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)

The aim of the present study was to determine whether N-methyl-D-aspartate (NMDA) stimulates somatostatin gene function in primary cultures of hypothalamic neurons. Neurons were either shortly (for 3, 8, 24 and 72 h) or chronically (for 11 days) exposed to NMDA (20 microM). Medium and cellular somatostatin contents were determined by radioimmunoassay, and steady-state preprosomatostatin mRNA levels by Northern blot analysis with an oligonucleotide probe. DNA content was measured as a cellular viability control. After 8 h incubation, NMDA induced a significant 2-fold increase in somatostatin mRNA accumulation, with a maximal 4-fold increase after 24 h incubation. A significant and dose-dependent (1.7-fold and 2.5-fold at 20 and 100 microM, respectively) stimulatory effect was also observed after chronic treatment. The kinetic patterns for medium and cellular somatostatin contents were similar to those obtained for somatostatin mRNA levels. Total DNA content was not modified under any experimental condition. The augmentations in cellular somatostatin and somatostatin mRNA determined after 24 h or chronic exposure to NMDA were blocked by (+)-5-methyl-10.11-dihydro-5H-dibenzo(a,d')cyclohepten-5,10-imine hydrogen maleate (MK-801), an NMDA receptor antagonist. MK-801 alone significantly (P < 0.05) reduced somatostatin mRNA. The stimulatory effect of NMDA on somatostatin mRNA was specific since it was not accompanied by any change in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA. After immunostaining with a specific antibody against somatostatin, no difference was observed in the number of immunostained neurons detected in control and NMDA exposed groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulatory effect of N-methyl-D-aspartate on somatostatin gene expression in cultured hypothalamic neurons. 809 1

The activity of gastric parietal cells in terms of hydrochloric acid (HCl) secretion is regulated by the interaction of stimulatory substances (e.g. gastrin) and inhibitors (e.g. somatostatin) acting in an endocrine and paracrine mode, as well as luminal factors. In the present study the following parameters were measured: the synthesis (mRNA), storage (tissue peptide concentration) and secretion (plasma peptide concentration) of somatostatin and gastrin following short-term treatment of rats with pentagastrin (acid stimulant), secretin, omeprazole (reduces gastric acidity by inactivating gastric H/K ATPase) and the somatostatin analogue octreotide (reduces gastric acidity by inhibiting both the parietal cell and gastrin). The mRNA coding for H/K ATPase and carbonic anhydrase II (CA II), the two enzymes responsible for the generation of hydrogen ions from the parietal cell, were also quantitated. In response to octreotide, somatostatin peptide and mRNA levels in the fundus rose to 180 +/- 16% (P < 0.001) and 1073 +/- 356% (P < 0.05) of control, respectively. In contrast, octreotide caused a decrease in antral somatostatin peptide and its mRNA did not change significantly. No significant changes in synthesis, secretion or storage of gastrin were observed except for omeprazole induced hypergastrinaemia (580 +/- 76%, P < 0.001). H/K ATPase and CA II mRNA were largely unaffected except for an increase in CA II mRNA following octreotide and a decrease in H/K ATPase mRNA after pentagastrin. These data support the concept of the differential control of antral and fundic somatostatin synthesis and provide evidence for a regulatory loop by which somatostatin can influence its own synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Secretory and biosynthetic responses of gastrin and somatostatin to acute changes in gastric acidity. 852 6

Recent studies have shown that somatostatin modulates lymphocyte function, but the effects of somatostatin on macrophage function are not clearly defined. In the present study, peritoneal macrophages (Mluminal diameter) obtained from male rats were treated in vitro with somatostatin or octreotide and their effects on the release of hydrogen peroxide (H2O2), nitrite, and tumor necrosis factor (TNF) determined. Macrophages treated with somatostatin (10(-9) M to 10(-7) M) or octreotide (10(-8) M and 10(-7) M) released significantly greater amounts of PMA-stimulated H2O2 than did the untreated controls. In addition, 10(-9) M of somatostatin significantly enhanced PMA-stimulated H2O2 release by LPS-treated Mluminal diameter. Octreotide had no effect on H2O2 release by LPS-treated Mluminal diameter. At concentrations of 10(-14) M, 10(-13) M, or greater than 10(-8) M, somatostatin or octreotide suppressed nitrite release by Mluminal diameter. Somatostatin or octreotide did not affect nitrite release by LPS-treated Mluminal diameter. On the other hand, Mluminal diameter treated with 10(-11) M of somatostatin or octreotide released greater amounts of TNF than did the untreated controls. In contrast, TNF release by Mluminal diameter treated with 10(-9) M to 10(-5) M of somatostatin or 10(-7) M to 10(-5) M of octreotide was less than that of the controls. Anti-TNF antibody (1:1000) caused a reduction in the release of H2O2 and nitrite. These findings demonstrate that somatostatin and octreotide modulate the release of H2O2, nitric oxide, and TNF by Mluminal diameter depending on the concentration of hormones used.
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PMID:Somatostatin and macrophage function: modulation of hydrogen peroxide, nitric oxide and tumor necrosis factor release. 857 Aug 54

