Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present work, we determined the activity of voltage-dependent dihydropyridine (DHP)-sensitive Ca2+ channels related to PRL, GH, and LH secretion in primary cultures of pituitary cells from male or female rats. We investigated their modulation by 17 beta-estradiol (E2) and their involvement in dopamine (DA) and somatostatin (SRIF) inhibition of PRL and GH release. BAY-K-8644 (BAYK), a DHP agonist which increases the opening time of already activated channels, stimulated PRL and GH secretion in a dose-dependent manner. The effect was more pronounced on PRL than on GH release. BAYK-evoked hormone secretion was further amplified by simultaneous application of K+ (30 or 56 mM) to the cell cultures; in parallel, BAYK-induced 45Ca uptake by the cells was potentiated in the presence of depolarizing stimuli. In contrast, BAYK was unable to stimulate LH secretion from male pituitary cells, but it potentiated LHRH- as well as K+-induced LH release; it had only a weak effect on LH secretion from female cell cultures. Basal and BAYK-induced pituitary hormone release were blocked by the Ca2+ channel antagonist nitrendipine. Under no condition did BAYK affect the hydrolysis of phosphoinositides or cAMP formation. Pretreatment of female pituitary cell cultures with E2 (10(-9) M) for 72 h enhanced LH and PRL responses to BAYK, but was ineffective on GH secretion. DA (10(-7) M) inhibited basal and BAYK-induced PRL release from male or female pituitary cells treated or not treated with E2 (10(-9) M). SRIF (10(-9) and 10(-8) M) reversed BAYK-evoked GH release to the same extent in cell cultures derived from male or female animals. It was ineffective on BAYK-induced PRL secretion in the absence of E2, but antagonized it after E2 pretreatment. The effect was dependent upon the time of steroid treatment and was specific, since 17 alpha-estradiol was inactive. In addition, DA and SRIF decreased the 45Ca uptake induced by the calcium agonist. These data demonstrate that DHP-sensitive voltage-dependent calcium channels of the L type present on different pituitary cells are not equally susceptible to BAYK activation under steady state basal conditions, indicating that their spontaneous activity and/or distribution vary according to the cell type; their activity is modulated by sex steroids. In addition, these data suggest that Ca2+ channels represent a possible site of DA and SRIF inhibition of PRL and GH release, respectively, by gating calcium entry into the corresponding cells.
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PMID:Dihydropyridine-sensitive calcium channel activity related to prolactin, growth hormone, and luteinizing hormone release from anterior pituitary cells in culture: interactions with somatostatin, dopamine, and estrogens. 246 51

Light microscopic double immunocytochemical stainings, performed on sea bass hypothalamo-hypophysial sections, revealed the projection of different neuropeptide-immunoreactive neurons innervating the hormone-producing cell populations in the pituitary gland. In the rostral pars distalis (PD) the ACTH cells were found in close proximity to fibers immunoreactive for somatostatin (SRIF), growth hormone-releasing hormone (GRF), corticotropin-releasing hormone (CRF), vasotocin (VT), isotocin (IT), substance P (SP), neurotensin, and galanin (GAL), while the PRL cell zone seemed only innervated by nerve fibers immunopositive for GAL. In the proximal PD, fibers immunoreactive for SRIF, GRF, VT, IT, cholecystokinin, SP, neuropeptide Y, and GAL formed a close relationship with the growth hormone cells. The gonadotrophs were observed near nerve fibers immunostained for gonadotropin-releasing hormone, IT, and less obviously GRF and VT, while fibers positive for GRF, CRF, VT, IT, SP, and GAL penetrated between and formed a close association with the thyrotrophs. In the pars intermedia the MSH cells and the PAS-positive (PAS+) cells seemed both innervated by separate nerve fibers immunoreactive for GRF, CRF, melanin concentrating hormone, VT, IT, and SP. All these results suggest a functional role of the neuropeptides in the adenohypophysis of the sea bass, possibly in the synthesis and/or release of hypophysial hormones from the different cell types.
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PMID:Immunocytochemical demonstration of close relationships between neuropeptidergic nerve fibers and hormone-producing cell types in the adenohypophysis of the sea bass (Dicentrarchus labrax). 246 54

