title: Diclofenac prolongs repolarization in ventricular muscle with impaired repolarization reserve.
abstract: BACKGROUND
  The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti-inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle.
  
  
  METHODS
  Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model.
  
  
  RESULTS
  Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 µM). The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl(2) application. Diclofenac (3 mg/kg) did not prolong while dofetilide (25 µg/kg) significantly lengthened the QT(c) interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QT(c). Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP) while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%). In single ventricular cells diclofenac (30 µM) decreased the amplitude of rapid (I(Kr)) and slow (I(Ks)) delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (I(Ca)) was slightly diminished, but the transient outward (I(to)) and inward rectifier (I(K1)) potassium currents were not influenced.
  
  
  CONCLUSIONS
  Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve.
authors.affiliation: Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Kristóf
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Husti
authors.forename: István
authors.initials: I
authors.lastname: Koncz
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Kohajda
authors.forename: Tamás
authors.initials: T
authors.lastname: Szél
authors.forename: Viktor
authors.initials: V
authors.lastname: Juhász
authors.forename: Péter
authors.initials: P
authors.lastname: Biliczki
authors.forename: Norbert
authors.initials: N
authors.lastname: Jost
authors.forename: István
authors.initials: I
authors.lastname: Baczkó
authors.forename: Julius Gy
authors.initials: JG
authors.lastname: Papp
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.forename: László
authors.initials: L
authors.lastname: Virág
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology*; D004285:Dogs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D016276:Ventricular Function / Q000187:drug effects*
chemical_list: D016861:Cyclooxygenase Inhibitors; D004008:Diclofenac