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Inhibition of glycogen synthase kinase enhances isoflurane-induced protection against myocardial infarction during early reperfusion in vivo. Anesth Analg 2006 May;102(5):1348-54

Date

04/25/2006

Pubmed ID

16632807

DOI

10.1213/01.ane.0000202379.61338.37

Abstract

Inhibition of glycogen synthase kinase (GSK)-beta protects against ischemia-reperfusion injury. Brief exposure to isoflurane before and during early reperfusion after coronary artery occlusion also protects against infarction. Whether GSK-beta mediates this action is unknown. We tested the hypothesis that GSK inhibition enhances isoflurane-induced postconditioning. Rabbits (n = 88; 6 to 7 per group) subjected to a 30-min coronary occlusion followed by 3 h reperfusion received saline, isoflurane (0.5 or 1.0 minimum alveolar concentration [MAC]) administered for 3 min before and 2 min after reperfusion, the selective GSK inhibitor SB216763 (SB21; 0.2 or 0.6 mg/kg), or 0.5 MAC isoflurane plus 0.2 mg/kg SB21. Other groups of rabbits pretreated with phosphatidylinositol-3 kinase (PI3K) inhibitor wortmannin (0.6 mg/kg), 70-kDa ribosomal protein s6 kinase (p70s6K) inhibitor rapamycin (0.25 mg/kg), or mitochondrial permeability transition pore (mPTP) opener atractyloside (5 mg/kg) received 0.6 mg/kg SB21 or 0.5 MAC isoflurane plus 0.2 mg/kg SB21. Additional groups received the mPTP inhibitor, cyclosporin A (5 mg/kg), plus 0.2 mg/kg SB21 with or without atractyloside pretreatment. Isoflurane (1.0 but not 0.5 MAC) and SB21 (0.6 but not 0.2 mg/kg) reduced (P < 0.05) infarct size (21% +/- 5%, 44% +/- 7%, 23% +/- 4%, and 46% +/- 2%, respectively, of left ventricular area at risk, mean+/- sd; triphenyltetrazolium staining) as compared with control (42% +/- 6%). Isoflurane (0.5 MAC) plus 0.2 mg/kg SB21 and cyclosporin A plus 0.2 mg/kg SB21 produced similar degrees of protection (24% +/- 4% and 27% +/- 6%, respectively). Atractyloside but not wortmannin or rapamycin abolished protection produced by 0.6 mg/kg SB21 and 0.5 MAC isoflurane plus 0.2 mg/kg SB21. Thus, GSK inhibition enhances isoflurane-induced protection against infarction during early reperfusion via a mPTP-dependent mechanism.

Author List

Pagel PS, Krolikowski JG, Neff DA, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC

Authors

Paul S. Pagel MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Professor in the Anesthesiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Drug Synergism
Glycogen Synthase Kinases
Isoflurane
Male
Myocardial Infarction
Myocardial Reperfusion Injury
Protein Kinase Inhibitors
Rabbits
jenkins-FCD Prod-387 b0ced2662056320369de4e5cd5f21c218c03feb3