Amiodarone antagonizes the effects of T3 at the receptor level: An additional mechanism for its in vivo hypothyroid-like effects

Abstract

Amiodarone is a diiodinated benzofuran derivative that has some structural similarities to the thyroid hormones and contains two iodine atoms per molecule. It has exhibited hypothyroid-like effects that are thought to be the result of an inhibition of thyroid hormone synthesis due to iodine load, a decrease in the T4 to T3 conversion, and (or) a competitive binding for T3 receptors. The aim of this study was to determine if this third mechanism contributes to the hypothyroid-like effects of amiodarone in vivo. To do so, some characteristic features known to be influenced by hypothyroidism were determined in surgically thyroidectomized rats (n = 48), which received replacement doses of T3 (0.5 and 1.0 μg∙100∙g−1∙day−1) with or without amiodarone (60 mg∙kg−1∙day−1). Thyroidectomy produced a hypothyroid state upon which amiodarone had no detectable effects except a negative body weight gain. T3 (0.5 μg) nearly normalized the thyroid status of the animals, but the concomitant administration of amiodarone induced hypothyroid-like effects suggesting that these effects are dependent on T3. Higher doses of T3 (1.0 μg) produced hyperthyroid-like effects and attenuated the effects of amiodarone. Unexpectedly, amiodarone decreased T3 plasma concentrations. To determine if the effects of amiodarone were the results of a decrease in T3 plasma and myocardial concentrations or a competition with T3 for its receptors, exogenous T3 pharmacokinetics were studied in thyroidectomized rats receiving T3 (0.5 μg) with or without amiodarone. The results suggested that amiodarone increased T3 cardiac concentrations. It was therefore concluded that, in addition to affecting thyroid hormone synthesis and T4 to T3 conversion, amiodarone seems to antagonize the effects of T3 at the receptor level by a competitive mechanism.Key words: amiodarone, hypothyroid-like effects, T3 receptors.