title: Carbon monoxide induces cardiac arrhythmia via induction of the late Na+ current.
abstract: BACKGROUND
  Clinical reports describe life-threatening cardiac arrhythmias after environmental exposure to carbon monoxide (CO) or accidental CO poisoning. Numerous case studies describe disruption of repolarization and prolongation of the QT interval, yet the mechanisms underlying CO-induced arrhythmias are unknown.
  
  
  OBJECTIVE
  To understand the cellular basis of CO-induced arrhythmias and to identify an effective therapeutic approach.
  
  
  METHODS
  Patch-clamp electrophysiology and confocal Ca(2+) and nitric oxide (NO) imaging in isolated ventricular myocytes was performed together with protein S-nitrosylation to investigate the effects of CO at the cellular and molecular levels, whereas telemetry was used to investigate effects of CO on electrocardiogram recordings in vivo.
  
  
  RESULTS
  CO increased the sustained (late) component of the inward Na(+) current, resulting in prolongation of the action potential and the associated intracellular Ca(2+) transient. In more than 50% of myocytes these changes progressed to early after-depolarization-like arrhythmias. CO elevated NO levels in myocytes and caused S-nitrosylation of the Na(+) channel, Na(v)1.5. All proarrhythmic effects of CO were abolished by the NO synthase inhibitor l-NAME, and reversed by ranolazine, an inhibitor of the late Na(+) current. Ranolazine also corrected QT variability and arrhythmias induced by CO in vivo, as monitored by telemetry.
  
  
  CONCLUSIONS
  Our data indicate that the proarrhythmic effects of CO arise from activation of NO synthase, leading to NO-mediated nitrosylation of Na(V)1.5 and to induction of the late Na(+) current. We also show that the antianginal drug ranolazine can abolish CO-induced early after-depolarizations, highlighting a novel approach to the treatment of CO-induced arrhythmias.
authors: Division of Cardiovascular and Neuronal Remodelling, LIGHT, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, UK.
authors: Mark L
authors: ML
authors: Dallas
authors: Zhaokang
authors: Z
authors: Yang
authors: John P
authors: JP
authors: Boyle
authors: Hannah E
authors: HE
authors: Boycott
authors: Jason L
authors: JL
authors: Scragg
authors: Carol J
authors: CJ
authors: Milligan
authors: Jacobo
authors: J
authors: Elies
authors: Adrian
authors: A
authors: Duke
authors: Jérôme
authors: J
authors: Thireau
authors: Cyril
authors: C
authors: Reboul
authors: Sylvain
authors: S
authors: Richard
authors: Olivier
authors: O
authors: Bernus
authors: Derek S
authors: DS
authors: Steele
authors: Chris
authors: C
authors: Peers
mesh_terms: D000083:Acetanilides / Q000627:therapeutic use; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects; D002248:Carbon Monoxide / Q000009:adverse effects / Q000494:pharmacology*; D002249:Carbon Monoxide Poisoning / Q000150:complications* / Q000503:physiopathology; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D004781:Environmental Exposure / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000627:therapeutic use; D000069458:Ranolazine; D051381:Rats; D017208:Rats, Wistar; D061566:Voltage-Gated Sodium Channels / Q000187:drug effects* / Q000502:physiology
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D061566:Voltage-Gated Sodium Channels; D002248:Carbon Monoxide; D000069458:Ranolazine