title: Role of nitric oxide in parasympathetic modulation of beta-adrenergic myocardial contractility in normal dogs.
abstract: In vitro studies indicate that muscarinic cholinergic inhibition of beta-adrenergic cardiac responses may be modulated in part by nitric oxide (NO). To evaluate the role of NO in parasympathetic inhibition of the beta-adrenergic contractile response in vivo, we assessed the inotropic response to dobutamine before and during bilateral vagus nerve stimulation in closed-chest dogs. Dobutamine administration and vagal stimulation were repeated during intracoronary infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 10 mumol/min) and again following infusion of L-arginine (100 mg/kg). In eight dogs, intracoronary dobutamine infusion at rates of 25 and 50 micrograms/min increased peak +dP/dt by 131 +/- 24 and 168 +/- 22%, respectively (P < 0.0001). Vagal stimulation (2.5 Hz) attenuated the responses to dobutamine (25 and 50 micrograms/min) by 23 +/- 4 and 21 +/- 4%, respectively (P < 0.001). L-NMMA reduced (by 44-62%; P < 0.001) and L-arginine restored vagal inhibition of the dobutamine-stimulated inotropic response. In a second group of nine dogs, dobutamine was administered systemically to assure a constant concentration in the coronary circulation. Vagal stimulation (2.5 Hz) attenuated the dobutamine-stimulated inotropic response (2.5 and 5.0 micrograms/kg per min) by 40 +/- 12% and 57 +/- 8%, respectively (P < 0.004). As with intracoronary dobutamine, L-NMMA diminished and L-arginine restored vagal inhibition of the inotropic response to dobutamine. Intracoronary infusion of atropine (12 micrograms/min) abolished the vagal inhibitory effect, and intracoronary infusion of 8-bromo-cyclic GMP (1 and 10 mM) caused a dose-dependent attenuation of the dobutamine-stimulated increase in +dP/dt. These data suggest that NO mediates, at least in part, vagal inhibition of the inotropic response to beta-adrenergic stimulation by dobutamine, and thus may play a role in normal physiologic regulation of myocardial autonomic responses.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.
authors.forename: J M
authors.initials: JM
authors.lastname: Hare
authors.forename: J F
authors.initials: JF
authors.lastname: Keaney
authors.forename: J L
authors.initials: JL
authors.lastname: Balligand
authors.forename: J
authors.initials: J
authors.lastname: Loscalzo
authors.forename: T W
authors.initials: TW
authors.lastname: Smith
authors.forename: W S
authors.initials: WS
authors.lastname: Colucci
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology*; D004285:Dogs; D004558:Electric Stimulation; D006321:Heart / Q000294:innervation; D006339:Heart Rate; D018727:Muscarinic Antagonists; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D014630:Vagus Nerve / Q000502:physiology*; D019323:omega-N-Methylarginine
chemical_list: D018727:Muscarinic Antagonists; D011943:Receptors, Adrenergic, beta; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D004280:Dobutamine; D001120:Arginine; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases