neuromedin-b and Hypothyroidism

Somatostatin inhibits growth hormone and thyrotropin (TSH) secretion. It also enhances the inhibitory effect of thyroid hormone (TH) on TSH by poorly understood mechanisms. We investigated the acute effect of the long-acting somatostatin analogue, octreotide (OCT), on anterior pituitary type 1 (D1) and 2 (D2) deiodinase activity, on liver D1, and on pituitary content of neuromedin B (NB), an autocrine inhibitor of TSH secretion, which is positively regulated by thyroid hormones. Euthyroid or hypothyroid rats were sacrificed at different times after a single subcutaneous injection of OCT (1 microg/kg body weight [BW]). D1 and D2 activities were measured by the release of 125I from 125I reverse triiodothyronine (rT3) under different assay conditions. NB, TSH, T3, and thyroxine (T4) were quantitated by radioimmunoassay (RIA). In euthyroid rats, liver and pituitary D1 activities were decreased (50%) 6 hours after OCT injection; pituitary D2 and NB remained unchanged. In hypothyroid rats, OCT increased near to the level of normal rats both pituitary D1 activity (but not liver) and NB content, at 24 hours and at 6 and 24 hours, respectively (p < 0.05). Pituitary D2, greatly increased by hypothyroidism, showed a small (25%) but significant reduction at 3 hours, persisting at 24 hours (p < 0.01), although it remained higher than that of euthyroid control. Serum thyroid hormones were not affected by OCT injection. The results show that octreotide acutely regulates pituitary deiodinases and NB content, both representing mechanisms that potentially can contribute to somatostatin and octreotide actions on pituitary growth hormone (GH) and TSH secretion and to modulate these cells sensitivity to thyroid hormone action.

Topics: Animals; Hypothyroidism; Iodide Peroxidase; Liver; Male; Neurokinin B; Octreotide; Pituitary Gland; Rats; Rats, Wistar

A role of neuromedin B (NB), a bombesin-like peptide, as an inhibitory paracrine/autocrine regulator of thyrotropin secretion has been suggested. We previously reported (10) that basal thyroid-stimulating hormone (TSH) release in vitro was decreased by NB and increased in the presence of a highly potent antiserum against NB (aNB). In these experiments, we studied the effects of NB (10(-11) - 10(-7) M) and antiserum against NB (aNB, 1:2000 dilution) on basal TSH release and the response to thyrotropin-releasing hormone (TRH) (0.5 x 10(-8) M) from incubated anterior pituitaries from eu-, hypo-, and hyperthyroid rats. As expected, in euthyroid rats NB decreased basal and TRH-stimulated TSH release, but only at the highest concentration tested (10(-7) M). Incubation of the pituitaries from euthyroid rats with the antiserum against NB increased basal TSH release above that from glands of normal rabbit serum-incubated controls, as anticipated based on the concept that NB inhibits TSH release from the pituitary glands of euthyroid animals. The antiserum did not augment the response to TRH, suggesting that NB released in this situation, although suppressing basal release, had no effort on the stimulated release induced by TRH. Glands from hypothyroid rats had a slightly lower basal TSH release and decreased response to TRH than glands from euthyroid rats. They responded with a decrease in basal TSH release at a much lower concentration of NB (10(-9) M) than pituitaries from euthyroid animals. Surprisingly, pituitaries from hypothyroid rats showed a paradoxical increased release of TSH in response to the lowest concentration of NB (10(-11) M), which decreased with increasing concentrations and was not distinguishable from control release in the presence of TRH at the highest concentration of NB (10(-7) M). We hypothesize that the increased responsiveness to the inhibition of basal TSH release by NB in the hypothyroid pituitaries may be related to an upregulation of NB receptors in this situation, in which the release of NB is diminished because of loss of feedback via thyroid hormones. The view that NB secretion was reduced in the hypothyroid situation was supported by the fact that there was no change in TSH release or the response to TRH following treatment with aNB in these animals. Remarkably, in the glands from the hyperthyroid rats, although basal TSH secretion was significantly lower than that from euthyroid pituitaries and response to TRH was also decrease

Topics: Animals; Hyperthyroidism; Hypothyroidism; Immune Sera; In Vitro Techniques; Male; Neurokinin B; Pituitary Gland, Anterior; Rats; Rats, Sprague-Dawley; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone

Neuromedin B (NB), a bombesin-like peptide, has been recently characterized as a physiological paracrine/autocrine inhibitor of thyrotropin (TSH) secretion. We hypothesized on the basis of our prior experiments that thyroid hormones stimulate pituitary NB secretion which mediates, at least in part, the TSH-suppressive effect of thyroid hormone. Here, we evaluated the time-course of the effect of thyroid hormones administration to eu- and hypothyroid rats on the anterior pituitary content of NB and on serum TSH. As previously reported, the pituitary content of NB increased in hyperthyroidism and decreased in hypothyroidism. Chronic treatment of hypothyroid rats with a physiological dose of thyroxine (0.8 microgram/100 g b.w. s.c, for 3 or 5 days) normalized pituitary NB content, while 5 days of treatment with a pharmacological dose of thriiodothyronine (0.4 microgram/100 g b.w.) induced an increase above that of normal pituitaries. Thyroxine and triiodothyronine injected once, s.c., into hypothyroid rats required 30 min to normalize NB content, which reached higher than normal values in 3-6 h. At these times, the increment in NB preceded or was simultaneous with the suppression of serum TSH. This rapid and marked effect on pituitary neuromedin B content, associated in time with TSH suppression, is in agreement with the hypothesis that neuromedin B may mediate at least in part, the acute suppression of TSH release by thyroid hormone, a hypothesis that still needs further verification.

