Stimulation of cardiac beta(2)-adrenergic receptor (beta(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(2+) concentration ([Ca(2+)](i)) transients in isolated rat ICA cells using fluorescence spectrophotometry. Exposing the selective delta-
opioid agonist D-[Pen(2,5)]
enkephalin (
DPDPE) to ICA cells increased [Ca(2+)](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 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 +/- 15% or myocyte death by 26 +/- 4%, respectively. beta(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(2)-AR signaling pathway as a result of ICA cell activation.