Gastrin Release Research Articles

The somatostatin-gastrin link of Helicobacter pylori infection.

Helicobacter pylori is the new-found cause of duodenal ulcers (DU), but acid secretion remains necessary and is elevated in DU patients. My group and others have asked whether H. pylori itself alters gastric physiology. This infection has been found to decrease local expression of the inhibitory peptide somatostatin, and to increase release of the acid-stimulating hormone gastrin. H. pylori infection can alter acid secretion in both directions. Acid disappears temporarily on first infection, and may dwindle later if H. pylori causes gastric atrophy. DU patients have approximately twice the normal parietal cell mass, which increases their maximal secretory capacity, but it is not clear whether or not this is due to H. pylori. However, the infection certainly does change physiological control of acid secretion, as expected from the endocrine changes. Acid secretion is elevated during fasting, during stimulation with an acidic meal and during infusions of gastrin-releasing peptide. The balance between these opposing effects of H. pylori on acid may be crucial in determining the clinical outcome of H. pylori infection. High-acid secretion leads to DUs whilst low acid secretion is found in patients with gastric ulcers and gastric cancer. Inflammatory cytokines released in H. pylori gastritis may cause some of these changes in gastric physiology.

Effect of acute exposure to alcohol and alcoholic beverages on gastrin and histamine release from the dog stomach

Effect of acute exposure to alcohol and alcoholic beverages on gastrin and histamine release from the dog stomach

Effect of endogenous opioids on vagally induced release of gastrin, somatostatin and bombesin-like immunoreactivity from the perfused rat stomach

The aim of the present study was to evaluate the effect of the opiate receptor antagonist naloxone on vagally stimulated secretion of bombesin-like immunoreactivity (BLI), somatostatin and gastrin from the isolated rat stomach, which was perfused via the celiac artery with Krebs-Ringer buffer. Vagal stimulation was performed for 10 min with 1 ms, 10 V and 2, 5, 10 or 20 Hz, respectively. In control experiments BLI release increased significantly above basal secretion during a stimulation frequency of 10 Hz (1367 ± 357 pg/10 min; P < 0.001) and 20 Hz (996 ± 202 pg/10 min; P < 0.01), but not at 2 and 5 Hz. In comparison to the controls naloxone (10 −6 M) significantly increased BLI secretion at 5 Hz by 573 ± 150 pg/10 min ( P < 0.05), but attenuated the BLI response to higher stimulation frequencies of 10 and 20 Hz to 284 ± 143 pg/10 min ( P < 0.001) and 490 ± 114 pg/10 min ( P < 0.01), respectively. At 2 Hz naloxone had no effect on BLI release. As shown previously the cholinergic blocker atropine (10 −7 M) induced a significant BLI release during vagal stimulation at 2 Hz (680 ± 233 pg/10 min; P < 0.01) and 5 Hz (935 ± 324 pg/10 min; P < 0.05), but was without effect at 10 and 20 Hz compared to the controls. The effects of the combination of naloxone and atropine were similar to naloxone and atropine alone. Naloxone had no effect on vagal or GRP-induced regulation of gastrin and somatostatin release. In conclusion, the present data demonstrate that endogenous opioids contribute to vagal regulation of BLI secretion. Stimulatory or inhibitory actions of endogenous opioids depend on the stimulation frequency employed. Further studies in isolated nerve endings are required to discriminate direct from indirect actions of endogenous opioids on the BLI neurons.

Gastrin, somatostatin and histamine release by bombesin from the dog stomach

It has recently been demonstrated that L-365,260, a CCK-B antagonist in mammals, causes an increase in food intake in chickens. In contrast, L-364,718, a CCK-A antagonist in mammals, shows this effect only at very high dose levels. It has been shown that L-365,260 has very low affinity for chicken CCK receptors. Thus, the mechanism of action of L-365,260 remains unknown. As L-365,260 is a benzodiazepine derivative, one may hypothesize that it would be acting on benzodiazepine binding sites. The aims of this work were to establish the existence of benzodiazepine binding sites in the chicken brain, and to check the possibility that L-365, 260 was acting on these receptors, determining the affinity of L-364,718 and L-365, 260 for them. We have found specific binding for tritiated flunitrazepam (a benzodiazepine agonist) ([3H]-flunitrazepam) in chicken brain membranes. A single binding site was detected with a Kd of 3.58 ± 0.97 nM and a Bmax of 451.6 ± 23.3 mol/mg protein. L-365,260 and L-364,718 exhibited very low affinity for these binding sites (Ki = 1.17 × 10−6 ± 0.16 × 10−6 M and Ki > 10−5 M, respectively). Thus, these results demonstrate that the increase in food intake caused by L-365,260 in the chicken is not due to a direct action on benzodiazepine receptors. Other possible explanations for its effect are discussed.

