Can inhibition of IKur promote atrial fibrillation?

Heart Rhythm. 2008 Sep;5(9):1304-9. doi: 10.1016/j.hrthm.2008.05.020. Epub 2008 Aug 6.

Abstract

Background: Block of ultrarapid delayed rectified potassium current (I(Kur)), present in atria but not in ventricles, is thought to be a promising approach for atrial-specific therapy of atrial fibrillation (AF). However, it has been shown that I(Kur) block may abbreviate atrial repolarization and that loss-of-function mutations in KCNA5, which encodes K(v) 1.5 channels responsible for I(Kur), is associated with familial AF.

Objective: Our objective in this study was to use low concentrations of 4-aminopyridine (4-AP, 10 to 50 microM), known to selectively block I(Kur), to assess the proarrhythmic and antiarrhythmic effects of I(Kur) block in healthy and remodeled atria.

Methods: Isolated canine coronary-perfused right atrial preparations were used. Acetylcholine or ischemia/reperfusion was used to acutely remodel the atria. Transmembrane action potentials and a pseudo-electrocardiogram were simultaneously recorded.

Results: Normal (healthy) atria typically displayed action potentials (AP) with a prominent plateau, whereas remodeled atria displayed triangular-shaped APs (remodeled). In healthy atria, in which AF could not be induced with programmed stimulation, 4-AP abbreviated action potential measured at 90% repolarization (APD(90)) and effective refractory period (ERP), permitting the induction of AF in 4 of 12 preparations (33%). In remodeled atria, 4-AP produced little (50 microM) to no (10 to 25 microM) prolongation of APD(90) or ERP and was either ineffective or poorly effective in terminating AF or preventing its induction.

Conclusion: Our findings suggest that block of I(Kur) can provide the substrate for development of AF in healthy canine atria, presumably via abbreviation of APD and ERP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / pharmacology*
  • Action Potentials / drug effects
  • Animals
  • Anti-Arrhythmia Agents / therapeutic use
  • Atrial Fibrillation / drug therapy*
  • Atrial Fibrillation / physiopathology
  • Delayed Rectifier Potassium Channels / drug effects
  • Dogs
  • Heart Atria / drug effects
  • Heart Atria / innervation*
  • Heart Atria / physiopathology
  • Models, Animal
  • Potassium Channel Blockers / pharmacology*
  • Potassium Channels / drug effects*
  • Potassium Channels, Voltage-Gated / drug effects
  • Risk Factors

Substances

  • Anti-Arrhythmia Agents
  • Delayed Rectifier Potassium Channels
  • Potassium Channel Blockers
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • 4-Aminopyridine