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)

Growth hormone-releasing hexapeptide (GHRP-6) is known to stimulate secretion of growth hormone (GH) in vivo and in vitro in a variety of species. However, the cellular effects of GHRP-6 remain largely unknown. We have tested the influence of GHRP-6 on the inositol phospholipid second messenger system in cultured anterior pituitary cells. Cultured pituitary cells responded upon challenge with GHRP-6 with a dose-dependent release of GH. Moreover, incubation of GHRP-6 with pituitary cell cultures labelled with myo-[3H]inositol resulted in a dose-dependent rise in [3H]inositol phosphates. Brief stimulation of pituitary cells with GHRP-6 increased phosphorylation of MBP4-14, a specific protein kinase C substrate, when incubated with the cytosol- or plasma membrane fraction from the stimulated cells. Furthermore, introduction of MBP4-14 into the cytosol in digitonin permeabilized pituitary cells caused increased phosphorylation of this substrate. GHRP-6 induced a rise in intracellular Ca2+ in individual somatotrophs loaded with the Ca2+ indicator, Fura-2. Preincubation (3 min) with somatostatin (SRIF) diminished the Ca2+ spike elicited by GHRP-6, while no effect of SRIF was observed when added simultaneously with GHRP-6. These results indicate that GHRP-6-stimulated GH-secretion involves the diacylglycerol/inositol(1,4,5)trisphosphate pathway with a resulting rise in cytosolic Ca2+.
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PMID:Growth hormone releasing hexapeptide (GHRP-6) activates the inositol (1,4,5)-trisphosphate/diacylglycerol pathway in rat anterior pituitary cells. 890 47

The synthetic hexapeptide GH-releasing peptide (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2; GHRP-6) and GH releasing hormone (GHRH) are both potent stimulators of GH release in rats. Using reverse hemolytic plaque assay (RHPA), we have compared the effects of human GHRH and GHRP-6 on GH release from the dispersed individual cells of rat anterior pituitary. In a single RHPA, we quantified the percentage of plaque forming cells (% PFC) and their mean plaque area (MPA) after 30 min-incubation, and calculated a total secretion index (TSI) by multiplying % PFC and MPA. 10 nM GHRH and 100 nM GHRP-6 each caused a significant increase in % PFC (%) (GHRH 39.15, GHRP-6 29.4, vs vehicle 24.3, P < 0.01), MPA (x 10(-2) microns2) (GHRH 124.04, GHRP-6 94.80, vs vehicle 44.57, P < 0.01) and TSI (x 10(-2)) (GHRP-6 32.87, vs vehicle 10.84, P < 0.01). Simultaneous addition of both secretagogues caused a further increase in GH release (%PFC 46.4, MPA 142.55, TSI 69.82, P < 0.01 vs vehicle), although the effect was additive but not synergistic. Somatostatin analog, SMS201-995 (SMS) partially suppressed all parameters in GH secretion after stimulation by GHRH and/or GHRP-6. A double RHPA was then performed to test whether all somatotrophs respond equally to GHRH and GHRP-6 or some cells formed plaques only be either GHRH or GHRP-6. There were somatotrophs responsive to only GHRH (23.3% vs control 6.2%, P < 0.01), those responsive to only GHRP-6 (11.9% vs control 6.1%, P < 0.01), and those responsive to both GHRH and GHRP-6 (7.8% vs control 0.2%, P < 0.01). These results confirmed the previous findings that GHRP-6 and GHRH directly but independently stimulate GH release from the pituitary cells, and further suggest that presence of at least three functionally distinct somatotroph subpopulations concerning the responsiveness to GHRP-6 and GHRH in rats.
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PMID:Growth hormone (GH)-releasing peptide and GH releasing hormone stimulate GH release from subpopulations of somatotrophs in rats. 893 59

