Fryer R M, Hsu A K, Gross G J
Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
J Mol Cell Cardiol. 2001 Apr;33(4):831-4. doi: 10.1006/jmcc.2001.1350.
We have previously demonstrated that K(ATP)channel openers administered just prior to and throughout reperfusion induce cardioprotection in the blood-perfused canine heart. However, a recent report suggests that the mitochondrial K(ATP)channel is only a trigger of ischemic preconditioning (IPC). These recent data are, however, in contrast to most previous investigations that suggested that activation of the mitochondrial K(ATP)channel is an important downstream mediator of cardioprotection. Therefore, we examined the role of the mitochondrial K(ATP)channel as a downstream mediator of IPC in a rat model by administering the selective mitochondrial K(ATP)channel antagonist, 5-hydroxydecanoate (5-HD), at several points during IPC. Infarct size (IS) was determined by tetrazolium chloride staining and expressed as a percent of the area at risk (AAR). Control animals had an IS/AAR of 58.4+/-0.6 and IS/AAR was reduced to 6.2+/-1.7 following IPC. 5-HD (10 mg/kg), attenuated cardioprotection when administered either 5 min prior to the IPC stimulus (40.4+/-1.4), during the reperfusion phase of the IPC stimulus (39.7+/-5.9), or 5 min prior to reperfusion during prolonged ischemia (34.3+/-6.9). Additionally, when 5-HD was administered at 5 mg/kg during the reperfusion phase of index ischemia plus 5 min prior to IPC or plus during the reperfusion phase of IPC, cardioprotection was also attenuated (36.3+/-5.5 and 43.8+/-6.9, respectively). These data suggest that activation of the mitochondrial K(ATP) channel is an important downstream regulator of myocardial protection with effects lasting into the reperfusion period following prolonged ischemia.
我们之前已经证明，在再灌注之前及整个再灌注过程中给予K(ATP)通道开放剂可在血液灌注的犬心脏中诱导心脏保护作用。然而，最近一份报告表明，线粒体K(ATP)通道仅仅是缺血预处理（IPC）的一个触发因素。然而，这些最新数据与之前大多数研究相反，之前的研究表明线粒体K(ATP)通道的激活是心脏保护作用的一个重要下游介质。因此，我们通过在IPC的几个时间点给予选择性线粒体K(ATP)通道拮抗剂5-羟基癸酸（5-HD），研究了线粒体K(ATP)通道作为大鼠模型中IPC下游介质的作用。通过氯化三苯基四氮唑染色确定梗死面积（IS），并表示为危险面积（AAR）的百分比。对照动物的IS/AAR为58.4±0.6，IPC后IS/AAR降至6.2±1.7。5-HD（10mg/kg）在IPC刺激前5分钟（40.4±1.4）、IPC刺激的再灌注阶段（39.7±5.9）或长时间缺血再灌注前5分钟（34.3±6.9）给药时，减弱了心脏保护作用。此外，当在指数缺血的再灌注阶段给予5mg/kg的5-HD，加上IPC前5分钟或IPC的再灌注阶段时，心脏保护作用也减弱了（分别为36.3±5.5和43.8±6.9）。这些数据表明，线粒体K(ATP)通道的激活是心肌保护的一个重要下游调节因子，其作用可持续到长时间缺血后的再灌注期。
