Long-Term Survival and Hemodynamics After Endothelin-A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition in Rats With Chronic Heart Failure: Monotherapy Versus Combination Therapy

Abstract

Background—In patients with congestive heart failure (CHF) receiving ACE inhibitors, acute administration of selective endothelin (ET) antagonists additionally improves systemic and cardiac hemodynamics. We investigated, in a rat model of CHF, whether such acute synergistic effects are sustained and accompanied, in the long term, by an additional limitation of left ventricular remodeling or an increase in survival. Methods and Results—Rats were subjected to coronary artery ligation and treated for 3 or 9 months with vehicle or with the ACE inhibitor trandolapril (Tr) (0.3 mg/kg−1 per day−1), the ETA antagonist LU 135252 (LU, 30 mg/kg−1 per day−1), or their combination starting 7 days after ligation. After 3 months, the combination decreased LV systolic- and end-diastolic pressures (−32% and −80%, respectively) more markedly than Tr (−21% and −61%, respectively) or LU alone (−14% and −48%, respectively). Echocardiographic studies revealed that all treatments limited LV dilatation and increased LV fractional shortening and cardiac index. All treatments equally reduced left ventricular collagen density, whereas only Tr or the combination reduced LV weight. Finally, although LU did not modify long-term survival, Tr and the combination of Tr with LU induced a similar improvement of survival. Conclusions—In this rat model, long-term combined administration of an ETA antagonist and an ACE inhibitor induces additional effects in terms of systemic and cardiac hemodynamics; however, this is not associated with an additional increase in long-term survival.