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)

A detailed analysis of structural and functional aspects of G-protein-coupled receptors, as well as discovery of novel pharmacophores that exert their effects on members of this class of receptors, will be facilitated by development of a yeast-based bioassay. To that end, yeast strains that functionally express the rat somatostatin receptor subtype 2 (SSTR2) were constructed. High-affinity binding sites for somatostatin ([125I-Tyr-11]S-14) comparable to those in native tissues were detected in yeast membrane extracts at levels equivalent to the alpha-mating pheromone receptor (Ste2p). Somatostatin-dependent growth of strains modified by deletion of genes encoding components of the pheromone response pathway was detected through induction of a pheromone-responsive HIS3 reporter gene, enabling cells to grow on medium lacking histidine. Dose-dependent growth responses to S-14 and related SSTR2 subtype-selective agonists that were proportional to the affinity of the ligands for SSTR2 were observed. The growth response required SSTR2, G alpha proteins, and an intact signal transduction pathway. The sensitivity of the bioassay was affected by intracellular levels of the G alpha protein. A mutation in the SST2 gene, which confers supersensitivity to pheromone, was found to significantly enhance the growth response to S-14. In sst2 delta cells, SSTR2 functionally interacted with both a chimeric yeast/mammalian G alpha protein and the yeast G alpha protein, Gpa1p; to promote growth. These yeast strains should serve as a useful in vivo reconstitution system for examination of molecular interactions of the G-protein-coupled receptors and G proteins.
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PMID:Functional coupling of a mammalian somatostatin receptor to the yeast pheromone response pathway. 756 71

Hexarelin (His-D-2-Methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a GHRP-6 analog with the substitution of D-tryptophan with its 2-methyl derivative. The aim of our study was to ascertain whether hexarelin was able to counteract the glucocorticoid-mediated increase in hypothalamic somatostatin tone and consequent inhibition on serum GH levels in acromegalic patients. Ten patients (5 males, 5 females; age range 27-71 years; BMI range 23.3-35 kg/m2) with active acromegaly underwent: 1) hydrocortisone alone: a bolus iv injection of 100 mg hydrocortisone succinate in 2 mL saline, at time -60 followed by a 120 min iv infusion of 250 mg hydrocortisone succinate in 250 mL saline, from -60 to 60 min; 2) hexarelin+hydrocortisone: a bolus iv injection of hexarelin 100 micrograms, 60 min after initiation of a 2-hour hydrocortisone infusion; 3) hexarelin alone: a bolus iv injection of hexarelin at time 0, 60 min after initiation of a 2-hour saline infusion. The mean GH peak, expressed as percent change with respect to baseline level (mean of -75 and -60 minute samples), after hexarelin (1750 +/- 1157%) did not differ significantly with respect to that observed after hexarelin+hydrocortisone (1120 +/- 770%). After hydrocortisone alone the patients showed a mean decrease in GH levels as compared to baseline levels, of 47 +/- 7%. Our data show that the GH response to hexarelin in acromegaly is resistant to the inhibitor action of an acute and sustained elevation of serum cortisol levels. That hexarelin counteracts the glucocorticoid-mediated inhibition of GH secretion supports the hypothesis of an hexarelin-induced decrease in endogenous somatostatin tone.
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PMID:Hexarelin, a novel GHRP-6 analog, counteracts the inhibitory effect of hydrocortisone on growth hormone secretion in acromegaly. 758 27

Using the indirect immunofluorescence method and in situ hybridization, the localization and levels of immunoreactivities and mRNAs for several neuropeptides were studied in lumbar dorsal root ganglia and spinal cord of untreated monkeys (Macaca mulatta) and after unilateral transection of the sciatic nerve. Immunoreactive galanin, calcitonin gene-related peptide, substance P and somatostatin and their mRNAs were found in cell bodies in dorsal root ganglia of untreated monkeys and on the contralateral side of the monkeys with unilateral sciatic nerve lesion. After axotomy there was a marked decrease in the number of calcitonin gene-related peptide-, substance P- and somatostatin-positive neurons in dorsal root ganglia ipsilateral to the lesion, whereas the number of galanin positive cells strongly increased. A few neuropeptide tyrosine-positive cells were seen in after axotomy, whereas no such neurons were found in controls. No vasoactive intestinal polypeptide-, peptide histidine isoleucine-, cholecystokinin-, dynorphin-, enkephalin-, neurotensin- or thyrotrophin releasing hormone-positive cell bodies were seen in dorsal root ganglia of any of the groups studied. In the dorsal horn of the spinal cord all peptide immunoreactivities described above, except thyrotropin releasing hormone, were found in varying numbers of nerve fibres with a similar distribution in untreated monkeys and in the contralateral dorsal horn in monkey with unilateral sciatic nerve lesion. Two cholecystokinin antisera were used directed against the C- and N-terminal portions, respectively, showing a distinctly different distribution pattern in the dorsal horn. Somatostatin- and dynorphin-like immunoreactivities were also observed in small neurons in the dorsal horn. No certain effect of axotomy on these interneurons could be seen. However, marked changes were observed after this type of lesion for some peptide containing fibres in the ipsilateral dorsal horn. Thus, there was a marked increase in galanin-like immunoreactivity, whereas calcitonin gene-related peptide-, substance P-, somatostatin-, peptide histidine isoleucine neurotensin- and cholecystokinin-like immunoreactivities decreased. No changes could be observed in neuropeptide tyrosine or enkephalin-positive fibres. The present results demonstrate marked ganglionic and transganglionic changes in peptide levels after peripheral axotomy. When compared to published results on the effect of axotomy on peptides in dorsal root ganglia and spinal cord of rat, both similarities and differences were encountered.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of peripheral nerve cut on neuropeptides in dorsal root ganglia and the spinal cord of monkey with special reference to galanin. 768 15

