Acute effects of thyroid hormone analogs on sodium currents in neonatal rat myocytes

Abstract

We previously reported that T3 (3,3',5-triiodo-L-thyronine) acutely increases sodium currents (I(Na)) in neonatal rat myocytes. Here we compare the effects of several thyroid hormone analogs, including T4 (3,3',5',5'-tetraiodo-L-thyronine), rT3 (3,3',5'-triiodo-L-thyronine), D-T3 (3,3',5-triiodo-D-thyronine), 3,5-T2 (3,5-diiodo-L-thyronine), DIT (3,5-diiodo-L-tyrosine), MIT (3-monoiodo-L-tyrosine), tetrac (3,3',5,5'-tetraiodo-thyroacetic acid), triac (3,3',5-triiodo-thyroacetic acid), and tyrosine, on I(Na) in cultured neonatal rat myocytes (n ranged from 9 to 28 for each comparison). T4, T3, 3,5-T2, and DIT (10 nM) 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 I(Na) nor did rT3, MIT or tyrosine. Pretreatment with rT3 inhibited 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 I(Na) was blocked when myocytes were pretreated with T3 (100 nM, n = 3), suggesting an interaction of T3 with amiodarone. The enhancement of I(Na) by T3 and 3,5-T2 could not be blocked by propranolol, suggesting that the effects are not mediated through β-adrenergic signaling pathways. In conclusion, the present results suggest that the acute effects of thyroid hormone and analogs on cardiac I(Na) are mediated by a non-genomic thyroid hormone receptor with a unique structure-activity relationship.