Thyroid hormone alpha1 and beta1 receptor mRNA are downregulated by amiodarone in mouse myocardium.
Amiodarone, a powerful antiarrhythmic drug, may exert its effect by antagonism of the thyroid hormone, probably at the receptor level. The aim of this study was to investigate whether amiodarone affects the levels of thyroid hormone receptor (TR) messenger RNA (mRNA) subtypes in mouse hearts. Mice were treated with 10, 25, and 50 mg/kg body weight (BW) amiodarone or vehicle (propyleneglycol) intraperitoneally, daily for 14 days. The heart rate dose-dependently decreased in the 25 mg/kg BW (p < 0.05) and 50 mg/kg BW (p < 0.005) amiodarone-treated mice compared with control. Serum T3 levels were significantly decreased by 25% (4.2 +/- 0.7 pM) in the 50 mg/kg BW amiodarone group in comparison to control (5.6 +/- 1.4 pM; p < 0.05). The serum T4 levels were 1.3 times higher in 50 mg/kg BW amiodarone-treated mice (13.2 +/-1.6 pM) compared with the control (10.3 +/- 1.3 pM; p < 0.005). Determination of TRalpha1, alpha2, beta1, and beta2 mRNA in the heart were performed by reverse transcriptase-polymerase chain reaction (RT-PCR)/enzyme-linked immunosorbent assay (ELISA). Both in treated and untreated mice, TRalpha2 mRNA had the highest density in mouse heart, whereas TRbeta2 mRNA had the lowest density. Amiodarone dose-dependently downregulated the levels of TRalpha1 and beta1 mRNA in comparison to the control. There were, however, no differences in the TRalpha2 and TRbeta2 mRNA levels in the mice heart treated with different doses of amiodarone in comparison with the control group. In conclusion, this study shows that amiodarone subtype selectively downregulates the TR mRNA levels in mouse myocardium in a dose-dependent manner. These results support a thyroid hormone-dependent action of amiodarone.
Shahrara
S
S
Department of Cardiology, Karolinska Institute, Huddinge Hospital, Sweden.
Drvota
V
V
D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis*; D011988:Receptors, Thyroid Hormone / Q000187:drug effects* / Q000235:genetics; D013963:Thyroid Hormones / Q000097:blood
D000889:Anti-Arrhythmia Agents; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D000638:Amiodarone