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

The central action of peptides to influence GI motility in experimental animals is summarized in Table 1. TRH stimulates gastric, intestinal, and colonic contractility in rats and in several experimental species. A number of peptides including calcitonin, CGRP, neurotensin, NPY, and mu opioid peptides act centrally to induce a fasted MMC pattern of intestinal motility in fed animals while GRF and substance P shorten its duration. The dorsal vagal complex is site of action for TRH-, bombesin-, and somatostatin-induced stimulation of gastric contractility, and for CCK-, oxytocin- and substance P-induced decrease in gastric contractions or intraluminal pressure. The mechanisms through which TRH, bombesin, calcitonin, neurotensin, CCK, and oxytocin alter GI motility are vagally mediated. An involvement of central peptidergic neurons in the regulation of gut motility has recently been demonstrated in Aplysia, indicating that such regulatory mechanisms are important in the phylogenesis. Alterations of the pattern of GI motor activity are associated with functional changes in transit. TRH is so far the only centrally acting peptide stimulating simultaneously gastric, intestinal, and colonic transit in various animals species. Opioid peptides acting on mu receptor subtypes in the brain exert the opposite effect and inhibit concomitantly gastric, intestinal, and colonic transit. Bombesin and CRF were found to act centrally to inhibit gastric and intestinal transit and to stimulate colonic transit in the rat. The antitransit effect of calcitonin and CGRP is limited to the stomach and small intestine. The delay in GI transit is associated with reduced GI contractility for most of the peptides except central bombesin that increases GI motility. Nothing is known about brain sites through which these peptides act to alter gastric emptying and colonic transit. Regarding brain sites influencing intestinal transit, TRH-induced stimulation of intestinal transit in the rat is localized in the lateral and medial hypothalamus and medial septum. The periaqueductal gray matter is a responsive site for mu receptor agonist- and neurotensin-induced inhibition of intestinal transit. The neural pathways from the brain to the gut whereby these peptides express their stimulatory or inhibitory effects on GI transit is vagal dependent with the exception of calcitonin. It is not known whether the vagally mediated inhibition of GI transit by these peptides results from a decrease activity of vagal preganglionic fibers synapsing with excitatory myenteric neurons or an activation of vagal preganglionic neurons synapsing with inhibitory myenteric neurons. The lack of specific antagonists for these peptides has hampered the assessment of their physiological role.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Central nervous system action of peptides to influence gastrointestinal motor function. 210 14

Human growth hormone release is affected by a variety of pharmacological and physiological stimuli. We have studied the effect of oral clonidine, insulin hypoglycemia, and exercise on plasma hGH and GHRH levels in 31 healthy short-stature children. Thirteen underwent an oral clonidine test (0.15 mg/m2), 12 an iv. insulin test (0.1 U/kg), and 6 performed exercise (running for 10 min in a defined route). GHRH-1-44 was extracted from plasma on silica columns and determined by RIA. Although all three stimuli induced a marked increase in plasma hGH levels, only clonidine induced a significant increase in plasma GHRH levels. Maximal increment in GHRH during clonidine was 6.82 +/- 1.05 pmol/l (mean +/- SEM) as compared with 0.51 +/- 0.28 and 0.53 +/- 0.62 during hypoglycemia and exercise (p less than 0.0005 and p less than 0.005), respectively. An additional 24 subjects received TRH 0.2 mg/kg iv: 8 TRH alone, 8 TRH and insulin, and 8 TRH and clonidine. Only insulin potentiated the TRH-induced TSH response with a peak of 22.0 +/- 3.2 vs 16.0 +/- 0.8 and 15.3 +/- 1.5 mU/l (p less than 0.025) for TRH alone and TRH and clonidine, respectively. It is suggested that clonidine stimulates hGH secretion mainly through an enhancement of GHRH release, whereas stress stimuli such as hypoglycemia and exercise achieve hGH release by a different mechanism, possibly inhibition of somatostatin.
 ...
PMID:Effect of oral clonidine, insulin-induced hypoglycemia and exercise on plasma GHRH levels in short-stature children. 210 91

