Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction: evidence for anesthetic-induced postconditioning in rabbits.
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.


CONCLUSIONS
Isoflurane acts during early reperfusion after prolonged ischemia to salvage myocardium from infarction and reduces the threshold of ischemic postconditioning by activating PI3K.
Chiari
Pascal C
PC
Departments of Anesthesiology, (Division of Cardiovascular Diseases), the Medical College of Wisconsin, the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, USA.
Bienengraeber
Martin W
MW
Pagel
Paul S
PS
Krolikowski
John G
JG
Kersten
Judy R
JR
Warltier
David C
DC
D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007530:Isoflurane / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
D018685:Anesthetics, Inhalation; D007530:Isoflurane; D019869:Phosphatidylinositol 3-Kinases