Acute Effects of Thyroid Hormone Analogs on Sodium Currents in Neonatal Rat Myocytes

We previously reported that T3(3,3′,5-triiodo- -thyronine) acutely increases sodium currents (INa) in neonatal rat myocytes. Here we compare the effects of several thyroid hormone analogs, including T4(3,3′,5,5′-tetraiodo- -thyronine), rT3(3,3′,5′-triiodo- -thyronine), D-T3(3,3′,5-triiodo- -thyronine), 3,5-T2(3,5-diiodo- -thyronine), DIT (3,5-diiodo- -tyrosine), MIT (3-monoiodo- -tyrosine), tetrac (3,3′,5,5′-tetraiodo-thyroacetic acid), triac (3,3′,5-triiodo-thyroacetic acid), and tyrosine, on INain cultured neonatal rat myocytes (nranged from 9 to 28 for each comparison). T4, T3, 3,5-T2, and DIT (10 n ) all increased current density relative to control to a similar degree: to 1.22±0.2, 1.21±0.03, 1.16±0.02 and 1.16±0.03, respectively,P<0.05. In contrast, thyroid hormone analogs with an altered side group of the inner iodophenyl ring, including tetrac, triac, and D-T3, had no effect on INanor did rT3, MIT or tyrosine. Pretreatment with rT3inhibited the effects of T4, T3, 3,5-T2, and DIT. Conversely, the dose-dependent inhibitory effect of amiodarone, an iodinated benzofuran derivative that antagonizes thyroid hormone actions, on INawas blocked when myocytes were pretreated with T3(100 n ,n=3), suggesting an interaction of T3with amiodarone. The enhancement of INaby T3and 3,5-T2could not be blocked by propranolol, suggesting that the effects are not mediated throughβ-adrenergic signaling pathways. In conclusion, the present results suggest that the acute effects of thyroid hormone and analogs on cardiac INaare mediated by a non-genomic thyroid hormone receptor with a unique structure-activity relationship.