AngI is <1% as potent as Angll on smooth muscle, heart, and the adrenal cortex. Angiotensin III (Anglll), also called [des-Asp1]AngII or angiotensin (2-8), can be formed either by the action of aminopeptidase on AngII or by the action of ACE on [des-Asp1]AngI (Figure 30-1). AngIII and AngII have qualitatively similar effects; both stimulate aldosterone secretion with equal potency, but AngIII is only 25% and 10% as potent as AngII in elevating blood pressure and stimulating the adrenal medulla, respectively.
Angiotensin(1-7) is formed by multiple pathways (Figure 30-1). ACE inhibitors increase tissue and plasma levels of angiotensin(1-7), both because AngI levels are increased and diverted away from AngII formation (Figure 30-1) and because ACE contributes importantly to the plasma clearance of angiotensin(1-7). The pharmacological profile of angiotensin(1-7) is distinct from that of AngII: angiotensin(1-7) does not cause vasoconstriction, aldosterone release, or facilitation of noradrenergic neurotransmission. Angiotensin(1-7) releases vasopressin, stimulates prostaglandin biosynthesis, elicits depressor responses when microinjected into certain brainstem nuclei, dilates some blood vessels, and exerts a natriuretic action on the kidneys. Angiotensin(1-7) also inhibits proliferation of vascular smooth muscle cells. The effects of angiotensin(1-7) may be mediated by a specific angiotensin(1-7) receptor; it has been proposed that angiotensin(1-7) serves to counterbalance the actions of AngII. Angiotensin(3-8), also called AnglV, is another biologically active angiotensin peptide that also appears to counteract the effects of AngII.
Various peptidases degrade and inactivate angiotensin peptides, including aminopeptidases, endopeptidases, and carboxypeptidases; none is specific.
LOCAL (TISSUE) RENIN-ANGIOTENSIN SYSTEMS
Circulating renin from the kidney acts on circulating angiotensinogen of hepatic origin to produce AngI in the plasma, circulating AngI is converted by ACE to AngII, and AngII then is delivered to its target organs via the bloodstream to induce a physiological response. This traditional view must be expanded to include local (tissue) renin-angiotensin systems, which consist of extrinsic and intrinsic local renin-angiotensin systems.
ACE is present on the luminal face of vascular endothelial cells throughout the circulation, and circulating renin of renal origin can be sequestered by the arterial wall and other tissues, permitting the local conversion of precursors to AngII. Indeed, many vascular beds locally produce AngI and II.
Many tissues (e.g., brain, pituitary, blood vessels, heart, kidney, and adrenal gland) express mRNAs for renin, angiotensinogen, and/or ACE, and can produce renin, angiotensinogen, ACE, and AngI, II, and III. These local renin-angiotensin systems may influence vascular, cardiac, and renal function and structure.
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