteins, which then become involved in initiating steroidogenesis.

Signals for Increased Angiotensin II Formation. Although angiotensin II is the final mediator in the physiological regulation of aldosterone secretion, its formation from angiotensinogen is dependent on the secretion of renin by the kidneys. The rate of renin secretion ultimately determines the rate of aldosterone secretion. Renin is secreted by the granular cells in the walls of the afferent arte-rioles of renal glomeruli. These cells are stimulated to secrete renin by three signals that indicate a possible loss of body fluid: a fall in blood pressure in the afferent arterioles of the glomeruli, a drop in sodium chloride concentration in renal tubular fluid at the macula densa, and an increase in renal sympathetic nerve activity (see Chapters 23 and 24).

^SpArg(Val)(Tyi)(i^ Angiotensinogen

J Renin

Angiotensin I

^ Converting enzyme

(HSxLfU Angiotensin II

^ Aminopeptidase

@ (Arg(va^Ty^55(H^(proCEhe Angiotensin III

The formation of an-giotensins I, II, and III from angiotensinogen.

Zona glomerulosa cell

Zona glomerulosa cell

Zona Glomerulosa Angiotensin Receptor

The action of angiotensin II on aldosterone

^BIIIlHII^synthesis. Angiotensin II (AII) binds to receptors on the plasma membrane of zona glomerulosa cells. This activates phospholipase C (PLC), which is coupled to the angiotensin II receptor by G proteins (Gq). PLC hydrolyzes phosphatidylinositol 4,5 bisphosphate (PIP2) in the plasma membrane, producing inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes intracellularly bound Ca2 + . The rise in Ca2+ and DAG activates protein kinase C (PKC) and calmodulin-dependent protein kinase (CMK). These enzymes phosphorylate proteins (P-Proteins) involved in initiating aldosterone synthesis.

The action of angiotensin II on aldosterone

^BIIIlHII^synthesis. Angiotensin II (AII) binds to receptors on the plasma membrane of zona glomerulosa cells. This activates phospholipase C (PLC), which is coupled to the angiotensin II receptor by G proteins (Gq). PLC hydrolyzes phosphatidylinositol 4,5 bisphosphate (PIP2) in the plasma membrane, producing inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes intracellularly bound Ca2 + . The rise in Ca2+ and DAG activates protein kinase C (PKC) and calmodulin-dependent protein kinase (CMK). These enzymes phosphorylate proteins (P-Proteins) involved in initiating aldosterone synthesis.

Increased renin secretion results in an increase in angiotensin II formation in the blood, thereby stimulating al-dosterone secretion by the zona glomerulosa. This series of events tends to conserve body fluid volume because aldosterone stimulates sodium reabsorption by the kidneys.

Extracellular Potassium Concentration and Aldosterone Secretion. Aldosterone secretion is also stimulated by an increase in the potassium concentration in extracellular fluid, caused by a direct effect of potassium on zona glomerulosa cells. Glomerulosa cells are sensitive to this effect of extracellular potassium and, therefore, increase their rate of aldosterone secretion in response to small increases in blood and interstitial fluid potassium concentration. This signal for aldosterone secretion is appropriate from a physiological point of view because aldosterone promotes the renal excretion of potassium (see Chapter 24).

A rise in extracellular potassium depolarizes glomerulosa cell membranes, activating voltage-dependent calcium channels in the membranes. The consequent rise in cytoso-lic calcium is thought to stimulate aldosterone synthesis by the mechanisms described above for the action of an-giotensin II.

Aldosterone and Sodium Reabsorption by Kidney Tubules. The physiological action of aldosterone is to stimulate sodium reabsorption in the kidneys by the distal tubule and collecting duct of the nephron and to promote the excretion of potassium and hydrogen ions. The mechanism of action of aldosterone on the kidneys and its role in water and electrolyte balance are discussed in Chapter 24.

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