Pretreatment with Sarafotoxin 6c Prior to Coronary Occlusion Protects Against Infarction and Arrhythmias via Cardiomyocyte Mitochondrial KATP Channel Activation in the Intact Rabbit Heart During Ischemia/Reperfusion

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Endothelial ET(B) receptor activation by exogenously administered sarafotoxin 6c(a snake venom peptide with a sequence homology to ET-1 prior to ischemia activates release of nitric oxide(NO) and previous studies have shown that NO facilitates mitochondrial K(ATP) activation in cardiac cells and cardioprotection. The aim of this investigation was to test whether the administration of sarafotoxin 6c(a selective ET(B) receptor agonist) has cardioprotective and antiarrhythmic effects against ischemia and reperfusion injury in a well-standardized model of reperfusion arrhythmias in anesthetized adult male rabbits (n = 53) subjected to 30 min occlusion of the left coronary artery followed by 120 min of reperfusion. Pretreatment with sarafotoxin 6c (0.24 nmol/kg, i.v.) prior to the period of coronary occlusion offers significant infarct size reduction (19.1 +/- 2.0% versus 39.7 +/- 3.7% in the saline control group; P < 0.01) and antiarrhythmic effects. Sarafotoxin 6c treatment significantly attenuated the incidence of life-threatening arrhythmias like sustained VT (13 versus 100% in the saline control group; P < 0.005) and other arrhythmias (25 versus 100% in the saline control group; P < 0.005), and increased the number of surviving animals without arrhythmias. Pretreatment with 5-HD but not HMR 1883 abolished the beneficial effects of sarafotoxin 6c on reperfusion induced arrhythmias and cardioprotection suggesting that benefits have been achieved via the selective activation of cardiomyocyte mitochondrial K(ATP) channels. Sarafotoxin 6c evoked NO release and selective activation of mitoK(ATP) channels in cardiomyocytes contributes to cardioprotection and antiarrhythmic activity during ischemia-reperfusion in the anesthetized rabbit. We conclude that the selective activation of ET(B) receptors by sarafotoxin 6c prior to coronary occlusion contributes to cardioprotective and antiarrhythmic properties.