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

Background 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. Objectives and methods 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. Results 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. Conclusions We conclude that the selective activation of ET_B receptors by sarafotoxin 6c prior to coronary occlusion contributes to cardioprotective and antiarrhythmic properties.