title: Nitric oxide and cardiac muscarinic control in humans.
abstract: Cardiac parasympathetic activity reduces susceptibility to potentially lethal ventricular arrhythmias in heart failure and ischemic heart disease. This influence is mediated in large part by antagonism of the adverse cardiac effects of sympathetic overactivity ("indirect" parasympathetic activity) in addition to the "direct" effects of muscarinic stimulation. Nitric oxide modulates parasympathetic cardiac signaling in some animal models, but human data are lacking. We have investigated the influence of endogenous nitric oxide on cardiac responses to parasympathetic stimulation in healthy humans. In 18 volunteers, we studied chronotropic and inotropic responses to muscarinic stimulation, both before and after prestimulation with isoproterenol. Cardiac muscarinic stimulation was achieved using an intravenous bolus of the short-acting cholinesterase inhibitor, edrophonium. Responses were assessed during a background infusion of a nitric oxide synthase inhibitor (N(G)-monomethyl-L-arginine [L-NMMA]), placebo (saline), or phenylephrine (vasoconstrictor control) in a single-blind, random order, crossover protocol. L-NMMA did not affect chronotropic responses to edrophonium alone (direct parasympathetic activity). The decrease in heart rate attributable to "indirect" parasympathetic activity (derived by comparison with the effect of edrophonium during concurrent adrenergic stimulation) was substantially attenuated by L-NMMA in comparison to both control infusions. No modification of muscarinic inotropic responses by L-NMMA was apparent in comparison to the vasoconstrictor control. Nitric oxide exerts a powerful facilitating influence on indirect (antiadrenergic) but not direct human cardiac parasympathetic control. Stimulation of the endogenous nitric oxide pathway might enhance parasympathetic protection against the adverse influences of cardiac sympathetic overactivity.
authors.affiliation: Department of Cardiovascular Medicine, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, UK. S.Chowdhary@bham.ac.uk
authors.forename: Saqib
authors.initials: S
authors.lastname: Chowdhary
authors.forename: Anna M
authors.initials: AM
authors.lastname: Marsh
authors.forename: John H
authors.initials: JH
authors.lastname: Coote
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Townend
mesh_terms: D000293:Adolescent; D058665:Adrenergic beta-1 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D001919:Bradycardia / Q000139:chemically induced; D002316:Cardiotonic Agents / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D018592:Cross-Over Studies; D004491:Edrophonium / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D010275:Parasympathetic Nervous System / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D016037:Single-Blind Method; D013045:Species Specificity; D013564:Sympathetic Nervous System / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D004491:Edrophonium; D007545:Isoproterenol