Effects of long-term angiotensin II AT1 receptor blockade on survival, hemodynamics and cardiac remodeling in chronic heart failure in rats

Objective: The beneficial effect of chronic angiotensin I converting enzyme (ACE) inhibition on survival has for long been established in the rat post-infarction model of chronic heart failure (CHF) and has subsequently been confirmed in humans. This study investigates in rats whether chronic angiotensin II AT(1) receptor blockade shares with ACE inhibition the same beneficial effect. Methods: Rats were subjected to coronary artery ligation and, from 7 days later, orally treated for 7.5 months with placebo or irbesartan (5 or 50 mg/kg/day). Results: Irbesartan dose-dependently increased survival (placebo: 27%, low dose: 52%, high dose: 82%, sham-ligated: 100%; high dose vs placebo: P<0.001 and vs low dose: P<0.05; low dose vs placebo: P=0.11). Irbesartan also dose-dependently decreased urinary cyclic GMP excretion throughout the study. At 7.5 months, it dose-dependently decreased left ventricular (LV) end diastolic pressure, normalized LV pressure maximal rate of rise (dP/dt) and cardiac index values and improved LV and right ventricular regional blood flows (radioactive microspheres) and resistances. At 7.5 months, irbesartan markedly decreased myocardial hypertrophy but had almost no effect on LV dilatation and subendocardial fibrosis. Conclusions: Long-term angiotensin II AT(1) receptor blockade with irbesartan strongly and dose-dependently increases survival in the rat model of coronary ligation-induced CI-IF. This effect is due to the combination of the beneficial effects that the drug exerts on systemic and coronary hemodynamics, on cardiac pump function and vs cardiac hypertrophy development. Long-term AT(1) receptor blockade might thus prove useful and prolong survival in human CHF. (C) 1999 Elsevier Science B.V. All rights reserved.