Lee Sung-Hun, Yang Min-Kyu, Lim Jong-Hyun, Seo Ho-Won, Yi Kyu-Yang, Yoo Sung-Eun, Lee Byung-Ho, Won Hyung-Sik, Lee Chang-Soo, Choi Wahn-Soo, Shin Hwa-Sup
Department of Applied Biochemistry, Division of Life Science, College of Biomedical and Health Science, Konkuk University, 322 Danwol-Dong, Chungju, Korea.
Arch Pharm Res. 2008 Apr;31(4):482-9. doi: 10.1007/s12272-001-1182-9. Epub 2008 May 1.
The cardioprotective effects of KR-31762, 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 followed by 30-min reperfusion, KR-31762 (3 and 10 microM) significantly increased the left ventricular developed pressure (LVDP) and double product (heart rate x LVDP) after 30-min reperfusion in a concentration-dependent manner, while decreasing the left ventricular end-diastolic pressure (LVEDP). KR-31762 also significantly increased the time to contracture (TTC) during ischemic period (20.0, 22.4 and 26.4 min for control, 3 and 10 microM, respectively), while decreasing the release of lactate dehydrogenase (LDH) from the heart during 30 min reperfusion (30.4, 14.3 and 19.7 U/g heart weight, respectively). All these parameters except LDH release were reversed by glyburide (1 microM), a nonselective blocker of K+(ATP) channel, but not by 5-hydroxydecanoate, a selective blocker of mitoK+(ATP) channel. In anesthetized rats subjected to 45-min occlusion of left anterior descending coronary artery followed by 90-min reperfusion, KR-31762 significantly decreased the infarct size (60.8, 40.5 and 37.8% for control, 0.3 and 1.0 mg/kg, iv, respectively). KR-31762 slightly relaxed the isolated rat aorta precontracted with methoxamine (IC(50): 23.5 microM). These results suggest that KR-31762 exerts potent cardioprotective effects through the opening of sarcolemmal K(ATP) channel in rat hearts with the minimal vasorelaxant effects.
在缺血/再灌注（I/R）性心脏损伤大鼠模型中评估了新合成的钾离子通道开放剂KR-31762的心脏保护作用。在离体大鼠心脏中，先进行30分钟全心缺血，随后再灌注30分钟，KR-31762（3和10微摩尔）在再灌注30分钟后以浓度依赖的方式显著增加左心室舒张末压（LVDP）和双乘积（心率×LVDP），同时降低左心室舒张末压（LVEDP）。KR-31762还显著延长了缺血期的挛缩时间（TTC）（对照组、3微摩尔和10微摩尔组分别为20.0、22.4和26.4分钟），同时减少了再灌注30分钟内心脏乳酸脱氢酶（LDH）的释放（分别为30.4、14.3和19.7单位/克心脏重量）。除LDH释放外，所有这些参数均被钾离子通道非选择性阻滞剂格列本脲（1微摩尔）逆转，但未被线粒体钾离子通道选择性阻滞剂5-羟基癸酸逆转。在麻醉大鼠中，结扎左冠状动脉前降支45分钟，随后再灌注90分钟，KR-31762显著减小梗死面积（对照组、静脉注射0.3和1.0毫克/千克组分别为60.8%、40.5%和37.8%）。KR-31762使用甲氧明预收缩的离体大鼠主动脉轻度舒张（半数抑制浓度（IC(50)）：23.5微摩尔）。这些结果表明，KR-31762通过开放大鼠心肌细胞膜上的钾离子通道发挥强大的心脏保护作用，且血管舒张作用最小。
