EFFECTS OF ANGIOTENSIN RECEPTOR ANTAGONISTS IN HEART-FAILURE - CLINICAL AND EXPERIMENTAL ASPECTS

In addition to inhibition of the circulating renin-angiotensin system, specific inhibition of the cardiac effects of angiotensin II (Ang II) represents an important therapeutic goal in the treatment goal in the treatment of clinical heart failure. Subtype 1-specific Ang II recept or (AT(1)) antagonists have been developed to overcome potential limit ations of angiotensin converting enzyme inhibitors, e.g. insufficient control of tissue Ang II production and bradykinin-related side effect s. Clinical studies have demonstrated beneficial effects of AT(1) anta gonists. In a single-dose study, the AT(1) antagonist losartan decreas ed the mean arterial pressure and pulmonary arterial pressure while in creasing the cardiac index. Effects were dose dependent. Haemodynamic effects were greater with higher doses, but neurohormonal counter-regu lation probably also increased, leading to relatively high levels of c irculation Ang II with the 150-mg dose. A decrease in plasma levels of noradrenaline, atrial natriuretic factor, and aldosterone reached par tial significance. Administration of multiple doses of losartan for 12 weeks also led to favourable haemodynamic and clinical results. Arter ial blood pressure, pulmonary capillary wedge pressure, and systemic v ascular resistance decreased. The neurohormonal effects of 12 weeks' a dministration of AT(1) antagonists consisted in a decrease in plasma a ldosterone concentrations. Whereas AT(1) antagonists may counteract th e effects are less clear. The subtype AT(2), which represents the domi nant receptor in both healthy and failing human myocardium, is not blo cked by AT(1) inhibition. Angiotensin receptors on isolated human card iac fibroblasts stimulate cellular proliferation via a yet undetermine d receptor subtype. AT(1) antagonists exert beneficial haemodynamic an d neurohormonal effects in human heart failure. Their direct myocardia l effects require further investigation.