Abstract
We tested the hypothesis that the high-conductance calciumactivated potassium (KCa) 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 KCa 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 KCa channels, reduced infarct size and LDH release, effects attenuated by Pax. The harmful and protective effects of blockade and activation of the KCa 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 KATP channel. Neither was the effect of 100 μM diazoxide, an activator of the KATP 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 KCa channel triggers cardioprotection of IPC, which involves mPTP.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|