CROSS-TALK BETWEEN OPIOID PEPTIDE AND ADRENERGIC-RECEPTOR SIGNALING IN ISOLATED RAT-HEART

Background Cardiac myocyte sarcolemma contains both catecholamine and opioid peptide receptors (OPRs). Opioid peptides are coreleased with c atecholamines from nerve terminals in the heart. We investigated wheth er OPR stimulation influences the effects of beta-adrenergic receptor (beta-AR) stimulation in the isolated, isovolumic rat heart and whethe r the mechanism of such an interaction involves both beta-AR subtypes or an alteration in beta-AR-mediated increase in cAMP. Methods and Res ults Norepinephrine (NE, 10(-7) mol/L) in creased peak left ventricula r systolic pressure (LVSP) and cAMP more than twofold compared with co ntrols. The delta-OPR agonist leucine-enkephalin (LE, 10(-8) mol/L) ma rkedly inhibited the beta(1)-AR-induced positive inotropic effect and increase in cAMP but alone had no effect on basal LVSP or basal cAMP l evels. The OPR antagonist naloxone 10(-8) mol/L added to LE+NE perfusa te reversed the LE-induced decrease in cAMP and LVSP even though nalox one alone had no effect on LVSP and cAMP levels. LE could not countera ct the twofold increase in LVSP produced by the nondegradable cAMP ana log CPT-cAMP 2.3x10(-5) mol/L or a high concentration of forskolin (10 (-7) mol/L) but did reverse the 173+/-11.8% and 135+/-13.6% increases in LVSP stimulated by 10(-8) and 0.5x10(-8) mol/L forskolin, respectiv ely. LE inhibited cAMP production at all concentrations of forskolin ( 10(-7), 10(-8), and 0.5x10(-8) mol/L). Pertussis toxin (PTX) pretreatm ent abolished LE effects on beta(1)-AR stimulation. Zinterol 10(-5) an d 10(-6) mol/L, a specific beta(2)-AR agonist that elicits a cAMP-inde pendent inotropic effect in rat heart, caused 225+/-14% and 182+/-5% i ncreases in LVSP that could not be reversed by addition of LE. Conclus ions Potent, inhibitory ''cross talk'' between delta-OPR and beta(1)-A R signaling pathways occurs via a PTX-sensitive G(i/o) protein involve d in adenylyl cyclase inhibition in rat heart.