title: Multi-walled carbon nanotubes impair Kv4.2/4.3 channel activities, delay membrane repolarization and induce bradyarrhythmias in the rat.
abstract: OBJECTIVE
  The potential hazardous effects of multi-walled carbon nanotubes (MWCNTs) on cardiac electrophysiology are seldom evaluated. This study aimed to investigate the impacts of MWCNTs on the Kv4/Ito channel, action potential and heart rhythm and the underlying mechanisms.
  
  
  METHODS
  HEK293 cells were engineered to express Kv4.2 or Kv4.3 with or without KChIP2 expression. A series of approaches were introduced to analyze the effects of MWCNTs on Kv4/Ito channel kinetics, current densities, expression and trafficking. Transmission electron microscopy was performed to observe the internalization of MWCNTs in HEK293 cells and rat cardiomyocytes. Current clamp was employed to record the action potentials of isolated rat cardiomyocytes. Surface ECG and epicardial monophasic action potentials were recorded to monitor heart rhythm in rats in vivo. Vagal nerve discharge monitoring and H&E staining were also performed.
  
  
  RESULTS
  Induction of MWCNTs into the cytosole through pipette solution soon accelerated the decay of IKv4 in HEK293 cells expressing Kv4.2/4.3 and KChIP2, and promoted the recovery from inactivation when Kv4.2 or Kv4.3 was expressed alone. Longer exposure (6 h) to MWCNTs decreased the IKv4.2 density, Kv4.2/Kv4.3 (but not KChIP2) expression and trafficking towards the plasma membrane in HEK293 cells. In acutely isolated rat ventricular myocytes, pipette MWCNTs also quickly accelerated the decay of IKv4 and prolonged the action potential duration (APD). Intravenous infusion of MWCNTs (2 mg/rat) induced atrioventricular (AV) block and even cardiac asystole. No tachyarrhythmia was observed after MWCNTs administration. MWCNTs did not cause coronary clot but induced myocardial inflammation and increased vagus discharge.
  
  
  CONCLUSIONS
  MWCNTs suppress Kv4/Ito channel activities likely at the intracellular side of plasma membrane, delay membrane repolarization and induce bradyarrhythmia. The delayed repolarization, increased vagus output and focal myocardial inflammation may partially underlie the occurrence of bradyarrhythmias induced by MWCNTs. The study warns that MWCNTs are hazardous to cardiac electrophysiology.
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
authors.forename: Xiao-Qiu
authors.initials: XQ
authors.lastname: Tan
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
authors.forename: Xiu-Li
authors.initials: XL
authors.lastname: Cheng
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan, China.
authors.forename: Bo-Wei
authors.initials: BW
authors.lastname: Wu
authors.affiliation: Department of Pathophysiology, Shanxi Medical University, Taiyuan, China.
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Biomedical Engineering, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Xu
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Cao
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001919:Bradycardia / Q000209:etiology*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D007700:Kinetics; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D037742:Nanotubes, Carbon / Q000737:chemistry / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D037742:Nanotubes, Carbon; D051672:Shal Potassium Channels