Involvement of ATP-sensitive potassium channels in preconditioning protection

Single or multiple brief periods of ischemia (preconditioning, PC) have been shown to protect the myocardium from infarction during a subsequent more prolonged ischemic insult. To test the hypothesis that opening of ATP-sensitive potassium channels (KATP) is involved in this mechanism, either bimakalim, a KATP channel opener, or glibenclamide, a KATP channel blocker, were administered to mimic or to block preconditioning protection in barbital-anesthetized pigs. PC was elicited by a single period of 10 min left anterior descending coronary artery (LADCA) occlusion followed by 15 min of reperfusion before the LADCA was reoccluded for 60 min. Instead of PC, bimakalim infusion was started 15 min before the 60 min LADCA occlusion (TCO) and stopped with the onset of ischemia. Glibenclamide was administered either for 10 min prior to the PC protocol, before bimakalim infusion, or before TCO. Regional wall function was quantified with ultrasonic crystals aligned to measure wall thickening (% delta WT). At the end of the protocol, infarct size was determined by incubating myocardium with p-nitrobluetetrazolium. In seven preconditioned pigs, infarct size was 9.9 +/- 5.1% of the risk region compared with 65.9 +/- 6.0% in the seven control pigs subjected to 60 min of ischemia only (p < 0.001). In seven pigs treated with bimakalim, infarct size was reduced to 35.3 +/- 6.6 (p < 0.05 vs. controls). Blocking ATP-sensitive potassium channels with glibenclamide prior to PC abolished its protective effect (infarct size, 62.2 +/- 4.5%; p < 0.001 vs. PC alone). Glibenclamide also antagonized the protective effect of bimakalim (infarct size, 55.2 +/- 4.0%), but did not affect infarct size, when solely administered prior to the prolonged ischemic period (62.2 +/- 4.3%). We conclude that in swine myocardium KATP channels are involved in the protective effect of ischemic preconditioning, since glibenclamide completely abolished the protective effect of preconditioning, while bimakalim could--at least in part--mimic it.