The conformation in dimethylsulfoxide of the somatostatin derivative angiopeptin and of three disulfide-free analogs was estimated by two-dimensional nuclear magnetic resonance spectroscopy at room temperature. The resulting 3D molecular graphics were compared and shown to reflect the observed differences in the inhibition of restenosis after rat aorta balloon injury by these octapeptide inhibitors. Angiopeptin and its active analog 2 displayed a relatively rigid conformation of the cyclic hexapeptide backbone due to the presence of two well-defined hydrogen bonds, further stabilized by a third hydrogen bond outside the ring. No such constraints were detected for the two biologically inactive analogs, which, compared to 2, had a two-atom longer or shorter hexapeptide ring. The well-defined structure of compound 2 may serve as an improved pharmacophore for this new class of drugs.
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PMID:Solution conformation by NMR and molecular modeling of three sulfide-free somatostatin octapeptide analogs compared to angiopeptin. 878 18

The aim of the study was to characterize the gastric and mesenteric vascular changes induced by diabetes and the implication of endothelial [nitric oxide (NO) and prostaglandins] and humoral (glucagon) factors in such changes. Diabetes was induced in rats by a single streptozotocin injection. Four weeks later, gastric mucosa, left gastric artery, and superior mesenteric artery blood flows were measured using hydrogen gas clearance and perivascular ultrasonic flowmeter techniques, respectively, in anesthetized and fasted diabetic and control rats. Blood pressure, hematocrit, blood volume, and blood viscosity were also measured. Left gastric (41 +/- 6 vs. 25 +/- 4 ml.min-1.100 g-1) and superior mesenteric artery blood flows (83 +/- 8 vs. 65 +/- 4 ml.min-1.100 g-1) were significantly higher in diabetic than in control rats. The increased blood flow in the left gastric artery was distributed to a hypertrophic mucosa in diabetic rats; therefore, the blood flow per 100 g tissue in the gastric mucosa was not significantly different in diabetic compared with control rats. Pretreatment with indomethacin reduced both increase gastric and mesenteric flows of the diabetic rats to the same levels as in control rats. NG-nitro-L-arginine methyl ester decreased gastric blood flow in a dose-dependent manner and to a similar extent in diabetic and control rats. In contrast, an increased sensitivity to the higher doses of the NO inhibitor was observed in the mesenteric vascular bed of diabetic rats. Glucagon reduction achieved by somatostatin infusion did not influence either gastric or mesenteric blood flow in diabetic rats. In summary, the present study revealed an increase in gastric and mesenteric arterial blood flows in streptozotocin-induced diabetic rats. The gastrointestinal hyperemia seems to be due, at least in part, to the increased demand of a hypertrophic mucosa and is mediated primarily by endogenous prostaglandins. Increased vascular sensitivity to NO may also contribute to the mesenteric vasodilation.
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PMID:Role of prostaglandins and nitric oxide in gastrointestinal hyperemia of diabetic rats. 892 99

Recent studies have shown that somatostatin modulates lymphocyte and peritoneal macrophage function, but the effects of somatostatin on hepatic macrophages (Kupffer cells) are not clearly defined. In the present study, hepatic macrophages obtained from male rats were treated in vitro with somatostatin or octreotide and their effects on the release of nitrite, tumor necrosis factor (TNF), and hydrogen peroxide (H2O2) determined. At concentrations of 10(-14) M to 10(-12) M, or greater than 10(-10) M, somatostatin suppressed nitrite release by Kupffer cells. At concentrations of less than 10(-9) M or greater than 10(-9) M, octreotide inhibited nitrite release by Kupffer cells. Kupffer cells treated with 10(-10) M to 10(-14) M or greater than 10(-8) M of somatostatin released significantly less amounts of TNF than did the untreated controls. TNF release by Kupffer cells treated with 10(-15) M to 10(-5) M of octreotide was significantly inhibited as compared to that of untreated controls. Kupffer cells treated with 10(-14) M to 10(-11) M and 10(-9) M to 10(-8) M of somatostatin released more H2O2 than did the untreated controls. The amount of H2O2 released by noncirrhotic Kupffer cells treated with 10(-6) M or 10(-5) M of somatostatin was less than that of controls. These findings demonstrate that somatostatin and octreotide modulate the release of nitric oxide, TNF, H2O be Kupffer cells depending on the concentration of hormones used.
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PMID:Somatostatin modulates the function of Kupffer cells. 922 98

