title: Infarct-remodeled myocardium is receptive to protection by isoflurane postconditioning: role of protein kinase B/Akt signaling.
abstract: BACKGROUND
  Postinfarct remodeled myocardium exhibits numerous structural and biochemical alterations. So far, it is unknown whether postconditioning elicited by volatile anesthetics can also provide protection in the remodeled myocardium.
  
  
  METHODS
  Myocardial infarct was induced in male Wistar rats by ligation of the left anterior descending coronary artery. Six weeks later, hearts were buffer-perfused and exposed to 40 min of ischemia followed by 90 min of reperfusion. Anesthetic postconditioning was induced by 15 min of 2.1 vol% isoflurane. In some experiments, LY294002 (15 microM), a phosphatidylinositol 3-kinase inhibitor, was coadministered with isoflurane. Masson's trichrome staining, immunohistochemistry, Western blot analysis, and reverse-transcription polymerase chain reaction served to confirm remodeling. In buffer-perfused hearts, functional recovery was recorded, and acute infarct size was measured using 1% triphenyltetrazolium chloride staining and lactate dehydrogenase release during reperfusion. Western blot analysis was used to determine phosphorylation of reperfusion injury salvage kinases including protein kinase B/Akt and its downstream targets after 15 min of reperfusion.
  
  
  RESULTS
  Infarct hearts exhibited typical macroscopic and molecular changes of remodeling. Isoflurane postconditioning improved functional recovery and decreased acute infarct size, as determined by triphenyltetrazolium (35 +/- 5% in unprotected hearts vs. 8 +/- 3% in anesthetic postconditioning; P < 0.05) and lactate dehydrogenase release. This protection was abolished by LY294002, which inhibited phosphorylation of protein kinase B/Akt and its downstream targets glycogen synthase kinase 3beta, endothelial nitric oxide synthase, and p70S6 kinase.
  
  
  CONCLUSIONS
  Infarct-remodeled myocardium is receptive to protection by isoflurane postconditioning via protein kinase B/Akt signaling. This is the first time to demonstrate that anesthetic postconditioning retains its marked protection in diseased myocardium.
authors.affiliation: Institute of Anesthesiology, University Hospital Zurich, Switzerland.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Feng
authors.forename: Gregor
authors.initials: G
authors.lastname: Fischer
authors.forename: Eliana
authors.initials: E
authors.lastname: Lucchinetti
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Lukas
authors.initials: L
authors.lastname: Bestmann
authors.forename: David
authors.initials: D
authors.lastname: Jegger
authors.forename: Margarete
authors.initials: M
authors.lastname: Arras
authors.forename: Thomas
authors.initials: T
authors.lastname: Pasch
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Perriard
authors.forename: Marcus C
authors.initials: MC
authors.lastname: Schaub
authors.forename: Michael
authors.initials: M
authors.lastname: Zaugg
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002316:Cardiotonic Agents; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000648:ultrastructure; D051058:Oncogene Protein v-akt / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D018685:Anesthetics, Inhalation; D002316:Cardiotonic Agents; D012333:RNA, Messenger; D007530:Isoflurane; D051058:Oncogene Protein v-akt; D051057:Proto-Oncogene Proteins c-akt