Pharmacological profile of the thyroid hormone receptor antagonist NH3 in rats.
NH3 is a thyroid hormone receptor (TR) antagonist that inhibits binding of thyroid hormones to their receptor and that inhibits cofactor recruitment. It was active in a tadpole tail resorption assay, with partial agonist activity at high concentrations. We determined the effect of NH3 on the cholesterol-lowering, thyroid stimulating hormone (TSH)-lowering, and tachycardic action of thyroid hormone (T(3)) in rats. Cholesterol-fed, euthyroid rats were treated for 7 days with NH3, and a dose response (46.2-27,700 nmol/kg/day) was determined. We also determined the effect of two doses of T(3) on the NH3 dose-response curve. NH3 decreased heart rate modestly starting at 46.2 nmol/kg/day, but the effect was lost at >2920 nmol/kg/day. At 27,700 nmol/kg/day, tachycardia was seen, suggesting partial agonist activity. NH3 increased plasma cholesterol to a maximum of 27% at 462 nmol/kg/day. At higher doses, cholesterol was reduced, suggesting partial agonist activity. Plasma TSH was increased from 46.2 to 462 nmol/kg/day NH3, but at higher doses, this effect was lost, and partial agonist effects were apparent. T(3) at 15.4 and 46.2 nmol/kg/day increased heart rate, reduced cholesterol, and reduced plasma TSH. NH3 inhibited the cholesterol-lowering, TSH-lowering and tachycardic effects of 15.4 nmol/kg/day T(3), but much of the effect was lost at >924 nmol/kg/day doses. NH3 had no effect on the cholesterol-lowering action of 46.2 nmol/kg/day T(3), but it inhibited the tachycardic and TSH suppressant effects up to the 924 nmol/kg/day dose. Single doses of 462 and 27,700 nmol/kg caused no TR inhibitory effects. In conclusion, NH3 has TR antagonist properties on T(3)-responsive parameters, but it has partial agonist properties at higher doses.
Grover
Gary J
GJ
Eurofins Scientific--Product Safety Laboratories, 2394 Hwy. 130, Dayton, NJ 08810, USA. garygrover@productsafetylabs.com
Dunn
Celeste
C
Nguyen
Ngoc-Ha
NH
Boulet
Jamie
J
Dong
Gao
G
Domogauer
Jason
J
Barbounis
Peter
P
Scanlan
Thomas S
TS
D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors*; D013972:Thyrotropin / Q000097:blood; D014284:Triiodothyronine / Q000494:pharmacology
D001555:Benzene Derivatives; C522204:NH3 compound; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D013972:Thyrotropin; D002784:Cholesterol