Published online before print October 18, 2001, doi: 10.1161/hh2201.100341
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Submitted on July 27, 2001
Revised on September 28, 2001
Accepted on October 8, 2001
Opening of Mitochondrial KATP Channels Attenuates the Ouabain-Induced Calcium Overload in Mitochondria
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.
* To whom correspondence should be addressed. E-mail: tsato{at}med.m.chiba-u.ac.jp.
We tested whether opening of mitochondrial ATP-sensitive K+ (mitoKATP) 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 mitoKATP 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 mitoKATP channel blocker 5-hydroxydecanoate (500 µmol/L). These results indicate that opening of mitoKATP channels prevents a mitochondrial Ca2+ overload in association with m depolarization and thereby protects myocardium against ischemic damage.
Key words: mitochondria • calcium • KATP channel
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