Wang Chen, Neff Donald A, Krolikowski John G, Weihrauch Dorothee, Bienengraeber Martin, Warltier David C, Kersten Judy R, Pagel Paul S
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Anesth Analg. 2006 May;102(5):1355-60. doi: 10.1213/01.ane.0000202463.28618.64.
Brief exposure to isoflurane or repetitive, transient ischemia during early reperfusion after prolonged coronary artery occlusion protects against myocardial infarction by inhibiting the mitochondrial permeability transition pore (mPTP). Inhibition of mPTP during delayed ischemic preconditioning occurred concomitant with enhanced expression of the antiapoptotic protein B cell lymphoma-2 (Bcl-2). We tested the hypothesis that Bcl-2 mediates myocardial protection by isoflurane or brief ischemic episodes during reperfusion in rabbits (n = 91) subjected to a 30-min left anterior descending coronary artery occlusion followed by 3 h reperfusion. Rabbits received 0.9% saline, isoflurane (0.5 or 1.0 minimum alveolar concentration, MAC) administered for 3 min before and 2 min after reperfusion, 3 cycles of postconditioning ischemia (10 or 20 s each) during early reperfusion, 0.5 MAC isoflurane plus 3 cycles of postconditioning ischemia (10 s), or the direct mPTP inhibitor cyclosporin A (CsA, 10 mg/kg) in the presence or absence of the selective Bcl-2 inhibitor HA14-1 (2 mg/kg, i.p.). Isoflurane (1.0, but not 0.5, MAC) and postconditioning ischemia (20 s but not 10 s) significantly (P < 0.05) reduced infarct size (mean +/- sd, 21% +/- 4%, 43% +/- 7%, 19% +/- 7%, and 39% +/- 11%, respectively, of left ventricular area at risk) as compared with control (44% +/- 4%). Isoflurane (0.5 MAC) plus 10 s postconditioning ischemia and CsA alone also exerted protection. HA14-1 alone did not affect infarct size nor block protection produced by CsA but abolished reductions in infarct size caused by 1.0 MAC isoflurane, 20 s postconditioning ischemia, and 0.5 MAC isoflurane plus 10 s postconditioning ischemia. The results suggest that Bcl-2 mediates isoflurane-induced and ischemic postconditioning by indirectly modulating mPTP activity in vivo.
在长时间冠状动脉闭塞后的早期再灌注期间，短暂暴露于异氟烷或进行重复性短暂缺血，可通过抑制线粒体通透性转换孔（mPTP）来预防心肌梗死。在延迟性缺血预处理期间，mPTP的抑制与抗凋亡蛋白B细胞淋巴瘤-2（Bcl-2）表达增强同时发生。我们对以下假说进行了验证：在经历30分钟左前降支冠状动脉闭塞并随后进行3小时再灌注的家兔（n = 91）中，Bcl-2介导异氟烷或再灌注期间短暂缺血发作对心肌的保护作用。家兔接受0.9%生理盐水、在再灌注前3分钟和后2分钟给予异氟烷（0.5或1.0最低肺泡浓度，MAC）、在早期再灌注期间进行3个周期的后适应缺血（每个周期10或20秒）、0.5 MAC异氟烷加3个周期的后适应缺血（10秒），或在有或无选择性Bcl-2抑制剂HA14-1（2 mg/kg，腹腔注射）的情况下给予直接mPTP抑制剂环孢素A（CsA，10 mg/kg）。与对照组（44%±4%）相比，异氟烷（1.0 MAC，但不是0.5 MAC）和后适应缺血（20秒，但不是10秒）显著（P < 0.05）减小了梗死面积（平均±标准差，分别为左心室危险区域面积的21%±4%、43%±7%、19%±7%和39%±11%）。异氟烷（0.5 MAC）加10秒后适应缺血以及单独使用CsA也发挥了保护作用。单独使用HA14-1既不影响梗死面积，也不阻断CsA产生的保护作用，但消除了1.0 MAC异氟烷、20秒后适应缺血以及0.5 MAC异氟烷加10秒后适应缺血所导致的梗死面积减小。结果表明，Bcl-2通过在体内间接调节mPTP活性来介导异氟烷诱导的和缺血后适应作用。
