Selective pharmacological agents implicate mitochondrial but not sarcolemmal KATP channels in ischemic cardioprotection
Selective pharmacological agents implicate mitochondrial but not sarcolemmal KATP channels in ischemic cardioprotection
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DOI：
10.1161/01.cir.101.20.2418
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发表时间：
2000-05-23
期刊：
影响因子：
37.8
通讯作者：
Marbán, E
中科院分区：
文献类型：
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作者：
Sato, T;Sasaki, N;Marbán, E
背景-药理学证据表明ATP敏感性K+（K-ATP）通道是心脏保护的效应器，但线粒体的相对作用（mitoK（ATP））和肌膜方法和结果：我们检测了K-ATP通道阻断剂HMR 1098和K-ATP通道开放剂P-1075对表面K（ATP）和线粒体K（ATP）的影响。在兔心室肌细胞的通道。HMR 1098（30 μ mol/L）抑制由代谢抑制激活的表面K（ATP）电流，而该药物不会钝化二氮嗪（100 μ mol/L）诱导的黄素蛋白氧化，这是线粒体K（ATP）通道活性的指标。P-1075（30 μ mol/L）没有增加黄素蛋白氧化，但确实引起了一个强大的表面K电流，该电流被HMR 1098完全抑制。这些结果表明，HMR 1098选择性抑制表面K（ATP）通道，而P-1075选择性激活表面K-ATP通道。在模拟缺血的细胞模型中，mitoK（ATP）通道开放剂二氮嗪（100 μ mol/L），而不是P-1075，钝化细胞损伤，由二氮嗪或预处理提供的心脏保护被mitoK阻止，通道阻断剂5-羟基癸酸酯（500 μ mol/L），但不被表面K（ATP）通道阻断剂HMR 1098（30 μ mol/L）。结论-线粒体或表面选择性试剂的细胞效应进一步支持了新出现的共识，即mitoK（ATP）通道而不是表面K（aATP）通道可能是心脏保护的效应器。
Background-Pharmacological evidence has implicated ATP-sensitive K+ (K-ATP) channels as the effecters of cardioprotection, but the relative roles of mitochondrial (mitoK(ATP)) and sarcolemmal (surfaceK(ATP)) channels remain controversial.Methods and Results-We examined the effects of the K-ATP channel blocker HMR1098 and the K-ATP channel opener P-1075 on surfaceK(ATP) and mitoK(ATP) channels in rabbit ventricular myocytes. HMR1098 (30 mu mol/L) inhibited the surfaceK(ATP) current activated by metabolic inhibition, whereas the drug did not blunt diazoxide (100 mu mol/L)-induced flavoprotein oxidation, an index of mitoK(ATP) channel activity. P-1075 (30 mu mol/L) did not increase flavoprotein oxidation but did elicit a robust surfaceK, current that was completely inhibited by HMR1098. These results indicate that HMR1098 selectively inhibits surfaceK(ATP) channels, whereas P-1075 selectively activates surface K-ATP channels. In a cellular model of simulated ischemia, the mitoK(ATP) channel opener diazoxide (100 mu mol/L), but not P-1075, blunted cellular injury, The cardioprotection afforded by diazoxide or by preconditioning was prevented by the mitoK, channel blocker 5-hydroxydecanoate (500 mu mol/L) but not by the surfaceK(ATP) channel blocker HMR1098 (30 mu mol/L).Conclusions-The cellular effects of mitochondria- or surface-selective agents provide further support for the emerging consensus that mitoK(ATP) channels rather than surfaceK(aATP) channels are the likely effectors of cardioprotection.