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Transcainide: biochemical evidence for state-dependent interaction with the class I antiarrhythmic drug receptor

Abstract : The mechanism of action of the lidocaine derivative transcainide was examined using [3H]batrachotoxinin 20 alpha-benzoate, which binds specifically to and stabilizes activated states of the sodium channel. Transcainide (IC50 0.3 microM) inhibited equilibrium [3H]batrachotoxinin binding to sodium channels present on freshly isolated rat cardiac myocytes. Scatchard analysis of [3H]batrachotoxinin binding showed that transcainide both reduced maximal binding and altered the KD for [3H]batrachotoxinin binding, indicating noncompetitive, allosteric inhibition. Inhibition by transcainide of [3H]batrachotoxinin binding was reversible within 60 min. We used state-dependent [3H]batrachotoxinin binding assays to examine whether transcainide preferentially binds to activated or nonactivated sodium channels. Transcainide had little effect on the k-1 of [3H]batrachotoxinin even at concentrations 1000-fold greater than its IC50, indicating low affinity of transcainide for activated channels. However, transcainide decreased the k + 1 of [3H]batrachotoxinin at a concentration very close to its IC50 concentration for inhibiting equilibrium [3H]batrachotoxinin binding. The results are discussed in terms of a model in which transcainide inhibits [3H]batrachotoxinin binding by binding specifically to and stabilizing a nonactivated state of the cardiac sodium channel.
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Submitted on : Friday, January 14, 2022 - 9:47:31 AM
Last modification on : Monday, January 17, 2022 - 4:19:45 PM

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Roger Hill, Ela Thakore, Mohammed Taouis, Henry Duff, Robert Sheldon. Transcainide: biochemical evidence for state-dependent interaction with the class I antiarrhythmic drug receptor. European Journal of Pharmacology, Elsevier, 1991, 203 (1), pp.51-58. ⟨10.1016/0014-2999(91)90789-s⟩. ⟨hal-03525794⟩

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