The Renin–Angiotensin System

THE RENIN–ANGIOTENSIN SYSTEM

The renin–angiotensin system is important for the regulation of vascular smooth muscle tone, fluid and electrolyte balance, and the growth of cardiac and vas-cular smooth muscle. A normally functioning renin– angiotensin system contributes to the routine control of arterial blood pressure. A variety of basic and clinical investigations have resulted in a broader understanding of the role of the renin–angiotensin system in the car-diovascular pathophysiology of hypertension, conges-tive heart failure, and more recently, atherosclerosis. Whether or not abnormal activity of the renin– angiotensin system contributes to the primary etiology of these diseases, pharmacological inhibition of the renin–angiotensin system has proved to be a valuable therapeutic strategy in the treatment of hypertension and congestive heart failure.

The classical renin–angiotensin system comprises a series of biochemical steps (Fig. 18.1) leading to the pro-duction of a family of structurally related peptides (e.g., angiotensin II, angiotensin III, and other smaller pep-tides with bioactivity). Sites for pharmacological inter-vention in this system include the enzymatic steps cat-alyzed by renin, angiotensin-converting enzyme (ACE), and angiotensin receptors that mediate a particular physiological response.

Renin

Renin is an enzyme that is synthesized and stored in the renal juxtaglomerular apparatus and that catalyzes the formation of a decapeptide, angiotensin I, from a plasma protein substrate. Renin has a narrow substrate specificity that is limited to a single peptide bond in an-giotensinogen, a precursor of angiotensin I. Renin is considered to control the rate-limiting step in the ulti-mate production of angiotensin II. Control of renin se-cretion by the juxtaglomerular apparatus is important in determining the plasma renin concentration.

Three generally accepted mechanisms are involved in the regulation of renin secretion (Fig. 18.2). The first depends on renal afferent arterioles that act as stretch receptors or baroreceptors. Increased intravascular pressure and increased volume in the afferent arteriole inhibits the release of renin. The second mechanism is the result of changes in the amount of filtered sodium that reaches the macula densa of the distal tubule. Plasma renin activity correlates inversely with dietary sodium intake. The third renin secretory control mech-anism is neurogenic and involves the dense sympathetic innervation of the juxtaglomerular cells in the afferent arteriole; renin release is increased following activation of α₁-adrenoceptors by the neurotransmitter norepi-nephrine.

Angiotensin II, the primary end product of the renin–angiotensin system, acts on the juxtaglomerular cells to inhibit the release of renin; this process is there-fore a negative feedback mechanism. The half-life of renin in the circulation is 10 to 30 minutes, with inacti-vation occurring primarily in the liver. Small amounts of renin are eliminated by the kidneys. Pure human rennin has been used to develop specific inhibitors of the en-zyme. Low-molecular-weight orally effective renin in-hibitors are under development.

Angiotensinogen

Human plasma contains a glycoprotein called an-giotensinogen, which serves as the only known substrate for renin. Angiotensinogen must undergo proteolysis before active portions of the protein are sufficiently un-masked to exert biological effects. Angiotensinogen is synthesized in many organs, including the liver, brain, kidney, and fat. Its gene transcription and plasma con-centrations increase following treatment with adreno-corticotropic hormone (ACTH), glucocorticoids, thy-roid hormone, and estrogens, as well as during pregnancy and inflammation and after nephrectomy. Angiotensinogen also has been found in large quanti-ties in cerebrospinal and amniotic fluid. Mutations in the angiotensinogen gene have been reported to be linked to human hypertension.

Angiotensin-Converting Enzyme: A Peptidyl Dipeptide Hydrolase

Metabolism of angiotensinogen by renin produces the decapeptide angiotensin I. This relatively inactive pep-tide is acted on by a dipeptidase-converting enzyme to produce the very active octapeptide angiotensin II. In addition to converting enzyme, angiotensin I can be acted on by prolyl endopeptidase, an enzyme that re-moves the first amino acid to form angiotensin 1-7, a peptide primarily active in the brain. ACE has been identified in vascular endothelial cells, epithelial cells of the proximal tubule and small intestine, male germinal cells, and the central nervous system. The lung vascular endothelium contains the highest concentration of ACE, and therefore, the lung serves as the major organ for the production of circulating angiotensin II. Although ACE was originally thought to be specific for the conversion of angiotensin I to II, it is now known to be a rather nonspecific peptidyl dipeptide hydrolase that can cleave dipeptides from the carboxy terminus of a number of endogenous peptides (e.g., substance P, bradykinin). Peptides with penultimate prolyl residues are not cleaved by converting enzyme; this accounts for the biological stability of angiotensin II. Inhibition of converting enzyme results in an elevated pool of an-giotensin I. A mutation deletion in the ACE gene has been linked to a higher risk factor for hypertension, left ventricular hypertrophy, and myocardial infarction.

The Angiotensins

The amino acid composition of the peptides and en-zymes involved in the synthesis and metabolism of the angiotensins is shown in Figure 18.1. Angiotensin I is be-lieved to have little direct biological activity and must be converted to angiotensin II or angiotensin 1-7 before characteristic responses of the renin–angiotensin system are manifested. Angiotensin I and II are metabolized at their animo terminus by aspartyl aminopeptidase, an en-zyme in plasma and numerous tissues. Angiotensin II is rapidly metabolized by aspartyl aminopeptidases, en-dopeptidases, and carboxypeptidases, while angiotensin III is hydrolyzed by aminopeptidases, endopeptidases, and carboxypeptidases (Fig. 18.1). The biological activity of angiotensin III ranges from one-fourth to equipotent with angiotensin II, depending on the response being monitored. The smallest biologically active peptide in this system is angiotensin IV, which exerts unique ac-tions in the central nervous system and periphery that are distinct from those of angiotensin II.