title: Role of late sodium current in modulating the proarrhythmic and antiarrhythmic effects of quinidine.
abstract: BACKGROUND
  Quinidine is used to treat atrial fibrillation and ventricular arrhythmias. However, at low concentrations, it can induce torsade de pointes (TdP).
  
  
  OBJECTIVE
  The purpose of this study was to examine the role of late sodium current (I(Na)) as a modulator of the arrhythmogenicity of quinidine in female rabbit isolated hearts and cardiomyocytes.
  
  
  METHODS
  Epicardial and endocardial monophasic action potentials (MAPs), ECG signals, and ion channel currents were measured. The sea anemone toxin ATX-II was used to increase late I(Na).
  
  
  RESULTS
  Quinidine had concentration-dependent and often biphasic effects on measures of arrhythmogenicity. Quinidine increased the duration of epicardial MAP (MAPD(90)), QT interval, transmural dispersion of repolarization (TDR), and ventricular effective refractory period. Beat-to-beat variability of MAPD(90) (BVR), the interval from peak to end of the T wave (Tpeak-Tend) and index of Tpeak-Tend/QT interval were greater at 0.1 to 3 micromol/L than at 10-30 micromol/L quinidine. In the presence of 1 nmol/L ATX-II, quinidine caused significantly greater concentration-dependent and biphasic changes of Tpeak-Tend, TDR, BVR, and index of Tpeak-Tend/QT interval. Quinidine (1 micromol/L) induced TdP in 2 and 13 of 14 hearts in the absence and presence of ATX-II, respectively. Increases of BVR, index of Tpeak-Tend/QT interval, and Tpeak-Tend were associated with quinidine-induced TdP. Quinidine inhibited I(Kr), peak I(Na), and late I(Na) with IC(50)s of 4.5 +/- 0.3 micromol/L, 11.0 +/- 0.7 micromol/L, and 12.0 +/- 0.7 micromol/L.
  
  
  CONCLUSIONS
  Quinidine had biphasic proarrhythmic effects in the presence of ATX-II, suggesting that late I(Na) is a modulator of the arrhythmogenicity of quinidine. Enhancement of late I(Na) increased proarrhythmia caused by low but not high concentrations of quinidine.
authors.affiliation: Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, California 94304, USA. lin.wu@cvt.com
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Donglin
authors.initials: D
authors.lastname: Guo
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: James
authors.initials: J
authors.lastname: Hackett
authors.forename: Gan-Xin
authors.initials: GX
authors.lastname: Yan
authors.forename: Zhen
authors.initials: Z
authors.lastname: Jiao
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011802:Quinidine / Q000494:pharmacology*; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D016171:Torsades de Pointes / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D015222:Sodium Channels; D012964:Sodium; D011802:Quinidine