Cholecystokinin is a negative regulator of gastric acid secretion and postprandial release of gastrin in humans

Background/Aims: The role of cholecystokinin (CCK) in the regulation of gastric acid secretion is still controversial. This study examined the effect of the CCK-A receptor antagonist loxiglumide (lox) on gastrin- or CCK-induced gastric acid secretion and meal-stimulated plasma gastrin levels in a placebo-controlled study. Methods: Acid output was studied in eight subjects who received intravenously gastrin-17 (15, 30, and 60 pmol·kg−1·h−1); gastrin-17 plus lox; cholecystokinin octapeptide (CCK-8) (15, 30, and 60 pmol·kg−1·h−1); CCK-8 plus lox; or gastrin plus CCK-8. Sham feeding-induced acid output and meal-stimulated gastrin secretion were studied during lox infusion. Results: Gastrin-17 dose-dependently stimulated acid output to near-maximal levels. CCK-8 (15 pmol· kg−1·h−1) increased acid secretion 2.5-fold over basal; higher infusion rates had less or no effect. When combined with lox, CCK-8 produced a near-maximal acid response (6-fold over basal). CCK-8 together with gastrin-17 inhibited gastrin-induced acid output by 67%. Meal-stimulated plasma gastrin concentrations were elevated 3.2-fold, whereas sham feeding-induced acid secretion was not modified by lox. Conclusions: Blockade of CCK-A receptors converts CCK-8 into a potent acid secretagogue and augments postprandial gastrin secretion. A CCK-mediated stimulation of paracrine somatostatin secretion from antrat and fundic D cells represents a candidate mechanism for the inhibition of the parietal and gastrin cell in humans.

Effects of ionophoretically applied bombesin-like peptides on hamster suprachiasmatic nucleus neurons in vitro

Ionophoresis of the smaller bombesin-like peptides (gastrin releasing peptide [GRP]-(18–27), neuromedin B, and bombesin) evoked responses from 30–60% of hamster suprachiasmatic nucleus cells recorded in a hypothalamic slice preparation, depending on the circadian phase. We also demonstrated for the first time that the putative bombesin-like peptide receptor antagonists [ D-F 5, D-Phe 6, D-Ala 11]bombesin-(6–13)methyl ester (BIM 26226) and [ D-Phe 6,Des-Met 14]bombesin- (6–14)ethyl amide can be applied ionophoretically to block physiological responses to bombesin-like peptides. Together with earlier findings, these results show that bombesin-like peptides administered by several methods can potently alter the firing rates of hamster suprachiasmatic nucleus neurons in vitro. These results indicate that bombesin-like peptides affect suprachiasmatic nucleus cells and could play a role in modulating suprachiasmatic nucleus-mediated circadian rhythm entrainment.

Functional characterization of a muscarinic receptor stimulating gastrin release from rabbit antral G-cells in primary culture.

In previous studies carbachol-induced stimulation of gastrin release from antral G-cells in primary culture suggested the presence of muscarinic acetylcholine receptors on this cell type. Therefore, we attempted to pharmacologically characterize the muscarinic acetylcholine receptor subtype involved. Enzymatically isolated rabbit antral mucosal cells (0.8% G-cells) were separated by counterflow elutriation yielding a fraction (1.7% G-cells) that was placed in culture on collagen-coated well plates. After 24-36 h of culture 13.0 +/- 2.4% of total adherent cells were immunoreactive for gastrin as shown by immunocytochemical staining using the avidin-biotin complex method. In this preparation basal gastrin release ranged from 3.3 +/- 0.3 to 4.1 +/- 0.3% of total cellular content. Maximal gastrin release in response to the acetylcholine receptor agonist carbachol (10(-4) M) or the selective muscarinic receptor agonist arecaidine propargyl ester (10(-4) M) was 8.5 +/- 0.4% and 7.6 +/- 0.4% of total cellular content, respectively. The EC50 values were 3.7 +/- 0.5 x 10(-6) M carbachol and 1.8 +/- 0.4 x 10(-6) M arecaidine propargyl ester. At a concentration of 10(-6) M the non-selective muscarinic receptor antagonist atropine and the muscarinic M3 receptor preferring antagonist hexahydro-sila-difenidol (HHSiD; M3 > or = M1 > M2) completely inhibited gastrin release in response to carbachol (Ki values: 52 x 10(-9) M atropine and 29 x 10(-9) M HHSiD) and arecaidine propargyl ester (Ki values: 11 x 10(-9) M atropine and 13 x 10(-9) M HHSiD).(ABSTRACT TRUNCATED AT 250 WORDS)