Dynamic studies of growth hormone (GH) secretion were performed in two patients with ectopic GHRH syndrome. Patient 1 (female, 33 years old) had a growth hormone releasing hormone (GHRH) producing carcinoid of the lung with clinical features of acromegaly while patient 2 (50 years old male) had small cell carcinoma of the lung without acromegaly. Insulin hypoglycemia stimulated GH secretion in both patients (i.e. from a basal level of 10 mU/l to 48 mU/l in patient 1, while the respective values in patient 2 were 5 mU/l and 61 mU/l), TRH acutely stimulated GH in both patients. Synthetic GHRH 1-29 (KABI) i.v. bolus 100 micrograms did not stimulate GH release in either patient (i.e. basal GH 14 mU/l and peak 18 mU/l (patient 1); basal GH 4.6 mU/l and peak 8.8 mU/l (patient 2). It is concluded that: 1. prolonged pituitary exposure to GHRH is associated with chronic GH hypersecretion with or without clinical acromegaly; 2. GH response to TRH may be mediated at the pituitary level and results from prolonged exposure to GHRH; 3. the discordant response of GH after GHRH and insulin induced hypoglycemia might suggest the involvement (at least partially) of somatostatin in the mechanism of GH release after hypoglycemia and after GHRH.
 ...
PMID:Discordance between growth hormone responses after growth hormone-releasing hormone (GHRH) and insulin hypoglycemia in ectopic GHRH syndrome. 211 55

Twelve acromegalic patients were treated (mean +/- SD) 26 +/- 15 months with daily doses of 440 +/- 330 micrograms of the somatostatin analogue octreotide acetate (SMS 201-995, Sandostatin). The levels of somatomedin-C (Sm-C) decreased by 63% from 8.1 +/- 7.7 U/ml to 3.0 +/- 1.3 U/ml. Before starting therapy a long oral glucose tolerance test (oGTT) and a TRH test were performed both without and after s.c. injection of 100 micrograms octreotide. Under long-term treatment with octreotide four of twelve patients reached normal Sm-C-values. The GH levels of all of these patients were continuously suppressed to less than 2 ng/dl in an oGTT after a test dose of 100 micrograms octreotide s.c. till the end of the test (5 1/2 hours after octreotide injection). The other eight patients had a relief of acromegalic symptoms and five had a decrease of their Sm-C-levels, but none of them reached normal Sm-C-values. None of these patients had a continuous suppression of GH after a test dose of octreotide in an oGTT. Hyperprolactinemia (n = 4) was observed only in those patients with an insufficient response to octreotide. The GH-response to TRH showed neither without nor after injection of octreotide a correlation with the results of long-term treatment. Thus it is concluded that GH-suppression in a long oGTT after administration of a test dose of 100 micrograms octreotide acetate s.c. allows to identify those acromegalic patients who will benefit from long-term treatment with the somatostatin analogue octreotide acetate.
 ...
PMID:[Long-term treatment of acromegaly with the somatostatin analog octreotide (Sandostatin). On the predictive significance of acute tests]. 212 67

Rolipram (4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) represents a new class of specific low Km cAMP phosphodiesterase (PDE) inhibitors. This compound enhances basal, hormone- and forskolin-elicited cAMP accumulation in prolactin (PRL) producing rat pituitary adenoma (GH4C1) cells in culture (ED50 = 5.10(-8) M). This effect is due to a selective inhibition of the low Km cAMP PDE (type III), since neither basal nor hormone-stimulated adenylate cyclase (AC) nor the Ca2+/calmodulin-dependent PDE were affected by rolipram. The drug enhanced vasoactive intestinal polypeptide (VIP)-stimulated PRL-secretion, while thyroliberin (TRH)- and 12-0-tetradecanoyl phorbol-13-acetate (TPA)-elicited PRL egress were slightly reduced indicating a cAMP-mediated reduction of protein kinase C (PK-C) mediated PRL release. Interestingly, inhibition of PRL secretion by somatostatin (SRIH) was completely suppressed suggesting cAMP-mediated inactivation of some GTP-binding protein(s) of the alpha i family (G alpha i2 or Gk). Rolipram did not affect phosphoinositide metabolism (i.e. IP3 accumulation), neither acutely nor after long term administration. Rolipram, like the cAMP PDE inhibitor Ro 20-1724, did not influence AC and PDE I, but dose-dependently inhibited PDE III activity. Long term incubation of GH4C1 cells with rolipram in the presence of noradrenaline (NA) exerted a marginal decrease of beta-receptor number, AC activation and cAMP accumulation, while Ro 20-1724 brought about a marked down-regulation and desensitization of the AC complex. In summary, rolipram selectively interacts with PDE III in rat pituitary adenoma cells in culture and does not result in beta-adrenoceptor AC downregulation. These features are not shared by the other drugs tested.
 ...
PMID:The pharmacodynamic action of the cyclic AMP phosphodiesterase inhibitor rolipram on prolactin producing rat pituitary adenoma (GH4C1) cells. 217 76

