ATP-sensitive K<SUP>+</SUP> channel openers prevent Ca<SUP>2+</SUP> overload in rat cardiac mitochondria

作     者：Holmuhamedov, EL Wang, LW Terzic, A 

作者机构：Mayo Clin & Mayo Fdn Dept Med & Pharmacol Div Cardiovasc Dis Rochester MN 55905 USA 

出 版 物：《JOURNAL OF PHYSIOLOGY-LONDON》 (生理学杂志)

年 卷 期：1999年第519卷第2期

页      面：347-360页

核心收录：

学科分类：0710[理学-生物学] 1001[医学-基础医学(可授医学、理学学位)] 07[理学] 071003[理学-生理学] 

基　　金：NHLBI NIH HHS [T32 HL007111  HL-07111] Funding Source: Medline 

主　　题：腺苷二磷酸/药理学 腺苷三磷酸/药理学 钙/代谢 环孢菌素/拮抗剂和抑制剂 环孢菌素/药理学 二氮嗪/拮抗剂和抑制剂 二氮嗪/药理学 离子载体/药理学 膜电位/药物作用 膜电位/生理学 膜蛋白质类/激动剂 膜蛋白质类/代谢 显微镜检查 共焦 线粒体 心脏/药物作用 线粒体 心脏/代谢 心肌/细胞学 心肌/代谢 氧耗量/药物作用 通透性 吡那地尔/拮抗剂和抑制剂 吡那地尔/药理学 钾通道 大鼠 Sprague-Dawley 缬氨霉素/药理学 动物 大鼠 

摘      要：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.