Growth hormone (GH)-releasing peptides (GHRPs), a family of synthetic oligopeptides which stimulate GH release, were identified more than a decade ago. The effects of these peptides on GH release have been described in vivo and in vitro, in both animals and humans, using various doses and administration routes. It is generally accepted that GHRPs stimulate the release of GH by acting at the level of the pituitary through a receptor different to that for the endogenous GH-releasing hormone (GHRH). In addition, it has been reported that there are specific binding sites for these peptides in the hypothalamus and that systemic administration of GHRPs increases the expression of the immediate early gene c-fos in a subpopulation of hypothalamic neurons. However, the identity of these hypothalamic neurons and the mechanism of action of GHRPs at both the hypothalamic and pituitary levels remain unknown. One interesting aspect of GHRPs is that they are orally active and this phenomenon has been demonstrated in both animals and humans. Furthermore, these drugs stimulate GH secretion in humans dose-dependently with the magnitude and duration of this response being comparable to that seen with an intravenous peptide bolus. We have studied the oral activity of GHRP-2 on GH release in normal children. In addition, we have analyzed the response to GHRP-2 of obese adolescents, as well as the effects of an intravenous bolus of GHRH alone and GHRH plus GHRP-2. Orally administered GHRP-2 stimulates GH secretion in normal children and, although it seems that this drug is more potent in girls, there were no statistical differences between the groups. Characteristically, GH levels started to increase by 15 min, peaked at 60 min and returned to basal concentrations by 180 min. The effect of GHRP-2 was synergistic with GHRH 1-29 NH2. In addition, obese subjects appeared to have a greater response to this peptide than did normal controls. To study the effects of GHRPs on hypothalamic GHRH and somatostatin neurons, female dwarf rats (dw/dw) were treated continuously with GHRP-6 (1 mg/kg per 24 h) for 14 days. In situ hybridization for GHRH and SS was performed. We found that GHRP-6 stimulated GHRH mRNA levels in the posterior arcuate nucleus (ARC), with no significant effect in the anterior ARC or ventromedial hypothalamic neurons. SS mRNA levels in the posterior periventricular nucleus (PeN) were decreased after GHRP-6 treatment, while no effect was seen in the anterior PeN, ARC, or lateral paraventricular nucleus. These results suggest that GHRP-6 treatment modulates hypothalamic neurons controlling GH secretion; however, whether this effect is direct or mediated through another factor remains to be elucidated.
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PMID:Growth hormone-releasing peptides: clinical and basic aspects. 895 Jun 13

Exogenous GH inhibits endogenous GH release by hypothalamic feedback. We have recently exploited this to generate transgenic growth-retarded (Tgr) rats, in which human GH is expressed in the hypothalamus, under the control of the rat GRF gene promoter. These rats show reduced pituitary size, GH deficiency, and dominant dwarfism, but are large enough for serial blood sampling studies to examine their spontaneous GH secretion and responses to GRF, somatostatin, and GH-releasing peptide-6 (GHRP-6). Like their normal wild-type littermates, Tgr rats show a sexually dimorphic pattern of GH secretion; males secrete GH in 3-h episodes, whereas females exhibit a more continuous irregular output, with higher baseline GH levels. In anesthetized male Tgr rats, the GH responses to GRF or GHRP-6 were markedly reduced compared with those of their nontransgenic littermates, but the differences were smaller in females. Despite the reduction in pituitary GH, peak plasma GH responses to serial GRF injections in conscious Tgr males or intermittent somatostatin infusions in conscious Tgr females were indistinguishable from the responses in their wild-type littermates. Furthermore, 7-day iv infusions of GRF (12.5-100 micrograms/day), given either continuously or as a pulsatile infusion stimulated growth in Tgr rats, as did pulsatile infusions of GHRP-6. Thus, despite their pituitary GH deficiency and dwarfism, Tgr rats maintain a sexually dimorphic pattern of GH release and can produce large GH secretory responses to exogenous secretagogues. They represent the first genetic model of GH deficiency in the rat in which dwarfism can be corrected by treatment with exogenous GH secretagogues.
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PMID:Effects of growth hormone secretagogues in the transgenic growth-retarded (Tgr) rat. 900 89

