title: Cardiac enkephalins attenuate vagal bradycardia: interactions with NOS-1-cGMP systems in canine sinoatrial node.
abstract: Endogenous opioids and nitric oxide (NO) are recognized modulators of cardiac function. Enkephalins and inhibitors of NO synthase (NOS) both produce similar interruptions in the vagal control of heart rate. This study was conducted to test the hypothesis that NO systems within the canine sinoatrial (SA) node facilitate local vagal transmission and that the endogenous enkephalin methionine-enkephalin-arginine-phenylalanine (MEAP) attenuates vagal bradycardia by interrupting the NOS-cGMP pathway. Microdialysis probes were inserted into the SA node, and they were perfused with nonselective (Nomega-nitro-l-arginine methyl ester) and neuronal (7-nitroindazole) NOS inhibitors. The right vagus nerve was stimulated and both inhibitors gradually attenuated the resulting vagal bradycardia. The specificity of these inhibitions was verified by an equally gradual reversal of the inhibition with an excess of the NOS substrate l-arginine. Introduction of MEAP into the nodal interstitium produced a quickly developing but quantitatively similar interruption of vagal bradycardia that was also slowly reversed by the addition of l-arginine and not by d-arginine. Additional support for convergence of opioid and NO pathways was provided when the vagolytic effects of MEAP were also reversed by the addition of the NO donor S-nitroso-N-acetyl-penicillamine, the protein kinase G activator 8-bromo-cGMP, or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. MEAP and 7-nitroindazole were individually combined with the direct acting muscarinic agonist methacholine to evaluate potential interactions with muscarinic receptors within the SA node. MEAP and 7-nitroindazole were unable to overcome the bradycardia produced by methacholine. These data suggest that NO and enkephalins moderate the vagal control of heart rate via interaction with converging systems that involve the regulation of cAMP within nodal parasympathetic nerve terminals.
authors.affiliation: Department of Integrative Physiology, Cardiovascular Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107-2699, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Farias
authors.forename: Keith
authors.initials: K
authors.lastname: Jackson
authors.forename: Michael
authors.initials: M
authors.lastname: Johnson
authors.forename: James L
authors.initials: JL
authors.lastname: Caffrey
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001919:Bradycardia / Q000188:drug therapy / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D016210:Methacholine Chloride / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D010277:Parasympathomimetics / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012849:Sinoatrial Node / Q000294:innervation / Q000502:physiology*; D014630:Vagus Nerve / Q000187:drug effects* / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D020030:Nitric Oxide Donors; D010277:Parasympathomimetics; D010726:Phosphodiesterase Inhibitors; C110881:S-nitro-N-acetylpenicillamine; D016210:Methacholine Chloride; C016276:8-bromocyclic GMP; D004744:Enkephalin, Methionine; C027511:enkephalin-Met, Arg(6)-Phe(7)-; D001120:Arginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D010396:Penicillamine; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester