Diabetes mellitus mitigates cardioprotective effects of remifentanil preconditioning in ischemia-reperfused rat heart in association with anti-apoptotic pathways of survival

Diabetes mellitus has been known to mitigate ischemic or pharmacologic preconditioning in ischemia–reperfusion injuries. Remifentanil is a widely used opioid in cardiac anesthesia that possesses a cardioprotective effect against ischemia–reperfusion. We evaluated whether diabetes affected remifentanil preconditioning induced cardioprotection in ischemia–reperfusion rat hearts in view of anti-apoptotic pathways of survival and Ca2+ homeostasis. Streptozotocin-induced, diabetic rats and age-matched wild-type Sprague–Dawley rats were subjected to a left anterior descending coronary artery occlusion for 30 min followed by 1 h of reperfusion. Each diabetic and wild-type rat was randomly assigned to the sham, ischemia–reperfusion only, or remifentanil preconditioning group. Myocardial infarct size, activities of ERK1/2, Bcl2, Bax and cytochrome c, and gene expression influencing Ca2+ homeostasis were assessed. Remifentanil preconditioning significantly reduced myocardial infarct size compared to ischemia–reperfusion only in wild-type rats but not in diabetic rats. Remifentanil preconditioning increased expression of ERK1/2 and anti-apoptotic protein Bcl-2 and decreased expression of pro-apoptotic proteins, Bax and cytochrome c, compared to ischemia–reperfusion only in wild-type rats. In diabetic rat hearts, however, remifentanil preconditioning failed to recover the phosphorylation state of ERK1/2 and to repress apoptotic signaling. In addition, diabetes minimized remifentanil induced modulation of abnormal changes in sarcoplasmic reticulum genes and proteins in ischemia–reperfusion rat hearts. In conclusion, diabetes mitigated remifentanil induced cardioprotection against ischemia–reperfusion, which might be associated with reduced recovery of the activities of proteins involved in anti-apoptotic pathways including ERK1/2 and the abnormal expression of sarcoplasmic reticulum genes as a result of ischemia–reperfusion in rat hearts.