title: Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of IKr blockade.
abstract: OBJECTIVE
  Drug-induced torsades de pointes (TdP) often occurs during bradycardia due to reverse use-dependence. We tested the hypothesis that inhibition or enhancement of late sodium current (I(Na,L) ) could modulate the drug-induced reverse use-dependence in QT and T(p-e) (an index of dispersion of repolarization), and therefore the liability for TdP.
  
  
  METHODS
  Arterially perfused rabbit left ventricular wedge preparations were used. Action potentials from the endocardium were recorded simultaneously with a transmural ECG. The effects of Anemonia sulcata toxin (ATX-II) (an I(Na,L) enhancer), d,l-sotalol, clarithromycin and ranolazine (an I(Na,L) blocker) on rate-dependent changes in QT, T(p-e) and proarrhythmic events were tested, either alone or in combination. Rate-dependent QT and T(p-e) slopes and TdP score (a combined index of TdP liability) were calculated at control and during drug infusion.
  
  
  RESULTS
  ATX-II (30 nM) and sotalol (300 µM) caused a marked increase in QT and T(p-e) intervals, steeper QT-basic cycle length (BCL) and T(p-e) -BCL slopes (i.e. reverse use-dependence), and TdP. Addition of ranolazine (15 µM) to ATX-II or sotalol significantly attenuated QT-BCL, T(p-e) -BCL slopes and the increased TdP scores. In contrast, clarithromycin (100 µM) moderately prolonged QT and T(p-e) without causing R-on-T extrasystole or TdP, but addition of ATX-II (1 nM) to clarithromycin markedly amplified the QT-BCL and T(p-e) -BCL slopes and further increased TdP score.
  
  
  CONCLUSIONS
  Modulation of I(Na,L) altered drug-induced reverse use-dependence related to QT as well as T(p-e) , indicating that inhibition of I(Na,L) can markedly reduce the TdP liability of agents that prolong QT intervals.
authors.affiliation: The First Hospital, Xi'An Jiaotong University, Xi'An, China.
authors.forename: Shaobin
authors.initials: S
authors.lastname: Jia
authors.forename: Jiangfan
authors.initials: J
authors.lastname: Lian
authors.forename: Donglin
authors.initials: D
authors.lastname: Guo
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Xue
authors.forename: Chinmay
authors.initials: C
authors.lastname: Patel
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Yuan
authors.forename: Aiqun
authors.initials: A
authors.lastname: Ma
authors.forename: Gan-Xin
authors.initials: GX
authors.lastname: Yan
mesh_terms: D000083:Acetanilides; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D017291:Clarithromycin / Q000494:pharmacology; D003064:Cnidarian Venoms / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects; D010879:Piperazines; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D011817:Rabbits; D000069458:Ranolazine; D015222:Sodium Channels; D013015:Sotalol / Q000494:pharmacology; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology*
chemical_list: D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D003064:Cnidarian Venoms; D010879:Piperazines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D015222:Sodium Channels; C059983:potassium channel protein I(sk); C028800:toxin II (Anemonia sulcata); D013015:Sotalol; D000069458:Ranolazine; D017291:Clarithromycin