Topics: Animals; Antithyroid Agents; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Neurokinin B; Pituitary Gland; Rats; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine

Neuromedin B (NB) is a bombesin-like peptide that has been recently characterized as a physiological paracrine/autocrine inhibitor of thyrotropin (TSH) secretion. We report here the time course of the effect of thyroxine (T4) administration to hypothyroid rats on the anterior pituitary content of NB. Dutch-Miranda male rats weighing 250-300 g received 0.03% methimazole in the drinking water for 3 weeks. T4 (0.8 microgram/100 g body weight, sc) was given 1/2, 1, 3 or 6 h before sacrifice. One group received saline rather than T4 (hypothyroid control). The groups contained 6 to 8 animals each. NB, extracted from tissue by boiling in acetic acid, was measured by radioimmunoassay, using a highly specific antiserum. Pituitary NB content was significantly increased 4-fold, as early as 1/2 h after T4 injection, while serum TSH level was similar to that of the hypothyroid control group. The peak response to T4 was at 3 h after injection, when NB content was increased 8-fold (hypothyroid: 45 +/- 8; 1/2 h, 223 +/- 15; 1 h, 203 +/- 48; 3 h, 383 +/- 31; 6 h, 224 +/- 30 fmol/mg protein) and serum TSH decreased to the level of normal rats (0.93-1.5 ng/ml) generally observed in our laboratory (hypothyroid: 31 +/- 3; 1/2 h, 26 +/- 3; 1 h, 31 +/- 2; 3 h, 1.3 +/- 0.1; 6 h, 3.7 +/- 0.6 ng/ml). These data suggest that NB synthesis is rapidly induced by thyroxine and this might represent a new regulatory path involved in the acute inhibitory effect of thyroid hormones on TSH secretion.

Topics: Animals; Hypothyroidism; Male; Neurokinin B; Pituitary Gland; Rats; Thyrotropin; Thyroxine

Neuromedin B (NB) is a recently discovered neuropeptide related to bombesin. It is localized to thyrotropes and we have previously shown that it directly inhibits thyrotropin (TSH) release from the anterior pituitary gland of euthyroid rats. In the current studies, we further evaluated the action of NB and antiserum directed against it in euthyroid rats and compared the actions with those in hypo- and hyperthyroid rats. Rats were rendered hypothyroid by treatment with propylthiouracil and hyperthyroid by treatment with thyroxine. In euthyroid rats, NB suppressed TSH release from hemipituitaries in vitro. Incubation of these pituitaries with highly specific antiserum against NB produced a stimulation of TSH release, whereas normal rabbit serum had no effect on the output of TSH. Thus, in euthyroid animals NB is a physiologically significant inhibitor of TSH release from the pituitary. In hypothyroid as in euthyroid animals, NB inhibited TSH release when microinjected into the third ventricle (3V) in the same dose (0.5 micrograms; 0.44 nmol) as in euthyroid rats. TSH release from hemipituitaries of hypothyroid animals was also suppressed by NB as in euthyroid animals. In hypothyroid animals, anti-NB antiserum was ineffective both in vivo after its microinjection into the 3V and in vitro on hemipituitaries, which suggests that the peptide has little physiologic significance in this condition, presumably because of its reduced release from the thyrotropes associated with diminished NB content in the pituitary of the hypothyroid rat. Intraventricular injection of NB failed to lower plasma TSH in hyperthyroid rats, which suggests that the action of the peptide is already maximal in hyperthyroidism. When antiserum to NB was microinjected twice into the 3V, there was a delayed increase in plasma TSH manifest 24 hr after the initial injection. TSH release from pituitaries of these animals was markedly increased in the presence of NB antiserum. Thus, NB has a physiologically significant TSH release-inhibiting action at the pituitary in the hyperthyroid as well as in the euthyroid rat. We conclude that in the euthyroid animal NB acts in an autocrine fashion to suppress TSH release from the thyrotropes directly. In hypothyroidism, NB synthesis and presumably release from the pituitary is decreased, such that there is no physiologic significance to the residual NB release, although the responsiveness to the inhibitory action of the peptide is increased, possibly via u

Topics: Animals; Hyperthyroidism; Hypothyroidism; In Vitro Techniques; Injections, Intraventricular; Neurokinin B; Pituitary Gland, Anterior; Rats; Rats, Inbred Strains; Thyrotropin