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The objective of the present study was to investigate the possible impact of specific endothelin-A (ETA) receptor blockage by BQ-123 on myocardial ischemia-reperfusion (MI/R) induced apoptosis in rats. To produce MI/R, a branch of the descending left coronary artery was occluded for 30 min followed by 2 h reperfusion. Thirty-two rats were randomly assigned to four groups equally: (1) sham-operated group, (2) MI/R group, (3) MI/R+BQ-123-treated group, and (4) MI/R+ET-1+BQ-123-treated group. TUNEL staining, caspase-3 and caspase-9 activities were determined immunohistologically. MI/R group revealed extensive TUNEL positive cardiomyocytes especially in the free wall of the left ventricule, interventicular septum, and apex zone. Intensity of TUNEL-positive cardiomyocytes reduced as a result of BQ-123 treatment compared to the sham group in the same sections. Result of the caspase activity was found to correlate with TUNEL evaluation. BQ-123 administrations to MI/R group with or without ET-1 caused significant decrease both in lipid peroxidation and nitric oxide (NO) generation. Also, BQ-123 leads to augmentation of superoxide dismutase, catalase and glutathione contents. We propose that selective ETA antagonism by BQ-123 has a worthwhile effect on apoptotic cell death following MI/R, and that scavenging of free radicals by selective ETA antagonist is part of this beneficial effect. [Med-Science 2012; 1(4.000): 254-70]

Abstract: Objective: Endothelins (ET) can be considered stress-responsive regulators working in paracrine and autocrine fashion. It has been suggested that elevated levels of ET may be responsible for the low coronary re-flow phenomena. Ischemia–reperfusion (I/R) was shown to stimulate ET release in rat heart; however, the mechanism(s) of this effect has not been clarified. Therefore, this study was focused to investigate the effect of BQ-123, selective ETA receptor antagonist, on three aspects of myocardial ischemia–reperfusion (MI/R) injury: hemodynamic parameters, infarct size and oxidant–antioxidant status in the absence and presence of ET-1 in an vivo rat model. Methods and results: To produce MI/R, a branch of the descending left coronary artery was occluded for 30min followed by 2h reperfusion. ECG changes, blood pressure (BP), and heart rate (HR) were measured before occlusion and continued both occlusion and reperfusion. Forty rats were randomly assigned to five groups equally: (1) sham-operated rats without coronary ligation, (2) I/R group, (3) I/R+BQ-123-treated group (10μg/kg/min i.v.), (4) I/R+ET-treated group (25ng/kg/min i.v.), (5) I/R+ET+BQ-123-treated group. The results are expressed as mean±S.E.M. In the ET-1 plus I/R group, the ratio between the infarcted area and area at risk 56±1% was significantly higher than I/R group (49±1%). In the BQ-123 group with or without exogenous ET-1 treatment in I/R group, this ratio was significantly lower at 40±2 and 37±1%, respectively. As compared to sham group, I/R increased lipid peroxidation whereas decreased nitric oxide (NO), glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) contents. This decreased antioxidant enzymatic defense could result in aggravated oxidative damage in I/R group rat hearts. ET-1 administration group showed severe oxidative damage. BQ-123 administrations to I/R group with or without ET-1 caused significantly decrease in lipid peroxidation and increased in SOD, CAT activities and NO generation and GSH content when compared with I/R group alone. Conclusions: The most important finding of the present study is that the ET blockade reduced I/R-induced myocardial injury. The mechanism of this reduction was speculated to be a resistance to ischemic injury in the subcellular levels of the myocardium conferred by a reduction of vascular constriction and improvement of imbalance in the antioxidant status. [Copyright &y& Elsevier]