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

Abstract

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.

• Authors: F Kolár, J Neckár, B Ostádal
• Journal: Physiological research (Physiol Res) Vol. 54 Issue 4 Pg. 467-71 ( 2005) ISSN: 0862-8408 [Print] Czech Republic
• PMID: 16117602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• Calcium Channel Blockers
• Imidazoles
• KATP Channels
• MCC 134
• Potassium Channels, Inwardly Rectifying
• Thioamides
• uK-ATP-1 potassium channel

Topics

• ATP-Binding Cassette Transporters (agonists)
• Adaptation, Physiological (drug effects, physiology)
• Animals
• 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, prevention & control)
• Myocardial Reperfusion Injury (pathology, prevention & control)
• Potassium Channels, Inwardly Rectifying (agonists)
• Rats
• Rats, Wistar
• Sarcolemma (drug effects, metabolism)
• Thioamides (pharmacology)