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

¹Mitochondrial Signaling Laboratory, Mitochondria Research Group, Department of Physiology and Biophysics, College of Medicine, Biohealth Products Research Center, Cardiovascular and Metabolic Disease Research Center, Inje University, Busan, Korea; and ²Department of Medicine, University of California, San Diego, La Jolla, California

Submitted 24 July 2006 ; accepted in final form 21 February 2007

We investigated the role of the mitochondrial ATP-sensitive K⁺ (K_ATP) channel, the mitochondrial big-conductance Ca²⁺-activated K⁺ (BK_Ca) 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 K_ATP or BK_Ca 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 K_ATP channel by 5-hydroxydecanoate, the mitochondrial BK_Ca 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 BK_Ca and K_ATP channels contribute to reduction of ouabain-induced mitochondrial Ca²⁺ overload, activation of the mitochondrial BK_Ca channel more efficiently reduces ouabain-induced mitochondrial Ca²⁺ overload in our experimental model.

mitochondrial BK_Ca channel; mitochondrial K_ATP channel; mitochondrial permeability transition pore; mitochondrial Ca²⁺; cardioprotection