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

• Published in: Physiological research Vol. 54; no. 4; pp. 467 - 471
• Main Authors: Kolár, F, Neckár, J, Ostádal, B
• Format: Journal Article
• Language: English
• Published: Czech Republic 2005
• Subjects: Adaptation, Physiological - drug effects; Adaptation, Physiological - physiology; Animals; ATP-Binding Cassette Transporters - agonists; Blood Pressure - drug effects; Calcium Channel Blockers - pharmacology; Heart Rate - drug effects; Hypoxia - physiopathology; Imidazoles - pharmacology; In Vitro Techniques; KATP Channels; Male; Mitochondria, Heart - drug effects; Myocardial Infarction - pathology; Myocardial Infarction - prevention & control; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Potassium Channels, Inwardly Rectifying - agonists; Rats; Rats, Wistar; Sarcolemma - drug effects; Sarcolemma - metabolism; Thioamides - pharmacology
• ISSN: 0862-8408; 1802-9973
• DOI: 10.33549/physiolres.930000.54.467

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 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.