Chronic Endothelin Receptor Blockade Attenuates Progressive Ventricular Dilation and Improves Cardiac Function in Rats With Myocardial Infarction

BACKGROUND: Left ventricular dilatation after myocardial infarction is associated with impaired ventricular function and heart failure and has important implications for survival. The purpose of this study was to investigate the role of endothelin-1 (ET-1) in ventricular dilatation and the effects of chronic endothelin receptor blockade by a mixed ET(A) and ET(B) receptor blocker (bosentan) on the circulating and cardiac endothelin systems. METHODS AND RESULTS: Three hours after coronary ligation or sham operation, bosentan (100 mg x kg body wt(-1) x d(-1)) or placebo was given by gavage. Seven days and 8 weeks after surgery, hemodynamic and left ventricular volume studies were performed. Acute bosentan treatment (7 days) had no effects on hemodynamic parameters and early left ventricular dilatation. In the rats with large infarcts, chronic bosentan treatment (8 weeks) versus placebo reduced left ventricular systolic pressure (116+/-2 versus 125+/-3 mm Hg, P<.05) and arterial pressure (93+/-2 versus 103+/-3 mm Hg, P<.05), improved stroke volume index (0.69+/-0.06 versus 0.52+/-0.04 mL/kg, P<.05), and prevented in part the rightward shift of the pressure-volume curve. Chronic bosentan treatment also decreased ET-1 levels (390+/-33 versus 475+/-22 pg/g tissue, P<.05) and density of ET-1 receptors (262+/-24 versus 346+/-31 fmol/mg protein, P<.05) in left ventricular myocardium. CONCLUSIONS: In the present study, a mixed ET(A) and ET(B) receptor antagonist (bosentan) partially prevented left ventricular dilatation and improved hemodynamics, suggesting that endothelin plays a role in left ventricular remodeling after myocardial infarction. Supporting this hypothesis, we show inhibitory effects of bosentan on the peripheral and myocardial endothelin system.