Calcium-activated potassium channel triggers cardioprotection of ischemic preconditioning.

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 microM 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 microM 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 microM 5-hydroxydecanoate, an inhibitor of the K(ATP) channel. Neither was the effect of 100 microM diazoxide, an activator of the K(ATP) channel, altered by Pax. Furthermore, opening of the mitochondrial permeability transition pore (mPTP) with 20 microM atractyloside abolished the beneficial effects of IPC or NS in the isolated rat heart and myocyte. Inhibition of mPTP opening with 0.2 microM 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.