Mediating delta -opioid-initiated heart protection via the beta sub(2)-adrenergic receptor: role of the intrinsic cardiac adrenergic cell

• Published in: American Journal of Physiology: Cell Physiology 2007-07, Vol.293 (1), p.H376-H384
• Main Authors: Huang, Ming-He, Wang, Hui-Qun, Roeske, William R, Birnbaum, Yochai, Wu, Yewen, Yang, Ning-Ping, Lin, Yu, Ye, Yumei, McAdoo, David J, Hughes, Michael G, Lick, Scott D, Boor, Paul J, Lui, Charles Y, Uretsky, Barry F
• Format: Article
• Language: English
• ISSN: 0363-6143; 1522-1563

Stimulation of cardiac beta sub(2)-adrenergic receptor ( beta sub(2)-AR) or delta -opioid receptor (DOR) exerts a similar degree of cardioprotection against myocardial ischemia in experimental models. We hypothesized that delta -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 Ca super(2+) concentration ([Ca super(2+)] sub(i)) transients in isolated rat ICA cells using fluorescence spectrophotometry. Exposing the selective delta -opioid agonist D-[Pen super(2,5)]enkephalin (DPDPE) to ICA cells increased [Ca super(2+)] sub(i) transients in a concentration-dependent manner. Such an effect was abolished by the Ca super(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 delta -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 plus or minus 15% or myocyte death by 26 plus or minus 4%, respectively. beta sub(2)-AR blockade markedly attenuated delta -opioid-initiated infarct size-limiting effect and abolished delta -opioid-initiated myocyte survival protection in rat ICA cell-myocyte coculture. Furthermore, delta -opioid agonist exerted no myocyte survival protection in the absence of cocultured ICA cells during ischemia-reperfusion. We conclude that delta -opioid-initiated myocardial infarct size reduction is primarily mediated via endogenous epinephrine/ beta sub(2)-AR signaling pathway as a result of ICA cell activation.