Hanley Peter J, Daut Jürgen
Institut für Normale und Pathologische Physiologie, Universität Marburg, Deutschhausstrasse 2, 35037 Marburg, Germany.
J Mol Cell Cardiol. 2005 Jul;39(1):17-50. doi: 10.1016/j.yjmcc.2005.04.002.
Preconditioning by one or several brief periods of ischemia activates an endogenous cardioprotective program that increases the resistance of cardiomyocytes to injury by subsequent prolonged periods of ischemia. Ischemic preconditioning can be mimicked by K(+) channel openers and various other substances, a phenomenon termed pharmacological preconditioning. Initially, ischemic preconditioning has been ascribed to the opening of ATP-sensitive K(+) channels at the surface membrane of cardiomyocytes. Since 1997, numerous publications have implicated mitochondrial ATP-sensitive K(+) channels (mK(ATP)) as a major trigger and/or end effector of preconditioning. Diazoxide has been suggested to be a specific activator of mK(ATP) channels, and the substituted fatty acid 5-hydroxydecanoate (5-HD) has been suggested to be a specific inhibitor. However, diazoxide and 5-HD have multiple K(+)-channel-independent actions, and the experimental evidence for an obligatory role of mK(ATP) channels in preconditioning, or even their existence, remains inconclusive. In contrast, surface K(ATP) channels have been well characterized, and we summarize the evidence suggesting that they make a major contribution to preconditioning. We also discuss a number of other factors involved in preconditioning: (1) generation of reactive oxygen species, (2) impairment of fatty acid metabolism, and (3) opening of the mitochondrial permeability transition pore. In the light of these emerging concepts, we critically re-examine the evidence for and against a role of mK(ATP) channels in ischemic and pharmacological preconditioning.
一次或数次短暂缺血预处理可激活内源性心脏保护程序，从而增强心肌细胞对随后长时间缺血损伤的抵抗能力。钾通道开放剂及其他多种物质可模拟缺血预处理，这一现象被称为药物预处理。最初，缺血预处理被认为是由于心肌细胞膜表面的ATP敏感性钾通道开放所致。自1997年以来，众多研究表明线粒体ATP敏感性钾通道（mK(ATP)）是预处理的主要触发因素和/或终末效应器。二氮嗪被认为是mK(ATP)通道的特异性激活剂，而取代脂肪酸5-羟基癸酸（5-HD）则被认为是特异性抑制剂。然而，二氮嗪和5-HD具有多种不依赖钾通道的作用，mK(ATP)通道在预处理中起关键作用甚至其存在的实验证据仍不确凿。相比之下，细胞膜表面的ATP敏感性钾通道已得到充分表征，我们总结了表明它们对预处理起主要作用的证据。我们还讨论了预处理涉及的其他一些因素：（1）活性氧的产生，（2）脂肪酸代谢受损，以及（3）线粒体通透性转换孔的开放。鉴于这些新出现的概念，我们审慎地重新审视了支持和反对mK(ATP)通道在缺血预处理和药物预处理中起作用的证据。