Both insulin-like growth factor I (IGF-I) and somatostatin (SRIH) have been shown to directly inhibit GH release and the total GH content of cultured pituitary cells. In the present study we evaluated the interrelationship between the effects of a recombinant human IGF-I analog ([Thr59]IGF-I) and SRIH on GH release by cultured normal rat pituitary cells together with the effects of glucocorticoids. In all experiments anterior pituitary cells were preincubated for 24 h without or with IGF-I, SRIH, and/or dexamethasone. Thereafter, 24-h incubations without or with IGF-I, dexamethasone, SRIH, and GHRH were performed. Both IGF-I and SRIH inhibited basal and GHRH-stimulated GH release in a dose-dependent manner; the maximal inhibitory concentrations were 5 nM IGF-I and 10 nM SRIH. These concentrations inhibited basal and GHRH-stimulated GH release by 23% and 40% (IGF-I) and 80% and 85% (SRIH), respectively. The combination of IGF-I and low concentrations of SRIH exerted an additive inhibitory effect on GHRH-stimulated GH release; IGF-I (1 nM) and SRIH (10 pM) together inhibited GH release by 50%, while the maximal inhibitory concentrations of 5 nM IGF-I and 10 nM SRIH virtually completely inhibited GH release (by 93%). Preincubation with 5 and 100 nM dexamethasone attenuated the sensitivity of somatotrophs to SRIH and completely abolished the inhibitory effects of IGF-I. This effect of dexamethasone could be reversed by coincubation with the glucocorticoid receptor antagonist RU 38486. High concentrations of 5-10 nM of the recombinant human IGF-I analog stimulated PRL cell content (5 and 10 nM) and release (10 nM), while a purified IGF-I preparation extracted from human blood exerted a parallel inhibitory effect on GH and PRL release. We conclude that 1) IGF-I and SRIH exert an additive direct inhibitory effect on basal and GHRH-stimulated GH secretion by normal cultured pituitary cells; 2) glucocorticoids directly attenuate the sensitivity of somatotrophs to SRIH, but completely prevent the inhibitory effects of IGF-I on GH secretion; and 3) in contrast to a purified IGF-I preparation extracted from human blood (which inhibits GH and PRL release) high concentrations of the recombinant IGF-I preparation (which inhibit GH release) stimulate PRL production.
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PMID:The interrelationship between the effects of insulin-like growth factor I and somatostatin on growth hormone secretion by normal rat pituitary cells: the role of glucocorticoids. 249 19

Acromegaly and hyperprolactinemia have been reported in association with the McCune-Albright syndrome, but the pathophysiology of the GH and PRL hypersecretion that occurs in patients with this disorder has not been defined. We studied GH and PRL secretory dynamics in three patients with McCune-Albright syndrome and hypersecretion of these hormones. Each patient had excessive linear growth, glucose-non-suppressible plasma GH concentration, and GH responsiveness to TRH and GHRH. In response to exogenous GHRH, plasma GH concentrations rose approximately 2-fold in all three patients. Plasma GHRH levels were 20-40 ng/L (normal, less than 30). Study of the spontaneous GH secretory pattern in two patients indicated nocturnal augmentation of GH release. Bromocriptine therapy failed to reduce plasma GH in all patients; in one patient treatment with octreotide, a long-acting somatostatin analog, partially suppressed plasma GH and insulin-like growth factor I levels. These results suggest that hypersecretion of GH in the McCune-Albright syndrome is not due to ectopic GHRH production or autonomous somatotroph function. The results are similar to those described in classic acromegaly due to GH-secreting pituitary tumors. However, the lack of radiographic pituitary enlargement, the variable pituitary pathology reported in similar patients, and frequent concordance of GH and PRL excess suggest that the pathogenesis of this disorder may differ fundamentally from other forms of acromegaly or gigantism. The pathophysiology may reflect abnormal hypothalamic regulation and/or an embryological defect in pituitary cellular differentiation and function.
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PMID:Hypersecretion of growth hormone and prolactin in McCune-Albright syndrome. 249 85

