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Induction of a novel cation current in cardiac ventricular myocytes by flufenamic acid and related drugs
Author(s) -
Macianskiene R,
Gwanyanya A,
Sipido KR,
Vereecke J,
Mubagwa K
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00901.x
Subject(s) - flufenamic acid , niflumic acid , chemistry , trpc3 , biophysics , extracellular , patch clamp , pharmacology , membrane potential , myocyte , biochemistry , transient receptor potential channel , endocrinology , trpc , receptor , biology
BACKGROUND AND PURPOSE Interest 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 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 α‐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.