ERK信号通路在吗啡或舒芬太尼抑制心肌缺血再灌注诱发大鼠心律失常中的作用：与Cx43表达的关系

Role of ERK signaling pathway in morphine- or sufentanil-induced inhibition of arrhythmia induced by myocardial ischemia-reperfusion in rats： the relationship with Cx43 expression

目的评价细胞外信号调节激酶（ERK）信号通路在吗啡或舒芬太尼抑制大鼠心肌缺血再灌注诱发大鼠心律失常中的作用及其与Cx43表达的关系。方法SPF级健康成年雄性SD大鼠48只，体重200～300 g。采用随机数字表法分为6组（n＝8）：假手术组（S组）、心肌缺血再灌注组（I/R组）、吗啡组（M组）、舒芬太尼组（Suf组）、吗啡＋ERK抑制剂PD98059组（MP组）和舒芬太尼＋PD98059组（SP组）。采用结扎左冠状动脉前降支30 min恢复灌注的方法制备大鼠心肌缺血再灌注损伤模型。M组和Suf组缺血前即刻分别股静脉输注吗啡0.3 mg/kg或舒芬太尼3 μg/kg，输注5 min，停止5 min，重复3次。MP组和SP组缺血前10 min静脉注射PD98059 10mg/kg。于缺血30 min和再灌注30 min内记录室性心律失常发生情况并评分（AS）。于再灌注120 min时处死大鼠取心肌，采用Western blot法检测心肌总Cx43（t-Cx43）、磷酸化Cx43（p-Cx43）及磷酸化ERK（p-ERK）的表达。结果与S组比较，其余组AS升高，心肌p-Cx43下调，I/R组、SP组和MP组心肌t-Cx43和p-ERK的表达下调（P〈0.05）；与I/R组比较，M组和Suf组AS降低，心肌t-Cx43、p-Cx43和p-ERK的表达上调（P〈0.05）；与M组和Suf组比较，SP组和MP组AS升高，心肌t-Cx43和p-Cx43的表达下调（P〈0.05）。结论吗啡或舒芬太尼抑制大鼠心肌缺血再灌注损伤诱发大鼠心律失常的机制与其激活ERK信号通路后上调心肌Cx43表达有关。

Objective To evaluate the role of extracellular signal-regulated kinase （ERK） signaling pathway in morphine- or sufentanil-induced inhibition of arrhythmia induced by myocardial ischemia-reperfusion （I/R） in rats and the relationship with connexin43 （Cx43）. Methods Forty-eight healthy SPF adult male Sprague-Dawley rats, weighing 200-300 g, were randomly divided into 6 groups （n = 8 each） using a random number table： sham operation group （group S） ; I/R group; morphine group （group M） ; sufentanil group （ group Suf） ; morphine ＋ ERK inhibitor PD98059 group （ group MP） ; sufentanil ＋ PD98059 group （group SP）. Myocardial ischemia was induced by 30 min occlusion of the left anterior descending branch of the coronary artery, followed by repcrfusion. In M and Suf groups, the animals were subjected to three cycles of 5-minute drug infusion （morphine 0.3 mg/kg and sufentanil 3 txg/kg, respectively） via the femoral vein interspersed with 5-minute drug-free periods starting from the time point immediately before ischemia. PD98059 10 mg/kg was injected intravenously at 10 min before ischemia in MP and SP groups. The development of ventricular arrhythmia was recorded within 30 rain of ischemia and 30 min of reperfusion, and the arrhythmia was scored （AS）. The animals were then sacrificed at 120 min of reperfusion, and the myo＇cardial specimens were obtained for determination of the expression of total Cx43 （t-Cx43） , phosphorylated Cx43 （p-Cx43）, and phosphorylated ERK （p-ERK） by Western blot. Results Compared with group S, the AS was significantly increased, and the expression of p-Cx43 was significantly down-regulated in the other groups, and the expression of t-Cx43 and p-ERK was significantly down-regulated in I/R, SP and MP groups （P〈0.05）. Compared with group I/R, the AS was significantly decreased, and the expression of t-Cx43, p-Cx43 and p-ERK was significantly up-regulated in M and Suf groups （P〈 0.05）. Compared with M and Suf groups, the AS was significantly increased, and the expression of t-Cx43 and p-Cx43 was significantly down-regulated in SP and MP groups （P 〈 0. 05 ）. Couehtsiou The mechanism by which morphine or sufentanil inhibits arrhythmia induced by myocardial I/R is associated with up-regulated expression of myocardial Cx43 after activation of ERK signaling pathway in rats.