ANGIOTENSIN-II RECEPTOR SUBTYPES - SELECTIVE ANTAGONISTS AND FUNCTIONAL CORRELATES

Angiotensin II (Ang II) receptor heterogeneity is currently defined by the new subtype-selective agents, losartan (AT(1)) and PD123177 (AT(2)). Although both subtypes have been cloned and sequenced, only the AT(1) receptor has been shown to have an important physiological or pathophysiological role. AT(1) and AT(2) receptors are found in both normal and failing cardiac tissue. They are found on myocytes, endothelial cells, fibroblasts, coronary arterial smooth muscle cells, and peripheral sympathetic nerves The AT(1) receptors mediate virtually all of the effects of Ang II in myocytes even though cardiac tissue may contain over 50 % AT(2) sites. In endothelial cells, functional responses are predominately AT(1). In fibroblasts, preliminary data suggest that AT(2) receptors may be involved in collagen synthesis. In isolated tissue, Ang II has a limited positive inotropic effect in atrial, bur not in ventricular tissue, which is blocked by losartan. Ang II may also have a tonic effect on coronary artery resistance as angiotensin inhibitors can increase coronary flow. Both ACE (Ang II synthesis) inhibitors and Ang II receptor antagonists produce beneficial effects in experimental models of heart failure, suggesting Ang II is an important mediator of heart failure. Because ACE inhibitors also potentiate bradykinin and are non-specific inhibitors of Ang II synthesis (availability of Ang II to both receptor subtypes) some differences can be anticipated. At the present time, however, the beneficial role of bradykinin is controversial and the predominant functional Ang II receptor in the heart and other tissues is the AT(1) subtype. Selective AT(1) antagonists represent an important new class of potential therapeutic agents not only in hypertension, which is now firmly established, but also in cardiac failure, renal failure, and stroke.