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(Circulation Research. 2001;89:856.)
© 2001 American Heart Association, Inc.

Reports

Opening of Mitochondrial K_ATP Channels Attenuates the Ouabain-Induced Calcium Overload in Mitochondria

Hideyuki Ishida, Yuki Hirota, Chokoh Genka, Hiroe Nakazawa, Haruaki Nakaya, Toshiaki Sato

From the Department of Physiology (H.I., Y.H., C.G., H. Nakazawa), Tokai University School of Medicine, Isehara, Japan; Department of Pharmacology (H. Nakaya, T.S.), Graduate School of Medicine, Chiba University, Chiba, Japan.

Correspondence to Toshiaki Sato, MD, PhD, Department of Pharmacology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, 260-8670 Japan. E-mail tsato{at}med.m.chiba-u.ac.jp

Abstract

We tested whether opening of mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channels depolarizes mitochondrial membrane potential (_m) and thereby prevents the mitochondrial Ca²⁺ overload. With the use of a Nipkow disk confocal system, the mitochondrial Ca²⁺ concentration ([Ca²⁺]_m) and _m in rat ventricular myocytes were measured by loading cells with Rhod-2 and JC-1, respectively. Exposure to ouabain (1 mmol/L) for 30 minutes produced mitochondrial Ca²⁺ overload, and the intensity of Rhod-2 fluorescence significantly increased to 173±16% of baseline (P<0.001). Treatment of myocytes with the mitoK_ATP channel opener diazoxide (100 µmol/L) blunted the ouabain-induced mitochondrial Ca²⁺ overload (131±10% of baseline; P<0.001 versus ouabain). Moreover, diazoxide significantly depolarized the _m and reduced the intensity of JC-1 fluorescence during application of ouabain to 89±2% of baseline (P<0.05). These effects of diazoxide were blocked by the mitoK_ATP channel blocker 5-hydroxydecanoate (500 µmol/L). These results indicate that opening of mitoK_ATP channels prevents a mitochondrial Ca²⁺ overload in association with _m depolarization and thereby protects myocardium against ischemic damage.

Key Words: mitochondria • calcium • K_ATP channel • cardioprotection

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