Luminal release of somatostatin, peptide YY and gastrin from isolated perfused rat intestine

Luminal release of somatostatin, peptide YY and gastrin from isolated perfused rat intestine

Effect of systemic gastric acid stimulation and intragastric pH changes on synchronous antral gastrin and somatostatin release in anesthetized, nonatropinized duodenal ulcer patients and controls

The synchronous changes in antral gastrin and somatostatin release in anesthetized, nonatropinized duodenal ulcer patients and control subjects were investigated by serial intraoperative blood sampling from the right gastroepiploic vein. The mean basal antral plasma gastrin and somatostatin concentrations of the two groups did not differ significantly. The significantly greater gastric acid secretory response to systemic gastric acid stimulation (pentagastrin stimulation) in duodenal ulcer patients compared with that of control subjects was not linked to any difference in antral somatostatin release pattern. The decrease in antral plasma gastrin release was significantly lower after acid instillation and the increase was significantly higher after alkali instillation in duodenal ulcer patients compared with those of controls, indicating an abnormal gastrin response to intragastric pH changes in duodenal ulcer patients, which was again not found to be coupled to any significant difference in antral somatostatin release. The results suggest that an abnormal somatostatin-mediated inhibition of gastrin release and/or gastric acid secretion does not exist in duodenal ulcer patients.

Regulation of gastrin release in the dog by alpha 2-adrenoceptors.

1. The purpose of the present study was to analyse the effects of the alpha 2-adrenoceptor agonist medetomidine and the antagonist yohimbine on gastrin release in conscious dogs. 2. Gastrin secretion was investigated under both basal conditions and stimulation by 2-deoxy-D-glucose, food or bombesin. 3. Basal gastrin under fasting conditions was significantly reduced by medetomidine and increased by yohimbine. 4. 2-deoxy-D-glucose-induced gastrin increase was fully inhibited by medetomidine; this effect was antagonized by yohimbine. 5. Medetomidine significantly inhibited food-induced increase in plasma gastrin; under these conditions yohimbine was without effect per se, but significantly antagonized the inhibitory action of medetomidine. 6. Gastrin release induced by bombesin was not affected by medetomidine or yohimbine. 7. These results suggest that alpha 2-adrenoceptors play an inhibitory role under conditions in which gastrin release is mainly mediated through cholinergic and non-cholinergic nervous pathways; in contrast, they do not indicate the presence of alpha 2-adrenoceptors on G cells of the dog stomach.

Effects of carbamylcholine chloride on human antral gastrin mRNA levels.

The effects of the muscarinic receptor agonist, carbamylcholine chloride (carbachol), on gastrin release and gastrin mRNA levels in human antral mucosa (n = 15) were determined. During a-2-h incubation period, carbachol (10(-6)-10(-4) M) decreased gastrin mRNA levels to 71 +/- 8% (10(-6) M), 40 +/- 8% (10(-5) M), and 33 +/- 5% (10(-4) M) of control levels. Carbachol (10(-5) M) decreased intracellular gastrin (from 1634 +/- 103 to 1272 +/- 126 pg/mg tissue protein), while it increased gastrin release into the medium (from 609 +/- 48 to 918 +/- 68 pg/ml per mg tissue protein). After 6- and 9-h culture, carbachol gradually increased gastrin mRNA levels, by 96 +/- 12% and 126 +/- 23%, respectively. Atropine sulfate (10(-5) M) completely inhibited the carbachol-induced changes. Cycloheximide markedly decreased tissue gastrin concentration, but increased gastrin mRNA levels, whereas it had no effects on gastrin release. These findings suggested that carbachol may have a time-related biphasic action on human antral gastrin biosynthesis.