Small peptides ions consisting of a comparable number of amino acid residues but varying in composition and sequence were allowed to undergo gas-phase deprotonation reactions. These multiply protonated ions were generated by electrospray ionization and analyzed in a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The peptides studied contain 11-14 amino acid residues and included adrenocorticotropic hormone (ACTH) fragment (11-24), fibrinopeptide B (human), gastrin I fragment (1-13) (human), renin substrate tetra-decapeptide (horse), somatostatin, substance P and tyrosine protein kinase. Rate constants were determined for the deprotonation reactions of the peptide ions with a series of reference compounds of known gas-phase basicities ranging from 190.0 to 232.6 kcal mol-1. From these values, apparent gas-phase acidities (GAapp) were assigned to [M + nH]n+ (n > or = 2), of each peptide. All of the multiply charged peptide ions were sequentially deprotonated to the +1 charge state by ion-molecule reactions. The GAapps ranged from 193.3 kcal mol-1 (for [M + 4H]4+ of renin substrate, the ion most readily deprotonated) to > 232.6 kcal mol-1 (for [M + 2H]2+ of ACTH (11-24), the ion most difficult to deprotonate). The proximity of intrinsically basic sites (and therefore potential protonation sites) has an effect on the observed deprotonation rates. Ions experiencing Coulomb repulsion resulting from adjacent protonation sites often show more facile deprotonation. However, the intrinsic basicity of a protonation site also plays a role in determining the case of deprotonation. As a result, some lower charge state peptide ions deprotonate more readily than other peptides with higher charges but with more basic protonation sites. In addition, conformation and the influence of intramolecular hydrogen bonding may affect the reactivity of some peptide ions. Also observed was non-linear kinetic behavior that indicates multiple isomers at certain charge states for some peptides, e.g. [M + nH]n+, (n = 2 and 3) for ACTH 11-24 and [M + 3H]3+ for somatostatin.
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PMID:Reactivity and gas-phase acidity determinations of small peptide ions consisting of 11 to 14 amino acid residues. 931 Nov 49

In the rat stomach, evidence has been provided that capsaicin-sensitive sensory nerves (CSSN) are involved in a local defense mechanism against gastric ulcer. In the present study capsaicin or resiniferatoxin (RTX), a more potent capsaicin analogue, was used to elucidate the role of these sensory nerves in gastric mucosal protection, mucosal permeability, gastric acid secretion and gastrointestinal blood flow in the rat. In the rat stomach and jejunum, intravenous RTX or topical capsaicin or RTX effected a pronounced and long-lasting enhancement of the microcirculation at these sites, measured by laser Doppler flowmetry technique. Introduction of capsaicin into the rat stomach in very low concentrations of ng-microg x mL(-1) range protected the gastric mucosa against damage produced by topical acidified aspirin, indomethacin, ethanol or 0.6 N HCl. Resiniferatoxin exhibited acute gastroprotective effect similar to that of capsaicin and exerted marked protective action on the exogenous HCl, or the secretagogue-induced enhancement of the indomethacin injury. The ulcer preventive effect of both agents was not prevented by atropine or cimetidine treatment. Capsaicin given into the stomach in higher desensitizing concentrations of 6.5 mM markedly enhanced the susceptibility of the gastric mucosa and invariably aggravated gastric mucosal damage evoked by later noxious challenge. Such high desensitizing concentrations of capsaicin, however, did not reduce the cytoprotective effect of prostacyclin (PGI2) or beta-carotene. Capsaicin or RTX had an additive protective effect to that of atropine or cimetidine. In rats pretreated with cysteamine to deplete tissue somatostatin, capsaicin protected against the indomethacin-induced mucosal injury. Gastric acid secretion of the pylorus-ligated rats was inhibited with capsaicin or RTX given in low non-desensitizing concentrations, with the inhibition being most marked in the first hour following pylorus-ligation. Low intragastric concentrations of RTX reduced gastric hydrogen ion back-diffusion evoked by topical acidified salicylates. It is concluded that the gastropotective effect of capsaicin-type agents involves primarily an enhancement of the microcirculation effected through local release of mediator peptides from the sensory nerve terminals. A reduction in gastric acidity may contribute to some degree in the gastric protective action of capsaicin-type agents. The vasodilator and gastroprotective effects of capsaicin-type agents do not depend on vagal efferents or sympathetic neurons, involve prostanoids, histaminergic or cholinergic pathways.
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PMID:Capsaicin-sensitive afferent sensory nerves in modulating gastric mucosal defense against noxious agents. 1067 23