In this study we investigated the neurochemical identity of the arcuate cells activated following GH-releasing peptide-6 (GHRP-6) injection by comparing, on consecutive sections, the distribution c-fos messenger RNA (mRNA) with that of mRNAs for peptides synthesized in arcuate cells, including neuropeptide Y (NPY), GH-releasing factor (GRF), tyrosine hydroxylase, POMC, and somatostatin. Rats bearing chronically implanted jugular catheters were injected with either 50 micrograms GHRP-6 or vehicle. Thirty minutes later they were terminally anesthetized and perfused with fixative. Paraffin-embedded sections of 7 microns thickness were processed using in situ hybridization for either c-fos mRNA or mRNAs for the neurochemical markers. In GHRP-6-treated rats the mean (+/-SEM) number of cells expressing c-fos mRNA in the arcuate nucleus (23 +/- 2 cells/section per rat; n = 5) was significantly higher than for vehicle-treated controls (2 +/- 1 cells/section per rat; n = 5; P < 0.001, Mann-Whitney U test). Superimposed camera lucida maps indicated that, in GHRP-6-injected rats, neurochemically identifiable cells expressing c-fos mRNA also express NPY mRNA (51 +/- 4%), GRF mRNA (23 +/- 1%) tyrosine hydroxylase mRNA (11 +/- 3%), POMC mRNA (11 +/- 2%), or somatostatin mRNA (4 +/- 1%). Thus, the majority of cells expressing c-fos mRNA following GHRP-6 injection are NPY and GRF-containing cells.
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PMID:Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6. 900 14

The present study was designed to examine the effects of intracerebroventricular injection of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP) on GH secretion in freely moving conscious male rats and to determine whether the central action of GHRP is mediated by increased GHRH and/or somatostatin (SRIF) release. A significant and dose-related suppression of natural fluctuations in plasma GH occurred immediately after intracerebroventricular injection of GHRP at the doses of 1, 3 and 10 mu g/rat and was sustained for more than 1 h. An intracerebroventricular injection of GHRP also suppressed plasma GH rises after an intravenous injection of [D-Ala2, Nle27] human GHRH (1-28)agmatine (hGHRH analog), but the GH suppression by intracerebroventricular GHRP was significantly blunted in rats treated with antirat SRIF gamma-globulin (SRIF-ab). In addition, the suppression by intracerebroventricular GHRP of hGHRH-analog-induced GH release was observed even in rats treated with anti-rat GHRH goat gamma-globulin (GHRH-ab) which does not cross-react with hGHRH analog, and again its suppression was significantly attenuated by simultaneous treatment with SRIF-ab and GHRH-ab. Furthermore, intracerebroventricularly injected GHRP was effective enough to inhibit the central-nervous-system (endogenous GHRH)-driven natural GH-secretory surges in SRIF-ab-treated rats. When 10 mu g/kg GHRP was injected intravenously every 1 h during a 7-hour observation period in control rats without antibody treatment, plasma GH levels were increased with the peak 10 min after each injection during the surge period of the GH-secretory rhythm, but the plasma GH response to GHRP was frequently absent during its trough period. In addition, in SRIF-ab-treated rats, basal GH levels as well as plasma GH peaks after GHRP injections were markedly elevated and the obvious plasma GH rises after GHRP could be observed even during the trough period. In GHRH-ab-treated rats, basal GH levels were lower, and the plasma GH response to GHRP was significantly attenuated as compared with those in control rats. Plasma GH peaks after GHRP injections in rats simultaneously treated with SRIF-ab and GHRH-ab were higher than those in rats given GHRH-ab alone, but its difference in GH response was obviously smaller than that observed between SRIF-ab-treated and control rats, suggesting a crucial role of endogenous GHRH in GHRP-induced GH release. To further clarify the interaction of GHRH and GHRP in GH release, hGHRH analog was injected intravenously alone or simultaneously with GHRP in rats treated with SRIF-ab and GHRH-ab. The peak GH values after simultaneous injection of hGHRH analog and GHRP were significantly higher than the sum of GH peaks after each injection of hGHRH analog and GHRP. In conclusion, an intracerebroventricular injection of GHRP suppresses GH secretion by a central mechanism which is likely to include increased SRIF release, reduced GHRH release or both. We have confirmed that intravenous injection of GHRP can stimulate GH release by itself in an immunologically nullified condition of circulating endogenous GHRH and SRIF in rats, and that endogenous SRIF modestly suppresses the GH-stimulating effect of intravenously injected GHRP while both endogenous and exogenous GHRH markedly enhance GH release by intravenously injected GHRP in a synergistic manner.
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PMID:Effect of intravenous or intracerebroventricular injections of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 on GH release in conscious, freely moving male rats. 905 85

