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 repolariz ation that is reversed by thyroid hormone (T-3) Some of the electrophy siologic effects are probably due to antagonism of T-3 at the receptor level. Such effects of T-3 are mediated by modulation of gene transcr iption. 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 repolar ization and whether DEA takes part in the autoregulation of the nuclea r thyroid hormone-receptor subtypes (ThR). Corrected monophasic action potentials (MAP,) and QT(c) were measured in Langendorff-perfused gui nea 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 C y, (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 antiarrhyth mic effects, 0.5 mu M almokalant, was used as a control, separately an d 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 wi th 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 repolarizatio n by DEA, but not almokalant, can be totally blocked by Cy and ActD. T his indicates that the class III action of DEA is at least in part dep endent on transcription rather than a direct effect on cell-membrane c hannels or receptors. The action of DEA could be reversed by T-3, indi cating an antagonism between DEA and T3 These results suggest a new an tiarrhythmic mechanism dependent on gene expression.