Plasma levels of secretin, vasoactive intestinal polypeptide (VIP), somatostatin (SRIH), motilin, and/or pancreatic polypeptide, as well as serum estradiol, progesterone, PRL, LH, FSH, and/or GH were measured during the follicular phase, midcycle, and luteal phase of a spontaneous menstrual cycle in eight women and during ovarian stimulation with clomiphene citrate/human menopausal gonadotropin and hCG for in vitro fertilization in nine women. Plasma SRIH concentrations were significantly (P less than 0.02) higher in the luteal phase of spontaneous menstrual cycles than in follicular phase and midcycle. Serum GH levels, however, did not change. Plasma motilin concentrations also were higher in the luteal phase than at mid-cycle (P less than 0.04). Plasma secretin, VIP, and pancreatic polypeptide concentrations did not change during the cycle. Throughout the spontaneous menstrual cycle we found significant positive correlations between plasma SRIH and serum progesterone (P less than 0.007; r = 0.5869), plasma motilin and serum progesterone (P less than 0.02; r = 0.5331), plasma secretin and serum estradiol (P less than 0.04; r = 0.4711), and plasma secretin and serum PRL (P less than 0.02; r = 0.5507). During ovarian stimulation both plasma secretin and VIP gradually increased to a peak on cycle days 0 and 1, respectively (day 0 = the day of hCG injection), whereas plasma SRIH did not change. Serum estradiol and PRL increased significantly, and both peaked on cycle day 1. During ovarian stimulation plasma secretin correlated significantly with serum estradiol (P less than 0.00001; r = 0.9333), serum PRL (P less than 0.03; r = 0.6521), and plasma VIP (P less than 0.03; r = 0.6534). In addition, plasma VIP and serum PRL both correlated significantly with serum estradiol (P less than 0.05; r = 0.6024 and P less than 0.04; r = 0.6384, respectively). These results indicate 1) a possible effect of progesterone on the release of SRIH and motilin during the spontaneous menstrual cycle; 2) the unaltered serum GH concentrations in the luteal phase of the spontaneous menstrual cycle despite elevated plasma SRIH levels are probably due to a stimulatory effect of both progesterone and motilin on GH release; and 3) the increase in plasma secretin and VIP concentrations during ovarian stimulation is probably secondary to the concomitant increase in serum estradiol and/or PRL. We suggest that estradiol and/or PRL beyond a certain threshold level stimulate the release of secretin, and possibly also VIP, into plasma.
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PMID:Plasma gastrointestinal hormones during spontaneous and induced menstrual cycles. 249 86

