Activation of ATP‐dependent potassium channels is a trigger but not a mediator of ischaemic preconditioning in pigs

Activation of ATP‐dependent potassium channels (K ATP ) is involved in ischaemic preconditioning (IP). In isolated buffer‐perfused rabbit hearts, activation of mitochondrial K ATP – through a generation of free radicals – acted as a trigger rather than a mediator of IP; the isolated buffer‐perfused heart preparation, however, favours free radical generation. In contrast, in vivo studies in rats and dogs suggested that activation of K ATP acts as a mediator of IP's protection. A detailed analysis on the role of K ATP in IP's protection in vivo by varying the time and dose of K ATP blocker administration is, however, lacking. In 54 enflurane‐anaesthetized pigs, the left anterior descending coronary artery was perfused by an extracorporeal circuit. Infarct size (IS, %, TTC) following 90 min sustained low‐flow ischaemia and 120 min reperfusion was 26.6±3.5 (s.e.m.) ( n =8). IP with one cycle of 10 min ischaemia and 15 min reperfusion reduced IS to 6.5±2.1 ( n =7, P <0.05). Blockade of K ATP with glibenclamide (0.5 mg kg −1 i.v., 50 μ g min −1 continuous infusion) starting 10 min before or immediately following the preconditioning ischaemia abolished IS reduction by IP (20.7±2.7, n =7 and 21.9±6.6, n =6, respectively) while having no effect on IS per se (22.2±5.2, n =7), supporting a trigger role of K ATP in IP. In contrast, starting glibenclamide following the preconditioning ischaemia 10 min prior to the sustained ischaemia did not prevent IS reduction by IP (3.7±2.3, n =6), even when its bolus dose was increased to 1.5 mg kg −1 (26.6±3.8 with IP vs 37.5±2.9 without IP; n =7 and 6 respectively, P <0.05), thereby refuting a mediator role of K ATP in IP. In conclusion, activation of K ATP in the immediate reperfusion following the preconditioning ischaemia is pivotal for triggering IP.British Journal of Pharmacology (2003) 139 , 65–72. doi: 10.1038/sj.bjp.0705225