Role of endogenous nitric oxide in the control of gastric acid secretion, blood flow and gastrin release in conscious dogs

Nitric oxide (NO) was shown to mediate gastric hyperemia following secretory stimulation but its role in the control of gastric secretion has not been clarified. Secretory studies were carried out on conscious dogs with chronic gastric fistula, Heidenhain pouch and esophageal fistula, while changes in gastric blood flow were measured in the mucosa of Heidenhain pouuch by laser Doppler flowmetry. Plasma gastrin was determined by radioimmunoassay. Infusion of N G - nitro- l-arginine ( l-NNA) (bolus i.v. injection of 2.5 mg/kg followed by infusion of 0.5 mg/kg/h), a potent inhibitor of nitric oxide synthase, failed to affect basal gastric secretion or plasma gastrin level but suppressed an increase of this secretion induced by sham-feeding, ordinary meat feeding or i.v. infusion of bombesin (0.5 μg/kg/h), pentagastrin (4 μg/kg/h) or histamine (40 μg/kg/h). In tests with feeding and bombesin infusion, l-NNA caused a significant and dose-dependent reduction in plasma gastrin levels. The inhibition by l-NNA of gastric acid secretory response to pentagastrin, histamine or feeding was accompanied by a decline in blood flow. Addition of l-arginine (bolus i.v. dose of 50 mg/kg followed by infusion of 5 mg/kg/h) significantly attenuated the l-NNA induced inhibition of gastric secretion and the reduction in plasma gastrin response as well as in the fall of gastric blood flow. We conclude that endogenous nitric oxide affects the gastric secretion and that this effect is mediated, at least in part, by the changes in the gastrin release and gastric blood flow.

Secretin: a physiological regulator of gastric emptying and acid output in dogs

Secretin has been known to inhibit gastric acid secretion in several species. However, the physiological role of secretin on the postprandial acid output and gastric emptying in an intact stomach remains controversial. In the present study, we reinvestigated the role of secretin in physiological dose range and endogenous secretin on gastric acid secretion and emptying in the stomach without influencing intragastric luminal pH in dogs. In seven conscious dogs with gastric cannulas, a 4% amino acid meal was administered intragastrically, and three different doses of secretin and an antisecretin serum were infused intravenously in each dog on separate days. Gastric emptying and net acid output were measured using a dye dilution technique, and plasma secretin and gastrin were determined by specific radioimmunoassays. After the meal, gastric emptying was exponential: acid output peaked at 25 min, and plasma concentrations of gastrin and secretin peaked at 15 and 60 min, respectively. Intravenous infusion of secretin at 1.25, 2.5, and 5.0 pmol.kg-1.h-1 dose dependently increased plasma levels of the peptide and suppressed postprandial plasma gastrin response and gastric acid output and emptying of the meal. Immunoneutralization of circulating secretin with a rabbit antisecretin serum abolished the postprandial rise of plasma secretin and significantly increased plasma gastrin, and augmented gastric emptying as well as acid output. It is concluded that, in dogs, secretin plays a physiological role in the regulation of gastric emptying and acid output after a liquid amino acid meal and that these effects may be mediated in part by suppression of the release of gastrin.

Signal transduction events involved in bombesin-stimulated gastrin release from human G cells in culture.

The mechanism of action of bombesin on human antral gastrin cells in culture was evaluated by modulating internal and external calcium levels and intracellular enzyme activities. Increasing extracellular calcium increased basal gastrin release and had an additive effect on bombesin-stimulated gastrin release. Removing extracellular calcium had no effect on bombesin-stimulated gastrin release. Inhibiting the activities of phospholipase C by neomycin and protein kinase C by staurosporine had no effect on basal release but decreased bombesin-stimulated gastrin release by up to 50%. Chelating intracellular calcium with BAPTA-AM also decreased bombesin-stimulated release by up to 50%. Increasing intracellular calcium levels with thapsigargin did not alter basal gastrin release and had no effect on bombesin-stimulated release. The preparation utilized was a mixed, primary cell culture. To demonstrate direct activation of gastrin cells, alterations in internal calcium levels were monitored by dual-excitation microfluorometry of fura 2-AM loaded cells. The individual cells were subsequently identified by immunocytochemistry, confirming that bombesin directly increases calcium levels in the G cells. The data indicated that bombesin acting directly on the G cells activated both arms of the phosphoinositol signalling pathway and that both activities were required for optimal gastrin release.

Somatostatin-receptor scintigraphy in gastroenteropancreatic tumors. An overview of European results.

