MCC-134, a blocker of mitochondrial and opener of sarcolemmal ATP-sensitive K+ channels, abrogates cardioprotective effects of chronic hypoxia

We examined the effect of MCC-134, a novel inhibitor of mitochondrial ATP-sensitive K+ (mitoK(ATP)) channels and activator of sarcolemmal ATP-sensitive K+ (sarcK(ATP)) channels, on cardioprotection conferred by adaptation to chronic hypoxia. Adult mate Wistar rats were exposed to intermittent hypobaric hypoxia (7000 m, 8 h/day, 5-6 weeks) and susceptibility of their hearts to ventricular arrhythmias and myocardial infarction was evaluated in anesthetized open-chest animals subjected to 20-min coronary artery occlusion and 3-h reperfusion on the day after the last hypoxic exposure. MCC-134 was administered intravenously 10 min before ischemia and 5 min before reperfusion in a total dose of 0.3 mg/kg or 3 mg/kg divided into two equal boluses. The infarct size (tetrazolium staining) was reduced from 59.2 +/- 4.4% of the area at risk in normoxic controls to 43.2 +/- 3.3 % in the chronically hypoxic group. Chronic hypoxia decreased the reperfusion arrhythmia score from 2.4 +/- 0.5 in normoxic animals to 0.7 +/- 0.5. Both doses of MCC-134 completely abolished the antiarrhythmic protection (score 2.4 +/- 0.7 and 2.5 +/- 0.5, respectively) but only the high dose blocked the infarct size-limiting effect of chronic hypoxia (54.2 +/- 3.7 %). MCC-134 had no effect in the normoxic group. These results support the view that the opening of mitoK(ATP) channels but not sarcK(ATP) channels plays a crucial role in the mechanism by which chronic hypoxia improves cardiac tolerance to ischemia/reperfusion injury.