DOWN-REGULATION OF THYROID-HORMONE RECEPTOR SUBTYPE MESSENGER-RNA LEVELS BY AMIODARONE DURING CATECHOLAMINE STRESS IN-VITRO

Amiodarone, a powerful antiarrhythmic drug, likely exerts its major effect by antagonism of thyroid hormone (T3), probably at the receptor level. T3 is known to regulate beta-adrenergic receptor density in the heart but the effects of sympathomimetic drugs on thyroid hormone receptors (T3R) is trot known. The aim of this study was to investigate: how amiodarone and isoproterenol affect T3R-mRNA in cultured cardiomyocytes. Confluent, isoproterenol pretreated, AT-1 cardiomyocytes were treated with isoproterenol free medium, amiodarone, T3 and amiodarone together with T3 for 48 hours. Solution hybridization for the determination of mRNA for T3R alpha(1), alpha(2), beta(1) and beta(2) were performed. In itself isoproterenol upregulated T3R alpha(1), T3R beta(1), T3R beta(2) (p<0.05), but did not affect the levels of T3R alpha(2). Amiodarone and T3, respectively, downregulated T3R alpha(1), T3R beta(1), T3R beta(2) (p<0.05), but did not affect the levels of T3R alpha(2). Amiodarone and and T3, added together, upregulated T3R alpha(2) and T3R beta(1) (p<0.05) as compared to amiodarone or T3 alone. There was an antagonistic effect between amiodarone and T3 for the regulation T3R beta(1). This is the first evidence showing that amiodarone regulates T3R-mRNA concentrations during cathecholamine stress. Isoproterenol regulation of T3R-mRNA levels provides further evidence for the close interaction between the thyroid hormone and the beta-adrenergic systems. (C) 1995 Academic Press, Inc.