Neurohormonal modulation in cardiovascular disease.
The renin-angiotensin system (RAS) is one of the oldest known hormone systems. Its effector hormone, angiotensin (Ang) II, acts through 2 receptor subtypes, AT(1) and AT(2). Most physiologic effects of Ang II, including vasoconstriction, renal salt and water retention, aldosterone and vasopressin release, and sympathetic facilitation, are mediated by AT(1). Recent data, however, suggest that Ang II also contributes to cell proliferation, left ventricular hypertrophy, vascular media hypertrophy, neointima formation in atherosclerosis, and nephrosclerosis by stimulation of AT(1) receptors. AT(2) receptors are associated with antiproliferation, cell differentiation and development, tissue regeneration, and apoptosis. They also antagonize AT(1) receptor-mediated effects, which suggests that the ratio of angiotensin receptors expressed on a particular cell can determine the net effect of Ang II. Selective AT(1) receptor antagonists ("sartans") have been used to treat several million hypertensive patients worldwide. These agents offer a powerful therapeutic alternative to angiotensin-converting enzyme (ACE) inhibitors, which reduce the generation of Ang II. Conversely, AT(1) receptor antagonists block the RAS by acting on cellular angiotensin receptors and do not interfere with the breakdown of kinins. These medications inhibit the RAS more completely than do the ACE inhibitors because their action is independent of Ang II-generating pathways. At the same time, early, preliminary data suggest that AT(1) receptor antagonists offer target-organ protection similar to that provided by the ACE inhibitors. Because AT(2) receptors are left unopposed and Ang II levels are increased with AT(1) receptor antagonist treatment, it is important to understand the function of AT(2) to fully appreciate the mechanisms of action of AT(1) receptor antagonists, especially their potential for target-organ protection.
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Institute of Pharmacology, Christian Albrechts University.
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000503:physiopathology*; D006801:Humans; D011945:Receptors, Angiotensin / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D011945:Receptors, Angiotensin; D000804:Angiotensin II