title: Mechanisms of altered vagal control in heart failure: influence of muscarinic receptors and acetylcholinesterase activity.
abstract: Parasympathetic control of the heart is attenuated in heart failure (HF). We investigated possible mechanisms and sites of altered vagal control in dogs with HF induced by rapid pacing. Muscarinic blockade reduced the R-R interval by 308 ms in controls but only by 32 ms in HF, indicating low levels of resting vagal tone. Vagomimetic doses of atropine sulfate prolonged the R-R interval by 109 ms in controls and increased standard deviation of the R-R interval by 66 ms but only by 46 and 16 ms, respectively, in HF. Bradycardia elicited by electrical stimulation of the vagus nerve was also attenuated in the HF group. Conversely, muscarinic receptor activation by bethanechol, and indirectly by neostigmine, elicited exaggerated R-R interval responses in HF. To investigate possible mechanisms, we measured muscarinic receptor density (Bmax) and acetylcholinesterase activity in different areas of the heart. In sinoatrial nodes, Bmax was increased (230 +/- 75% of control) and acetylcholinesterase decreased (80 +/- 6% of control) in HF. We conclude that muscarinic receptors are upregulated and acetylcholinesterase is reduced in the sinus node in HF. Therefore, reduced vagal control in HF is most likely due to changes of presynaptic function (ganglionic), because postsynaptic mechanisms augment vagal control in HF.
authors.affiliation: Department of Medicine-Cardiology, Louis Stokes Cleveland Veterans Affairs Medical Center, Medical Research Service 151W, 10701 East Blvd., Cleveland, OH 44106, USA. mark.dunlap@med.va.gov
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dunlap
authors.forename: Steve
authors.initials: S
authors.lastname: Bibevski
authors.forename: Terrone L
authors.initials: TL
authors.lastname: Rosenberry
authors.forename: Paul
authors.initials: P
authors.lastname: Ernsberger
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D018723:Bethanechol / Q000494:pharmacology; D001667:Binding, Competitive; D002303:Cardiac Output, Low / Q000378:metabolism / Q000503:physiopathology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004285:Dogs; D004558:Electric Stimulation; D006150:Guanine Nucleotides / Q000494:pharmacology; D006325:Heart Atria; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D009388:Neostigmine / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012965:Sodium Chloride / Q000494:pharmacology; D014630:Vagus Nerve / Q000503:physiopathology*
chemical_list: D002800:Cholinesterase Inhibitors; D006150:Guanine Nucleotides; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D018723:Bethanechol; D009388:Neostigmine; D012965:Sodium Chloride; D011813:Quinuclidinyl Benzilate; D001285:Atropine; D000110:Acetylcholinesterase