title: Contribution of late sodium current (I(Na-L)) to rate adaptation of ventricular repolarization and reverse use-dependence of QT-prolonging agents.
abstract: BACKGROUND
  Abnormal rate adaptation of ventricular repolarization is arrhythmogenic. There is controversy on the underlying ionic mechanisms for rate-dependent change in repolarization.
  
  
  OBJECTIVE
  The purpose of this study was to examine the role of the late sodium current (I(Na-L)) in normal rate-dependence of ventricular repolarization and reverse use-dependence of QT-prolonging agents.
  
  
  METHODS
  The effects of I(Na-L) blockade, I(Na-L) enhancement, I(Kr) blockade, and changes in extracellular potassium concentration ([K(+)](o)) on rate adaptation of the QT interval and action potential duration (APD) were examined in isolated rabbit ventricular wedges and single myocytes. Rate dependence of I(Na-L), delayed rectifier potassium current (I(K)), and L-type calcium current (I(Ca)) was determined using a whole-cell, voltage clamp technique.
  
  
  RESULTS
  At control, APD exhibited rate-dependent changes in the multicellular preparations as well as in the isolated single ventricular myocytes when [K(+)](o) remained constant. The rate dependence of APD was significantly enhanced by reduction of [K(+)](o) from 4 to 1 mM or by I(Na-L) enhancement but was markedly blunted by the selective sodium channel blocker tetrodotoxin. The I(Kr) blocker dofetilide (3 nM) amplified the QT to basic cycle length slope (71.2 ± 13.1 ms/s vs 35.1 ± 8.8 ms/s in control, n = 4, P <.05). This reverse use-dependence was abolished by tetrodotoxin at 5 μM (11.4 ± 4.3 ms/s, n = 4, P <.01). There were no significant differences in I(Ca) or I(K) over the range of basic cycle lengths from 2,000 to 500 ms. However, I(Na-L) exhibited a significant rate-dependent reduction.
  
  
  CONCLUSIONS
  I(Na-L) is sensitive to rate change due to its slow inactivation and recovery kinetics and plays a central role in the rate dependence of APD/QT and in the reverse use-dependence of select APD/QT-prolonging agents.
authors.affiliation: Lankenau Institute for Medical Research and Main Line Health Heart Center, Wynnewood, Pennsylvania 19096, USA.
authors.forename: Donglin
authors.initials: D
authors.lastname: Guo
authors.forename: Jianfang
authors.initials: J
authors.lastname: Lian
authors.forename: Tengxian
authors.initials: T
authors.lastname: Liu
authors.forename: Robert
authors.initials: R
authors.lastname: Cox
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.forename: Peter R
authors.initials: PR
authors.lastname: Kowey
authors.forename: Gan-Xin
authors.initials: GX
authors.lastname: Yan
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology*; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology*; D011817:Rabbits; D012964:Sodium; D015222:Sodium Channels / Q000502:physiology*; D016276:Ventricular Function / Q000502:physiology*
chemical_list: D002317:Cardiovascular Agents; D015222:Sodium Channels; D012964:Sodium