Acute effects of thyroid hormone analogs on sodium currents in neonatal rat myocytes.
We previously reported that T3(3,3',5-triiodo-L-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-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 INa in cultured neonatal rat myocytes (n ranged from 9 to 28 for each comparison). T4, T3, 3,5-T2, and DIT (10 n m) 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 INa 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 INa was blocked when myocytes were pretreated with T3(100 n m, n=3), suggesting an interaction of T3 with amiodarone. The enhancement of INa by T3 and 3, 5-T2 could not be blocked by propranolol, suggesting that the effects are not mediated through beta -adrenergic signaling pathways. In conclusion, the present results suggest that the acute effects of thyroid hormone and analogs on cardiac INa are mediated by a non-genomic thyroid hormone receptor with a unique structure-activity relationship.
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects*; D008564:Membrane Potentials; D007470:Monoiodotyrosine / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000187:drug effects; D012964:Sodium / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013963:Thyroid Hormones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014285:Triiodothyronine, Reverse / Q000494:pharmacology