Cardiac triiodothyronine nuclear receptor binding capacities in amiodarone-treated, hypo- and hyperthyroid rats

Abstract

Parameters that are assumed to be under direct control by thyroid hormonal state were evaluated in amiodarone-treated, hypo- and hyperthyroid rats. Special attention was paid to evaluating similarities between hypothyroid and amiodarone-treated rats, with special focus on myocardial nuclear triiodothyronine (T3) receptor binding characteristics. Rats were rendered hypothyroid by adding KClO4 to the drinking water for 6 weeks (N = 14). Hyperthyroidism was induced by adding 0.003% L-thyroxine to the drinking water for 6 weeks (N = 14). Fourteen rats were treated orally for 6 weeks with amiodarone, whereas 14 rats served as untreated controls. Equilibrium binding characteristics for T3 nuclear receptors were determined by means of a simple and rapid method with excellent reproducibility and sensitivity. Body temperature and heart rate were lowered in hypothyroid and amiodarone-treated rats. Maximum binding capacities of beta-adrenergic receptors were reduced by 39% and 14% (p < 0.05) in hypothyroid and amiodarone-treated rats, respectively, and increased by 28% (p < 0.05) in hyperthyroid rats. Maximum binding capacities for voltage-operated Ca2+ channels were increased by 35% and 16% in hypothyroid and amiodarone-treated rats (p < 0.05), respectively, and decreased by 24% in hyperthyroid rats (p < 0.05). Maximum binding capacities for T3 receptors (expressed per unit of DNA) were reduced by 39% and 32% in hypothyroid and amiodarone-treated rats (p < 0.05), respectively, and increased by 63% in hyperthyroid rats (p < 0.05). In hypothyroid and amiodarone-treated rats, myocardial T3 content was extremely reduced (less than 0.05 nmol/kg and 0.06 +/- 0.08 nmol/kg, respectively, compared with control levels of 1.55 +/- 0.46 nmol/kg). In vitro competition studies of amiodarone and its desethyl analogue revealed that both drugs are potentially capable of displacing T3 from its nuclear receptor at concentrations close to what are considered therapeutic drug levels. Myocardial nuclear T3 receptor maximum binding capacities decreased to a similar degree in hypothyroid and amiodarone-treated rats and increased in hyperthyroid rats. Several other similarities between hypothyroid and amiodarone-treated rats suggest that amiodarone may act by inducing a state of thyroid hormonal resistance.