title: Induction of a novel cation current in cardiac ventricular myocytes by flufenamic acid and related drugs.
abstract: OBJECTIVE
  Interest in non-selective cation channels has increased recently following the discovery of transient receptor potential (TRP) proteins, which constitute many of these channels.
  
  
  METHODS
  We used the whole-cell patch-clamp technique on isolated ventricular myocytes to investigate the effect of flufenamic acid (FFA) and related drugs on membrane ion currents.
  
  
  RESULTS
  With voltage-dependent and other ion channels inhibited, cells that were exposed to FFA, N-(p-amylcinnamoyl)anthranilic acid (ACA), ONO-RS-082 or niflumic acid (NFA) responded with an increase in currents. The induced current reversed at +38 mV, was unaffected by lowering extracellular Cl(-) concentration or by the removal of extracellular Ca(2+) and Mg(2+), and its inward but not outward component was suppressed in Na(+)-free extracellular conditions. The current was suppressed by Gd(3+) but was resistant to 2-aminoethoxydiphenyl borate (2-APB) and to amiloride. It could not be induced by the structurally related non-fenamate anti-inflammatory drug diclofenac, nor by the phospholipase-A(2) inhibitors bromoenol lactone and bromophenacyl bromide. Muscarinic or alpha-adrenoceptor activation or application of diacylglycerol failed to induce or modulate the current.
  
  
  CONCLUSIONS
  Flufenamic acid and related drugs activate a novel channel conductance, where Na(+) is likely to be the major charge carrier. The identity of the channel remains unclear, but it is unlikely to be due to Ca(2+)-activated (e.g. TRPM4/5), Mg(2+)-sensitive (e.g. TRPM7) or divalent cation-selective TRPs.
authors.affiliation: Division of Experimental Cardiac Surgery, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Macianskiene
authors.forename: A
authors.initials: A
authors.lastname: Gwanyanya
authors.forename: K R
authors.initials: KR
authors.lastname: Sipido
authors.forename: J
authors.initials: J
authors.lastname: Vereecke
authors.forename: K
authors.initials: K
authors.lastname: Mubagwa
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005439:Flufenamic Acid / Q000737:chemistry / Q000494:pharmacology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D013552:Swine; D050053:TRPM Cation Channels / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels; D005439:Flufenamic Acid; D002118:Calcium