Activation of ATP-dependent potassium channels is a trigger but not a mediator of ischaemic preconditioning in pigs.
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 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 microg 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. 3. In conclusion, activation of K(ATP) in the immediate reperfusion following the preconditioning ischaemia is pivotal for triggering IP.
Schulz
Rainer
R
Institut für Pathophysiologie, Zentrum Innere Medizin, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany. rainer.schulz@uni-essen.de
Gres
Petra
P
Heusch
Gerd
G
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004594:Electrophysiology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology* / Q000503:physiopathology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D013552:Swine; D013997:Time Factors
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D005905:Glyburide