We recently reported isolation, characterization and synthesis of a novel ovine hypothalamic peptide with 38 residues which stimulates accumulation of cAMP in rat anterior pituitary cell cultures. The peptide was named PACAP38 (pituitary adenylate cyclase-activating polypeptide with 38 residues). The presence of another peptide corresponding to the N-terminal 1-27 residues (PACAP27) was also demonstrated. Both PACAP38 and PACAP27 have an amidated C-terminus. Antisera against synthetic PACAP27 were generated in rabbits. These antisera were tested for titer and specificity in enzyme-linked immunosorbent assay. One of the antisera (no. 88121-3) exhibited a high titer of antibody, which was specific to PACAP27 and PACAP38 with exception of slight cross-reactivity with ovine CRF (oCRF). Therefore, the antibodies against oCRF were removed from the antiserum using a solid phase method. Removal of oCRF antibodies was confirmed by enzyme-linked immunosorbent assay. A dense immunoreactive fiber network was found in both external and internal zones of the median eminence and pituitary stalk. The fibers were demonstrated to be in close contact with the hypophysial portal capillaries. The preabsorption of antiserum with vasoactive intestinal polypeptide or with the mixture containing TRH, LHRH, oCRF, ovine GH-releasing factor, somatostatin, and bovine thyroglobulin did not affect the immunostaining. On the other hand, the preabsorption of antiserum with an excess of PACAP27 or PACAP38 abolished the immunostaining. Therefore, the staining is considered specific for PACAP27 and PACAP38. Stained fibers were also present in the posterior pituitary. A dense fiber network was observed and the lateral hypothalamus the fibers appeared to cling to unstained neuronal cell bodies and their dendrites. In the lateral septum the fibers surrounded some blood vessels. Immunolabeled cell bodies were found in the paraventricular and supraoptic nuclei. These findings support the view that PACAP may play a multifunctional role, including that of a hypophysiotropic hormone, neurotransmitter, neuromodulator, and vasoregulator.
 ...
PMID:Immunohistochemical demonstration of a novel hypothalamic peptide, pituitary adenylate cyclase-activating polypeptide, in the ovine hypothalamus. 219 97

A 42-year-old woman had acromegaly and a large macroadenoma with supra- and parasellar extension. Her GH levels (median 85 ng/ml, range 63-170 ng/ml) were not responsive to TRH (200 micrograms iv), GHRH (100 micrograms iv) and bromocriptine (Br 2.5 mg po) acute tests; Sm-C level was 8 U/ml. She was treated with octreotide (SMS) (up to 1500 micrograms daily) for 3 months. No changes of clinical, biochemical and radiological findings were seen, therefore she underwent transsphenoidal surgery. After surgery, hypopituitarism and diabetes insipidus appeared: GH levels remained high (median 45 ng/ml; range 37-56 ng/ml), but became responsive to Br acute test. The patient was given SMS again, and this resulted in clinical improvement, marked reduction of GH and Sm-C levels and slight shrinkage of the residual tumor. Speculative hypotheses about this previously unreported phenomenon might be either an excess of both GHRH and somatostatin, caused by a primary increase of dopaminergic tone, or a primary excess only of GHRH; in both cases the surgical lesion of the hypothalamic-pituitary region might have impaired the neurohormones inflow to the residual pituitary and so let SMS and Br exert their inhibitory actions on GH secretion.
 ...
PMID:Resistance to a long-acting somatostatin analog (SMS 201-995) reversed by surgery in acromegaly. 227 11

