title: Vagus nerve stimulation initiated late during ischemia, but not reperfusion, exerts cardioprotection via amelioration of cardiac mitochondrial dysfunction.
abstract: BACKGROUND
  We previously reported that vagus nerve stimulation (VNS) applied immediately at the onset of cardiac ischemia provides cardioprotection against cardiac ischemic-reperfusion (I/R) injury.
  
  
  OBJECTIVE
  This study aimed to determine whether VNS applied during ischemia or at the onset of reperfusion exerts differential cardioprotection against cardiac I/R injury.
  
  
  METHODS
  Twenty-eight swine (25-30 kg) were randomized into 4 groups: Control (sham-operated, no VNS), VNS-ischemia (VNS applied during ischemia), VNS-reperfusion (VNS applied during reperfusion), and VNS-ischemia+atropine (VNS applied during ischemia with 1 mg/kg atropine administration). Ischemia was induced by left anterior descending (LAD) coronary artery occlusion for 60 minutes, followed by 120 minutes of reperfusion. VNS was applied either 30 minutes after LAD coronary artery occlusion or at the onset of reperfusion and continued until the end of reperfusion. Cardiac function, infarct size, myocardial levels of connexin 43, cytochrome c, tumor necrosis factor α, and interleukin 4, and cardiac mitochondrial function were determined.
  
  
  RESULTS
  VNS applied 30 minutes after LAD coronary artery occlusion, but not at reperfusion, markedly reduced ventricular fibrillation incidence and infarct size (~59%), improved cardiac function; attenuated cardiac mitochondrial reactive oxygen species production, depolarization, swelling, and cytochrome c release; and increased the amount of phosphorylated connexin 43 and interleukin 4 as compared with the Control group. These beneficial effects of VNS were abolished by atropine.
  
  
  CONCLUSIONS
  VNS could provide significant cardioprotective effects even when initiated later during ischemia, but was not effective after reperfusion. These findings indicate the importance of timing of VNS initiation and warrant the potential clinical application of VNS in protecting myocardium at risk of I/R injury.
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Department of Physiology, Faculty of Medicine. Electronic address: kshinlap@gmail.com.
authors.forename: Krekwit
authors.initials: K
authors.lastname: Shinlapawittayatorn
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Department of Physiology, Faculty of Medicine.
authors.forename: Kroekkiat
authors.initials: K
authors.lastname: Chinda
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Department of Physiology, Faculty of Medicine.
authors.forename: Siripong
authors.initials: S
authors.lastname: Palee
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Department of Physiology, Faculty of Medicine.
authors.forename: Sirirat
authors.initials: S
authors.lastname: Surinkaew
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Department of Physiology, Faculty of Medicine.
authors.forename: Sirinart
authors.initials: S
authors.lastname: Kumfu
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Department of Physiology, Faculty of Medicine.
authors.forename: Sarawut
authors.initials: S
authors.lastname: Kumphune
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Department of Physiology, Faculty of Medicine; Department of Oral Biology and Diagnostic Science, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Siriporn
authors.initials: S
authors.lastname: Chattipakorn
authors.affiliation: Emerging Therapies, Cyberonics Inc, Houston, Texas.
authors.forename: Bruce H
authors.initials: BH
authors.lastname: KenKnight
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Department of Physiology, Faculty of Medicine.
authors.forename: Nipon
authors.initials: N
authors.lastname: Chattipakorn
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000379:methods; D008929:Mitochondria, Heart / Q000473:pathology* / Q000648:ultrastructure; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011897:Random Allocation; D012016:Reference Values; D018570:Risk Assessment; D013552:Swine; D016896:Treatment Outcome; D055536:Vagus Nerve Stimulation / Q000379:methods*; D016277:Ventricular Function, Left / Q000502:physiology*
chemical_list: D001285:Atropine
keywords: Acetylcholine; Cardioprotection; Heart; Ischemic-reperfusion injury; Vagus nerve stimulation