Mitochondrial Ca2+-activated K+ channels more efficiently reduce mitochondrial Ca2+ overload in rat ventricular myocytes

초록

We investigated the role of the mitochondrial ATP-sensitive K+ (KATP) channel, the mitochondrial big-conductance Ca 2+-activated K+ (BKCa) channel, and the mitochondrial permeability transition pore (MPTP) in the ouabain-induced increase of mitochondrial Ca2+ in native rat ventricular myocytes by loading cells with rhod 2-AM. To overload mitochondrial Ca2+, we pretreated cells with ouabain before applying mitochondrial KATP or BKCa channel and/or MPTP opener. Ouabain (1 mM) increased the rhod 2-sensitive fluorescence intensity (160 ± 5.0% of control), which was dramatically decreased to the control level on application of diazoxide and NS-1619 in a dose-dependent manner (half-inhibition concentrations of 78.3 and 7.78 μM for diazoxide and NS-1619, respectively). This effect was reversed by selective inhibition of the mitochondrial KATP channel by 5-hydroxydecanoate, the mitochondrial BKCa channel by paxilline, and the MPTP by cyclosporin A. Although diazoxide did not efficiently reduce mitochondrial Ca2+ during prolonged exposure to ouabain, NS-1619 reduced mitochondrial Ca2+. These results suggest that although mitochondrial BKCa and KATP channels contribute to reduction of ouabain-induced mitochondrial Ca2+ overload, activation of the mitochondrial BKCa channel more efficiently reduces ouabain-induced mitochondrial Ca2+ overload in our experimental model. Copyright © 2007 the American Physiological Society.

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