Department of Anesthesiology, The First Affiliated Hospital, China Medical University, Shenyang 110001, China.
Exp Biol Med (Maywood). 2011 Dec;236(12):1427-36. doi: 10.1258/ebm.2011.011165. Epub 2011 Nov 10.
Obesity is a major risk factor for coronary artery disease, but its impact on anesthetic-induced cardioprotective actions is unexplored. We tested whether obesity inhibits anesthetic sevoflurane-induced preconditioning and whether this effect is mediated via the AMP-activated protein kinase (AMPK) signaling pathway. Sprague-Dawley rats were fed a high-fat (HF, 45% kcal as fat) or low-fat (LF, 10% kcal as fat) diet for 12 weeks. HF-fed rats developed metabolic disturbances including visceral obesity, hyperinsulinemia, hyperleptinemia and dyslipidemia. HF- or LF-fed rats subjected to 25 min of myocardial ischemia followed by 120 min of reperfusion were assigned to the following groups: control, sevoflurane preconditioning, sevoflurane plus AMPK inhibitor ara-A or AMPK activator A769662 alone. Infarct size was similar between the two control groups. Sevoflurane preconditioning significantly reduced infarct size in LF-fed rats but failed to induce cardioprotection in HF-fed rats. Phosphorylation of AMPK and endothelial nitric oxide synthase, as well as myocardial nitrite and nitrate, were also increased by sevoflurane preconditioning in LF-fed rats but not in HF-fed rats. Pretreatment with ara-A inhibited phosphorylation of AMPK and reversed sevoflurane preconditioning-induced cardioprotection in LF-fed rats, whereas it had no effects in HF-fed rats. In addition, sevoflurane preconditioning failed to enhance reactive oxygen species (ROS) generation in the myocardium of HF-fed rats compared with LF-fed rats. Direct activation of AMPK with A769662 equally increased phosphorylation of AMPK and reduced infarct size in both LF- and HF-fed rats. The results suggest that diet-induced obesity suppresses sevoflurane preconditioning-induced cardioprotective action, probably due to a diminished effect of sevoflurane preconditioning on activation of the ROS-mediated AMPK signaling pathway.
肥胖是冠状动脉疾病的一个主要危险因素，但它对麻醉诱导的心脏保护作用的影响尚不清楚。我们测试了肥胖是否抑制麻醉七氟醚诱导的预处理，以及这种效应是否通过 AMP 激活的蛋白激酶 (AMPK) 信号通路介导。Sprague-Dawley 大鼠喂食高脂肪 (HF，45%的热量来自脂肪) 或低脂肪 (LF，10%的热量来自脂肪) 饮食 12 周。HF 喂养的大鼠出现代谢紊乱，包括内脏肥胖、高胰岛素血症、高瘦素血症和血脂异常。接受 25 分钟心肌缺血和 120 分钟再灌注的 HF 或 LF 喂养的大鼠被分配到以下组：对照组、七氟醚预处理组、七氟醚加 AMPK 抑制剂 ara-A 或 AMPK 激活剂 A769662 单独给药组。两组对照大鼠的梗死面积相似。七氟醚预处理显著减少 LF 喂养大鼠的梗死面积，但不能诱导 HF 喂养大鼠的心脏保护作用。LF 喂养大鼠的 AMPK 和内皮型一氧化氮合酶的磷酸化以及心肌亚硝酸盐和硝酸盐也因七氟醚预处理而增加，但 HF 喂养大鼠则不然。用 ara-A 预处理抑制 AMPK 的磷酸化，并逆转 LF 喂养大鼠中七氟醚预处理诱导的心脏保护作用，而对 HF 喂养大鼠则无影响。此外，与 LF 喂养大鼠相比，七氟醚预处理未能增加 HF 喂养大鼠心肌中的活性氧 (ROS) 生成。用 A769662 直接激活 AMPK 同样增加了 AMPK 的磷酸化并减少了 LF 和 HF 喂养大鼠的梗死面积。结果表明，饮食诱导的肥胖抑制了七氟醚预处理诱导的心脏保护作用，这可能是由于七氟醚预处理对 ROS 介导的 AMPK 信号通路的激活作用减弱所致。