GH release is thought to occur under the reciprocal regulation of two hypothalamic peptides, GH releasing hormone (GHRH) and somatostatin, via their engagement with specific cell surface receptors on the anterior pituitary somatotroph. In addition, GH-releasing peptides, such as GHRP-6 and the nonpeptide mimetics, L-692,429 and MK-0677, stimulate GH release through their activation of a distinct receptor, the GH secretagogue receptor (GHS-R). The recent cloning of the GHS-R from human and swine pituitary gland identifies yet a third G protein-coupled receptor (GPC-R) involved in the control of GH release and further supports the existence of an undiscovered hormone that may activate this receptor. Using the human GHS-R as a probe, we report the isolation of a rat pituitary GHS-R cDNA derived from an unspliced, precursor mRNA. The rat cDNA encodes a protein of 364 amino acids containing seven transmembrane domains (7-TM) with >90% sequence identity to both the human and swine GHS-Rs. A single intron of approximately 2 kb divides the open reading frame into two exons encoding TM 1-5 and TM 6-7, thus placing the GHS-R into the intron-containing class of GPC-Rs. The intron maps to the site of sequence divergence between the human and swine type 1a and 1b GHS-R mRNAs. In addition, determination of the nucleotide sequence for the human GHS-R gene confirmed the position of an intron in the human GHS-R gene at this position. A full-length contiguous cDNA from rat hypothalamus was isolated and shown to be identical in its nucleotide and deduced amino acid sequence to the rat pituitary GHS-R. The cloned rat GHS-R binds [35S]MK-0677 with high affinity [dissociation constant (K(D)) = 0.7 nM] and is functionally active when expressed in HEK-293 cells. Expression of the rat GHS-R was observed specifically in the pituitary and hypothalamus when compared with control tissues.
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PMID:Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. 909 93

In insulin-dependent diabetes mellitus (IDDM), inappropriate growth hormone (GH) responses to several stimuli, including GH-releasing hormone (GHRH), have been described. A decreased hypothalamic somatostatinergic tone is one of the most likely explanations for these findings. His-DTrp-Ala-Trp-DPhe-Lys-NH2 [GH-releasing peptide-6 [GHRP-6]] is a synthetic hexapeptide that stimulates GH release in vitro and in vivo. The mechanism of action of GHRP-6 is unknown, but it probably does not inhibit hypothalamic somatostatin secretion. Also, GHRH and GHRP-6 apparently activate different intracellular pathways to release GH. The aim of this study was to evaluate whether there is a differential effect of IDDM on GHRP-6- and GHRH-induced GH secretion. Six patients with IDDM and seven control subjects were studied. Each subject received GHRP-6 (1 microgram/kg intravenously [IV]), GHRH (100 micrograms IV), and GHRP-6 + GHRH on 3 separate days. GH peak values (mean +/- SE in micrograms per liter) were similar in controls and diabetics after GHRH (22.5 +/- 7.8 v 24.0 +/- 9.7) and after GHRP-5 (20.5 +/- 5.3 v 24.4 +/- 6.3). The association of GHRP-6 and GHRH induced a significantly higher GH release than administration of the isolated peptides in both groups. The synergistic GH response to combined administration of GHRP-6 and GHRH was not different in controls (70.5 +/- 20.0) and diabetics (119.0 +/- 22.2). In summary, the effectiveness of GHRP-6 in IDDM could reinforce the evidence that this peptide probably does not release GH through a decrease in hypothalamic somatostatin secretion. Moreover, our data suggest that both GHRH and GHRP-6 releasing mechanisms are unaltered in IDDM.
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PMID:Growth hormone (GH) response to GH-releasing peptide-6 in patients with insulin-dependent diabetes mellitus. 918 9

