title: Ranolazine improves oxidative stress and mitochondrial function in the atrium of acetylcholine-CaCl2 induced atrial fibrillation rats.
abstract: OBJECTIVE
  Ranolazine, an antianginal agent used for chronic stable angina treatment, was demonstrated to be effective in atrial fibrillation (AF) treatment. The aim of this study was to explore the molecular mechanisms of its anti-AF effects.
  
  
  METHODS
  AF rat model was established using acetylcholine (ACh)-CaCl2 injection for 7days followed by ACh infusion into the heart. Prior to ACh infusion, ranolazine at 10.7mg/kg/0.5ml was injected into vein and followed by 0.56mg/kg/min infusion. Blood pressure and electrocardiogram were monitored during the infusion. Histological changes of atrial tissue were observed after H&E staining. Activities and protein expression of NADPH oxidase-4, xanthine oxidase, glutathione peroxidase and superoxide dismutase were examined using commercial assay kits and Western botting, respectively. Mitochondrial functions were evaluated through membrane potential, ATP production, activities of complex I and III and reactive oxygen species production. Apoptosis was measured using TUNEL staining. Protein expression of apoptotic proteins Bcl-2, Bax and cleaved-caspase 3 and Akt/mTOR signaling proteins were detected using Western blotting.
  
  
  RESULTS
  Results demonstrated that ranolazine attenuated AF in ACh-CaCl2-exposed rats. In addition, ranolazine restored mitochondrial function, suppressed oxidative stress, and inhibited atrial cells apoptosis. Furthermore, the activated Akt/mTOR signaling pathway induced by AF was further activated by ranolazine.
  
  
  CONCLUSIONS
  The present study confirms the effects of ranolazine on AF rats induced by ACh-CaCl2, and provides evidence that the anti-AF effects are associated with the restoration of mitochondrial function and activation of the Akt/mTOR signaling pathway in atrial tissue.
authors.affiliation: Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China. Electronic address: zoudlsy@163.com.
authors.forename: Deling
authors.initials: D
authors.lastname: Zou
authors.affiliation: Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Ning
authors.initials: N
authors.lastname: Geng
authors.affiliation: Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.affiliation: Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Xingli
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Jiye
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Sicong
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Shaojun
authors.initials: S
authors.lastname: Wang
mesh_terms: D000109:Acetylcholine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001281:Atrial Fibrillation / Q000473:pathology*; D002122:Calcium Chloride; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000069458:Ranolazine / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000069458:Ranolazine; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002122:Calcium Chloride; D000109:Acetylcholine
keywords: Akt/mTOR; Atrial fibrillation; Mitochondrial function; Ranolazine