Calcium-activated potassium channel triggers cardioprotection of ischemic preconditioning

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