Pharmacological Actions

PHARMACOLOGICAL ACTIONS

While the following discussion addresses the pharma-cology of angiotensin II that is mediated through the AT1 receptor, most of these responses also follow ad-ministration of angiotensin III. Generally, angiotensin is less potent than angiotensin II. Angiotensin 1-7 is considered to be biologically active and has been demonstrated to exert effects that are similar to, oppo-site of, or totally distinct from those of angiotensin II.

Vascular Smooth Muscle Contraction

The intravenous injection of angiotensin II results in a sharp rise in systolic and diastolic pressures. The response is consistently reproducible when small doses of an-giotensin II are injected; however, larger amounts of the peptide produce tachyphylaxis (loss of response on re-peated administration).The mechanism underlying tachy-phylaxis to angiotensin II is unknown, but it may involve receptor internalization and/or desensitization. Subcu-taneous and intramuscular injections are much less potent and have a longer duration of action than do comparable doses given intravenously. Infusions that cause an imme-diate pressor response tend to result in tachyphylaxis over several hours. On a molar basis, angiotensin II is about 40 times as potent as norepinephrine. The pressor response to angiotensin II is caused by its direct receptor-mediated effect on vascular smooth muscle. The peptide stimulates the formation of the second messenger inositol 1,4,5-triphosphate, which results in a release of intracellular Ca⁺⁺ and ultimately smooth muscle contraction.

Heart Rate and Contractility

The administration of angiotensin II to an animal with intact baroreceptor reflexes results in reflex bradycardia in response to the marked vasoconstriction. When baroreceptor reflexes are depressed (barbiturate anes-thesia) or if vagal tone is inhibited (atropine or vago-tomy), angiotensin directly induces cardiac acceleration.

Angiotensin II stimulates the influx of Ca⁺⁺ into cardiac muscle cells and can exert a direct inotropic ef-fect at cardiac muscle. In addition, angiotensin II can stimulate the sympathoadrenal system and thereby in-crease myocardial contractility. In contrast to its effects on vascular smooth muscle, the ability of angiotensin to increase the contractile force of the heart is far less po-tent. Therefore, in spite of the positive chronotropic and inotropic effects produced by angiotensin II, cardiac output is rarely increased. In fact, angiotensin II may decrease cardiac output through reflex bradycardia in-duced by the rise in peripheral resistance that it causes. In contrast, centrally administered angiotensin II in-creases both blood pressure and cardiac output.

Vascular Permeability

Angiotensin II can cause a net fluid accumulation in tis-sues and has been shown to increase the permeability of the endothelium in large arteries and to widen the in-terendothelial spaces in the aorta and in coronary, mesenteric, and peripheral arteries. This response to an-giotensin II probably reflects the effect of elevated pres-sure on the endothelial permeability barrier. The pep-tide also stimulates the release of the vasodilator prostacyclin from arterial endothelial cells.

Growth

Angiotensin II alters the growth of vascular smooth muscle, cardiac myocytes, and cardiac fibroblasts through mechanisms related to increased cell prolifera-tion (hyperplasia) and protein deposition (hypertro-phy). These actions of angiotensin II on cell growth in-volve interactions with other growth factors and are relevant to the pathophysiology of both hypertension and congestive heart failure.

Central Nervous System

Administration of angiotensin II into the vertebral cir-culation increases peripheral blood pressure. This hy-pertensive action, mediated by the central nervous sys-tem, is primarily the result of an increase in central efferent sympathetic activity going to the periphery. The area postrema of the caudal medulla appears to be the structure responsible for the central cardiovascular ac-tions of angiotensin II.

Angiotensin II produces changes in body hydration and thirst by a direct action in the central nervous sys-tem. The administration of angiotensin II into the sep-tal, anterior hypothalamic, and medial preoptic areas stimulates drinking behavior in several species. Part of the volume response also may be caused by the antina-triuretic and antidiuretic effects of angiotensin II.

Angiotensin II, administered into the central nerv-ous system, increases the release of luteinizing hor-mone, adrenocortical hormone, thyroid-releasing hor-mone, -endorphin, vasopressin, and oxytocin from the anterior pituitary. In contrast, centrally administered angiotensin II inhibits the release of anterior pituitary growth hormone and prolactin.

Sympathetic Nervous System

Angiotensin II, acting at presynaptic receptors on nora-drenergic nerve terminals, potentiates the release of norepinephrine during low-frequency sympathetic nerve stimulation. Aside from its action on the nerve terminals of postganglionic sympathetic neurons, an-giotensin II can directly stimulate sympathetic neurons in the central nervous system, in peripheral autonomic ganglia, and at the adrenal medulla.

Adrenal Cortex and Aldosterone Secretion

Angiotensin II stimulates aldosterone synthesis and se-cretion from the glomerulosa cells of the adrenal cortex. The aldosterone secretion induced by angiotensin II in humans is not accompanied by an increase in glucocor-ticoid plasma levels. Chronic administration of an-giotensin II will maintain elevated aldosterone secretion for several days to weeks unless hypokalemia ensues.