Effects of toxic doses of a novel histamine (H2) antagonist on the rat thyroid gland.

The oral administration of high doses of a histamine H2 antagonist SK&F 93479 (up to 1000 mg/kg/day) to male rats for up to 21 days resulted in alterations in thyroid morphology indicative of increased activity of the thyroid gland. Measurement of thyroidal 125I incorporation substantiated these findings. Treatment with SK&F 93479 resulted in a dose-dependent increase in thyroidal iodide incorporation. This was apparent after a single dose of the compound and was reversible after dosing for 7 days. The increased incorporation of 125I into the thyroid gland was apparently dependent on thyroid-stimulating hormone (TSH) since both hypophysectomy and pretreatment with thyroxine (T4) markedly reduced thyroidal 125I uptake. Hypothalamic thyrotropin-releasing hormone (TRH) and pituitary TSH concentrations were not altered by SK&F 93479 treatment, and in TRH challenge experiments circulating TSH concentrations showed no change from control levels. These data suggest that hypothalamic-pituitary sensitivity was unaltered by treatment with SK&F 93479. Pharmacological ablation of thyroidal mast-cell function did not alter the thyroid response to 125I accumulation after SK&F 93479 dosing, indicating that the action of the compound is probably not dependent on changes in thyroid mast-cell histamine. Circulating T4 and TSH levels were altered in SK&F 93479-treated rats. Generally, T4 levels were reduced 6 hr after dosing and TSH levels were elevated 24 hr after dosing. Triiodothyronine (T3) levels were unaffected by SK&F 93479 treatment. The effect of SK&F 93479 treatment on T4 clearance was measured by examining the elimination of radioactivity from the circulation of rats previously injected with 125I-labelled T4. One oral dose of 1000 mg SK&F 93479/kg markedly increased T4 clearance. These results suggest that SK&F 93479 affects thyroid activity indirectly by a primary effect on T4 clearance. Reductions in circulating T4 lead to increased TSH levels and subsequent stimulation of thyroid activity.