title: 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.
abstract: The cardiovascular and electrophysiological effects of amiodarone resemble those of hypothyroidism. The drug has a structural resemblance to thyroid hormone (T3). Previous studies indicate that amiodarone exerts its major effect through antagonism of T3, probably as a result of inhibition of ligand binding to the thyroid hormone receptor (ThR). There are five subtypes of ThR, of which the beta 1 is the most prominent in the human heart. Our first aim was to investigate whether ThR is involved in a general antiarrhythmic mechanism for antiarrhythmic drugs or whether this action is specific for amiodarone. Therefore, we studied the affinity of one antiarrhythmic drug from every Vaughan-Williams group on T3 binding to human ThR beta 1 (hThR beta 1). Second, we wished to investigate whether amiodarone is a competitive or noncompetitive inhibitor. hThR beta 1, expressed in insect cells using a recombinant baculovirus, was used in regular binding competition assays. Disopyramide, lignocaine, propafenone, metoprolol, dl-sotalol, and verapamil had no effect on T3 binding to hThR beta 1. Amiodarone showed a noncompetitive binding pattern at low concentrations (0.25-2 microM) and a competitive binding at high concentrations (2-8 microM). Among the antiarrhythmics tested, only amiodarone had affinity for hThR beta 1. This may represent a novel type of antiarrhythmic mechanism. The finding that amiodarone, in concentrations corresponding to therapeutic range in plasma, shifts from a noncompetitive to a competitive inhibitor, is of clinical interest in comparisons of low- and high-dose treatment.
mesh_terms: D000638:Amiodarone / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D004206:Disopyramide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology; D008790:Metoprolol / Q000494:pharmacology; D011405:Propafenone / Q000494:pharmacology; D011988:Receptors, Thyroid Hormone / Q000187:drug effects* / Q000378:metabolism; D013015:Sotalol / Q000494:pharmacology; D014284:Triiodothyronine / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D011405:Propafenone; D008012:Lidocaine; D013015:Sotalol; D014700:Verapamil; D008790:Metoprolol; D004206:Disopyramide; D000638:Amiodarone