七氟烷后处理与心肌β肾上腺素能信号转导通路的交互作用

Sevoflurane is a commonly used volatile anesthetic. It has been proved that, sevoflurane postconditioning could protect animal hearts against ischemia-reperfusion injury. However, the cardio-protective effect of sevoflurane in cardiac surgical patients is not that obvious. β-adrenergic receptors play an important role in myocardial ischemia reperfusion injury. Evidence suggests that, β-blockers may account for the failed cardio-protection induced by sevoflurane in clinical settings. The current study is designed to investigate, in isolated myocytes, isolated myocardial strips, isolated hearts, and in vivo hearts, the interaction between sevoflurane postconditioning and β-adrenergic signaling pathways: 1) the role of β-adrenergic receptors in cardio-proteciton induced by sevoflurane postconditioning 2) the effects of sevoflurane postconditioning on β-adrenergic receptors and downstream targets 3) the effects of short-and long-term β-blockade on sevoflurane postconditioning-induced cardio-protection 4) the combined effects of sevoflurane postconditioning and β-blockers on cardiac remodeling after myocardial infarction. The study will be focused upon β-adrenergic receptor subtypes, their downstream targets.

七氟烷是临床常用的挥发性麻醉药。七氟烷缺血后处理对缺血-再灌注心肌具有保护作用，但七氟烷麻醉对心脏手术患者的心肌保护作用却不及实验研究显著。β受体与心肌缺血再灌注损伤密切相关。循证证据提示，同样具有心肌保护作用的β肾上腺素能受体（β受体）阻断剂可能是导致临床上七氟烷心肌保护效果大打折扣的重要原因。为研究七氟烷缺血后处理与缺血-再灌注心肌β受体系统的交互作用，本课题拟从离体细胞、离体心肌条、离体心脏、在体心脏4个水平，首次研究1）β受体是否参与介导七氟烷缺血后处理的心肌保护机制2）七氟烷缺血后处理对β受体及其下游信号转导通路的影响3）β受体不同（急性、慢性）阻断状态对七氟烷缺血后处理心肌保护效果的影响4）联合β受体阻断剂和七氟烷后缺血处理对心肌梗死后重构的影响。研究将重点关注不同亚型β受体及其下游关键靶点。

过去3年，课题组按计划围绕“七氟烷缺血后处理和β肾上腺素能受体系统在大鼠心肌缺血-再灌注损伤模型中的互动”进行了研究，所取得的研究成果如下：一、通过对评估心脏手术患者实施远隔缺血预处理（RIPC）心肌保护效果影响因素的随机对照临床研究进行荟萃分析发现，围术期使用β受体阻断剂或挥发性麻醉药将消弱RIPC的心肌保护效果。二、但课题组在随后的大样本的临床观察中却发现，体外循环心脏手术阻断主动脉前给予β受体阻断剂阿替洛尔却可显著提高主动脉阻断钳开放后的自动复跳率。三、通过离体动物实验课题组发现，Esmolol停搏液（缺血前干预）联合七氟烷后处理（缺血后干预）可增加对后者对缺血心肌的保护效果。四、七氟烷后处理联合β受体阻断剂使用可减弱七氟烷后处理的心肌保护作用。五、此外，我们还针对七氟烷缺血后处理抗心肌缺血-再灌注损伤的机制进行了拓展性探索，包括心肌细胞自噬、年龄相关、自主神经活性（迷走神经刺激）等。