Stimulation of cardiac β2-adrenergic receptor (β2-AR) or δ-opioid receptor (DOR) exerts a similar degree of cardioprotection against myocardial ischemia in experimental models. We hypothesized that δ-opioid-initiated cardioprotection is mediated by the intrinsic cardiac adrenergic (ICA) cell via enhanced epinephrine release. Using immunohistochemical and in situ hybridization methods, we detected in situ tyrosine hydroxylase (TH) mRNA and TH immunoreactivity that was colocalized with DOR immunoreactivity in ICA cells in human and rat hearts. Western blot analysis detected DOR protein in ICA cells isolated from rat ventricular myocytes. The physiology of DOR expression was examined by determining changes of cytosolic Ca2+ concentration ([Ca2+]i) transients in isolated rat ICA cells using fluorescence spectrophotometry. Exposing the selective δ-opioid agonist D-[Pen2,5]enkephalin (DPDPE) to ICA cells increased [Ca2+]i transients in a concentration-dependent manner. Such an effect was abolished by the Ca 2+ channel blocker nifedipine. HPLC-electrochemical detection demonstrated a 2.4-fold increase in epinephrine release from ICA cells following DPDPE application. The significance of the ICA cell and its epinephrine release in δ-opioid-initiated cardioprotection was demonstrated in the rat myocardial infarction model and ICA cell-ventricular myocyte coculture. DPDPE administered before coronary artery occlusion or simulated ischemia-reperfusion reduced left ventricular infarct size by 54 ± 15% or myocyte death by 26 ± 4%, respectively. β2-AR blockade markedly attenuated δ-opioid-initiated infarct size-limiting effect and abolished δ-opioid-initiated myocyte survival protection in rat ICA cell-myocyte coculture. Furthermore, δ-opioid agonist exerted no myocyte survival protection in the absence of cocultured ICA cells during ischemia-reperfusion. We conclude that δ-opioid-initiated myocardial infarct size reduction is primarily mediated via endogenous epinephrine/β2-AR signaling pathway as a result of ICA cell activation.
|Original language||English (US)|
|Journal||American Journal of Physiology - Heart and Circulatory Physiology|
|Publication status||Published - Jul 2007|
- δ-opioid receptor
- Myocardial ischemia
ASJC Scopus subject areas