Desethylamiodarone (DEA) is the major metabolite of amiodarone and has similar 
electrophysiologic effects with prolongation of the repolarization that is 
reversed by thyroid hormone (T3). Some of the electrophysiologic effects are 
probably due to antagonism of T3 at the receptor level. Such effects of T3 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 (MAPc) and QTc were measured in Langendorff-perfused guinea pig 
hearts for 1 h. The hearts were continuously perfused with (a) vehicle, (b) 7.5 
microM Cy, (c) 5 microM DEA, (d) 5 microM DEA + 7.5 microM Cy, (e) 1 microM T3, 
(f) 5 microM DEA + 1 microM T3, (g) 1.5 microM ActD, and (h) ActD + DEA. A 
potassium channel blocker with class III antiarrhythmic effects, 0.5 microM 
almokalant, was used as a control, separately and together with Cy. Western blot 
analysis for the ThR subtypes alpha, beta1, and beta2 was performed on vehicle- 
and DEA-treated hearts. DEA increased MAPc by 19% (p < 0.0005) and QTc by 18% (p 
< 0.0005). There was no effect on MAPc or QTc when Cy, ActD, or T3 was added 
with DEA. Almokalant increased MAPc by 14% (p < 0.005) and QTc by 13% (p < 
0.0005). When Cy was present, almokalant still induced a similar prolongation of 
MAPc by 14% (p < 0.005) and QTc 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 T3, 
indicating an antagonism between DEA and T3. These results suggest a new 
antiarrhythmic mechanism dependent on gene expression.