Cardioprotection by long-term ETA receptor blockade and ACE inhibition in rats with congestive heart failure:: mono-versus combination therapy

Objectives: We investigated the effects of long-term endothelin A (ETA) receptor blockade and ACE inhibition, either alone or in combination, on the hemodynamics, neurohormonal activation and cardiac remodeling in rats with congestive heart failure (CHF) after extensive myocardial infarction (MI). Methods: Rats were treated with placebo, the ETA antagonist LU135252 (30 mg/kg/d), the ACE inhibitor trandolapril (0.3 mg/kg/d), or a combination of both for 11 weeks, starting 7 days after MI. Results: Despite comparable effects on left ventricular (LV) systolic pressure among all drug treatments, only combined ETA and ACE inhibition significantly reduced LV end-diastolic pressure (P<0.01), improved LV dP/dt(max) (P<0.01) and normalized sympathetic activation (P<0.05) in rats with CHF. The combination therapy was more effective in reducing type I and III collagen mRNA levels, MMP-2 zymographic activity and collagen accumulation in the surviving LV myocardium. Moreover, the increases in cardiac beta-myosin heavy chain and skeletal alpha-actin mRNAs, markets of hypertrophy or failure, were attenuated to a greater degree by the combination therapy than monotherapy, whereas right ventricular hypertrophy and ANF mRNA upregulation were significantly (P<0.01) prevented only by combined ETA and ACE inhibition. Conclusion: Long-term combined ETA receptor and ACE inhibition improved cardiac failure after extensive MI more effectively than monotherapy. We show additive effects on LV fibrosis and fetal gene expression. ETA receptor antagonists could be a therapeutical option in CHF in addition to an ACE inhibitor. (C) 2002 Elsevier Science B.V. All rights reserved.