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 ef fect by antagonism of thyroid hormone (T3), probably at the receptor l evel. T3 is known to regulate beta-adrenergic receptor density in the heart but the effects of sympathomimetic drugs on thyroid hormone rece ptors (T3R) is trot known. The aim of this study was to investigate: h ow amiodarone and isoproterenol affect T3R-mRNA in cultured cardiomyoc ytes. Confluent, isoproterenol pretreated, AT-1 cardiomyocytes were tr eated with isoproterenol free medium, amiodarone, T3 and amiodarone to gether with T3 for 48 hours. Solution hybridization for the determinat ion of mRNA for T3R alpha(1), alpha(2), beta(1) and beta(2) were perfo rmed. In itself isoproterenol upregulated T3R alpha(1), T3R beta(1), T 3R beta(2) (p<0.05), but did not affect the levels of T3R alpha(2). Am iodarone 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 T 3R beta(1) (p<0.05) as compared to amiodarone or T3 alone. There was a n 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 r egulation of T3R-mRNA levels provides further evidence for the close i nteraction between the thyroid hormone and the beta-adrenergic systems . (C) 1995 Academic Press, Inc.