Effects of long-term angiotensin II AT(1) 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 angiot ensin II AT(1) receptor blockade shares with ACE inhibition the same benefi cial 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 surviv al (placebo: 27%, low dose: 52%, high dose: 82%, sham-ligated: 100%; high d ose vs placebo: P<0.001 and vs low dose: P<0.05; low dose vs placebo: P=0.1 1). Irbesartan also dose-dependently decreased urinary cyclic GMP excretion throughout the study. At 7.5 months, it dose-dependently decreased left ve ntricular (LV) end diastolic pressure, normalized LV pressure maximal rate of rise (dP/dt) and cardiac index values and improved LV and right ventricu lar regional blood flows (radioactive microspheres) and resistances. At 7.5 months, irbesartan markedly decreased myocardial hypertrophy but had almos t no effect on LV dilatation and subendocardial fibrosis. Conclusions: Long -term angiotensin II AT(1) receptor blockade with irbesartan strongly and d ose-dependently increases survival in the rat model of coronary ligation-in duced CI-IF. This effect is due to the combination of the beneficial effect s that the drug exerts on systemic and coronary hemodynamics, on cardiac pu mp function and vs cardiac hypertrophy development. Long-term AT(1) recepto r blockade might thus prove useful and prolong survival in human CHF. (C) 1 999 Elsevier Science B.V. All rights reserved.