Microinjection of synthetic GRF into the cerebroventricles or hypothalamus of the rat produces a number of neural effects, including the suppression of GH secretion, possibly representing a negative ultrashort loop autoregulation of GRF and/or stimulation of somatostatin neurosecretion. To demonstrate that such neuromodulation acts physiologically through endogenous GRF activity, the peptidic GRF antagonist (N-Ac-Tyr1,D-Arg2)GRF-(1-29)-NH2 was used to block the action of GRF on its presumed receptors in the hypothalamus. First, to establish the efficacy of the antagonist to block GRF receptors in the anterior pituitary, we injected the antagonist iv at doses of 2, 20, and 50 micrograms or saline (controls) into conscious male rats fitted with jugular cannulae. Sequential blood sampling every 15 min for 6 h between 1000-1600 h showed that 50 micrograms antagonist, iv, significantly suppressed the two periods of spontaneous release of radioimmunoassayable GH in controls in the morning and afternoon. A dose of 20 micrograms, iv, lowered mean plasma GH between 1400-1500 h (P less than 0.025), while the 2-microgram dose was without effect. The GRF antagonist was then microinjected into the third ventricle (3V) of conscious male rats at doses of 0.5 and 8.0 ng in 2 microliter sterile saline. The 8.0-ng dose of 3V antagonist elicited a 3-fold increase in the morning peak of GH (nanograms per ml): 3V antagonist, 159.0 +/- 62.0; 3V control, 51.0 +/- 21.9 (P less than 0.05). The 0.5-ng dose was without effect. Finally, we observed that pretreatment with the GRF antagonist 3V (10 ng), followed 15 min later by 10 ng rat GRF administered 3V, completely blocked the GRF-induced suppression of pulsatile GH release observed earlier. Both the systemic and central effects of the antagonist were specific to the control of GH, since PRL concentrations were unaltered. These results 1) have demonstrated the ability of a peptidic GRF antagonist to specifically suppress pulsatile GH release after its systemic administration, presumably by acting on pituitary GRF receptors, and 2) support the notion that GRF receptors are also present in the hypothalamus and are available for the physiological mediation of GRF-induced inhibition of GH release by a central mechanism.
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PMID:Blockade of growth hormone-releasing factor (GRF) activity in the pituitary and hypothalamus of the conscious rat with a peptidic GRF antagonist. 253 85

Insulin-like growth factor I (IGF-I) suppresses GH gene transcription and GH secretion, while somatostatin (SRIF) only suppresses GH secretion. The interaction of these inhibitors of GH was, therefore, tested in primary rat pituitary cells grown in serum-free medium. Maximal inhibition of GH secretion (to 30% of the control value) was achieved by 13 nM IGF-I, while 5 nM SRIF suppressed GH to 36% of control secretion. The respective ED50 values for IGF-I and SRIF inhibition of GH secretion were similar (approximately 2.5 nM). Treatment of cells with the two agents together resulted in a further inhibition of basal GH secretion to 18% of control untreated cells (P less than 0.005). Increasing doses of SRIF (2.5-10 nM) in the presence of IGF-I caused a dose-dependent suppression of GH secretion. PRL levels were not altered by these treatments, indicating a selective effect on GH. GRH-induced GH secretion was further attenuated by combined IGF-I and SRIF treatment compared to the effect of either of these two agents alone. Northern analysis showed that IGF-I suppressed GH mRNA transcripts, while SRIF did not alter GH mRNA levels. The results indicate that physiological concentrations of both IGF-I and SRIF suppress long term basal GH secretion. Only IGF-I alters GH mRNA levels. These two peptides, therefore, appear to attenuate in vitro GH secretion by different mechanisms.
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PMID:Insulin-like growth factor-I action on growth hormone secretion and messenger ribonucleic acid levels: interaction with somatostatin. 256 39

In an attempt to delineate the mechanism(s) of PRL secretion from human lactotrophs, the effects of dopamine and somatostatin on PRL release from adenomatous and nonadenomatous human pituitary cells in culture was studied. High K+ and the divalent cation ionophore A23187 both elevated PRL secretion, which was blocked by dopamine and somatostatin. When the cells were incubated in low calcium medium, PRL secretion was significantly inhibited. The addition of dopamine or somatostatin to low calcium medium further decreased PRL release. The stimulatory action of ionophore A23187 on PRL release was found even in the absence of extracellular calcium. Theophylline and isobutylmethylxanthine, when added to the incubation medium, increased PRL secretion, and dopamine as well as somatostatin again inhibited PRL release induced by phosphodiesterase inhibitors. No qualitative difference in these PRL responses was found in adenomatous and nonadenomatous human lactotrophs. In prolactinoma cells obtained from three different patients, cAMP generation was correlated with hormone release. Exposure of the cells to dopamine or somatostatin resulted in a parallel decrease in intracellular cAMP content and PRL secretion. The inhibitory effect of dopamine on PRL secretion and cAMP accumulation was blocked by coincubation of the cells with haloperidol. These results suggest that an increase in cytosol calcium caused by either mobilization from intracellular calcium pools or influx from the extracellular compartment and intracellular cAMP accumulation may be involved in the mechanism of PRL secretion from human lactotrophs, and dopamine and somatostatin may influence these two messengers to suppress PRL secretion.
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PMID:Mechanism of the inhibitory action of dopamine and somatostatin on prolactin secretion from human lactotrophs in culture. 257 87

