Induction of a novel cation current in cardiac ventricular myocytes by flufenamic acid and related drugs.

background and purposeInterest in non-selective cation channels has increased recently following the discovery of transient receptor potential (TRP) proteins, which constitute many of these channels. EXPERIMENTAL APPROACH: 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. KEY

resultsWith 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 AND IMPLICATIONS: 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.