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CARDIOVASCULAR

Calcium-Activated Potassium Channel Triggers Cardioprotection of Ischemic Preconditioning

Department of Physiology, University of Hong Kong, Hong Kong SAR, China (C.-M.C., M.C., T.-M.W.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (Q.X., Q.G.)

We tested the hypothesis that the high-conductance calciumactivated potassium (K_Ca) channel is involved in the cardioprotection of preconditioning with ischemic insults. In the isolated perfused rat heart subjected to ischemia/reperfusion, effects of ischemic preconditioning (IPC) on infarct size and lactate dehydrogenase (LDH) release were abolished by 1 µM paxilline (Pax), an inhibitor of the K_Ca channel, administered 30 min before, but not during, ischemia. In isolated ventricular myocytes subjected to metabolic inhibition and anoxia (MI/A), preconditioning with MI/A increased their viability, and the effect was abolished by administering Pax before MI/A. Like IPC, 10 µM NS1619 (1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-trifluoromethyl-2Hbenzimidazol-2-one; NS), an opener of K_Ca channels, reduced infarct size and LDH release, effects attenuated by Pax. The harmful and protective effects of blockade and activation of the K_Ca channel were accompanied by impaired and improved left ventricular contractile functions, respectively. In addition, the effect of NS was not altered by 100 µM 5-hydroxydecanoate, an inhibitor of the K_ATP channel. Neither was the effect of 100 µM diazoxide, an activator of the K_ATP channel, altered by Pax. Furthermore, opening of the mitochondrial permeability transition pore (mPTP) with 20 µM atractyloside abolished the beneficial effects of IPC or NS in the isolated rat heart and myocyte. Inhibition of mPTP opening with 0.2 µM cyclosporin A decreased the infarct size and LDH release and improved the contractile function, effects not attenuated by Pax. In conclusion, the study provides evidence that the K_Ca channel triggers cardioprotection of IPC, which involves mPTP.

Address correspondence to: Prof. Tak Ming Wong, Department of Physiology, 4/F, Laboratory Block, Faculty of Medicine Building, The University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China. E-mail: wongtakm{at}hkucc.hku.hk

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