Myocardioprotection Against Ischemia and Reperfusion Injury by Endothelin Receptor Antagonists

Abstract

Prolonged myocardial ischemia without reperfusion results in myocardial cell death. Early coronary artery reperfusion is important to minimize tissue injury. However, reperfusion itself exerts deleterious effects, that result in enhanced myocardial injury. Endothelin-1 (ET-1) is a powerful vasoconstrictor of coronary arteries, and several studies have suggested a role for ET in a number of cardiovascular disorders. The present study was designed to evaluate the potential of bosentan, a mixed ETA-ETB receptor antagonist and BMS 182874, a selective ETA receptor antagonist in limiting myocardial infarct size and to determine the hemodynamic and metabolic basis of such effects in a cat model of ischemia (MI) and reperfusion (R) induced myocardial injury. Twenty six adult mongrel cats of either sex (2.6–3.4kg; body weight) anesthetized with ether followed by alpha chloralose (80mg/kg), were tracheotomized and positive pressure ventilation was instituted. The animals were submitted to left anterior descending coronary artery (LAD) occlusion for 40 minutes; thereafter, reperfusion was instituted for a period of 3 h by untying the ligature. Animals were randomly assigned to either (i) saline-treated MI/R control group (CON), (ii) bosentan-treated MI/R group (BOS) or (iii) BMS 182874-treated MI/R group (BMS). Myocardial ischemia and reperfusion resulted in severe myocardial injury, profound hemodynamic alterations and marked metabolic derangements in the control group as assessed at the end of the experimental period (3h and 40 min). Administration of bosentan (3mg/kg; i.v.) and BMS 182874 (1mg/kg; i.v.) 20min after the onset of ischemia resulted in the salvage of 36% (BOS) and 22% (BMS) of the left ventricle at risk of infarction. Bosentan slightly increased heart rate, and affected a significant (p < 0.05) fall in systolic and diastolic arterial blood pressures. The sharp rise in LVEDP post-occlusion was significantly (p < 0.01) lowered by both BOS and BMS and the correction of this variable was sustained for the entire reperfusion period (3h). Administration of BOS and BMS afforded a modest correction of the LVdP/dtmax and attenuated reperfusion ectopy. Furthermore, administration of bosentan significantly decreased the level of lactate accumulation and corrected the myocardial energy profile as compared to the control group. These data highlight the possible role of endogenous endothelin-1 in exacerbating myocardial ischemia and reperfusion injury. It is further concluded that endothelin receptor blockade is expected to be an effective approach in the treatment of ischemic heart disease.