title: Differential responses of rabbit ventricular and atrial transient outward current (Ito) to the Itomodulator NS5806.
abstract: Transient outward potassium current (Ito) in the heart underlies phase 1 repolarization of cardiac action potentials and thereby affects excitation-contraction coupling. Small molecule activators of Itomay therefore offer novel treatments for cardiac dysfunction, including heart failure and atrial fibrillation. NS5806 has been identified as a prototypic activator of canine ItoThis study investigated, for the first time, actions of NS5806 on rabbit atrial and ventricular ItoWhole cell patch-clamp recordings of Itoand action potentials were made at physiological temperature from rabbit ventricular and atrial myocytes. 10μmol/L NS5806 increased ventricular Itowith a leftward shift in Itoactivation and accelerated restitution. At higher concentrations, stimulation of Itowas followed by inhibition. The EC50for stimulation was 1.6μmol/L and inhibition had an IC50of 40.7μmol/L. NS5806 only inhibited atrial Ito(IC50of 18μmol/L) and produced a modest leftward shifts in Itoactivation and inactivation, without an effect on restitution. 10μmol/L NS5806 shortened ventricular action potential duration (APD) at APD20-APD90but prolonged atrial APD NS5806 also reduced atrial AP upstroke and amplitude, consistent with an additional atrio-selective effect on Na+channels. In contrast to NS5806, flecainide, which discriminates between Kv1.4 and 4.x channels, produced similar levels of inhibition of ventricular and atrial ItoNS5806 discriminates between rabbit ventricular and atrial Ito,with mixed activator and inhibitor actions on the former and inhibitor actions against the later. NS5806 may be of significant value for pharmacological interrogation of regional differences in native cardiac Ito.
authors.affiliation: School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences Building, University Walk, Bristol, U.K.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Cheng
authors.affiliation: School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences Building, University Walk, Bristol, U.K jules.hancox@bristol.ac.uk mark.cannell@bristol.ac.uk.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Cannell
authors.affiliation: School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences Building, University Walk, Bristol, U.K jules.hancox@bristol.ac.uk mark.cannell@bristol.ac.uk.
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D005424:Flecainide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology*; D015221:Potassium Channels / Q000819:agonists*; D011817:Rabbits; D013777:Tetrazoles / Q000494:pharmacology*; D061567:Voltage-Gated Sodium Channel Blockers / 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; D061567:Voltage-Gated Sodium Channel Blockers; D005424:Flecainide
keywords: Ito; Kv4.3, Kv 4.2, Kv1.4; NS5806; action potential; flecainide; potassium channels; transient outward current