Additional effects of endothelin receptor blockade and angiotensin converting enzyme inhibition in rats with chronic heart failure
Abstract
Aim: To evaluate the acute effects of tezosentan, a new dual parenteral endothelin receptor antagonist, on hemodynamics in a rat model of chronic heart failure (CHF), and further investigated if the combination of tezosentan with the angiotensin converting enzyme (ACE) inhibitor, enalapril, had additive hemodynamic effect.
Methods: Hemodynamics was measured in rats with CHF, induced by ligation of the left coronary artery.
Results: At 3 to 5 weeks after myocardial infarction, rats developed CHF. This was evidenced by a marked increase in left ventricular end-diastolic pressure (LVEDP) with mean 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 administration of either tezosentan (10 mg . kg) or enalapril (1 mg . kg) markedly decreased MAP and LVEDP, without affecting heart rate or dp/dtmax. Tezosentan had additive effects on MAP and LVEDP when given with enalapril compared with tezosentan (P < 0.05) or enalapril (P < 0.05) alone. There were no significant changes in heart rate and dp/dtmax with the combination treatment compared with tezosentan- or enalapril-treated CHF rats.
Conclusion: Acute intravenous tezosentan improves cardiac hemodynamics and decreases LVEDP and afterload (MAP) without changes in heart rate and cardiac contractility dp/dtmax) in CHF rats. 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.
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Methods: Hemodynamics was measured in rats with CHF, induced by ligation of the left coronary artery.
Results: At 3 to 5 weeks after myocardial infarction, rats developed CHF. This was evidenced by a marked increase in left ventricular end-diastolic pressure (LVEDP) with mean 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 administration of either tezosentan (10 mg . kg) or enalapril (1 mg . kg) markedly decreased MAP and LVEDP, without affecting heart rate or dp/dtmax. Tezosentan had additive effects on MAP and LVEDP when given with enalapril compared with tezosentan (P < 0.05) or enalapril (P < 0.05) alone. There were no significant changes in heart rate and dp/dtmax with the combination treatment compared with tezosentan- or enalapril-treated CHF rats.
Conclusion: Acute intravenous tezosentan improves cardiac hemodynamics and decreases LVEDP and afterload (MAP) without changes in heart rate and cardiac contractility dp/dtmax) in CHF rats. 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.