Pharmacological profile of the thyroid hormone receptor antagonist NH3 in rats

Gary J. Grover, Celeste Dunn, Ngoc Ha Nguyen, Jamie Boulet, Gao Dong, Jason Domogauer, Peter Barbounis, Thomas S. Scanlan

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

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 (T3) 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 T3 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. T3 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 T3, but much of the effect was lost at >924 nmol/kg/day doses. NH3 had no effect on the cholesterollowering action of 46.2 nmol/kg/day T3, 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 T3-responsive parameters, but it has partial agonist properties at higher doses.

Original languageEnglish (US)
Pages (from-to)385-390
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume322
Issue number1
DOIs
StatePublished - Jul 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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