We investigated the effect of BQ-123, a selective endothelin-A (ET_A) receptor antagonist in ischemia-reperfusion (IR) induced myocardial infarction (MI) with and without endothelin-1 (ET-1) challenge. MI was produced in rats by occlusion of left anterior descending coronary artery for 40min and reperfusion for 120min. ET-1 was administered immediately prior to coronary occlusion whereas vehicle or BQ-123 was administered 20min after the occlusion. IR control group exhibited marked hemodynamic changes along with significant impairment of left ventricular functions. In addition, oxidative stress was increased, as evidenced by marked reduction in the activities of antioxidants and cardiac injury markers in myocardium. Furthermore, light microscopic and ultrastructural changes revealed myocardial necrosis, edema and inflammation. Prior administration of ET-1 acts synergistically with IR injury and further aggravates the impairment of ventricular functions, increased percent infarct area and decreased antioxidant levels. However, treatment with BQ-123 (1mg/kg, IV) with or without ET-1 caused significant improvement in cardiac functions, percent infarct area, decreased malonaldehyde level, restored myocardial enzymes activities and maintained the redox status of the myocardium as compared to IR control group. Further, histopathological and ultrastructural studies reconfirmed the protective action of BQ-123. The results of present study suggest that ET-1 acting via ET_A receptor may exaggerate myocardial damage produced by IR injury and selective blockade of ET_A receptor by BQ-123 might offer potential cardioprotective action.