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-inducedtissue 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.Abdominal aortic surgery; reperfusion injury; reactive oxygen species; acute-phase reaction; endothelin-1. Tohoku

The effects of sildenafil and n-acetylcysteine on ischemia and reperfusion injury in gastrocnemius muscle and femoral artery endothelium

“…Kiris et al 7 found significant increases in the levels of malonydialdehyde, catalase and superoxide dismutase and myeloperoxidase activity in rats in the aortic I/R group in which 60 minutes of reperfusion was applied after a 30-minute ischemia compared to the control group. Narin et al 9 found significant increases in the levels of malonydialdehyde, catalase and superoxide dismutase and myeloperoxidase activity in rats in the aortic I/R group in which 120 minutes of reperfusion was applied after a 120-minute ischemia compared to the control group. We applied 120 minutes of ischemia followed by a 120 minutes of reperfusion in the study groups of this study.…”

Acetaminophen Mitigates Myocardial Injury Induced by Lower Extremity Ischemia-Reperfusion in Rat Model

“…Hydrogen peroxide, hydroxyl and superoxide radicals, the main reactive oxygen products, are shown to result in peroxidation in membrane phospholipids of myocardial tissues cells [ 4 ] . In addition, I/R injury is suggested to increase by remote organ infiltration of activated neutrophils due to aortic I/R and the myeloperoxidase enzyme released by them [ 4 , 18 , 19 ] . Moreover, released cytokines, particularly tumor necrosis factor-, induce leukocyte activation and also damage capillary continuity [ 17 ] .…”

“…As understood, distant organ I/R injury is not a single reaction, but rather a complex process with intracellular and extracellular pathophysiologic changes. Histological changes in the heart, resulting from I/R, can be seen via the light microscope [ 19 ] . Variables such as myofibrillar edema and focal hemorrhage detected under the light microscope were recorded in the I/R group, but not in the control group, which is suggested to be an indicator of distant organ I/R injury in the heart due to abdominal aorta operation.…”

Potential of endothelin-1 and vasopressin antagonists for the treatment of congestive heart failure

“…On the contrary, tezosentan, a dual receptor antagonist, given on the first day after MI increased long term survival and improved hemodynamic conditions [107]. It was also shown to have protective effects on myocardial injury induced by ischemia-reperfusion [121]. Even a selcective ET-A receptor blocker in acute setting has been documented to be superior to chronic blockade in attenuating ischemia/reperfusion injury in failing hearts [122].…”