Infarct-remodeled myocardium is receptive to protection by isoflurane postconditioning: role of protein kinase B/Akt signaling.
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.
Feng
Jianhua
J
Institute of Anesthesiology, University Hospital Zurich, Switzerland.
Fischer
Gregor
G
Lucchinetti
Eliana
E
Zhu
Min
M
Bestmann
Lukas
L
Jegger
David
D
Arras
Margarete
M
Pasch
Thomas
T
Perriard
Jean-Claude
JC
Schaub
Marcus C
MC
Zaugg
Michael
M
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*
D018685:Anesthetics, Inhalation; D002316:Cardiotonic Agents; D012333:RNA, Messenger; D007530:Isoflurane; D051058:Oncogene Protein v-akt; D051057:Proto-Oncogene Proteins c-akt