Pagel Paul S, Krolikowski John G, Neff Donald A, Weihrauch Dorothee, Bienengraeber Martin, Kersten Judy R, Warltier David C
Department of Anesthesiology, Medical College of Wisconsin and the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin 53226, USA.
Anesth Analg. 2006 May;102(5):1348-54. doi: 10.1213/01.ane.0000202379.61338.37.
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.
糖原合酶激酶（GSK）-β的抑制可预防缺血再灌注损伤。在冠状动脉闭塞后的早期再灌注之前及期间短暂暴露于异氟烷也可预防梗死。GSK-β是否介导此作用尚不清楚。我们检验了GSK抑制增强异氟烷诱导的后适应这一假说。对88只兔子（每组6至7只）进行30分钟冠状动脉闭塞，随后3小时再灌注，分别给予生理盐水、在再灌注前3分钟及再灌注后2分钟给予异氟烷（0.5或1.0最低肺泡浓度[MAC]）、选择性GSK抑制剂SB216763（SB21；0.2或0.6毫克/千克），或0.5 MAC异氟烷加0.2毫克/千克SB21。其他几组预先用磷脂酰肌醇-3激酶（PI3K）抑制剂渥曼青霉素（0.6毫克/千克）、70-kDa核糖体蛋白s6激酶（p70s6K）抑制剂雷帕霉素（0.25毫克/千克）或线粒体通透性转换孔（mPTP）开放剂阿托伐醌（5毫克/千克）处理的兔子，给予0.6毫克/千克SB21或0.5 MAC异氟烷加0.2毫克/千克SB21。另外几组给予mPTP抑制剂环孢素A（5毫克/千克）加0.2毫克/千克SB21，有或没有阿托伐醌预处理。与对照组（42%±6%）相比，异氟烷（1.0 MAC而非0.5 MAC）和SB21（0.6毫克/千克而非0.2毫克/千克）可减小（P<0.05）梗死面积（分别为左心室危险区域面积的21%±5%、44%±7%、23%±4%和46%±2%，平均值±标准差；三苯基四氮唑染色）。异氟烷（0.5 MAC）加0.2毫克/千克SB21和环孢素A加0.2毫克/千克SB21产生相似程度的保护作用（分别为24%±4%和27%±6%）。阿托伐醌而非渥曼青霉素或雷帕霉素消除了0.6毫克/千克SB21和0.5 MAC异氟烷加0.2毫克/千克SB21产生的保护作用。因此，GSK抑制通过mPTP依赖机制增强异氟烷诱导的早期再灌注期间对梗死的保护作用。
