title: Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve.
abstract: BACKGROUND
  The central nervous origins of functional parasympathetic innervation of cardiac ventricles remain controversial.
  
  
  OBJECTIVE
  This study aimed to identify a population of vagal preganglionic neurons that contribute to the control of ventricular excitability. An animal model of synuclein pathology relevant to Parkinson's disease was used to determine whether age-related loss of the activity of the identified group of neurons is associated with changes in ventricular electrophysiology.
  
  
  METHODS
  In vivo cardiac electrophysiology was performed in anesthetized rats in conditions of selective inhibition of the dorsal vagal motor nucleus (DVMN) neurons by pharmacogenetic approach and in mice with global genetic deletion of all family members of the synuclein protein.
  
  
  RESULTS
  In rats anesthetized with urethane (in conditions of systemic beta-adrenoceptor blockade), muscarinic and neuronal nitric oxide synthase blockade confirmed the existence of a tonic parasympathetic control of cardiac excitability mediated by the actions of acetylcholine and nitric oxide. Acute DVMN silencing led to shortening of the ventricular effective refractory period (vERP), a lowering of the threshold for triggered ventricular tachycardia, and prolongation of the corrected QT (QTc) interval. Lower resting activity of the DVMN neurons in aging synuclein-deficient mice was found to be associated with vERP shortening and QTc interval prolongation.
  
  
  CONCLUSIONS
  Activity of the DVMN vagal preganglionic neurons is responsible for tonic parasympathetic control of ventricular excitability, likely to be mediated by nitric oxide. These findings provide the first insight into the central nervous substrate that underlies functional parasympathetic innervation of the ventricles and highlight its vulnerability in neurodegenerative diseases.
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom; Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom.
authors.forename: Asif
authors.initials: A
authors.lastname: Machhada
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom; William Harvey Heart Centre, Barts & The London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Ang
authors.affiliation: Department of Medicine, University College London, London, United Kingdom.
authors.forename: Gareth L
authors.initials: GL
authors.lastname: Ackland
authors.affiliation: School of Biosciences, University of Cardiff, Cardiff, United Kingdom.
authors.forename: Natalia
authors.initials: N
authors.lastname: Ninkina
authors.affiliation: School of Biosciences, University of Cardiff, Cardiff, United Kingdom.
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Buchman
authors.affiliation: Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors.forename: Stefan
authors.initials: S
authors.lastname: Trapp
authors.affiliation: William Harvey Heart Centre, Barts & The London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors.forename: Nephtali
authors.initials: N
authors.lastname: Marina
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. Electronic address: a.tinker@qmul.ac.uk.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Gourine
mesh_terms: D000818:Animals; D054849:Cardiac Electrophysiology; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000294:innervation*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D017764:Parasympathectomy / Q000379:methods; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D014630:Vagus Nerve / Q000502:physiology*; D055536:Vagus Nerve Stimulation
chemical_list: D052248:Nitric Oxide Synthase Type I
keywords: Arrhythmia; Atrioventricular; Brain; Cardiac electrophysiology; Nitric oxide; Parkinson’s disease; Vagus nerve; Ventricle; parasympathetic