Roles of PI3K and ERK signaling pathways in reduction of ischemia-reperfusion injury to isolated hearts by morphine preconditioning in rats with chronic heart failure / 中华麻醉学杂志

ABSTRACT

Objective To evaluate the roles of 1-phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) signaling pathways in reduction of ischemia-reperfusion (I/R) injury to the isolated hearts by morphine preconditioning in the rats with chronic heart failure.Methods Adult male Sprague-Dawley rats,weighing 200-230 g,in which doxorubicin 2.0 mg/kg was injected via the tail vein once a week for 6 weeks to induce chronic heart failure,were studied.At the end of 8th week,42 rats with chronic heart failure were randomly divided into 7 groups (n =6 each) using a random number tablesham operation group (group S),I/R group,morphine preconditioning group (group MP),PD98059 (ERK inhibitor) + morphine preconditioning group (group PD + MP),wortmannin (PI3K inhibitor) + morphine preconditioning group (group WT + MP),PD98059 group (group PD) and wortmannin group (group WT).The hearts were quickly excised and passively perfused in a Langendorff apparatus and subjected to 30 min of occlusion of the left coronary artery followed by 2 h of reperfusion to establish the model of I/R injury.In group S,the hearts were only sutured,but not ligated and were continuously perfused with K-H solution for 195 min.In group I/R,the hearts were perfused with K-H solution for 45 min before ischemia.In group MP,the hearts were perfused with K-H solution for 15 min,with K-H solution containing morphine 1 μmol/L for 5 min and then with K-H solution for 5 min (3 cycles in total) before ischemia.In PD + MP and WT + MP groups,the hearts were perfused with K-H solution containing PD98059 (10 μmol/L) and wortmannin (100 nmol/L),respectively,starting from 10 min before morphine preconditioning until 5 min of ischemia.In PD and WT groups,the hearts were perfused with K-H solution containing PD98059 (10 μmol/L) and wortmannin (100 nmol/L),respectively,starting from 40 min before ischemia until 5 rin of ischemia.At 15 min of equilibration (baseline) and 5 and 10 min of reperfusion,the coronary flow was collected to detect the activity of lactate dehydrogenase (LDH).Infarct size (IS) and area at risk (AAR) were measured at the end of reperfusion and IS/AAR ratio was calculated.Results Compared with group S,LDH activity was significantly increased at 5 and 10 min of reperfusion,IS and IS/AAR ratio were also increased (P ＜ 0.05),and no significant change was found in AAR in group I/R (P ＞ 0.05).Compared with group I/R,LDH activity was significantly decreased at 5 min of reperfusion,IS and IS/AAR ratio were also decreased (P ＜ 0.05),and no significant change was found in AAR in group MP,and no significant change was found in LDH activity,IS,AAR and IS/AAR ratio in WT and PD groups (P ＞ 0.05).Compared with group MP,LDH activity was significantly increased at 5 and 10 min of reperfusion (P ＜ 0.05),and IS and IS/AAR ratio were decreased in group PD + MP,and no significant change was found in LDH activity,IS,AAR and IS/AAR ratio in group WT + MP (P ＞ 0.05).Conclusion Activation of ERK signaling pathway is involved in reduction of I/R injury to isolated hearts by morphine preconditioning in rats with chronic heart failure,however,PI3K signaling pathway has no such effect.