Selective cardiac plasma-membrane KATP channel inhibition is defibrillatory and improves survival during acute myocardial ischemia and reperfusion

ATP-dependent potassium channels (KATP) have been implicated in cardioprotection both during myocardial ischemia and reperfusion. We compared the effect of a non-selective KATP inhibitor glibenclamide, a selective mitochondrial KATP inhibitor 5-hydroxy-decanoate (5-HD) and a selective sarcolemmal KATP blocker HMR 1883, on survival and incidence of arrhythmias during myocardial ischemia in conscious, and during ischemia-reperfusion in pentobarbitone anesthetized rats. Glibenclamide (5 mg/kg i.p.) or HMR 1883 (3 mg/kg i.v.) reduced ischemia-induced irreversible ventricular fibrillation and improved survival during myocardial ischemia (64% and 61% vs. 23% in controls, respectively). 5-HD (5 mg/kg i.v.) did not influence survival and the incidence of ventricular arrhythmias. The incidence of reperfusion-induced arrhythmias was reduced by both glibenclamide and HMR 1883 (3 or 10 mg/kg) resulting in improved survival during reperfusion (81%, 82% and 96% vs. 24% in controls, respectively) in anesthetized rats. 5-HD did not reduce the incidence of lethal reperfusion arrhythmias. Glibenclamide and HMR 1883 prolonged (89 ± 4.6 and 89 ± 4.9 ms vs. 60 ± 2.4 ms in controls), while 5-HD did not change the QT interval. In conclusion, inhibition of sarcolemmal KATP reduces the incidence of lethal ventricular arrhythmias and improves survival both during acute myocardial ischemia and reperfusion in rats. This beneficial effect correlates with the prolongation of repolarization. Inhibition of mitochondrial KATP does not improve survival or reduce the occurrence of ischemia and/or reperfusion-induced arrhythmias and does not prolong the QT interval. The present results also suggest that the antiarrhythmic effect of KATP inhibitors is not influenced by pentobarbitone anesthesia.