Department of Anesthesiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Shock. 2012 May;37(5):485-91. doi: 10.1097/SHK.0b013e318249b7b6.
The aim of the current study was to determine whether hypercholesterolemia affects the delayed sevoflurane preconditioning against myocardial ischemia-reperfusion (IR) injury and, if so, the underlying mechanism. Male Sprague-Dawley rats fed 2% cholesterol-enriched chow for 8 weeks were subjected to sevoflurane preconditioning (2.4% vol/vol, 1 h) 24 h before myocardial ischemia was induced by occluding the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min. The hemodynamic parameters left ventricular developed pressure, left ventricular end-diastolic pressure, and maximal rise/fall rate of left ventricular pressure were continuously monitored, and myocardial infarct size was determined at the end of reperfusion. The protein expression of myocardial nitric oxide synthase (NOS), Bcl-2, and Bad was assessed before ischemia. We found that the left ventricular hemodynamic parameters during the whole IR procedure and the myocardial infarct size did not significantly differ between the normocholesterolemic and hypercholesterolemic control groups. The hemodynamic parameters were all markedly improved during the reperfusion period, and the myocardial infarct size was significantly reduced by delayed sevoflurane preconditioning in normocholesterolemic rats, but all of these improvements were reversed by N-(3-(aminomethyl)benzyl) acetamidine (1400W, 1 mg/kg; i.v., 10 min before ischemia), a selective inducible NOS (iNOS) inhibitor, and 5-hydroxy decanoate sodium (5 mg/kg, i.v., 10 min before ischemia), a mitochondrial ATP-dependent K⁺ channel blocker. Such cardiac improvement induced by delayed sevoflurane preconditioning did not occur in hypercholesterolemic rats and was not exacerbated by 1400W or 5-hydroxy decanoate sodium. The expression of myocardial iNOS was markedly enhanced by delayed sevoflurane preconditioning in normocholesterolemic, but not in hypercholesterolemic rats. The expression of endothelial NOS and Bad did not differ among all groups. The expression of myocardial phosphorylated endothelial NOS, Bcl-2, and phosphorylated Bad in normocholesterolemic rats was not affected by delayed sevoflurane preconditioning but was decreased in the hypercholesterolemic control group, and this was not reversed by sevoflurane, compared with the normocholesterolemic control group. Taken together, these results indicate that sevoflurane preconditioning exerts delayed cardioprotection against IR injury in normocholesterolemic rats, which is blocked by hypercholesterolemia potentially via interference with the iNOS/mitochondrial ATP-dependent K⁺ channel pathway.
本研究旨在探讨高胆固醇血症是否影响七氟醚预处理对心肌缺血再灌注（IR）损伤的延迟保护作用，如果有影响，其潜在机制是什么。雄性 Sprague-Dawley 大鼠喂食 2%胆固醇强化饲料 8 周后，通过结扎左前降支冠状动脉 30 分钟诱导心肌缺血，再灌注 120 分钟前 24 小时进行七氟醚预处理（2.4%体积/体积，1 小时）。连续监测左心室发展压、左心室舒张末期压和左心室压力最大上升/下降率等血流动力学参数，并在再灌注结束时确定心肌梗死面积。在缺血前评估心肌一氧化氮合酶（NOS）、Bcl-2 和 Bad 的蛋白表达。结果发现，在整个 IR 过程中，正常胆固醇血症和高胆固醇血症对照组之间的左心室血流动力学参数和心肌梗死面积无显著差异。在再灌注期间，所有血流动力学参数均明显改善，延迟七氟醚预处理可显著减少正常胆固醇血症大鼠的心肌梗死面积，但这些改善均被 N-（3-（氨甲基）苄基）乙酰胺（1400W，1mg/kg；静脉注射，缺血前 10 分钟），一种选择性诱导型 NOS（iNOS）抑制剂，和 5-羟基癸酸钠盐（5mg/kg，静脉注射，缺血前 10 分钟），一种线粒体 ATP 依赖性钾通道阻滞剂所逆转。这种由延迟七氟醚预处理引起的心脏改善在高胆固醇血症大鼠中并未发生，并且 1400W 或 5-羟基癸酸钠也未加剧这种情况。延迟七氟醚预处理可显著增强正常胆固醇血症大鼠心肌 iNOS 的表达，但在高胆固醇血症大鼠中则无。各组内皮型 NOS 和 Bad 的表达无差异。正常胆固醇血症大鼠心肌磷酸化内皮型 NOS、Bcl-2 和磷酸化 Bad 的表达不受延迟七氟醚预处理的影响，但在高胆固醇血症对照组中降低，与正常胆固醇血症对照组相比，七氟醚也未能逆转这种情况。综上所述，这些结果表明，七氟醚预处理对正常胆固醇血症大鼠的 IR 损伤具有延迟的心脏保护作用，而高胆固醇血症可能通过干扰 iNOS/线粒体 ATP 依赖性钾通道途径来阻断这种作用。
