Desethylamiodarone prolongation of cardiac repolarization is dependent on gene expression:: A novel antiarrhythmic mechanism

Desethylamiodarone (DEA) is the major metabolite of amiodarone and has similar electrophysiologic effects with prolongation of the repolarization that is reversed by thyroid hormone (T-3) Some of the electrophysiologic effects are probably due to antagonism of T-3 at the receptor level. Such effects of T-3 are mediated by modulation of gene transcription. The aim of this study was to investigate whether cycloheximide (Cy), an inhibitor of protein synthesis, and actinomycin D (ActD), a RNA-synthesis inhibitor, block DEA-induced prolongation of the repolarization and whether DEA takes part in the autoregulation of the nuclear thyroid hormone-receptor subtypes (ThR). Corrected monophasic action potentials (MAP,) and QT(c) were measured in Langendorff-perfused guinea pig hearts for 1 h. The hearts were continuously perfused with (a) vehicle. (b) 7.5 mu M Cy, (c) 5 mu M DEA, (d) 5 mu M DEA + 7.5 mu M Cy, (e) 1 mu M T-3 (f) 5 mu M DEA + 1 mu M T-3, (g) 1.5 mu M ActD, and (h) ActD + DEA. A potassium channel blocker with class III antiarrhythmic effects, 0.5 mu M almokalant, was used as a control, separately and together with Cy. Western blot analysis for the ThR subtypes alpha, beta(1), and beta(2) was performed on vehicle- and DEA-treated hearts. DEA increased MAPc by 19% (p < 0.0005) and QT(c) by 18% (p < 0.0005). There was no effect on MAP or QT(c) when Cy, ActD, or T3 was added with DEA. Almokalant increased MAP, by 14% (p < 0.005) and QT(c) by 13% (p < 0.0005). When Cy was present, almokalant still induced a similar prolongation of MAP, by 14% (p < 0.005) and QT(c) by 17% (p < 0.0005). Western blot analysis revealed no change in the expression of the ThR protein. In conclusion, the prolongation of the cardiac repolarization by DEA, but not almokalant, can be totally blocked by Cy and ActD. This indicates that the class III action of DEA is at least in part dependent on transcription rather than a direct effect on cell-membrane channels or receptors. The action of DEA could be reversed by T-3, indicating an antagonism between DEA and T3 These results suggest a new antiarrhythmic mechanism dependent on gene expression.