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.