Opening of Ca 2+-activated K + channels is involved in ischemic preconditioning in canine hearts

Abstract

Brief periods of ischemia that precede sustained ischemia can markedly reduce infarct size (IS), a phenomenon that is known as ischemic preconditioning (IP). Several investigators have shown that elevation of the intracellular Ca 2+ level ([Ca 2+] i) during the antecedent brief periods of ischemia triggers the cardioprotective mechanism of IP. Since opening of Ca 2+ activated K + (K Ca) channels is reported to be cardioprotective, we hypothesized that these channels may be involved in the cardioprotective mechanism of IP. In anesthetized open-chest dogs, myocardial ischemia/reperfusion injury was created by occlusion of the left anterior descending coronary artery (LAD) for 90 min followed by 6 h of reperfusion. First, we showed that the treatment with NS1619, a K Ca channel opener, reduced IS (IS in NS1619 group and control group, 19.8 ± 5.5% vs. 45.4 ± 3.5% of the area at risk, P < 0.05). Next, four cycles coronary occlusion for 5 min and reperfusion (IP) were performed before the 90-min occlusion with or without the infusion of potent K Ca channel inhibitors, iberiotoxin (IbTX) and charybdotoxin (ChTX). IP markedly reduced IS (IS in the IP group was 8.2 ± 1.8%, P < 0.01 vs. control group). Infusion of either of K Ca channel blockers during IP blunted the IS-limiting effect of IP (IS in the IP + IbTX and IP + ChTX groups was 30.7 ± 7.0% and 35.5 ± 3.7%, respectively, P < 0.05, vs. IP group). However, the cardioprotective effect of IP was not blunted by the treatment with ChTX when treated only during reperfusion (14.0 ± 4.1%). Thus, we conclude that the opening of K Ca channel is involved in early trigger phase of the molecular mechanism of IP.