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

Abstract

1. 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. 2. In 54 enflurane-anaesthetized pigs, the left anterior descending coronary artery was perfused by an extracorporeal circuit. Infarct size (IS, %, TTC) following 90min 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 μgmin -1 continuous infusion) starting 10min 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 10min 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. 3. In conclusion, activation of K ATP in the immediate reperfusion following the preconditioning ischaemia is pivotal for triggering IP.