title: A transient outward potassium current activator recapitulates the electrocardiographic manifestations of Brugada syndrome.
abstract: OBJECTIVE
  Transient outward potassium current (I(to)) is thought to be central to the pathogenesis of the Brugada syndrome (BrS). However, an I((to)) activator has not been available with which to validate this hypothesis. Here, we provide a direct test of the hypothesis using a novel I(to) activator, NS5806.
  
  
  RESULTS
  Isolated canine ventricular myocytes and coronary-perfused wedge preparations were used. Whole-cell patch-clamp studies showed that NS5806 (10 microM) increased peak I(to) at +40 mV by 79 +/- 4% (24.5 +/- 2.2 to 43.6 +/- 3.4 pA/pF, n = 7) and slowed the time constant of inactivation from 12.6 +/- 3.2 to 20.3 +/- 2.9 ms (n = 7). The total charge carried by I(to) increased by 186% (from 363.9 +/- 40.0 to 1042.0 +/- 103.5 pA x ms/pF, n = 7). In ventricular wedge preparations, NS5806 increased phase 1 and notch amplitude of the action potential in the epicardium, but not in the endocardium, and accentuated the ECG J-wave, leading to the development of phase 2 re-entry and polymorphic ventricular tachycardia (n = 9). Although sodium and calcium channel blockers are capable of inducing BrS only in right ventricular (RV) wedge preparations, the I(to) activator was able to induce the phenotype in wedges from both ventricles. NS5806 induced BrS in 4/6 right and 2/10 left ventricular wedge preparations.
  
  
  CONCLUSIONS
  The I(to) activator NS5806 recapitulates the electrographic and arrhythmic manifestation of BrS, providing evidence in support of its pivotal role in the genesis of the disease. Our findings also suggest that a genetic defect leading to a gain of function of I(to) could explain variants of BrS, in which ST-segment elevation or J-waves are evident in both right and left ECG leads.
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences 12.5.10, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. kirstinec@mfi.ku.dk
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cordeiro
authors.forename: José M
authors.initials: JM
authors.lastname: Di Diego
authors.forename: Rie S
authors.initials: RS
authors.lastname: Hansen
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.forename: Søren Peter
authors.initials: SP
authors.lastname: Olesen
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000200:Action Potentials; D000818:Animals; D053840:Brugada Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004699:Endocardium / Q000187:drug effects / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010496:Pericardium / Q000187:drug effects / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C541204:1-(3,5-bis-trifluoromethylphenyl)-3-(2,4-dibromo-6-(1H-tetrazol-5-yl)phenyl)urea; D049990:Membrane Transport Modulators; D010671:Phenylurea Compounds; D015221:Potassium Channels; D013777:Tetrazoles; D011188:Potassium