title: Inhibition of IKr potentiates development of atrial-selective INa block leading to effective suppression of atrial fibrillation.
abstract: BACKGROUND
  The availability of safe and effective drugs for the management of atrial fibrillation (AF) remains an unmet medical need.
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that the inhibition of the rapidly activating delayed rectifier potassium current (IKr) greatly potentiates the development of atrial-selective sodium channel current (INa) block, leading to more effective suppression of AF.
  
  
  METHODS
  Electrophysiological and anti-AF effects of highly selective INa and IKr blockers (lidocaine and E-4031) individually and in combination were determined in canine coronary-perfused atrial and ventricular preparations. Acetylcholine (1 µM) was used to induce persistent AF.
  
  
  RESULTS
  Lidocaine (10 µM) caused a relatively small abbreviation of the action potential duration measured at 90% repolarization in both atria and ventricles, but caused atrial-selective prolongation of the effective refractory period owing to the induction of post-repolarization refractoriness. Lidocaine also caused modest atrial-selective depression of other INa-mediated parameters including excitability, maximum rate of rise of the action potential upstroke, and conduction time. E-4031 (1 µM) prolonged the action potential duration measured at 90% repolarization and effective refractory period in an atrial-predominant manner. A combination of lidocaine and E-4031 caused a greater atrial-selective depression of INa-mediated parameters. Persistent acetylcholine-mediated AF developed in 100% of atria under control conditions, in 80% (4 of 5) after pretreatment with lidocaine (10 µM), in 100% (4 of 4) after E-4031 (1 µM), and in only 14% (1 of 7) after the combination of lidocaine and E-4031.
  
  
  CONCLUSIONS
  Our results provide a proof of concept that IKr block greatly potentiates the effects of rapidly dissociating INa blockers to depress sodium channel-dependent parameters in the canine atria but not in the ventricles, thus contributing significantly to suppression of AF.
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York.
authors.forename: Alexander
authors.initials: A
authors.lastname: Burashnikov
authors.affiliation: Gilead Sciences, Inc., Foster City, California.
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York. Electronic address: cantzelevitch@gmail.com.
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004285:Dogs; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D008012:Lidocaine / Q000494:pharmacology*; D008953:Models, Anatomic; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D010880:Piperidines; D011725:Pyridines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C063968:E 4031; D008012:Lidocaine
keywords: Antiarrhythmic drugs; Atrial fibrillation; Electrophysiology; Lidocaine; Pharmacology