Sato T, Sasaki N, O'Rourke B, Marbán E
Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
J Am Coll Cardiol. 2000 Feb;35(2):514-8. doi: 10.1016/s0735-1097(99)00552-5.
To determine the mechanism of cardioprotection afforded by nicorandil, an orally efficacious antianginal drug, we examined its effects on ATP-dependent potassium (K(ATP)) channels.
Nicorandil can mimic ischemic preconditioning, while mitochondrial K(ATP) (mitoK(ATP)) channels rather than sarcolemmal K(ATP) (surfaceK(ATP)) channels have emerged as the likely effectors.
Flavoprotein fluorescence and membrane current in intact rabbit ventricular myocytes were measured simultaneously to assay mitoK(ATP) channel and surface K(ATP) channel activities, respectively. In a cell-pelleting model of ischemia, cells permeable to trypan blue were counted as killed by 60 and 120 min of ischemia.
Nicorandil (100 micromol/liter) increased flavoprotein oxidation but not membrane current; a 10-fold higher concentration recruits both mitoK(ATP) and surfaceK(ATP) channels. Pooled dose-response data confirm that nicorandil concentrations as low as 10 micromol/liter turn on mitoK(ATP) channels, while surfaceK(ATP) current requires exposure to millimolar concentrations. Nicorandil blunted the rate of cell death in a pelleting model of ischemia; this cardioprotective effect was prevented by the mitoK(ATP) channel blocker 5-hydroxydecanoate but was unaffected by the surfaceK(ATP) channel blocker HMR1098.
Nicorandil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by selective activation of mitoK(ATP) channels.
为确定口服有效的抗心绞痛药物尼可地尔的心脏保护机制，我们研究了其对ATP敏感性钾（K(ATP)）通道的影响。
尼可地尔可模拟缺血预处理，而线粒体K(ATP)（mitoK(ATP)）通道而非肌膜K(ATP)（表面K(ATP)）通道已成为可能的效应器。
同时测量完整兔心室肌细胞中的黄素蛋白荧光和膜电流，分别测定mitoK(ATP)通道和表面K(ATP)通道活性。在缺血的细胞沉淀模型中，将能透过台盼蓝的细胞计为在缺血60分钟和120分钟时死亡的细胞。
尼可地尔（100微摩尔/升）增加了黄素蛋白氧化，但未增加膜电流；浓度高10倍时可同时激活mitoK(ATP)和表面K(ATP)通道。汇总的剂量反应数据证实，低至10微摩尔/升的尼可地尔浓度可开启mitoK(ATP)通道，而表面K(ATP)电流需要暴露于毫摩尔浓度。在缺血的沉淀模型中，尼可地尔减缓了细胞死亡速率；mitoK(ATP)通道阻滞剂5-羟基癸酸可阻止这种心脏保护作用，但表面K(ATP)通道阻滞剂HMR1098对其无影响。
尼可地尔对心肌细胞具有直接的心脏保护作用，该作用由mitoK(ATP)通道的选择性激活介导。
