Oral nicorandil recaptures the waned protection from preconditioning in vivo

I Protection from preconditioning (PC) wanes and is eventually lost when multiple bouts of short ischemia or a prolonged reperfusion interval precedes. the following sustained ischemia. The activation of mitochondrial K-ATP channels plays a pivotal role in the intracellular signaling of PC. We tested whether the K-ATP channel opener nicorandil (nic) preserves the given protection from PC in conditions where this benefit decays and is lost. 2 Eight groups of rabbits were divided into two equal series of experiments, one without nic (placebo) and one with nic treatment. Nic was given orally for 5 consecutive days in a dose of 5 mg kg(-1) d(-1). In a second step, four additional groups were treated with nic plus the K-ATP channel blocker 5HD and 1 additional control group with nitroglycerin only. All the animals were anesthetized and then subjected to 30 min of myocardial ischemia and 2 h of reperfusion with one of the following interventions before the sustained ischemia: Control groups to no intervention; 3PC groups to three cycles of 5-min ischemia-10-min reperfusion; 8PC groups to eight cycles of 5-min ischemia - 10-min reperfusion; and 3PC90 groups to the same interventions as the 3PC groups but with a prolonged (90 min) intervening reperfusion interval before the sustained ischemia. The infarcted and the risk areas were expressed in percent. 3 There was no significant change in infarct size between the placebo, the nic and the 5HD-nic in the control groups (41.5+/-4.7, 43.9+/-7.1 and 48.7+/-6.4%) and 3PC groups (10.3+/-3.4, 12.2+/-3.9 and 12.6+/-4.5%). However, there was a significant decrease after nic treatment in groups 8PC (47.7+/-8.8% vs 13.0+/-2.6%, P<0.01) and 3PC90 (37.3+/-6.0% vs 14.2+/-2.4%, P<0.01), which was abrogated (38.2+/-4.7 and 42.7+/-4.4%, respectively, for 8PC and 3PC90 groups). Nitroglycerin had no effect on infarct size (39.1+/-3.1%, P = NS vs other controls). 4 Oral treatment with nic recaptures the waned protection of PC, both after repetitive bouts of short ischemia or after a prolonged reperfusion interval, preserving the initially obtained benefit. Nic by itself is insufficient to initiate PC in vivo. British Journal of Pharmacology (2003) 138, 1101-1106. doi:10.1038/sj.bjp.705149.