OPIOID PEPTIDE RECEPTOR STIMULATION REVERSES BETA-ADRENERGIC EFFECTS IN RAT-HEART CELLS

Opioid peptide receptor (OPR) agonists are co-released with the beta-a drenergic receptor (beta-AR) agonist norepinephrine (NE) from nerve te rminals in the heart during sympathetic stimulation. Whereas recent st udies indicate that OPR and beta-AR coexist on the surface of cardiac myocytes, whether significant ''cross talk'' occurs between OPR and be ta-AR signaling cascades within heart cells is unknown. In the present study we demonstrate a marked effect of delta-OPR stimulation to modu late beta-adrenergic responses in single isolated rat ventricular myoc ytes. Nanomolar concentrations (10(-8) M) of the OPR agonist leucine e nkephalin (LE), a naturally occurring delta-opioid peptide, inhibited NE-induced increases in sarcolemmal L-type Ca2+ current, cytosolic Ca2 + transient, and contraction. The antiadrenergic effect of LE was pert ussis toxin sensitive and abolished by naloxone, an opioid receptor an tagonist. In contrast, LE was unable to inhibit the positive inotropic effects induced by equipotent concentrations of 8-(4 chlorophenylthio )adenosine 3',5'-cyclic monophosphate, a cell-permeant adenosine 3',5' -cyclic monophosphate analog, or by the non-receptor-induced increase in contraction by elevated bathing Ca2+ concentration. These results i ndicate that an interaction of the OPR and beta-AR systems occurs prox imal to activation of the adenosine 3',5'-cyclic monophosphate-depende nt protein kinase of the beta-AR intracellular signaling pathway. This modulation of beta-adrenergic effects by OPR activation at the myocyt e level may have important implications in the regulation of cardiac C a2+ metabolism and contractility, particularly during the myocardial r esponse to stress.