ATP-sensitive K+ channel openers prevent Ca2+ overload in rat cardiac mitochondria
ATP-sensitive K+ channel openers prevent Ca2+ overload in rat cardiac mitochondria
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DOI：
10.1111/j.1469-7793.1999.0347m.x
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发表时间：
1999-09-01
影响因子：
5.5
通讯作者：
Terzic, A
中科院分区：
文献类型：
--
作者：
Holmuhamedov, EL;Wang, LW;Terzic, A
1.线粒体功能障碍，继发于钙离子过度积聚，与心脏损伤有关。我们在这里研究了钾通道开放剂对线粒体钙稳态的作用，因为这些心肌保护性离子通道调节剂最近被证明以线粒体ATP敏感的钾通道为靶点。在分离的心肌线粒体中，二氮嗪和吡那地尔降低线粒体基质中钙摄取的速率和幅度，其IC50分别为65和128mU M。在钙摄取的所有阶段，钾通道开放剂使线粒体膜去极化，从而减少钙离子通过电位依赖性线粒体膜通道的内流。二氮嗪和吡那地尔也以浓度依赖的方式激活线粒体钙的释放。这可以被环孢菌素A阻止，环孢菌素A是一种通过线粒体通透性转换点释放钙离子的抑制剂。用甘露醇替代线粒体外K+可消除二氮嗪和吡那地尔对线粒体钙离子的影响，而钾离子载体伐林霉素则与钾通道开放剂的作用相似。阻断线粒体对ATP敏感的K+通道的K+流量的ATP和ADP可抑制钾通道开放剂的作用，而不呈现呋喃霉素的作用。在完整的心肌细胞中，二氮嗪还能诱导线粒体去极化，降低线粒体钙含量。线粒体ATP敏感性K+通道阻滞剂5-羟基癸酸可抑制上述作用。因此，钾通道开放剂通过降低钙摄取的驱动力和激活对环孢素敏感的钙释放来防止线粒体钙超载。在这一点上，ATP敏感的线粒体K+电导的调节剂可能有助于维持线粒体的钙稳态。
1. Mitochondrial dysfunction, secondary to excessive accumulation of Ca2+, has been implicated in cardiac injury. We here examined the action of potassium channel openers on mitochondrial Ca2+ homeostasis, as these cardioprotective ion channel modulators have recently been shown to target a mitochondrial ATP-sensitive K+ channel.2. In isolated cardiac mitochondria, diazoxide and pinacidil decreased the rate and magnitude of Ca2+ uptake into the mitochondrial matrix with an IC50 of 65 and 128 mu M, respectively. At all stages of Ca2+ uptake, the potassium channel openers depolarized the mitochondrial membrane thereby reducing Ca2+ influx through the potential-dependent mitachondrial uniporter.3. Diazoxide and pinacidil, in a concentration-dependent manner, also activated release of Ca2+ from mitochondria. This was prevented by cyclosporin A, an inhibitor of Ca2+ release through the mitochondrial permeability transition pore.4. Replacement of extramitochondrial K+ with mannitol abolished the effects of diazoxide and pinacidil on mitochondrial Ca2+, while the K+ ionophore valinomycin mimicked the effects of the potassium channel openers.5. ATP and ADP, which block K+ flux through mitochondrial ATP-sensitive K+ channels, inhibited the effects of potassium channel openers, without presenting the action of valinomycin.6. In intact cardiomyocytes, diazoxide also induced mitochondrial depolarization and decreased mitochondrial Ca2+ content. These effects mere inhibited by the mitochondrial ATP-sensitive K+ channel blocker 5-hydroxydecanoic acid.7. Thus, potassium channel openers prevent mitochondrial Ca2+ overload by reducing the driving force for Ca2+ uptake and by activating cyclosporin-sensitive Ca2+ release. In this regard, modulators of an ATP-sensitive mitochondrial K+ conductance may contribute to the maintenance of mitochondrial Ca2+ homeostasis.