Brief periods of ischemia that precede sustained ischemia can markedly reduce infarct size (IS). a phenomenon that is known its ischemic preconditioning (IP). Several investigators have shown that elevation of the intracellular Ca2+ level (\Ca2+\(i)) during the antecedent brief periods of ischemia triggers the cardioprotective mechanism of IP. Since opening of Ca2+ 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 channel opener, reduced IS (IS in NS1619 group and followed by 6 h of reperfusion. First. we showed that the treatment with NS1619, a K-Ca control group, 19.8 +/- 5.5% vs. 45.4 +/- 3.5% of the area at risk, P < 0.05). Next, four Cycles coronary occulsion 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,,,, 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 MAP wits 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. (C) 2004 Elsevier Ltd. All rights reserved.