Additional effects of endothelin receptor blockade and angiotensin converting enzyme inhibition in rats with chronic heart failure

AIM: To evaluate the acute effects of tezosentan, a new dual parenteral end othelin receptor antagonist, on hemodynamics in a rat model of chronic hear t failure (CHF), and further investigated if the combination of tezosentan with the angiotensin converting enzyme (ACE) inhibitor, enalapril, had addi tive hemodynamic effect. METHODS: Hemodynamics was measured in rats with CH F, induced by ligation of the left coronary artery. RESULTS: At 3 to 5 week s after myocardial infarction, rats developed CHF. This was evidenced by a marked increase in left ventricular end-diastolic pressure (LVEDP) with mea n values of 23 to 26 mmHg, by a 30 % to 40 % reduction in left ventricular dp/dt(max) and by a more than 10 % decrease in mean arterial pressure (MAP) as compared to sham-operated rats. In CHF rats, acute intravenous administ ration of either tezosentan (10 mg kg-l) or enalapril (1 mg . kg(-1)) marke dly decreased MAP and LVEDP, without affecting heart rate or dp/dt(max). Te zosentan had additive effects on MAP and LVEDP when given with enalapril co mpared with tezosentan (P < 0.05) or enalapril (P < 0.05) alone. There were no significant changes in heart rate and dp/dt(max) with the combination t reatment compared with tezosentan- or enalapril-treated CHF rats. CONCLUSIO N: Acute intravenous tezosentan improves cardiac hemodynamics and decreases LVEDP and afterload (MAP) without changes in heart rate and cardiac contra ctility (dp/dt(max)) in CHF mts. These favorable effects of tezosentan are similar to those of enalapril. Furthermore, the benefits of tezosentan are apparent in addition to ACE inhibition. Thus, tezosentan could be a useful therapeutic agent in the acute treatment of heart failure.