期刊
PHARMACOLOGY
卷 70, 期 2, 页码 74-82出版社
KARGER
DOI: 10.1159/000074671
关键词
KR-31372; adenosine triphosphate-sensitive potassium; channel; ischemia; cardioprotection
The cardioprotective effects of (2S, 3R, 4S)-N)-benzyl-N- cyano-N-(3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2- methyl-6-nitro-2H-benzopyran-4-yl)-guanidine (KR-31372) were evaluated against ischemic/reperfusion injury in isolated rat hearts in vitro and in anesthetized rats and dogs in vivo. In isolated perfused rat hearts subjected to a 30-min global ischemia/30-min reperfusion, KR-31372 ( 1 - 10 muM) significantly improved severe contracture (end-diastolic pressure and time to contracture), markedly reduced reperfusion lactate dehydrogenase release, and enhanced the recovery of reperfusion contractile function ( left ventricular developed pressure and double product) in a concentration-dependent manner compared with the vehicle-treated group. In anesthetized rats subjected to a 45-min coronary occlusion and a 90-min reperfusion, intravenous KR-31372 dose- dependently reduced infarct size from 58.6% to 48.5, 48.1 and 39.6% at 0.3, 1.0 and 3.0 mg/kg, respectively (p < 0.05). In anesthetized beagle dogs that underwent a 1.5-hour occlusion followed by a 5-hour reperfusion, KR-31372 (2 mg/kg, i.v.) markedly reduced infarct size from 57.0% in controls to 28.0% (p < 0.05). The cardioprotective effects of KR-31372 on contractile function in globally ischemic rat hearts and on reperfusion injury in anesthetized rats were significantly reversed by pretreatment with selective adenosine triphosphate-sensitive potassium (K-ATP) channel blockers, sodium 5-hydroxydecanoate and glibenclamide. Taken together, these results indicate that KR-31372 possesses potent cardioprotective effects in rats and dogs and its effects may be mediated by activation of mitochondrial K-ATP channels. Copyright (C) 2004 S. Karger AG, Basel.
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