Hexarelin (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a new synthetic growth hormone (GH)-releasing hexapeptide. The mechanism of action of hexarelin in man is not fully elucidated. As for other GH-releasing peptides, an action on both the pituitary gland and the hypothalamus has been hypothesized. In the present study, we evaluated the modulation of GH-releasing activity of hexarelin in man. In a first experiment conducted on 6 healthy male volunteers, we studied the interaction of the maximally effective intravenous dose of hexarelin (2 micrograms/kg i.v.) with GH-releasing hormone (GHRH, 2 micrograms/kg i.v.) and somatostatin (2 micrograms/kg/h i.v.). In a second experiment involving another 6 male subjects, we evaluated the interaction of hexarelin with neuroactive substances, such as pirenzepine (0.6 mg/kg i.v.), pyridostigmine (120 mg p.o.) and arginine (0.5 g/kg i.v.), thought to modulate endogenous somatostatin secretion. Hexarelin induced a higher increase in GH levels as compared to GHRH (integrated output calculated as area under the curve AUC0-120 4,693 +/- 691 vs. 1,494 +/- 102 micrograms.min/l, p < 0.01). Coadministration of hexarelin and GHRH produced a higher GH response than hexarelin alone (AUC0-120 7,395 +/- 450 micrograms.min/l, p < 0.05). Somatostatin abolished the GH response to GHRH (AUC0-120 363 +/- 89 micrograms.min/l, p < 0.01), while it only blunted that to hexarelin (AUC0-120 1,314 +/- 297 micrograms.min/l, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of growth hormone-releasing activity of hexarelin in man. 773 98

Somatostatinomas are rare neuroendocrine tumors that can result in a variety of symptoms depending on the secretion of other peptides in association with or in response to somatostatin. The rarity and variable clinical presentation of these tumors present problems in diagnosis and management. This report details the treatment of a 66-yr-old male who had a somatostatinoma with an atypical location and presentation. His clinical course was one of recurrent disease treated surgically and the interval development of cholelithiasis. He has survived 5 yr with his tumor, illustrating that monitoring peptide levels and an aggressive surgical approach are warranted for this condition. Prophylactic cholecystectomy should be considered at the time of exploration.
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PMID:Somatostatinoma: atypical presentation of a rare pancreatic tumor. 773 95

Neuropeptidergic innervation of the human prostate, seminal vesicle and vas deferens was investigated by immunohistochemical methods. The innervation pattern of all organs was very dense. Neuropeptide Y- and tyrosine hydroxylase-positive nerve fibers were most abundant and localized mainly in the smooth muscle layer. On the contrary, vasoactive intestinal polypeptide-positive nerve fibers were mainly found beneath the epithelium. Also leu-enkephaline-, peptide histidine isoleusine- and calcitonin gene-related peptide-positive nerve fibers could be observed in all organs, but somatostatin-positive nerves only in the prostate and seminal vesicle and met-enkephalin- and substance P-positive nerves only in the prostate.
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PMID:Peptidergic innervation of the human prostate, seminal vesicle and vas deferens. 777 Nov 81

