Isoflurane Protects against Myocardial Infarction during Early Reperfusion by Activation of Phosphatidylinositol-3-Kinase Signal Transduction: Evidence for Anesthetic-induced Postconditioning in Rabbits

Abstract

Background: Brief episodes of ischemia during early reperfusion after coronary occlusion reduce the extent of myocardial infarction. Phosphatidylinositol-3-kinase (PI3K) signaling has been implicated in this "postconditioning" phenomenon. The authors tested the hypothesis that isoflurane produces cardioprotection during early reperfusion after myocardial ischemia by a PI3K-dependent mechanism.Methods: Pentobarbital-anesthetized rabbits (n ‫؍‬ 80) subjected to a 30-min coronary occlusion followed by 3 h reperfusion were assigned to receive saline (control), three cycles of postconditioning ischemia (10 or 20 s each), isoflurane (0.5 or 1.0 minimum alveolar concentration), or the PI3K inhibitor wortmannin (0.6 mg/kg, intravenously) or its vehicle dimethyl sulfoxide. Additional groups of rabbits were exposed to combined postconditioning ischemia (10 s) and 0.5 minimum alveolar concentration isoflurane in the presence and absence of wortmannin. Phosphorylation of Akt, a downstream target of PI3K, was assessed by Western blotting.Results: Postconditioning ischemia for 20 s, but not 10 s, reduced infarct size (P < 0.05) (triphenyltetrazolium staining; 20 ؎ 3% and 34 ؎ 3% of the left ventricular area at risk, respectively) as compared with control (41 ؎ 2%). Exposure to 1.0, but not 0.5, minimum alveolar concentration isoflurane decreased infarct size (21 ؎ 2% and 43 ؎ 3%, respectively). Wortmannin abolished the protective effects of postconditioning (20 s) and 1.0 minimum alveolar concentration isoflurane. Combined postconditioning (10 s) and 0.5 minimum alveolar concentration isoflurane markedly reduced infarct size (17 ؎ 5%). This action was also abolished by wortmannin (44 ؎ 2%). Isoflurane (1.0 minimum alveolar concentration) increased Akt phosphorylation after ischemia (32 ؎ 6%), and this action was blocked by wortmannin.

Role of Erk1/2, p70s6K, and eNOS in isofluraneinduced cardioprotection during early reperfusionin vivo

“…We have previously demonstrated that 1.0 MAC isoflurane administered using this technique produces reductions in myocardial infarct size that are similar to those observed during preconditioning with this volatile anesthetic. 1,5 We have also previously shown that the sample size used in the current investigation is adequate to provide statistically significant differences in infarct size between interventions. 1,5 PD 098059 and rapamycin were dissolved in dimethylsulfoxide and administered intravenously ten minutes before reperfusion.…”

“…[2][3][4][5] This "anesthetic-induced postconditioning" produces reductions in myocardial infarct size that are very similar to those observed during preconditioning with these agents 1,5 and may be clinically relevant because the precise timing of coronary artery occlusion is unknown in the vast majority of patients with acute myocardial infarction. We recently demonstrated that isoflurane-induced postconditioning is mediated by activation of the prosurvival phosphatidylinositol-3-kinase (PI3K)-Akt signaling cascade.…”

“…5,17 Briefly, a tracheostomy was performed through a midline incision, and each rabbit was ventilated with positive pressure using an air-oxygen mixture (fractional inspired oxygen concentration = 0.33). Heparin-filled catheters were inserted into the right carotid artery and the left jugular vein for measurement of mean arterial blood pressure and fluid or drug administration, respectively.…”

“…We recently demonstrated that isoflurane-induced postconditioning is mediated by activation of the prosurvival phosphatidylinositol-3-kinase (PI3K)-Akt signaling cascade. 5,6 This pathway has also been implicated in myocardial protection during early reperfusion produced by brief, repetitive ischemic stimuli 5,[7][8][9] (termed "ischemic postconditioning") 8 and other drugs including bradykinin, 10 adenosine receptor agonists, 10 statins, 11 and opioids. 12 The extracellular signal-related kinases (Erk1/2) are mitogen-activated protein kinases that play important roles in cell differentiation, proliferation, and survival.…”

The protective effects of emulsified isoflurane on myocardial ischemia and reperfusion injury in rats

“…It has been indicated that the PI3K/Akt signalling pathway has been involved in isoflurane-induced preconditioning 34 and postconditioning. 35 Additionally, apart from rendering the myocardium resistant to I/R injury, preconditioning also potentiates angiogenesis. 36 Hypoxia inducible factor 1 (HIF-1) serves to promote vascular endothelial growth factor (VEGF) gene expression; thus, it ultimately triggers the cascade of angiogenesis.…”