Endothelin receptor blockade with tezosentan ameliorates myocardial injury induced by abdominal aortic ischemia-reperfusion

Abstract

Endothelin is both a potent vasoconstrictor and an important mediator of ischemia-reperfusion (IR) injury. Therefore, the role of endothelin receptor antagonism in IR-induced-tissue injury carries great interest. Here, we examined the effect of tezosentan, a nonselective antagonist for endothelin receptors, on myocardial injury induced by abdominal aortic IR, which represents a model of the IR injury in distant organs frequently occurred after vascular surgery. Thirty-two Wistar rats were randomized into four groups (n = 8) as follows: control (sham laparotomy), aortic IR (120 min ischemia and 120 min reperfusion), aortic IR + tezosentan (10 mg/kg intravenous injection before ischemia plus continuous intravenous infusion of 1 mg/kg/hr during the IR injury), and control + tezosentan. Biochemical analysis showed that aortic IR significantly increased (p < 0.05 vs control) the plasma levels of troponin-I, interleukin-6 and tumor necrosis factor-alpha, and the myocardial tissue levels of malondialdehyde, superoxide dismutase and catalase, whereas tezosentan significantly decreased these same factors (p < 0.05 vs aortic IR). Histological evaluation also showed that aortic IR significantly increased (p < 0.05 vs control) myocardial disorganization, myofiber swelling and myofiber eosinophilia in myocardial tissue samples, whereas tezosentan significantly decreased these factors (p < 0.05 vs aortic IR). These results indicate that tezosentan has protective effects against myocardial injury induced by abdominal aortic IR in rats. We propose that the mechanisms underlying this protective effect of tezosentan involves the reduction of oxidative stress and subsequent lipid peroxidation, the inhibition of systemic inflammatory response, and acting cytoprotective on myocytes after aortic IR.