17 beta-Estradiol (E2) alters different functions of pituitary cells, including cell sensitivity to several neurohormones such as LHRH, TRH, somatostatin, or dopamine, presumably by affecting receptor coupling mechanisms. Attempting to pinpoint the membrane processes underlying this modulation, we studied the effect of E2 on pituitary kinase-C (PKC) activity, a major signal transduction enzyme. The distribution of calcium- and phospholipid-dependent partially purified PKC (chromatography on DEAE-52 cellulose columns) was evaluated in membrane and cytosol fractions from anterior pituitaries of ovariectomized (OVX) or OVX plus E2-treated rats. E2 administration by implants to OVX animals increased significantly both soluble and particulate enzyme activity. The effect increased progressively from 24 h to 5 days after E2 treatment. Administration of 17 alpha-estradiol, an inactive stereoisomer of E2, was ineffective, pointing to stereospecific interaction. Total destruction of neural connections to the pituitary (complete hypothalamic lesions) did not modify the enzyme response to E2 administration, indicating a direct effect of the steroid on pituitary PKC activity. A direct E2 (10(-9) M) effect was confirmed in primary mixed cultures of pituitary cells; it was time dependent (15-96 h) and specific, and reflects a genomic E2 action. E2 treatment for shorter times had no effect on the enzyme levels or the membrane redistribution of PKC activity. In contrast, under the same experimental conditions phorbol esters (12-O-tertadecanoyl-phorbol-13-acetate (TPA] induced a rapid and sustained translocation of the enzyme. PKC activity was found in all pituitary cell types, with maximal activity in fractions of gonadotropes and thyrotropes, as evaluated in cultures enriched in certain types of pituitary cells separated by means of unit gravity gradient sedimentation. E2 treatment (10(-9) M; 72 h) significantly increased both soluble and particulate enzyme levels in all cell types. In addition, administration of E2 (10(-9) M; 72 h) to cell cultures strongly increased the TPA-evoked LH and PRL release. These results indicate that E2-induced changes in pituitary function include selective effects of the steroid on PKC activity involved at different levels in the coupling mechanisms.
 ...
PMID:Estradiol modulates protein kinase C activity in the rat pituitary in vivo and in vitro. 229 3

A 40-yr-old man who had acromegaly and hyperthyroidism due to a GH/TSH-secreting pituitary adenoma is described. Serum free T4 was 2.8 ng/dl, free T3 was 1.1 ng/dl, and TSH was 1.2-1.5 microU/ml; the latter was measured in an immunoradiometric assay with a sensitivity of 0.07 microU/ml. Serum TSH was immunologically identical to standard TSH and did not decrease during a T3 suppression test. Serum free alpha-subunit and the molar alpha-subunit to TSH ratio were high (6.1 ng/ml and 31.2, respectively). TRH administration induced significant increases in both GH (+129%) and alpha-subunit (+156%) levels. Conversely, dopamine infusion resulted in a decrease in serum GH (-66%) and alpha-subunit (-43%) levels, and subsequent administration of the dopamine antagonist sulpiride induced significant increases in both GH and alpha-subunit (+393% and +106%, respectively). Similarly, somatostatin infusion inhibited GH (-43%) and alpha-subunit (-61%) secretion. Serum TSH levels were not affected by TRH, dopamine, or somatostatin. The biological to immunological activity ratio of serum TSH purified by immunoaffinity chromatography and measured in an adenylate cyclase assay was significantly increased compared to that in serum from hypothyroid or euthyroid subjects [biological to immunological activity ratio, 6.9 +/- 0.2 (+/- SD) vs. 4.4 +/- 1.1; P less than 0.001]. In gel chromatography, the apparent mol wt of the patient's TSH was smaller than that of the controls. After adenomectomy, all of the altered parameters of pituitary function became normal. Double gold particle immunostaining of the adenomatous tissue showed that all of the cells contained secretory granules positive for GH and alpha-subunit, while very few cells were positive for TSH beta as well as GH and alpha-subunit. These data indicate that in this patient serum TSH had an apparent mol wt smaller than that of normal TSH and an increased biological activity which, along with the autonomous TSH secretion, account for hyperthyroidism in the presence of low normal TSH levels; alpha-subunit originated from the same adenomatous cells that secreted GH but not TSH, thus explaining the in vivo observation that alpha-subunit responses to several agents were dissociated from TSH responses and parallel to GH responses; and TSH and GH were colocalized in a minority of the neoplastic cells.
 ...
PMID:Endocrine, biochemical, and morphological studies of a pituitary adenoma secreting growth hormone, thyrotropin (TSH), and alpha-subunit: evidence for secretion of TSH with increased bioactivity. 241 56

The basis for understanding clinical disorders in the neuroregulation of GH secretion is derived from the complexity of the CNS-hypothalamic-pituitary axis. Studies in animals and humans demonstrate an anatomic, physiological and pharmacological evidence for neurosecretory control over GH secretion including neurohormones (GRH, somatostatin), neurotransmitters (dopaminergic, adrenergic, cholinergic, serotonergic, histaminergic, GABAergic), and neuropeptides (gut hormones, opioids, CRH, TRH, etc). The observation of a defect in the neuroregulatory control of GH secretion in CNS-irradiated humans and animals led to the hypothesis of a disorder in neurosecretion, GHND, as a cause for short stature. We speculate that in this heterogeneous group of children a disruption in the neurotransmitter-neurohormonal functional pathway could modify secretion ultimately expressed as poor growth velocity and short stature.
 ...
PMID:Growth hormone neurosecretory dysfunction. 242 94


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>