We conducted this study to investigate the mechanisms of action of growth hormone-releasing peptide-2 (D-Ala-D-beta Nal-Ala-Trp-D-Phe-Lys-NH2; GHRP-2) in bovine anterior pituitary primary cell culture. Doses of GHRP-2 from 10(-13) to 10(-7) M) increased (P < .05) GH secretion. The GHRP-2 (10(-7) M) and GH-releasing factor (GRF; 10(-7) M) administered together had an additive effect on the release of GH (P < .05). Somatostatin (1 microM) decreased GH secretion in response to GHRP-2 and(or) GRF (P < .05). Secretion of GH in response to GHRP-2 was blocked (P < .01) by a GRF receptor antagonist (.1 microM). Nifedipine (10 microM), a voltage-dependent Ca2+ channel blocker, inhibited (P < .01) GHRP-2-stimulated GH release. The GH release in response to GHRP-2 and 4 beta-phorbol-12-myristate-13-acetate (10(-7) M), a protein kinase C activator, was additive (P < .01). Forskolin (30 microM), a cAMP elevating agent, further stimulated (P < .01) the GH release in response to GHRP-2. Bovine GH concentrations in culture media were assayed by indirect competitive enzyme immunoassay. These results showed that GHRP-2 1) stimulates GH secretion from bovine pituitary cells, 2) may partially act via GRF receptor, 3) has GH secretion activity caused by Ca2+ influx via Ca2+ channels, and 4) may increase GH secretion via protein kinase C and cAMP pathways.
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PMID:Mechanisms of action of growth hormone-releasing peptide-2 in bovine pituitary cells. 933 79

We set out to determine whether the central action of growth hormone (GH) secretagogues to induce Fos protein expression in the arcuate nucleus is influenced by central somatostatin action. Conscious male rats were injected i.v. with 100 micrograms sandostatin (octreotide, a long-acting somatostatin analogue) or saline, 10 min before an i.v. injection of either 50 micrograms GH-releasing peptide (GHRP-6), 50 micrograms MK-0677 (a non-peptide GH secretagogue) or saline. In a separate study, conscious male rats were injected i.c.v. with either 2 micrograms sandostatin or artificial cerebrospinal fluid (aCSF) vehicle 20 min before an i.v. injection of 50 micrograms GHRP-6. In all studies, rats were anaesthetized 90 min following GH secretagogue injection, perfused with fixative and the brains processed for the immunocytochemical detection of Fos protein. The number of Fos-positive nuclei detected in the arcuate nucleus of the i.v. sandostatin/i.v. GHRP-6 treated rats (28 +/- 5 nuclei/section) and the i.v. sandostatin/i.v. MK-0677-injected rats (8 +/- 2 nuclei/section) was significantly less than the i.v. saline/i.v. GHRP-6-treated group (56 +/- 5 nuclei/section) and the i.v. saline/ i.v. MK-0677-treated group (20 +/- 2 nuclei/section) respectively. Intracerebroventricular sandostatin injection attenuated the GHRP-6-induced Fos response, from 53 +/- 6 nuclei/section in the i.c.v. aCSF/i.v. GHRP-6 group, to 39 +/- 5 nuclei/section in the i.c.v. sandostatin/i.v. GHRP-6 group. Thus, the central action of GH secretagogues to induce Fos protein expression in the arcuate nucleus appears to be subject to central inhibitory control by somatostatin.
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PMID:Attenuation of the growth hormone secretagogue induction of Fos protein in the rat arcuate nucleus by central somatostatin action. 938 Feb 76


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