Isoflurane mimics ischemic preconditioning via activation of K(ATP) channels: reduction of myocardial infarct size with an acute memory phase

Abstract

Background: The authors tested the hypothesis that isoflurane directly preconditions myocardium against infarction via activation of K(ATP) channels and that the protection afforded by isoflurane is associated with an acute memory phase similar to that of ischemic preconditioning.

Methods: Barbiturate-anesthetized dogs (n = 71) were instrumented for measurement of systemic hemodynamics. Myocardial infarct size was assessed by triphenyltetrazolium chloride staining. All dogs were subjected to a single prolonged (60 min) left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Ischemic preconditioning was produced by four 5-min LAD occlusions interspersed with 5-min periods of reperfusion before the prolonged LAD occlusion and reperfusion. The actions of isoflurane to decrease infarct size were examined in dogs receiving 1 minimum alveolar concentration (MAC) isoflurane that was discontinued 5 min before prolonged LAD occlusion. The interaction between isoflurane and ischemic preconditioning on infarct size was evaluated in dogs receiving isoflurane before and during preconditioning LAD occlusions and reperfusions. To test whether the cardioprotection produced by isoflurane can mimic the acute memory of ischemic preconditioning, isoflurane was discontinued 30 min before prolonged LAD occlusion and reperfusion. The mechanism of isoflurane-induced cardioprotection was evaluated in two final groups of dogs pretreated with glyburide in the presence or absence of isoflurane.

Results: Myocardial infarct size was 25.3 +/- 2.9% of the area at risk during control conditions. Isoflurane and ischemic preconditioning produced significant (P < 0.05) and equivalent reductions in infarct size (ischemic preconditioning alone, 9.6 +/- 2.0; isoflurane alone, 11.8 +/- 2.7; isoflurane and ischemic preconditioning, 5.1 +/- 1.9%). Isoflurane-induced reduction of infarct size also persisted 30 min after discontinuation of the anesthetic (13.9 +/- 1.5%), independent of hemodynamic effects during LAD occlusion. Glyburide alone had no effect on infarct size (28.3 +/- 3.9%), but it abolished the protective effects of isoflurane (27.1 +/- 4.6%).

Conclusions: Isoflurane directly preconditions myocardium against infarction via activation of K(ATP) channels in the absence of hemodynamic effects and exhibits acute memory of preconditioning in vivo.