RT Journal Article
SR Electronic
T1 Pharmacological Profile of the Thyroid Hormone Receptor Antagonist NH3 in Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 385
OP 390
DO 10.1124/jpet.106.116152
VO 322
IS 1
A1 Gary J. Grover
A1 Celeste Dunn
A1 Ngoc-Ha Nguyen
A1 Jamie Boulet
A1 Gao Dong
A1 Jason Domogauer
A1 Peter Barbounis
A1 Thomas S. Scanlan
YR 2007
UL http://jpet.aspetjournals.org/content/322/1/385.abstract
AB 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 cholesterol-lowering 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. The American Society for Pharmacology and Experimental Therapeutics