title: Remifentanil preconditioning protects rat cardiomyocytes against hypoxia-reoxygenation injury via δ-opioid receptor mediated activation of PI3K/Akt and ERK pathways.
abstract: Remifentanil preconditioning has been demonstrated to reduce myocardial ischemia reperfusion injury in rat hearts, while the mechanisms are not fully understood. This study investigated the protective effects of remifentanil against hypoxia-reoxygenation injury in adult rat cardiomyocytes and the mechanisms involving opioid receptors and downstream phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinase (ERK) signaling pathways. Adult rat cardiomyocytes were pretreated with remifentanil at different concentrations and then subjected to 90min hypoxia followed by 120min reoxygenation. The δ- (naltrindole), κ- (nor-binaltorphimine), or μ-opioid receptor antagonist (CTOP), as well as ERK inhibitor (PD98059) or PI3K inhibitor (wortmannin) was added before remifentanil preconditioning, respectively. Remifentanil showed significant protective effects against hypoxia-reoxygenation injury by increasing cell survival (Trypan blue staining) while reducing LDH activity and cell apoptosis (Hoechst staining). These effects were markedly reversed by naltrindole and were partially blocked by nor-binaltorphimine. Pretreatment of either PD98059 or wortmannin also abolished the protective effects of remifentanil. Following remifentanil preconditioning, the phosphorylation level of Akt reached peak at 10min of reoxygenation. ERK phosphorylation, however, was subsequently enhanced at 120min of reoxygenation. The phosphorylation levels of Akt and ERK were both blocked by naltrindole, but not nor-binaltorphimine or CTOP. Wortmannin inhibited the phosphorylation of both Akt and ERK, whereas PD98059 suppressed the phosphorylation of ERK only. In conclusion, our results suggested that remifentanil protected adult rat cardiomyocytes from hypoxia-reoxygenation injury and its effects appears to be dependent on the δ-opioid receptor mediated activation of PI3K/Akt and subsequent ERK signaling pathways.
authors: Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
authors: Meng-Yun
authors: MY
authors: Dou
authors: Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors: Hao
authors: H
authors: Wu
authors: Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Anesthesiology, Anhui Women and Child Health Care Hospital, Hefei, China.
authors: Hai-Juan
authors: HJ
authors: Zhu
authors: Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
authors: Shi-Yun
authors: SY
authors: Jin
authors: Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China. Electronic address: zhangye_hassan@aliyun.com.
authors: Ye
authors: Y
authors: Zhang
authors: Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China. Electronic address: hsf77@163.com.
authors: Shu-Fang
authors: SF
authors: He
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D019157:Ischemic Preconditioning, Myocardial; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D000077208:Remifentanil
chemical_list: D002316:Cardiotonic Agents; D010880:Piperidines; D017465:Receptors, Opioid, delta; D007770:L-Lactate Dehydrogenase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077208:Remifentanil; D010100:Oxygen
keywords: Cardiomyocytes; Extracellular-signal regulated protein kinase; Hypoxia-reoxygenation injury; Opioid receptor; Phosphatidylinositol-3-kinase/protein kinase B; Remifentanil preconditioning