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)

Somatostatin receptors in rat brain, pituitary, and pancreas were labeled with two radioiodinated analogs of somatostatins 14 and 28. Two cyclic analogs of somatostatin, SMS201-995 and cyclo(Ala-Cys-Phe-D-Trp-Lys-Thr-Cys), showed biphasic displacement of binding to somatostatin receptors by these radioligands. In contrast, all other somatostatin analogs, including somatostatin-14, competed for the receptor sites with monophasic displacement of radioligand receptor binding. Thus two types of somatostatin receptors were identified. It was found that the pituitary and pancreas have predominantly one type of somatostatin receptor whereas the brain has both, and that different regions of the brain have various proportions of the two types. These findings suggest methods to characterize other types of somatostatin receptors subserving somatostatin's diverse physiological functions, including a potential role in cognitive function and extrapyramidal motor system control.
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PMID:Two types of somatostatin receptors differentiated by cyclic somatostatin analogs. 285 17

Cyclic octapeptide analogues of somatostatin (SS) like SMS 201-995 [H-(D) Phe-Cys-Phe-(D) Trp-Lys-Thr-Cys-Thr(ol)] or its Tyr3-derivative 204-090, displaced [125I-Tyr11]-SS 100% from pancreatic membranes but only 62-75% from brain membranes; the remaining sites were displaced by SS. These data indicate that some mini-somatostatins bind to a subpopulation of SS receptors in rat brain. The iodinated Tyr3-derivative (125I-204-090) can be considered a selective radioligand for one rat brain SS receptor subpopulation: It shows saturable and high affinity binding (KD = 0.29 nM; Bmax = 350 fmoles/mg protein) to rat cortex. The pharmacological properties of 125I-204-090 binding sites are similar to those of [125I-Tyr11]-SS sites. Distribution of these sites correspond to SS receptor-rich areas such as cortex, hippocampus, striatum, pituitary, pancreatic beta-cell. SS as well as SMS 201-995 bind to these sites with high affinity. The stability and high specific vs non-specific binding ratio makes 204-090 a radioligand of choice to measure this SS receptor subpopulation in CNS but also the SS receptors in pituitary and pancreas.
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PMID:New specific radioligand for one subpopulation of brain somatostatin receptors. 285 10

Somatostatin inhibited secretin-stimulated cyclic AMP formation in pancreatic acinar cells. The inhibition was only partial. Maximal inhibition reached about 50%. Somatostatin analogs tested inhibited secretin-stimulated cyclic AMP formation with a lower potency than somatostatin. Cys-Aza Ala-Phe-Phe-DTrp-Lys-Thr-Phe-Phe-Cys was found to be an antagonist of somatostatin in inhibiting secretin-stimulated cyclic AMP. Analogs inhibited the binding of 125I-[Tyr11] somatostatin to pancreatic acini. There was a good correlation (r = 0.97) between concentration for inhibiting 50% secretin-stimulated cyclic AMP and receptor binding affinities.
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PMID:Somatostatin analogs: correlation of receptor affinity with inhibition of cyclic AMP formation in pancreatic acinar cells. 285 71

To characterize the functional aspect of prolactin (Prl) cells coexisting with corticotroph adenomas, pituitary adenoma cells obtained from a patient with Cushing's disease and a patient with Nelson's syndrome, who were associated with hyperprolactinaemia, were cultured in monolayer and their Prl responses to various secretagogues were compared with those of prolactinoma cells in culture. Immunohistochemistry performed in one of these two adenomas demonstrated the presence of Prl-containing cells in addition to ACTH cells. When ACTH-Prl adenoma cells were exposed to ovine corticotrophin-releasing factor (CRF), a dose-dependent increase in both ACTH and Prl secretion was observed, which was blocked by coincubation with hydrocortisone. In contrast, no stimulatory effect of CRF on Prl release was observed in all of the experiments using prolactinoma cells. Thyrotrophin-releasing hormone, which consistently stimulated Prl secretion in ACTH-Prl adenomas, was effective in triggering Prl release in only 25% of the prolactinomas. Exposure of the cultured cells to lysine vasopressin, growth hormone-releasing factor and vasoactive intestinal peptide resulted in an increase in ACTH and Prl secretion in one ACTH-Prl adenoma, however, none of the prolactinomas responded to these stimuli to secrete Prl. Dopamine and somatostatin, on the other hand, uniformly suppressed Prl secretion from ACTH-Prl adenomas as well as from prolactinoma cells. These results suggest that the mode of Prl secretion by mixed ACTH-Prl pituitary adenomas is not identical to that by pure prolactinomas and is, at least in part, common to that of ACTh secretion.
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PMID:Prolactin secretion by mixed ACTH-prolactin pituitary adenoma cells in culture. 285 25