Hexarelin (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a new potent synthetic growth hormone (GH)-releasing hexapeptide. The mechanism of action of hexarelin in man has never been evaluated. Hexarelin may act directly on specific pituitary receptors and indirectly on the hypothalamus. To elucidate its mechanism of action in man, we studied the interaction of hexarelin with glucose and free fatty acids (FFA), two metabolic factors known to inhibit both basal and GH-releasing hormone (GHRH) stimulated GH secretion. Glucose is thought to inhibit GH secretion via stimulation of endogenous somatostatin release, whereas FFA could also act directly on somatotrope cells. Therefore, we investigated the effect of oral glucose (100 g) and lipid-heparin infusion (250 mL of a 10% lipid solution + 2,500 U heparin) on the GH response to a maximal dose (2 micrograms/kg intravenously [IV]) of hexarelin or GHRH in six normal men. Hexarelin elicited a clear-cut GH response (mean +/- SEM; peak, 62.6 +/- 8.0 micrograms/L) that was higher (P < .01) than that observed after GHRH (peak, 19.8 +/- 2.4 micrograms/L). Although similar increases in plasma glucose were observed with the two peptides, oral glucose almost abolished the GH response to GHRH (peak, 5.6 +/- 0.9 micrograms/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 38.4 +/- 7.9 micrograms/L, P < .05). Similarly, lipid-heparin infusion nearly abolished the GH response to GHRH (peak, 4.9 +/- 1.0 micrograms/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 34.2 +/- 4.5 micrograms/L, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabolic modulation of the growth hormone-releasing activity of hexarelin in man. 785 59

The effect of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP) on growth hormone (GH) release from cultured bovine anterior pituitary (AP) cells was studied in vitro with the interactive effects of GH-releasing factor (GRF: hpGRF (1-29)-NH2) and somatostatin (SRIF). The AP cells (5 x 10(4) cells per well) were incubated with media, and the media were changed 3 days after plating. After 3.5 days in culture, cells were incubated for 2 h with the peptides. GHRP stimulated GH release from cultured cells in a dose-related manner. At doses from 10(-11) to 10(-7) M GHRP, the amount of GH released was significantly greater than the controls (P < 0.05 to P < 0.001). The amounts of GH released at lower doses of GHRP (10(-14) to 10(-12) M) were not significantly different from the controls. GH concentrations after treatment with 10(-11) and 10(-7) M GHRP were 3.98 +/- 0.27 and 4.81 +/- 0.16 ng/ml, respectively. In experiments performed similarly, the 10(-7) M GHRH, GHRP, and combined treatment with GHRP plus GHRH increased GH 126, 57, and 139%, respectively (P < 0.001). The GH releasing effects of either GHRH alone or GHRP plus GHRH were significantly more potent than that of GHRP alone (P < 0.001). The additive effect was not significant when compared with GHRH alone. GH release induced by either GHRH or GHRP was significantly inhibited by SRIF (P < 0.01) compared with the untreated control. The inhibitory effect of SRIF in combined treatment with GHRP plus GHRH was significantly less than that of SRIF with GHRH or with GHRP (P < 0.01). The present study suggests that GH-releasing peptide (GHRP) induced GH release in cattle via a direct action on anterior pituitary cells in vitro.
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PMID:Effect of growth hormone (GH)-releasing peptide (GHRP) on the release of GH from cultured anterior pituitary cells in cattle. 788 21

Direct screening of preselected compounds in a rat primary pituitary cell culture assay, followed by chemical modification of selected pharmacophores led to the identification of a novel non-peptidyl class of GH secretagogues (substituted benzolactams). The prototype compound of this class, L-692,429, stimulated GH release from rat primary pituitary cells in a time- and dose-dependent manner with an EC50 value of 60 nM. Under the same conditions, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GH-releasing peptide, GHRP-6) and GH-releasing factor (GRF) had EC50 values of 10(-8) and 5 x 10(-10) M, respectively. L-692,428, the S-enantiomer, of L-692,429, was inactive at a concentration as high as 2 microM. GH release induced by L-692,429 was inhibited by somatostatin as well as by GHRP-6 and substance P antagonists but not by GRF or opiate antagonists. L-692,400, which is structurally related to L-692,429 but biologically inactive, inhibited GH response not only to L-692,429 but also GHRP-6. Like GHRP-6, L-692,429 alone had no effect on intracellular cAMP levels; however, it synergized with GRF to further increase both the accumulation of cAMP and the release of GH. Maximal effects of L-692,429 and GHRP-6 on GH release were comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause an additional GH release when compared with either secretagogue alone. L-692,429 had a small effect on prolactin release but not adrenocorticotropin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A novel non-peptidyl growth hormone secretagogue. 790 55

Growth hormone (GH) secretion is regulated by a complex system of central and peripheral signals. Recently, a new GH-releasing hexapeptide (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) called GHRP-6 which specifically releases GH has been studied. In the present work the mechanism of action of GHRP-6 has been addressed in experimental animal models as well as in obese subjects. GHRP-6 releases GH independently of the hypothalamic factors GHRH and somatostatin and is a powerful GH releaser in obesity.
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PMID:Regulation of growth hormone secretion by the growth hormone releasing hexapeptide (GHRP-6). 792 Sep 95


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