Abstract
Recent studies have shown the importance of mitochondrial ATP-sensitive potassium channels (KATP) in cardioprotection, and studies in vitro have shown that the benzopyran analog (3R)-trans- 4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride (BMS-191095) is a selective mitochondrial KATP opener with cardioprotective activity. The goal of this study was to show selective cardioprotection for BMS-191095 in vivo without hemodynamic or cardiac electrophysiological effects expected for nonselective KATP openers. BMS-191095 reduced infarct size in anesthetized dogs (90-min ischemia + 5-h reperfusion) in a dose-dependent manner (ED25 = 0.4 mg/kg i.v.) with efficacious plasma concentrations of 0.3 to 1.0 μM, which were consistent with potency in vitro. None of the doses of BMS-191095 tested caused any effect on peripheral or coronary hemodynamic status. Further studies in dogs showed no effects of BMS-191095 on cardiac conduction or action potential configuration within the cardioprotective dose range. In a programmed electrical stimulation model, BMS-191095 showed no proarrhythmic effects, which is consistent with its lack of effects on cardiac electrophysiological status. BMS-191095 is a potent and efficacious cardioprotectant that is devoid of hemodynamic and cardiac electrophysiological side effects of first generation KATPopeners, which open both sarcolemmal and mitochondrial KATP. Selective opening or activation of mitochondrial KATP seems to be a potentially effective strategy for developing well tolerated and efficacious KATP openers.
Footnotes
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DOI: 10.1124/jpet.102.036988
- Abbreviations:
- KATP
- ATP-sensitive potassium channel
- BMS-191095
- (3R)-trans-4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride
- 5-HD
- sodium 5-hydroxydecanoate
- LCX
- left circumflex coronary artery
- ET
- excitation threshold
- APD
- action potential duration
- CT
- conduction time
- CV
- conduction velocity
- ERP
- effective refractory period
- RVOT
- right ventricular outflow tract
- LAD
- left anterior descending coronary artery
- BCL
- basic cell length
- PES
- programmed electrical stimulation
- Received April 17, 2002.
- Accepted May 16, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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