Regitz-Zagrosek V, Neuss M, Fleck E
Department of Internal Medicine, Cardiology/Angiology, Virchow-Klinikum, Humboldt University, Berlin, Germany.
Eur Heart J. 1995 Dec;16 Suppl N:86-91. doi: 10.1093/eurheartj/16.suppl_n.86.
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 of clinical heart failure. Subtype 1-specific Ang II receptor (AT1) antagonists have been developed to overcome potential limitations of angiotensin converting enzyme inhibitors, e.g. insufficient control of tissue Ang II production and bradykinin-related side effects. Clinical studies have demonstrated beneficial effects of AT1 antagonists. In a single-dose study, the AT1 antagonist losartan decreased the mean arterial pressure and pulmonary arterial pressure while increasing the cardiac index. Effects were dose dependent. Haemodynamic effects were greater with higher doses, but neurohormonal counter-regulation probably also increased, leading to relatively high levels of circulating Ang II with the 150-mg dose, A decrease in plasma levels of noradrenaline, atrial natriuretic factor, and aldosterone reached partial significance. Administration of multiple doses of losartan for 12 weeks also led to favourable haemodynamic and clinical results. Arterial blood pressure, pulmonary capillary wedge pressure, and systemic vascular resistance decreased. The neurohormonal effects of 12 weeks' administration of AT1 antagonists consisted in a decrease in plasma aldosterone concentrations. Whereas AT1 antagonists may counteract the effects of Ang II on the vasculature, and therefore are effective vasodilators, their direct myocardial effects are less clear. The subtype AT2, which represents the dominant, receptor in both healthy and failing human myocardium, is not blocked by AT1 inhibition. Angiotensin receptors on isolated human cardiac fibroblasts stimulate cellular proliferation via a yet undertermined receptor subtype. AT1 antagonists exert beneficial haemodynamic and neurohormonal effects in human heart failure. Their direct myocardial effects require further investigation.
