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

We previously reported that T-3 (3,3',5-triiodo-L-thyronine) acutely increa ses sodium currents (I-Na) in neonatal rat myocytes. Here we compare the ef fects of several thyroid hormone analogs, including T-4 (3,3',5,5'-tetraiod o-L-thyronine), rT(3) (3,3',5'-triiodo-L-thyronine), D-T-3 (3,3',5-triiodo- D-thyronine), 3,5-T-2 (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-triiodothyroacetic acid), and tyrosine, on I-Na in culture d neonatal rat myocytes (n ranged from 9 to 28 for each comparison). T-4, T -3, 3,5-T-2, and DIT (10nM) all increased current density relative to centr al 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-T-3, had no effect on I-Na nor did rT(3), MIT or tyrosine. Pre treatment with rT(3) inhibited the effects of T-4, T-3, 3,5-T-2, and DIT. C onversely, the dose-dependent inhibitory effect of amiodarone, an iodinated benzofuran derivative that antagonizes thyroid hormone actions, on I-Na wa s blocked when myocytes were pretreated with T-3 (100nM, n=3), suggesting a n interaction of T-3 with amiodarone. The enhancement of I-Na by T-3 and 3, 5-T-2 could not be blocked by propranolol, suggesting that the effects are not mediated through P-adrenergic signaling pathways. In conclusion, the pr esent results suggest that the acute effects of thyroid hormone and analogs on cardiac I-Na are mediated by a non-genomic thyroid hormone receptor wit h a unique structure-activity relationship. (C) 1999 Academic Press.