title: Inhibition of atrial fibrillation by low-level vagus nerve stimulation: the role of the nitric oxide signaling pathway.
abstract: OBJECTIVE
  We examined the role of the phosphatidylinositol-3 kinase (PI3K)/nitric oxide (NO) signaling pathway in low-level vagus nerve stimulation (LLVNS)-mediated inhibition of atrial fibrillation (AF).
  
  
  METHODS
  In 17 pentobarbital anesthetized dogs, bilateral thoracotomies allowed the attachment of electrode catheters to the superior and inferior pulmonary veins and atrial appendages. Rapid atrial pacing (RAP) was maintained for 6 h. Each hour, programmed stimulation was used to determine the window of vulnerability (WOV), a measure of AF inducibility, at all sites. During the last 3 h, RAP was overlapped with right LLVNS (50 % below that which slows the sinus rate). In group 1 (n = 7), LLVNS was the only intervention, whereas in groups 2 (n = 6) and 3 (n = 4), the NO synthase inhibitor N (G)-nitro-L-arginine methyl ester (L-NAME) and the PI3K inhibitor wortmannin, respectively, were injected in the right-sided ganglionated plexi (GP) during the last 3 h. The duration of acetylcholine-induced AF was determined at baseline and at 6 h. Voltage-sinus rate curves were constructed to assess GP function.
  
  
  RESULTS
  LLVNS significantly decreased the acetylcholine-induced AF duration by 8.2 ± 0.9 min (p < 0.0001). Both L-NAME and wortmannin abrogated this effect. The cumulative WOV (the sum of the individual WOVs) decreased toward baseline with LLVNS (p < 0.0001). L-NAME and wortmannin blunted this effect during the fifth (L-NAME only, p < 0.05) and the sixth hour (L-NAME and wortmannin, p < 0.05). LLVNS suppressed the ability of GP stimulation to slow the sinus rate, whereas L-NAME and wortmannin abolished this effect.
  
  
  CONCLUSIONS
  The anti-arrhythmic effects of LLVNS involve the PI3K/NO signaling pathway.
authors.affiliation: Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Stavros
authors.initials: S
authors.lastname: Stavrakis
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Scherlag
authors.forename: Youqi
authors.initials: Y
authors.lastname: Fan
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Mao
authors.forename: Vandana
authors.initials: V
authors.lastname: Varma
authors.forename: Ralph
authors.initials: R
authors.lastname: Lazzara
authors.forename: Sunny S
authors.initials: SS
authors.lastname: Po
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000517:prevention & control*; D004285:Dogs; D004599:Electric Stimulation Therapy / Q000379:methods*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D015398:Signal Transduction; D014630:Vagus Nerve / Q000503:physiopathology*
chemical_list: D009569:Nitric Oxide; D058539:Phosphatidylinositol 3-Kinase