KR-31761, a Novel K+ATP-Channel Opener, Exerts Cardioprotective Effects by Opening Both Mitochondrial K+ATP and Sarcolemmal K+ATP Channels in Rat Models of Ischemia/Reperfusion-Induced Heart Injury

Min-Kyu Yang, Sung-Hun Lee, Ho-Won Seo, Kyu-Yang Yi, Sung-Eun Yoo, Byung-Ho Lee, Hun-Jong Chung, Hyung-Sik Won, Chang-Soo Lee, Suk-Hyung Kwon, Wahn-Soo Choi, Hwa-Sup Shin
2009 Journal of Pharmacological Sciences  
The cardioprotective effects of KR-31761, a newly synthesized K + ATP opener, were evaluated in rat models of ischemia / reperfusion (I/ R) heart injury. In isolated rat hearts subjected to 30-min global ischemia / 30-min reperfusion, KR-31761 perfused prior to ischemia significantly increased both the left ventricular developed pressure (% of predrug LVDP: 17.8, 45.1, 54.2, and 62.6 for the control, 1 μM, 3 μM, and 10 μM, respectively) and double product (DP: heart rate × LVDP; % of predrug
more » ... 17.5, 44.9, 56.2, and 64.5 for the control, 1 μM, 3 μM, and 10 μM, respectively) at 30-min reperfusion while decreasing the left ventricular end-diastolic pressure (LVEDP). KR-31761 (10 μM) significantly increased the time to contracture during the ischemic period, whereas it concentration-dependently decreased the lactate dehydrogenase release during reperfusion. All these parameters were significantly reversed by 5-hydroxydecanoate (5-HD, 100 μM) and glyburide (1 μM), selective and nonselective blockers of the mitochondrial K + ATP (mitoK + ATP ) channel and K + ATP channel, respectively. In anesthetized rats subjected to 30-min occlusion of left anterior descending coronary artery / 2.5-h reperfusion, KR-31761 administered 15 min before the onset of ischemia significantly decreased the infarct size (72.2%, 55.1%, and 47.1% for the control, 0.3 mg / kg, i.v., and 1.0 mg / kg, i.v., respectively); and these effects were completely and almost completely abolished by 5-HD (10 mg / kg, i.v.) and HMR-1098, a selective blocker of sarcolemmal K + ATP (sarcK + ATP ) channel (6 mg / kg, i.v.) administered 5 min prior to KR-31761 (72.3% and 67.9%, respectively). KR-31761 only slightly relaxed methoxamine-precontracted rat aorta (IC 50 : >30.0 μM). These results suggest that KR-31761 exerts potent cardioprotective effects through the opening of both mitoK + ATP and sarcK + ATP channels in rat hearts with a minimal vasorelaxant effect.
doi:10.1254/jphs.08132fp pmid:19234365 fatcat:4qa5jxp6k5gvvpdilib74z3xme