AMIODARONE IS A DOSE-DEPENDENT NONCOMPETITIVE AND COMPETITIVE INHIBITOR OF T3 BINDING TO THYROID-HORMONE RECEPTOR SUBTYPE BETA-1, WHEREAS DISOPYRAMIDE, LIGNOCAINE, PROPAFENONE, METOPROLOL, DL-SOTALOL, AND VERAPAMIL HAVE NO INHIBITORY EFFECT

The cardiovascular and electrophysiological effects of amiodarone rese mble those of hypothyroidism. The drug has a structural resemblance to thyroid hormone (T3). Previous studies indicate that amiodarone exert s its major effect through antagonism of T3, probably as a result of i nhibition of ligand binding to the thyroid hormone receptor (ThR). The re are five subtypes of ThR, of which the beta(1) is the most prominen t in the human heart. Our first aim was to investigate whether ThR is involved in a general antiarrhythmic mechanism for antiarrhythmic drug s or whether this action is specific for amiodarone. Therefore, we stu died the affinity of one antiarrhythmic drug from every Vaughan-Willia ms group on T3 binding to human ThR beta(1) (hThR beta(1)). Second, we wished to investigate whether amiodarone is a competitive or noncompe titive inhibitor. hThR beta(1), expressed in insect cells using a reco mbinant baculovirus, was used in regular binding competition assays. D isopyramide, lignocaine, propafenone, metoprolol, dl-sotalol, and vera pamil had no effect on T3 binding to hThR beta(1). Amiodarone showed a noncompetitive binding pattern at low concentrations (0.25-2 mu M) an d a competitive binding at high concentrations (2-8 mu M). Among the a ntiarrhythmics tested, only amiodarone had affinity for hThR beta(1). This may represent a novel type of antiarrhythmic mechanism. The findi ng that amiodarone, in concentrations corresponding to therapeutic ran ge in plasma, shifts from a noncompetitive to a competitive inhibitor, is of clinical interest in comparisons of low- and high-dose treatmen t.