title: Use-dependent block of cardiac late Na(+) current by ranolazine.
abstract: BACKGROUND
  Ranolazine is an antianginal drug that inhibits the cardiac late Na+ current (INa). The selectivity of ranolazine to block late INa relative to peak INa at rapid heart rates has not been determined, but is potentially important to drug efficacy and safety.
  
  
  OBJECTIVE
  This study sought to quantify use-dependent block (UDB) of cardiac peak and late INa by ranolazine.
  
  
  METHODS
  Wild-type (WT) and long QT3 mutation R1623Q channels were expressed in HEK293 cells and studied using whole-cell patch-clamp technique.
  
  
  RESULTS
  Ranolazine (1 to 300 microM caused tonic (0.1 Hz) and UDB (1, 2, and 5 Hz) of WT and R1623Q peak INa. The IC50 values for block of WT and R1623Q peak INa at 0.1, 1, 2, and 5 Hz were 430, 260, 157, and 154 microM, and 95, 77, 37, and 25 microM, respectively. The IC50 values for block of R1623Q late INa at 0.1, 1, 2, and 5 Hz were 7.5, 7.3, 2.2, and 1.9 microM, respectively. Ranolazine (10 microM) caused a hyperpolarizing shift of WT and R1623Q peak INa steady-state inactivation without affecting steady-state activation, suggesting that ranolazine interacts with inactivated states of the channels. Ranolazine (30 microM) significantly slowed the recovery from inactivation of peak INa of both WT and R1623Q and late INa of R1623Q.
  
  
  CONCLUSIONS
  Ranolazine slowed recovery of late INa from inactivation and thus caused UDB of late INa. These data suggest that the effect of ranolazine to block late INa may be increased and the selectivity to block late INa relative to peak INa may be retained during tachycardia.
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Palo Alto, California 94304, USA. Sridharan.rajamani@gilead.com
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.forename: Nesrine
authors.initials: N
authors.lastname: El-Bizri
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000083:Acetanilides / Q000494:pharmacology* / Q000627:therapeutic use; D000200:Action Potentials / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D000069458:Ranolazine; D015222:Sodium Channels / Q000187:drug effects*; D013610:Tachycardia / Q000188:drug therapy
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D015222:Sodium Channels; D000069458:Ranolazine