Mediating δ-opioid-initiated heart protection via the β₂-adrenergic receptor: role of the intrinsic cardiac adrenergic cell

Abstract

Uretsky BF. Mediating ␦-opioid-initiated heart protection via the ␤ 2-adrenergic receptor: role of the intrinsic cardiac adrenergic cell. Am J Physiol Heart Circ Physiol 293: H376-H384, 2007. First published March 16, 2007; doi:10.1152/ajpheart.01195.2006.-Stimulation of cardiac ␤ 2-adrenergic receptor (␤2-AR) or ␦-opioid receptor (DOR) exerts a similar degree of cardioprotection against myocardial ischemia in experimental models. We hypothesized that ␦-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. ]i transients in a concentration-dependent manner. Such an effect was abolished by the Ca 2ϩ 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 ␦-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 Ϯ 15% or myocyte death by 26 Ϯ 4%, respectively. ␤2-AR blockade markedly attenuated ␦-opioid-initiated infarct size-limiting effect and abolished ␦-opioid-initiated myocyte survival protection in rat ICA cell-myocyte coculture. Furthermore, ␦-opioid agonist exerted no myocyte survival protection in the absence of cocultured ICA cells during ischemia-reperfusion. We conclude that ␦-opioid-initiated myocardial infarct size reduction is primarily mediated via endogenous epinephrine/␤2-AR signaling pathway as a result of ICA cell activation.␦-opioid receptor; epinephrine; myocardial ischemia STIMULATION OF ␤ 2 -adrenergic receptor (␤ 2 -AR) before myocardial ischemia confers cardioprotection via infarct size reduction (13, 14) and facilitated ventricular contractile recovery (25) during ischemia-reperfusion in experimental models. Numerous studies indicate that ␦-opioid agonists precondition the heart against ischemia (2,7,19,22,23). The extent of heart protection conferred by ␦-opioids is comparable with that elicited by myocardial ␤ 2 -AR stimulation. It has been suggested that ␦-opioid-initiated cardioprotection is partially mediated by ␤ 2 -AR in the murine heart (20). Although ␦-opioid agonists exert potent cardioprotection, it is unclear which type of cardiac cells actually express ␦-opioid receptor (DOR). Despite the receptor-binding study of DOR (11,27,33) and its gene expression in human and animal hearts (2, 28), no clear immunohistochemical evidence has demonstrated in situ DOR expression in cardiac myocytes. The intrinsic cardiac adrenergic (ICA) ce...

Developmental expression of δ‐opioid receptors during maturation of the parasympathetic, sympathetic, and sensory innervations of the neonatal heart: Early targets for opioid regulation of autonomic control

“…Our results strongly support the existence of DORs in the mammalian heart by the identification of DOR mRNA, receptor protein, and membrane-associated binding sites in the rat heart atria. This is in line with recent Western blot analyses identifing DOR-IR bands in left ventricular cardiomyocytes of hamsters (Bolte et al, 2009) or in intrinsic cardiac adrenergic cells of rats (Huang et al, 2007). In addition, [ 3 H]diprenorphine binding sites in cultured cardiomyocytes were displaced by unlabeled DOR-(DPDPE) selective ligands, indicating the presence of DORs (Zimlichman et al, 1996).…”

“…Consistently, Western blot analysis in P1 and P7 and adult rat heart atria also revealed that cardiac DOR proteins significantly increased from the first day of birth toward adulthood. In parallel, the number of membrane-associated DOR-specific binding sites increased, further substantiating existing evidence (Huang et al, 2007;Deo et al, 2008;Bolte et al, 2009). Taken together, our findings of DOR mRNA, receptor protein, and membrane binding sites strongly support the existence of rat cardiac DORs already at birth, with a gradual increase in expression toward adulthood.…”

Cholinergic location of δ-opioid receptors in canine atria and SA node

“…Canine right atrial and sinus node tissues were obtained from mixed-gender adult (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) kg) mongrel dogs. The Institutional Animal Care and Use Committee, in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, approved all procedures.…”

“…The location of the responsible receptors remains undefined, but studies in vitro (21,27,35,39) support the widely held presumption that postjunctional DORs are involved. Intrinsic adrenergic cells, cardiomyocytes, adipocytes, fibroblasts, and resident leukocytes are all potential sites for nonneural DORs (21,27,29,35).…”

“…opioids; vagal function ENKEPHALINS, the presumed endogenous agonists for the ␦-opioid receptor (DOR), are abundant in the heart (20, 26, 39). Although locally administered enkephalin produces robust physiological responses in heart (10 -13, 33), the location of the DORs mediating these responses remains a matter of discussion (5,21,27). Myocardial enkephalin content is relatively low (20, 39), and the enzymes that degrade enkephalin are both aggressive and pervasive (19, 36).…”