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.
Institut für Pathophysiologie, Zentrum Innere Medizin, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany. rainer.schulz@uni-essen.de
Rainer
R
Schulz
Petra
P
Gres
Gerd
G
Heusch
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