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.