RAPID COMMUNICATION

MCC-134, a Blocker of Mitochondrial and Opener of Sarcolemmal ATP-Sensitive K+ Channels, Abrogates Cardioprotective Effects of Chronic Hypoxia

F. KOLÁŘ, J. NECKÁŘ, B. OŠŤÁDAL

Institute of Physiology, Academy of Sciences of the Czech Republic and Center for Cardiovascular Research, Prague, Czech Republic

Received January 31, 2005
Accepted March 30, 2005

Summary
We examined the effect of MCC-134, a novel inhibitor of mitochondrial ATP-sensitive K+ (mitoKATP) channels and activator of sarcolemmal ATP-sensitive K+ (sarcKATP) channels, on cardioprotection conferred by adaptation to chronic hypoxia. Adult male 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 mitoKATP channels but not sarcKATP channels plays a crucial role in the mechanism by which chronic hypoxia improves cardiac tolerance to ischemia/reperfusion injury.

Key words
Chronic hypoxia • Ischemia/reperfusion • Cardioprotection • MCC-134 • KATP channels