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Remifentanil preconditioning (RPC) exerts protection in normal hearts, but has not been investigated in heart failure. The aim of the present study was to evaluate the effect of RPC in a chronic failing rat heart model and the mechanisms involving mitogen-activated protein kinases (MAPK) and Bcl-2 protein family. The doxorubicin induced failing rat hearts were subjected to 30 min ischemia / 120 min reperfusion (IR) with or without RPC by using Langendorff apparatus. RPC was induced by three cycles of 5 min remifentanil / 5 min drug-free perfusion before IR, with three different concentrations: 25, 50 and 100 μg/l. An extracellular signal regulated kinases (ERK) inhibitor PD98059, p38MAPK inhibitor SB203580, c-Jun NH2-terminal kinases (JNK) inhibitor SP600125 were perfused at 10 min before RPC. Infarct size, cardiac function and protein kinase activity were determined. RPC significantly reduced infarct size and the rise in lactate dehydrogenase (LDH) level caused by IR injury in failing heart. The JNK inhibitor SP600125 and ERK inhibitor PD98059 abolished the RPC mediated reduction effect on the infarct size and LDH activity after reperfusion. In addition, RPC increased the phosphorylation of JNK, ERK1/2 and the downstream GSK-3β, as well as the Bcl-2/Bax ratio, while, these changes were completely reversed by SP600125 and PD98059. And of note, SB203580 had no effect. In conclusion, our results suggested that the activation of JNK and ERK pathways, by leading to inhibition of GSK-3β and regulating Bcl-2 protein family, is a major mechanism that RPC confers cardioprotection in failing rat heart.

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.

Evidences from previous studies confirmed that intrathecal morphine preconditioning (ITMP) reduces the cardiac injury of ischemia-reperfusion (IR) via the central nervous system. However, the molecular mechanism is not fully understood. The breath of central nerve growth factor (NGF) during nociceptive transmission has been well documented, and little is known about the significance of NGF in myocardial injury of IR and intrathecal morphine-induced cardioprotection. To address these questions, we over-expressed or silenced NGF in the spinal cord by using intrathecal injection of lentivirus-NGF or shRNA respectively, accompanied by ITMP in the IR rat model. The levels of NGF and tropomyosin receptor kinase A (Trka) as well as transient receptor potential vanilloid 1 (TRPV1) in the T2-6 spinal cord were evaluated. The results showed that cardiac damage indicators induced by IR, including the increased infarct size, arrhythmia score and serum troponin levels were attenuated after ITMP. However, overexpression of spinal NGF significantly reversed these decreases, as well as reduced the expression and phosphorylation of TRPV1 that was elicited by ITMP. Conversely, silencing of spinal NGF enhanced ITMP-induced cardioprotective effects. Phosphorylation and expression of TRPV1 in the spinal cord were significantly decreased after regional NGF silencing. These findings suggested that the cardioprotective effects of ITMP may implement by mediating through spinal NGF expression, wherein it involves the nociceptor TRPV1. NGF may act as a potential therapeutic target in the development of new agents for the treatment of cardiac injury induced by IR.