title: Effects of the antianginal drug, ranolazine, on the brain sodium channel Na(V)1.2 and its modulation by extracellular protons.
abstract: OBJECTIVE
  Ranolazine is an antianginal drug currently approved for treatment of angina pectoris in the United States. Recent studies have focused on its effects on neuronal channels and its possible therapeutic uses in the nervous system. We characterized how ranolazine affects the brain sodium channel, Na(V)1.2, and how its actions are modulated by low pH. In this way, we further explore ranolazine's potential as an anticonvulsant and its efficacy in conditions like those during an ischaemic stroke.
  
  
  METHODS
  We performed whole-cell patch-clamp experiments on the voltage-gated sodium channel, Na(V)1.2. Experiments were performed with extracellular solution titrated to either pH 7.4 or pH 6.0 before and after ranolazine perfusion.
  
  
  RESULTS
  Ranolazine accelerates onset and slows recovery of fast and slow inactivation. Ranolazine increases the maximum probability of use-dependent inactivation and reduces macroscopic and ramp sodium currents at pH 7.4. pH 6.0 reduced the slowing of fast inactivation recovery and inhibited use-dependent block by ranolazine. In the presence of ranolazine, the time constants of slow inactivation recovery and onset were significantly increased at pH 6.0 relative to pH 7.4 with 100 μM ranolazine.
  
  
  CONCLUSIONS
  Our work provides novel insights into the modulation of brain sodium channel, Na(V)1.2, by ranolazine. We demonstrate that ranolazine binds Na(V)1.2 in a state-dependent manner, and that the effects of ranolazine are slowed but not abolished by protons. Our results suggest that further research performed on channels with epilepsy-causing mutations may prove ranolazine to be an efficacious therapy.
authors.affiliation: Molecular Cardiac Physiology Group, Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada. pruben@sfu.ca
authors.forename: C H
authors.initials: CH
authors.lastname: Peters
authors.forename: S
authors.initials: S
authors.lastname: Sokolov
authors.forename: S
authors.initials: S
authors.lastname: Rajamani
authors.forename: P C
authors.initials: PC
authors.lastname: Ruben
mesh_terms: D000083:Acetanilides / Q000494:pharmacology* / Q000627:therapeutic use; D000787:Angina Pectoris / Q000188:drug therapy; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D016466:CHO Cells; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003412:Cricetulus; D045604:Extracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011522:Protons; D000069458:Ranolazine; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D059010:Single-Cell Analysis; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D002316:Cardiotonic Agents; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D010879:Piperazines; D011522:Protons; D011994:Recombinant Proteins; C568253:Scn2A protein, rat; D061567:Voltage-Gated Sodium Channel Blockers; D000069458:Ranolazine