The acute effect of the somatostatin analog SMS 201-995 (SMS) was investigated in eight acromegalic patients. This substance is an octapeptide [DPhe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-(ol)] that inhibits GH release in experimental animals and man. After a control day, 50 micrograms SMS were injected sc, and plasma GH and insulin and blood glucose levels were measured at multiple intervals for 24 h. GH significantly (P less than 0.001) decreased in seven of eight acromegalic patients from 30 +/- 5 (+/- SE) to an average of 10.7 +/- 4 micrograms/l from 1-10 h after drug administration. No rebound effect occurred. Postprandial blood glucose levels were significantly (P less than 0.01) higher between 2 and 4 h after SMS treatment compared with control day values, and there was a substantial reduction in insulin secretion, as estimated by the area under the curve (P less than 0.01), during the first 3 h after SMS administration. Circulating GH was not altered by SMS or the dopamine agonist mesulergine in one patient, but the combination of both substances (50 micrograms SMS, sc, and 0.5 mg mesulergine, orally) reduced GH to below 50% of basal. In vitro studies showed that 1 PM, 0.1 nM, and 10 nM SMS or natural somatostatin exerted a similar inhibitory effect (12-39% reduction; P less than 0.01 for all three strengths) on GH release by cultured human pituitary tumor cells. In conclusion, the somatostatin derivative SMS exerts a potent and prolonged inhibitory action on GH secretion and a shorter lasting suppression of insulin in acromegalic patients. Therefore, it may represent a useful tool in the chronic management of this condition.
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PMID:The somatostatin analog SMS 201-995 induces long-acting inhibition of growth hormone secretion without rebound hypersecretion in acromegalic patients. 286 Jan 19

The in vivo effects on tumour growth of a potent somatostatin analogue, SMS 201-995 [H-(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-(ol)], were measured in two characterised transplantable tumours: a) the Swarm rat chondrosarcoma, known to be insulin-, growth hormone (GH)-, somatomedin- and corticosteroid-dependent, b) a hamster insulinoma, bearing specific high affinity somatostatin receptors. SMS 201-995 (1.25 mg/kg/day) given for 25 days to rats bearing freshly transplanted chondrosarcomas inhibited tumour volume by 48%. A significant tumour growth inhibition was measured also in well developed tumours treated with high doses of SMS 201-995 (1.25mg/kg/day) for 7 days. In the treated animals, GH was significantly inhibited. In hamsters bearing a freshly transplanted insulinoma, the daily application of SMS 201-995 (200 micrograms/kg/day, sc) for 33 days could significantly inhibit the growth (as measured by tumour volume) of the tumour. A moderate inhibitory effect of SMS 201-995 on the growth of well grown insulinomas could also be observed. This study shows that SMS 201-995 under the present experimental conditions has a moderate but significant growth inhibitory effect in two different transplantable tumour models. In the rat chondrosarcoma, the effect of SMS 201-995 is probably indirect, due to inhibition of GH, somatomedin and insulin. In the hamster insulinoma, the effect is possibly due to a more direct action of SMS 201-995 on specific somatostatin receptors present in this tumour.
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PMID:A somatostatin analogue inhibits chondrosarcoma and insulinoma tumour growth. 286 Jul 68

Previous studies have shown that somatostatin-14 (S-14) is rapidly metabolized in the liver through the action of aminopeptidases and endopeptidases, resulting in separate cleavages at the N-terminus and the cyclized (ring) portion of the molecule. In the present study we have characterized the hepatic metabolism of somatostatin-28 (S-28) and compared it with that of S-14 to determine whether S-28 is degraded by a process similar to that for S-14, and additionally, whether the hepatic metabolism of S-28 results in significant conversion to S-14. Isolated rat livers were perfused with synthetic S-28, somatostatin-25[(S-25), an N-terminal metabolite of S-28], C- and N-terminally radioiodinated analogs of S-28, S-14, and des-Ala1-S-14[(S-13), an N-terminal metabolite of S-14]. The metabolic products were characterized by separate N-terminally directed S-14 and S-28 RIAs, a common ring-directed RIA for S-14, S-28, S-13, and S-25, immunoprecipitation, gel chromatography, and HPLC. Hepatic extractions of S-28 and S-25, monitored as ring-directed immunoreactivity, were equivalent, but both occurred 4 times more slowly than that of S-14 or S-13. By contrast, the N-terminal metabolism of S-14 and S-28 monitored by specific N-terminal RIAs occurred at similar rates (hepatic extraction of 54% and 44%, respectively). Both S-14 and S-28 were degraded significantly more rapidly at the N-terminus than at the ring segment. Immunochemical characterization of the radioactive metabolites of N- and C-terminally radioiodinated S-28 analogs confirmed the more rapid N-terminal cleavage of S-28 compared with its ring breakdown. Gel chromatography of S-28 perfusates followed by RIA of the column fractions for N-terminal and ring-reactive metabolites, showed a time-dependent conversion of S-28 to a peak coeluting with S-14 (27% conversion by 60 min). That S-14 was a significant metabolite of S-28 was further confirmed by HPLC analysis of the hepatic perfusate. The main hepatic metabolite of S-28 coeluted with S-28 on Sephadex columns but showed reduced N-terminal reactivity compared to intact S-28. This product thus appeared to be a N-terminally modified form of S-28 as also suggested by HPLC analysis where it coeluted with synthetic S-25. These data have demonstrated that the hepatic metabolism of S-28 occurs via three separate processes, two of which are similar to those for S-14. These include 1) endopeptidase cleavage through the cyclized (ring) segment; 2) N-terminal aminopeptidase cleavage to yield metabolites such as S-25; and 3) tryptic-like cleavage of the Arg-Lys region of S-28 to generate S-14.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hepatic metabolism of somatostatin-14 and somatostatin-28: immunochemical characterization of the metabolic fragments and comparison of cleavage sites. 286 Oct 82

