Inhibition of IKr potentiates development of atrial-selective INa block leading to effective suppression of atrial fibrillation

Heart Rhythm. 2015 Apr;12(4):836-44. doi: 10.1016/j.hrthm.2014.12.033. Epub 2014 Dec 26.


Background: The availability of safe and effective drugs for the management of atrial fibrillation (AF) remains an unmet medical need.

Objectives: 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.

Conclusion: 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.

Keywords: Antiarrhythmic drugs; Atrial fibrillation; Electrophysiology; Lidocaine; Pharmacology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Anti-Arrhythmia Agents / pharmacology
  • Atrial Fibrillation* / drug therapy
  • Atrial Fibrillation* / metabolism
  • Atrial Fibrillation* / physiopathology
  • Delayed Rectifier Potassium Channels / antagonists & inhibitors
  • Delayed Rectifier Potassium Channels / metabolism*
  • Dogs
  • Electrophysiological Phenomena / drug effects
  • Heart Atria / drug effects
  • Heart Atria / physiopathology
  • Heart Rate / drug effects
  • Heart Ventricles / drug effects
  • Heart Ventricles / physiopathology
  • Lidocaine / pharmacology*
  • Models, Anatomic
  • Piperidines / pharmacology*
  • Pyridines / pharmacology*
  • Sodium Channel Blockers* / metabolism
  • Sodium Channel Blockers* / pharmacology
  • Sodium Channels / metabolism


  • Anti-Arrhythmia Agents
  • Delayed Rectifier Potassium Channels
  • Piperidines
  • Pyridines
  • Sodium Channel Blockers
  • Sodium Channels
  • E 4031
  • Lidocaine