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Distinct myoprotective roles of cardiac sarcolemmal and mitochondrial K_ATP channels during metabolic inhibition and recovery

PETER E. LIGHT¹, HUSSEIN D. KANJI^*, JOCELYN E. MANNING FOX and ROBERT J. FRENCH^*

Department of Pharmacology, University of Alberta, Edmonton, Alberta; and
^* Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada

¹Correspondence: 9–58 Medical Sciences, Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada. T6G 2H7. E-mail: peter.light{at}ualberta.ca

The protective roles of sarcolemmal (sarc) and mitochondrial (mito) K_ATP channels are unclear despite their apparent importance to ischemic preconditioning. We examined these roles by monitoring intracellular calcium ([Ca]_int), using fura-2 and fluo-3, in enzymatically isolated rat right ventricular myocytes. Myocyte mortality, estimated using a trypan blue assay, changed approximately in parallel with changes in [Ca]_int. Chemically induced hypoxia (CIH), induced by application of cyanide and 2-deoxy-glucose, caused a steady rise in [Ca]_int. Calcium increased more rapidly on ‘reoxygenation’ by return to control solutions. The protein kinase C (PKC) activator PMA abolished both phases of calcium increase. The mitoK_ATP channel-selective blocker 5-hydroxydecanoate partially prevented the PMA-induced protection during CIH, but not during reoxygenation. In contrast, HMR 1098, a sarcK_ATP channel-selective blocker, abolished protection only during the reoxygenation. Adenosine (A₁) receptor activation prevented or reduced increases in [Ca]_int and improved cell viability via a PKC and mito/sarcK_ATP channel-dependent mechanism. PKC-dependent protection against cytoplasmic calcium increases was also observed in a human cell line (tsA201) transiently expressing sarcK_ATP channels. Protection was abolished only during the reoxygenation phase by the amino acid substitution (T180A) in the pore-forming Kir6.2 subunit, a mutation previously shown to prevent PKC-dependent modulation. Our data suggest that sarc and mitoK_ATP channel populations play distinct protective roles, triggered by PKC and/or adenosine, during chemically induced hypoxia/reoxygenation.—Light, P. E., Kanji, H. D., Manning Fox, J. E., French, R. J. Distinct myoprotective roles of cardiac sarcolemmal and mitochondrial K_ATP channels during metabolic inhibition and recovery.

Key Words: ischemic preconditioning • protein kinase C • adenosine

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