To determine whether human calcitonin inhibits GH secretion in acromegaly, as previously described for healthy subjects, the effect of an i.v. bolus injection of calcitonin or saline on GH levels in patients with active acromegaly was studied and compared to that of an i.v. bolus injection of the synthetic somatostatin analogue, octreotide. After the injection of calcitonin, GH levels decreased by 46% of initial values, whereas octreotide reduced GH levels by 87% and saline had no significant effect. Administration of calcitonin to acromegalics did not cause the transient rise in plasma PRL and TSH levels seen in normal subjects. Octreotide induced a decrease in plasma PRL in three out of seven patients. It is concluded that human calcitonin suppresses GH secretion in acromegaly, but not to normal levels; moreover the effect is less than that found for octreotide. In addition, acromegalic patients did not exhibit the PRL and TSH-releasing activity of calcitonin found in normal subjects, while octreotide inhibited PRL secretion in some acromegalic patients.
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PMID:The effect of calcitonin on growth hormone secretion in acromegaly. 262 52

Bromocriptine therapy normalizes PRL secretion in most, but not all, patients with prolactinomas. This study was undertaken to determine the mechanism(s) responsible for bromocriptine resistance in patients with a PRL-secreting macroadenomas (n = 5) or microadenomas (n = 3). Their mean basal plasma PRL value was 807 +/- 220 (+/- SE) micrograms/L before treatment, and their nadir mean value was 354 +/- 129 micrograms/L during chronic therapy with 15-30 mg bromocriptine daily; four of the eight patients had an increase in tumor size during therapy. In cultures of prolactinoma cells from patients normally responsive to bromocriptine therapy (n = 10), considered as controls, 10(-9) mol/L bromocriptine inhibited PRL release by 71 +/- 6% (+/- SE), and the half-inhibitory dose was 7 x 10(-11) mol/L. In contrast, in cultures of prolactinoma cells from five patients resistant to bromocriptine, PRL release was inhibited by only 3-42% at 10(-9) mol/L bromocriptine. This partial inhibition was reversed by a 100-fold excess of haloperidol. In contrast, the effects of other inhibitors of PRL release (10(-8) mol/L T3 and 10(-8) mol/L somatostatin) or of a stimulator (10(-8) mol/L angiotensin-II) on cells from resistant and normally responsive patients were similar. In cell membranes from five bromocriptine-responsive adenomas the density of dopaminergic binding sites, labeled by [3H] spiroperidol was 243 +/- 65 (+/- SE) fmol/mg protein. In adenomas from the eight patients resistant to bromocriptine therapy the density of [3H]spiroperidol-binding sites lower (145 +/- 31 fmol/mg protein). In adenomas from five resistant patients whose tumor had grown during therapy the density of binding sites was 25 +/- 3 fmol/mg protein, 10% of that in normally responsive patients. The effects of dopamine on adenylate cyclase activity also were different in the three groups of adenomas. Dopamine inhibited adenylate cyclase activity by 28.8 +/- 5.6% in five bromocriptine-responsive tumors and by 16.5 +/- 4.3% in adenomas from eight resistant patients. In contrast, in the five patients whose tumors grew during therapy dopamine paradoxically stimulated adenylate cyclase activity (+26.4 +/- 9.8%). There was a very good correlation between the density of dopaminergic binding sites and maximal inhibition of adenylate cyclase activity in bromocriptine-responsive prolactinoma patients (r = 0.90) and resistant patients who had no tumor growth during therapy (r = 0.94).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Resistance to bromocriptine in prolactinomas. 276 Jan 67


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