The characterization of GH-releasing peptides in vivo has been complicated by the effects of endogenous hypothalamic regulation of GH secretion. We describe a model to minimize endogenous hypothalamic interference by pretreating adult male rats with iv diethyldithiocarbamate and antisomatostatin serum. This pretreatment regimen established stable, detectable basal levels of plasma GH and eliminated spontaneous GH pulses for 12 h. Repeated pulsatile administration of 400 ng/kg iv rat hypothalamic GH-releasing factor (rGRF) produced consistent GH responses. Linear, nearly identical, dose responses (from 300-5000 ng/kg) were observed with rGRF and human pancreatic GH-releasing factor (GRF44) with ED50 values of 1059.3 and 1116.9 ng/kg, respectively. We also investigated a synthetic hexapeptide, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP), which was previously reported to have potent GH-releasing activity. In contrast to either rGRF or GRF44, repeated administration of the same dose of GHRP did not produce consistent GH responses. The first bolus of GHRP produced a larger GH pulse than the second (P less than 0.01), followed by increasing GH responses from injections 2 to 7. GHRP was about 2 log orders less potent than either rGRF or GRF44 on a molar basis. The disparity between the native peptides and GHRP suggests that the synthetic peptide may act to release GH through a different mechanism(s). In summary, these data indicate that the diethyldithiocarbamate/anti-somatostatin serum-treated animal may be a useful model for investigating the pituitary actions of GH-releasing peptides.
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PMID:Dose-response characteristics of various peptides with growth hormone-releasing activity in the unanesthetized male rat. 286 Oct 83

The somatostatin antagonist analogue cyclo Ahep-Phe-D-Trp-Lys-Thr(Bzl) stimulates growth in young female rats, while somatostatin itself has only equivocal effects on inhibiting growth.
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PMID:Somatostatin antagonist analogue stimulates growth in rats. 286 50

Two distinct somatostatin precursors are synthesized in anglerfish (AF) islets. In addition to a precursor which has somatostatin 14 (SS-14) as a C-terminal cleavage product, a precursor which contains at its C-terminus [Tyr7, Gly10] SS-14 as a potential cleavage product is also synthesized. However, even though an Arg-Lys pair is located immediately N-terminal to Ala1 of the C-terminal tetradecapeptide, [Tyr7, Gly10]SS-14 was not found in significant amounts in extracts of AF islets. Instead, a 28 residue peptide having [Tyr7, Gly10]SS-14 (AF SS-28) at its C-terminus was found to be a primary cleavage product of this form of pro-SS. A question which arises from these observations is whether the differential cleavage of pro-SS-14 (PSS-I) and pro-SS-28 (PSS-II) is the result of differences in primary and/or secondary structure of the two precursors which in turn modulate the activity of the same converting enzyme, or whether separate cleavage enzymes exist for each precursor. Experiments were designed to address this question. Microsomes (M) and secretory granules (SG) were isolated from AF pancreatic islets. Fraction purity was monitored by RIA for islet hormones, and by assays for plasma membrane and lysosomal enzymes. The ability of lysed M and SG preparations to mediate conversion of radiolabeled islet prohormones to products was monitored by gel filtration and HPLC analysis of the products. The pH optimum for converting activity in M and SG was found to be near 5.0. Incubations in the presence of selective proteinase inhibitors and prohormones containing Arg and Lys analogs demonstrated that a cysteine proteinase(s) which cleaves at basic amino acid residues is involved in granule-mediated conversion. A significant proportion of the converting activity in granules was found to co-precipitate with SG membranes. Washing these membranes with 1M KC1 resulted in dissociation of most of the converting activity from the membranes suggesting that the proteinase(s) involved is membrane-associated. The processing activities for proinsulin and pro-SS-28 which were observed in SG were also found to be active, and membrane-associated, in M. However, converting activity for pro-SS-14 was found only in SG. Much of the PSS-I to SS-14 processing activity was membrane-associated in SG. By contrast, pro-SS-28 converting activity in SG was entirely soluble. These results suggest that two or more separate enzymes are involved in processing pro-SS-14 and pro-SS-28 and that these enzymes have differential activity in M and SG.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Post-translational processing of anglerfish islet somatostatin precursors. 286 27


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