Selective endothelin a (ET A) receptor antagonist (BQ-123) reduces both myocardial infarct size and oxidant injury

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 ET A 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 30 min followed by 2 h 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 (10 μg/kg/min i.v.), (4) I/R + ET-treated group (25 ng/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.