ANG II inhibits renin release. The inhibition results from increased blood pressure acting by way of the renal baroreceptor and macula densa mechanisms, and from a direct action of the peptide on the juxtaglomerular cells. The direct inhibition is mediated by increased intracellular Ca2+ concentration and forms the basis of a short-loop negative feedback mechanism controlling renin release. Interruption of this feedback with drugs that inhibit the renin-angiotensin system results in stimulation of renin release.
E. Intracellular Signaling Pathways
The release of renin by the juxtaglomerular cells is controlled by interplay among three intracellular messengers: cAMP, cyclic guanosine monophosphate (cGMP), and free cytosolic Ca2+ concentration (Figure 17–2). cAMP plays a major role; maneuvers that increase cAMP levels, including activation of adenylyl cyclase, inhibition of cAMP phosphodiesterases, and administration of cAMP analogs, increase renin release. In experimental studies, selective deficiency of Gsα in the juxtaglomerular cells was associated with a marked reduction in basal renin secretion and in the response to several stimuli to renin secretion.
Increases in intracellular Ca2+ can result from increased entry of extracellular Ca2+ or mobilization of Ca2+ from intracellular stores, while increases in cGMP levels can result from activation of soluble or particulate guanylyl cyclase. Ca2+ and cGMP appear to alter renin release indirectly, primarily by changing cAMP levels.
F. Pharmacologic Alteration of Renin Release
The release of renin is altered by a wide variety of pharmacologic agents. It is stimulated by vasodilators (hydralazine, minoxidil, nitroprusside), β-adrenoceptor agonists, α-adrenoceptor antagonists, phosphodiesterase inhibitors (eg, theophylline, milrinone, rolipram), and most diuretics and anesthetics. This stimulation can be accounted for by the control mechanisms just described. Drugs that inhibit renin release are discussed below.
Many of the peptides reviewed in this chapter also alter renin release. Release is stimulated by adrenomedullin, bradykinin, and calcitonin gene-related peptide, and inhibited by atrial natriuretic peptide, endothelin, substance P, and vasopressin.
Angiotensinogen is the circulating protein substrate from which renin cleaves ANG I. It is synthesized in the liver. Human angiotensinogen is a glycoprotein with a molecular weight of approximately 57,000. The 14 amino acids at the amino terminal of the molecule are shown in Figure 17–1. In humans, the concentration of angiotensinogen in the circulation is less than the Km of the renin-angiotensinogen reaction and is therefore a determinant of the rate of formation of angiotensin.
The production of angiotensinogen is increased by corticosteroids, estrogens, thyroid hormones, and ANG II. It is elevated during pregnancy and in women taking estrogen-containing oral contraceptives. The increased plasma angiotensinogen concentration is thought to contribute to the hypertension that may occur in these situations.
Although ANG I contains the peptide sequences necessary for all of the actions of the renin-angiotensin system, it has little or no biologic activity. Instead, it must be converted to ANG II by