The cAMP responsive element-binding protein (CREB) is central to second messenger regulated transcription. To elucidate the structural mechanisms of DNA binding and selective dimerization of CREB, we determined to 3.0 A resolution, the structure of the CREB bZIP (residues 283-341) bound to a 21-base pair deoxynucleotide that encompasses the canonical 8-base pair somatostatin cAMP response element (SSCRE). The CREB dimer is stabilized in part by ionic interactions from Arg(314) to Glu(319') and Glu(328) to Lys(333') as well as a hydrogen bond network that links the carboxamide side chains of Gln(322')-Asn(321)-Asn(321')-Gln(322). Critical to family selective dimerization are intersubunit hydrogen bonds between basic region residue Tyr(307) and leucine zipper residue Glu(312), which are conserved in all CREB/CREM/ATF-1 family members. Strikingly, the structure reveals a hexahydrated Mg(2+) ion bound in the cavity between the basic region and SSCRE that makes a water-mediated DNA contact. DNA binding studies demonstrate that Mg(2+) ions enhance CREB bZIP:SSCRE binding by more than 25-fold and suggest a possible physiological role for this ion in somatostatin cAMP response element and potentially other CRE-mediated gene expression.
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PMID:The structure of a CREB bZIP.somatostatin CRE complex reveals the basis for selective dimerization and divalent cation-enhanced DNA binding. 1095 92

The search for synthetic analogues of somatostatin which exhibit selective affinities for the five receptor subtypes is of considerable basic and therapeutic interest and has generated a large number of potent agonist analogues with a wide spectrum of binding profiles. In the past, conformational restriction of side chain groups and the peptide backbone has yielded the most interesting results. Under the latter category and as part of the present study, we were interested in the potential effects of N-methylation of peptide bond NH groups on binding affinity since this approach had not been systematically examined with these peptides. This was aided by new chemistries for introducing an N-Me group during regular solid-phase peptide synthesis using Boc protection. A number of interesting effects were noted on relative binding affinities of the two series of agonist sequences chosen, DPhe(5)(or Tyr(5))-c[Cys(6)-Phe(7)-DTrp(8)-Lys(9)-Thr(10)-Cys(11)]Thr(12)-NH(2) (SRIF numbering), at the five known human somatostatin receptors transfected into and stably expressed by CHO cells. N-Methylation of residues 7 (Phe), 10 (Thr), 11 (Cys), and 12 (Thr) largely destroyed affinities for all five receptors. N-Methylation of DTrp in the DPhe series gave an analogue with extraordinarily high affinity for the type 5 receptor for which it was also quite selective. N-Methylation of Lys in both series resulted in retention of type 2 affinity despite this residue constituting the "active center" of somatostatin peptides. N-Methylation of either the N-terminal Tyr residue or of Cys(6) in the Tyr series resulted in analogues with extraordinarily high affinity for the type 3 receptor, also with a degree of specificity. N-Methylation of the peptide bond constrains the conformational space of the amino acid and eliminates the possibility of donor hydrogen bond formation from the amide linkage. The beta-bend conformation of the agonists around DTrp-Lys is stabilized by a transannular intramolecular hydrogen bond(s) between Phe(7) and Thr(10) so methylation of these residues eliminates this source of stabilization. It is expected that several of these analogues will provide additional tools for determining some of the physiological roles played by type 3 and 5 somatostatin receptors which are still far from being fully elucidated.
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PMID:N-Methyl scan of somatostatin octapeptide agonists produces interesting effects on receptor subtype specificity. 1131 Oct 64


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