Opioid peptide receptor stimulation reverses beta-adrenergic effects in rat heart cells.
Opioid peptide receptor (OPR) agonists are co-released with the beta-adrenergic receptor (beta-AR) agonist norepinephrine (NE) from nerve terminals in the heart during sympathetic stimulation. Whereas recent studies indicate that OPR and beta-AR coexist on the surface of cardiac myocytes, whether significant "cross talk" occurs between OPR and beta-AR signaling cascades within heart cells is unknown. In the present study we demonstrate a marked effect of delta-OPR stimulation to modulate beta-adrenergic responses in single isolated rat ventricular myocytes. Nanomolar concentrations (10(-8) M) of the OPR agonist leucine enkephalin (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 pertussis toxin sensitive and abolished by naloxone, an opioid receptor antagonist. 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 indicate that an interaction of the OPR and beta-AR systems occurs proximal to activation of the adenosine 3',5'-cyclic monophosphate-dependent protein kinase of the beta-AR intracellular signaling pathway. This modulation of beta-adrenergic effects by OPR activation at the myocyte level may have important implications in the regulation of cardiac Ca2+ metabolism and contractility, particularly during the myocardial response to stress.
Xiao
R P
RP
Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.
Pepe
S
S
Spurgeon
H A
HA
Capogrossi
M C
MC
Lakatta
E G
EG
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004553:Electric Conductivity; D004743:Enkephalin, Leucine / Q000494:pharmacology; D006352:Heart Ventricles; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D037342:Pertussis Toxin; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000502:physiology*; D012508:Sarcolemma / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D009292:Narcotic Antagonists; D011943:Receptors, Adrenergic, beta; D017465:Receptors, Opioid, delta; D013873:Thionucleotides; D010566:Virulence Factors, Bordetella; D009270:Naloxone; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D004743:Enkephalin, Leucine; D000242:Cyclic AMP; D037342:Pertussis Toxin; D002118:Calcium; D009638:Norepinephrine