title: Comparison of the effects of a transient outward potassium channel activator on currents recorded from atrial and ventricular cardiomyocytes.
abstract: BACKGROUND
  NS5806 activates the transient outward potassium current (I(to) ) in canine ventricular cells. We compared the effects of NS5806 on canine atrial versus ventricular tissues and myocytes.
  
  
  RESULTS
  NS5806 (10 μM) was evaluated in arterially perfused canine right atrial and right ventricular wedge preparations. In ventricular wedges NS5806 (10 μM) accentuated phase 1 in epicardium (Epi), with little effect in endocardium (Endo), resulting in augmented J-waves on the ECG. In contrast, application of NS5806 (10 μM) to atrial preparations had no effect on phase 1 repolarization but significantly decreased upstroke velocity (dV/dt) and depressed excitability, consistent with sodium channel block. Current and voltage-clamp recordings were made in the absence and presence of NS5806 in (10 μM) enzymatically dissociated atrial and ventricular myocytes. In ventricular myocytes, NS5806 increased I(to) magnitude by 80% and 16% in Epi and Endo, respectively (at +40 mV). In atrial myocytes, NS5806 increased peak I(to) by 25% and had no effect on the sustained current, I(Kur) . Under control conditions, I(Na) density in atrial myocytes was nearly double that in ventricular myocytes. NS5806 caused a shift in steady-state mid-inactivation (V(1/2)) from -73.9 ± 0.27 to -77.3 ± 0.21 mV in ventricular and from -82.6 ± 0.12 to -85.1 ± 0.11 mV in atrial cells, resulting in reduction of I(Na) in both cell types. Expression of mRNA encoding putative I(Na) and I(to) channel subunits was evaluated by qPCR.
  
  
  CONCLUSIONS
  NS5806 produces a prominent augmentation of I(to) with little effect on I(Na) in the ventricles, but a potent inhibition of I(Na) with little augmentation of I(to) in atria.
authors: Danish National Research Foundation Center for Cardiac Arrhythmias, University of Copenhagen, Copenhagen, Denmark.
authors: Kirstine
authors: K
authors: Calloe
authors: Eyal
authors: E
authors: Nof
authors: Thomas
authors: T
authors: Jespersen
authors: José M
authors: JM
authors: Di Diego
authors: Natalie
authors: N
authors: Chlus
authors: Søren-Peter
authors: SP
authors: Olesen
authors: Charles
authors: C
authors: Antzelevitch
authors: Jonathan M
authors: JM
authors: Cordeiro
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D004285:Dogs; D005260:Female; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D015221:Potassium Channels / Q000819:agonists* / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: C541204:1-(3,5-bis-trifluoromethylphenyl)-3-(2,4-dibromo-6-(1H-tetrazol-5-yl)phenyl)urea; D010671:Phenylurea Compounds; D015221:Potassium Channels; D013777:Tetrazoles