title: The heart rate-lowering agent ivabradine inhibits the pacemaker current I(f) in human atrial myocytes.
abstract: BACKGROUND
  It has been speculated that pacemaker current (I(f)) in human atria could play a role in causing ectopic atrial automaticity. Ivabradine is a novel selective and specific I(f) inhibitor in the sinus node that reduces heart rate without any negative inotropic effect. The aim of the study was to explore possible effects of ivabradine on I(f) in atrial myocytes.
  
  
  RESULTS
  Using patch-clamp technique, we studied effects of ivabradine on I(f) present in atrial myocytes isolated from human right appendages of patients undergoing cardiac surgery. The identification of HCN isoforms was obtained by means of multiplex single-cell RT-PCR. Ivabradine induced a marked concentration and use-dependent I(f) inhibition with an IC50 at steady state of 2.9 microM. Time constant of block development (Tau(on)) decreases with the increase in the ivabradine concentration. Use-dependent inhibition induced by ivabradine (3 microM) was not modified in the presence of cAMP (10 microM) in the pipette solution. Multiplex single-cell RT-PCR indicates that the major HCN gene subtype detected in atria was HCN2. HCN4 is detected weakly and HCN1 is not significantly detected.
  
  
  CONCLUSIONS
  Ivabradine inhibits I(f) current in the nonpacemaker cell with characteristics similar to those described previously in rabbit sinus node cells, but revealed a lesser sensitivity for I(f) recorded in human atrial cell than hHCN4 subunits considered as the major contributors to native f-channels in human sinoatrial node. A potential protection of atrial arrhythmias by ivabradine is discussed.
authors.affiliation: Institut de Physiologie et Biologie Cellulaires, CNRS UMR 6187, Université de Poitiers, Poitiers Cedex, France.
authors.forename: Antoun
authors.initials: A
authors.lastname: El Chemaly
authors.forename: Christophe
authors.initials: C
authors.lastname: Magaud
authors.forename: Sylvie
authors.initials: S
authors.lastname: Patri
authors.forename: Christophe
authors.initials: C
authors.lastname: Jayle
authors.forename: Romain
authors.initials: R
authors.lastname: Guinamard
authors.forename: Patrick
authors.initials: P
authors.lastname: Bois
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006325:Heart Atria / Q000187:drug effects*; D006801:Humans; D000077550:Ivabradine; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010138:Pacemaker, Artificial; D018408:Patch-Clamp Techniques; D011817:Rabbits
chemical_list: D001552:Benzazepines; D000077550:Ivabradine