title: Blockade of atrial-specific K+-currents increases atrial but not ventricular contractility by enhancing reverse mode Na+/Ca2+-exchange.
abstract: BACKGROUND
  AVE0118 (2'-{[2-(4-Methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide) blocks atrial ultrarapid delayed rectifier currents (I(Kur)) and prolongs the atrial action potential (AP) plateau without affecting ventricular repolarisation. In patients with atrial contractile dysfunction due to atrial tachyarrhythmias, this response might increase atrial contractility without risk of ventricular proarrhythmia. This study was designed to evaluate the inotropic mechanisms of AVE0118.
  
  
  RESULTS
  In isometrically contracting atrial trabeculae, AVE0118 increased contractile force by 55.4% in sinus rhythm patients (n = 9) and by 107.4% in patients with atrial fibrillation (n = 8). In freshly isolated canine atrial myocytes studied under perforated patch current clamp (37 degrees C), AVE0118 increased myocyte fractional shortening from 3.8+/-0.6 to 9.6+/-0.8% and prolonged action potential duration at 30% repolarisation from 9+/-2 to 102+/-11 ms. Clamping cells to an AP waveform recorded during exposure to AVE0118 produced the same inotropic response as the drug itself. In action potential clamp, peak Ca2+ inward current (I(CaL)) current declined from 5.5+/-1.3 pA/pF during control to 4.1+/-0.7 pA/pF when an AP recorded in the presence of AVE0118 was used as command waveform. However, I(CaL) was more sustained with AVE0118 and the time integral did not change (135+/-37 vs. 173+/-30 pA/pFms, p = ns). Importantly, blockade of reverse mode Na+/Ca2+-exchanger activity with 5 microM KBR7943 or using a Na+-free pipette solution abolished the positive inotropic effect of the AP recorded in the presence of AVE0118. In ventricular myocytes AVE0118 did not elicit a positive inotropic response.
  
  
  CONCLUSIONS
  Block of I(Kur) by AVE0118 enhances atrial contractility both in patients with sinus rhythm and atrial fibrillation. The positive inotropic effect is atrial-specific and due to the changes of the action potential configuration which enhances Ca2+ entry via reverse mode Na+/Ca2+ exchange.
authors.affiliation: Department of Physiology, University Maastricht, The Netherlands. schotten@fys.unimaas.nl
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schotten
authors.forename: Sunniva
authors.initials: S
authors.lastname: de Haan
authors.forename: Sander
authors.initials: S
authors.lastname: Verheule
authors.forename: Erik G A
authors.initials: EG
authors.lastname: Harks
authors.forename: Dirk
authors.initials: D
authors.lastname: Frechen
authors.forename: Eva
authors.initials: E
authors.lastname: Bodewig
authors.forename: Maura
authors.initials: M
authors.lastname: Greiser
authors.forename: Rashmi
authors.initials: R
authors.lastname: Ram
authors.forename: Jos
authors.initials: J
authors.lastname: Maessen
authors.forename: Malte
authors.initials: M
authors.lastname: Kelm
authors.forename: Maurits
authors.initials: M
authors.lastname: Allessie
authors.forename: David R
authors.initials: DR
authors.lastname: Van Wagoner
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D020517:Atrial Appendage; D001281:Atrial Fibrillation / Q000378:metabolism; D016275:Atrial Function / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects*; D004285:Dogs; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D013268:Stimulation, Chemical; D016276:Ventricular Function / Q000187:drug effects
chemical_list: C501729:AVE 0118; D001713:Biphenyl Compounds; D015220:Calcium Channels; D051668:Delayed Rectifier Potassium Channels; D026902:Potassium Channel Blockers; D019831:Sodium-Calcium Exchanger