The time course of the effect of bovine TSH (bTSH) on serum concentrations of thyroxine (T4) and triiodothyronine (T3) was measured in the normal mouse. The basal, unstimulated levels were 3.2+/-1.1 mug/100 ml T4 and 104+/-25 ng/100 ml T3 (mean+/-SD). With doses of bTSH from 0.5 to 100 mU the peak levels of the thyroid hormones were only 2.6 and 1.8 times the basal level for T4 and T3, respectively. With increasing doses of bTSH there was a proportional prolongation of the increased serum levels of thyroid hormones, i.e., about 2 h for 0.5mU to 12 h for 100 mU TSH. The integrated response with time was linearly related to the log dose. This would suggest a control mechanism which prevents excessive concentration of thyroid hormones in the serum. This pattern of response to TSH differs somewhat from that obtained by following radioiodine release in the McKenzie type bio-assay. To avoid the problems of changing blood concentrations of thyroid hormones and TSH, the release of T4 and T3 from the mouse thyroid was measured in vitro. The secretion increased with bTSH concentrations in the range of 0.02-0.8 mU/ml for T4 and 0.02-0.4 mU/ml for T3. The maximal response was 8.8+/-0.5 ng T4/3h/thyroid and 3.6+/-0.3 ng T3/3h/thyroid as against the basal secretion of 2.4+/-0.2ng T4 and 0.8+/-0.1 ng T3 (mean+/-SEM). Further in crease in bTSH concentration was associated with a decreased rate of thyroid hormone release. Thyroidal cAMP accumulation was enhanced with increasing bTSH concentration, even when there was a decrease in secretion. The dichotomy in the dose-response pattern between the two parameters indicated that the effect of high TSH concentrations on the release was induced at a step beyond cAMP accumulation. This was corroborated by the similar pattern of release induced by increasing concentration of DBcAMP. These findings indicate the existence of an intrathyroidal autoregulatory mechanism which prevents excess increase of thyroid hormone levels in the blood.
Iodide, administered to mice either acutely or chronically, depressed the thyroidal cyclic adenosine monophosphate (cAMP) response to 20 mU bovine TSH. When iodide was administered acutely there was a 60% reduction in the cAMP accumulation after 100 μg, or 1 μg KI given to mice on normal iodine diet (NID), or low iodine diet (LID), respectively. When iodide was administered chronically by supplementing the LID with graded doses of KI for 11 days, the cAMP response to TSH was found to be inversely related to the dietary iodine. Inhibition occurred after 5 μg KI, a dose similar to the daily iodine intake. Iodide depressed, but did not abolish, the thyroidal cAMP response to TSH. Iodide had no effect on phosphodiesterase activity, whereas thyroidal adenyl cyclase activity was diminished by the prior administration of 100 μg KI. The iodide effect was abolished by pre-treatment with methylmercaptoimidazole i.e. the inhibition is related to iodide oxidation. The newly organified thyroidal iodine (NOTI), formed at 2 h from 0.1–1000 μg KI was determined. The amount of NOTI was highly correlated to the degree of inhibition, irrespective of the iodine content of the diet. This relationship was continuous up to 100 ng NOTI and 70% inhibition, which are the maximal values obtained for NOTI formation and inhibition of cAMP accumulation. These plateau levels were reached with 100 or 1 μg KI in mice on NID or LID, respectively. These results indicate that the inhibitor is an iodinated substance whose intrathyroidal formation is quantitatively parallel to, or a part of NOTI.
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