ANG II exerts important actions at vascular smooth muscle, adrenal cortex, kidney, heart, and brain via the receptors described below. Through these actions, the renin-angiotensin system plays a key role in the regulation of fluid and electrolyte balance and arterial blood pressure. Excessive activity of the renin-angiotensin system can result in hypertension and disorders of fluid and electrolyte homeostasis.
ANG II is a potent pressor agent—on a molar basis, approximately 40 times more potent than norepinephrine. The pressor response to intravenous ANG II is rapid in onset (10–15 seconds) and sustained during long-term infusions. A large component of the pressor response is due to direct contraction of vascular— especially arteriolar—smooth muscle. In addition, however, ANG II can also increase blood pressure through actions on the brain and autonomic nervous system. The pressor response to ANG II is usually accompanied by little or no reflex bradycardia because the peptide simultaneously acts on the brain to reset the baroreceptor reflex control of heart rate to a higher pressure.
ANG II also interacts with the autonomic nervous system. It stimulates autonomic ganglia, increases the release of epinephrine and norepinephrine from the adrenal medulla, and most important, facilitates sympathetic transmission by an action at adrenergic nerve terminals. The latter effect involves both increased release and reduced reuptake of norepinephrine. ANG II also has a less important direct positive inotropic action on the heart.
ANG II acts directly on the zona glomerulosa of the adrenal cortex to stimulate aldosterone synthesis and release. At higher concentrations, ANG II also stimulates glucocorticoid synthesis. ANG II acts on the kidney to cause renal vasoconstriction, increase proximal tubular sodium reabsorption, and inhibit the release of renin.
In addition to its central effects on blood pressure, ANG II acts on the central nervous system to stimulate drinking (dipsogenic effect) and increase the secretion of vasopressin and adrenocorticotropic hormone (ACTH). The physiologic significance of these effects is not known.
ANG II is mitogenic for vascular and cardiac muscle cells and may contribute to the development of cardiac hypertrophy. It also exerts a variety of important effects on the vascular endothelium. Indeed, overactivity of the renin-angiotensin system has been implicated as one of the most significant factors in the development of hypertensive vascular disease. Considerable evidence now indicates that inhibition of the renin-angiotensin system (see below) slows or prevents morphologic changes (remodeling) following myocardial infarction that would otherwise lead to heart failure. The stimulation of vascular and cardiac growth by ANG II is mediated by other pathways, probably receptor and nonreceptor tyrosine kinases such as the Janus tyrosine kinase Jak2, and by increased transcription of specific genes (see Chapter 2).
ANG II receptors are widely distributed in the body. Like the receptors for other peptide hormones, ANG II receptors are G protein-coupled and located on the plasma membrane of target cells, and this permits rapid onset of the various actions of ANG
II. Two distinct subtypes of ANG II receptors, termed AT1 and AT2, have been identified. ANG II binds equally to both subtypes. The relative proportion of the two subtypes varies from tissue to tissue: AT1 receptors predominate in vascular smooth muscle. Most of the known actions of ANG II are mediated by the AT1 receptor, a Gq protein-coupled receptor. Binding of ANG II to AT1 receptors in vascular smooth muscle results in activation of phospholipase C and generation of inositol trisphosphate and diacylglycerol (see Chapter 2). These events, which occur within seconds, result in smooth muscle contraction.