title: Characterization of human cardiac Kv1.5 inhibition by the novel atrial-selective antiarrhythmic compound AVE1231.
abstract: OBJECTIVE
  Atrial-selective drug therapy represents a novel therapeutic approach for atrial fibrillation management. The aim of the present study was to investigate the mechanism of hKv1.5 channel inhibition by the atrial-selective compound AVE1231.
  
  
  METHODS
  Ionic currents were recorded from CHO cells transfected with KCNA5 cDNA with whole-cell patch-clamp technique. The effect of AVE1231 on human atrial cell action potentials was explored with a computer model.
  
  
  RESULTS
  KCNA5 expression resulted in typical K currents that activated and inactivated voltage dependently. Ascending concentrations of AVE1231 (0.1-100 microM) led to concentration- and voltage-dependent current inhibition (IC50 at +40 mV: 2.0 +/- 0.5 microM, Hill coefficient 0.69 +/- 0.12). Acceleration of hKv1.5 current inactivation occurred with increasing AVE1231 concentrations, indicating channel inhibition in the open state (eg, taufast at +40 mV: 318 +/- 92 milliseconds under control; 14 +/- 1 milliseconds with 3 microM, P < 0.05). Using 1/taufast as an approximation of the time course of drug-channel interaction, association rate (K+1) and dissociation rate (K-1) constants were 8.18 x 10 M/s and 45.95 seconds, respectively (KD = 5.62 microM). The onset of current inhibition occurred more rapidly with higher concentrations along with a prominent tail current crossover phenomenon after AVE1231 application. Drug inhibition remained effective through a range of stimulation frequencies. Computer modeling suggested more pronounced prolongation of action potential duration under conditions of atrial remodeling.
  
  
  CONCLUSIONS
  AVE1231 is an inhibitor of hKv1.5 currents with predominant action on channels in their open state; thus, it may be suitable for the treatment of AF.
authors.affiliation: Division of Cardiology, J.W. Goethe-Universität, Frankfurt, Germany. j.ehrlich@em.uni-frankfurt.de
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Ehrlich
authors.forename: Hellen
authors.initials: H
authors.lastname: Ocholla
authors.forename: Daniel
authors.initials: D
authors.lastname: Ziemek
authors.forename: Hartmut
authors.initials: H
authors.lastname: Rütten
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Hohnloser
authors.forename: Heinz
authors.initials: H
authors.lastname: Gögelein
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D008955:Models, Cardiovascular; D018408:Patch-Clamp Techniques
chemical_list: D000889:Anti-Arrhythmia Agents; C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel