title: Vagus nerve stimulation protects against ventricular fibrillation independent of muscarinic receptor activation.
abstract: OBJECTIVE
  The role of the vagus in the ventricle is controversial, although the vagus can protect against ventricular fibrillation (VF) via nitric oxide (NO). This study aims to determine whether the mechanisms involved are dependent on post-ganglionic release and muscarinic receptor activation. For this purpose, NO release and electrophysiological effects of vagus nerve stimulation (VNS) were evaluated in relation to acetylcholine and vasoactive intestinal peptide (VIP). In addition, the role of the coronary endothelium and afferent nerves was tested.
  
  
  RESULTS
  Using the isolated innervated rabbit heart, we measured ventricular NO release using 4,5-diaminofluorescein (DAF-2) fluorescence and ventricular fibrillation threshold (VFT) during VNS after muscarinic, ganglionic, and VIP inhibition [atropine, hexamethonium, and VIP (6-28), respectively] and after Triton-X endothelial functional dysfunction. The vagal-mediated increases in NO and VFT were not significantly affected (P> 0.05) during (i) atropine perfusion [increase in NO: 196.8 ± 35.2 mV (control) vs. 156.1 ± 20.3 mV (atropine) and VFT 3.1 ± 0.5 mA (control) vs. 2.7 ± 0.4 mA (atropine)], (ii) VIP inhibition-increase in NO: 243.0 ± 42.4 mV (control) vs. 203.9 ± 28.5 mV [VIP(6-28)] and VFT 3.3 ± 0.3 mA (control) vs. 3.9 ± 0.6 mA [VIP(6-28)], or (iii) after endothelial functional dysfunction [increase in NO: 127.7 ± 31.7 mV (control) vs. 172.1 ± 31.5 mV (Triton-X) and VFT 2.6 ± 0.4 mA (control) vs. 2.5 ± 0.5 mA (Triton-X)]. However, the vagal effects were inhibited during ganglionic blockade [increase in NO: 175.1 ± 38.1 mV (control) vs. 0.6 ± 25.3 mV (hexamethonium) and VFT 3.3 ± 0.5 mA (control) vs. -0.3 ± 0.3 mA (hexamethonium)].
  
  
  CONCLUSIONS
  We show that the vagal anti-fibrillatory action in the rabbit ventricle occurs via post-ganglionic efferent nerve fibres, independent of muscarinic receptor activation, VIP, and the endothelium. Together with our previous publications, our data support the possibility of a novel ventricular nitrergic parasympathetic innervation and highlight potential for new therapeutic targets to treat ventricular dysrhythmias.
authors.affiliation: Department of Cardiovascular Sciences, Cardiology Group, University of Leicester, Glenfield Hospital, Leicester, UK.
authors.forename: Kieran E
authors.initials: KE
authors.lastname: Brack
authors.forename: John H
authors.initials: JH
authors.lastname: Coote
authors.forename: G André
authors.initials: GA
authors.lastname: Ng
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism; D005730:Ganglionic Blockers / Q000494:pharmacology; D006339:Heart Rate; D006352:Heart Ventricles / Q000294:innervation*; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D026602:Nitrergic Neurons / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D017777:Parasympathetic Fibers, Postganglionic / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D012032:Refractory Period, Electrophysiological; D013997:Time Factors; D014630:Vagus Nerve / Q000503:physiopathology*; D055536:Vagus Nerve Stimulation; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016276:Ventricular Function
chemical_list: D005730:Ganglionic Blockers; D018727:Muscarinic Antagonists; D010446:Peptide Fragments; D011976:Receptors, Muscarinic; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; D000109:Acetylcholine