Somatostatin has been demonstrated in high concentrations in the hypothalamus, the cerebral cortex, the brain stem, the gastrointestinal tract, and the pancreas. In the central nervous system, it acts as a neurotransmitter, whereas its hormonal activities include the inhibition of the release of growth hormone, insulin, glucagon, and gastrin (for a review, see ref. 1). Also, antiproliferative effects have been reported, both in vitro on tumor cell lines, and in vivo on neuroendocrine human tumors. High-affinity somatostatin receptors have been identified in the brain and on many cells of neuroendocrine origin, like the somatotroph cells of the anterior pituitary and the pancreatic islet cell^.^.^ Also, cells not known classically as neuroendocrine, such as lymphocytes, may possess these receptor^.^ Besides, somatostatin receptors have been demonstrated on a variety of human tumors by classical biochemical binding techniques, as well as by in vitro autoradiography. These tumors include those with APUD (amine precursor uptake and decarboxylation) characteristics (pituitary tumors, endocrine pancreatic tumors, carcinoids, paragangliomas, small cell lung cancers, medullary thyroid carcinomas, pheochromocytomas} as well as meningiomas, well-differentiated brain tumors (astrocytomas), neuroblastomas, and some human breast cancers. Because of the short plasma half-life of somatostatin (2-4 min), analogues more suitable for medical treatment have been developed. The somatostatin analogue, octreotide, has been shown to bind to somatostatin receptors on both tumorous and nontumorous tissues. An 'In-labeled somatostatin analogue ([DTPA-D-Phe'l-octreotide] was developed for its use in scintigraphy. [DTPA-D-Phe'l-octreotide was shown to bind 'In efficiently in a single-step labeling procedure. The binding as well as the biological

Pharmacological analysis of receptors for bombesin-related peptides on guinea pig gallbladder smooth muscle

The aim of this study was to characterize the receptor(s) for bombesin (BN) and its homologues (gastrin releasing peptide, GRP; neuromedin B, NMB; neuromedin C, NMC) in guinea pig gallbladder muscle strips. Dose-dependent contractions were induced by all peptides tested (potency: BN = GRP > NMC > NMB, but with similar efficacy: BN = GRP = NMC = NMB). The contractions were resistant to tetrodotoxin, atropine, phentolamine, and propranolol. BN tachyphylaxis (1 μM) abolished subsequent contractile responses to BN, GRP and NMC; and partially antagonized the response to NMB (66 ± 7% inhibition). NMB tachyphylaxis (10 μM) markedly inhibited subsequent contractile responses to NMB (78 ± 5%); and partially antagonized the contractile response to BN (36 ± 4%), GRP (31 ± 12%) and NMC (22 ± 2%). At 1 μM, both [ d-Phe 6, Des-Met 14]-BN(6–14) ethylamide and ICI 216,140, two BN receptor antagonists, reduced the contractile actions of BN (82 ± 4% and 59 ± 8% inhibition, respectively), GRP (75 ± 11% and 45 ± 5%), and NMC (73 ± 9% and 51 ± 6%) while having no marked effect on NMB contractions. Our pharmacological approaches (receptor tachyphylaxis and differential antagonism) provide support for two types of receptors for BN-like peptides on guinea pig gallbladder smooth muscle: a GRP-preferring receptor and a NMB-preferring receptor.

Gastrin regulates histidine decarboxylase activity and mRNA abundance in rat oxyntic mucosa.

Gastrin release histamine from the oxyntic mucosa, stimulates the enzymatic activity of histidine decarboxylase (HDC), increases HDC mRNA abundance, and has a trophic effect on the enterochromaffin-like (ECL) cell. In the present study, we examined the effect of exogenous gastrin on HDC activity and mRNA and the time scale of increase and decline of HDC activity and mRNA. Rats received intravenous infusion of gastrin-(1-17) in different doses or periods of time. Oxyntic mucosal HDC activity and mRNA abundance increased significantly with serum gastrin concentrations in the physiological range. The onset of response was rapid and maximal for both parameters after 2 h. Poststimulatory decrease was maximal 2 h after cessation of gastrin infusion. Those observations suggest that HDC enzymatic activity and mRNA abundance are important in meal-to-meal regulation of gastric secretion. Furthermore, HDC enzymatic activity and mRNA abundance varied in parallel, indicating that HDC mRNA abundance is important in the overall regulation of gastric mucosal HDC activity.

Effect of CGRP antagonist, alpha-CGRP 8-37, on acid secretion in the dog.

The recently synthesized calcitonin gene-related peptide (CGRP) antagonist, human alpha-CGRP 8-37, was used to study its effects on gastric acid secretion. Four dogs with gastric fistula were used to measure the antagonist's physiologic effects in the stomach. All dogs received a bactopeptone dextrose meal (intragastric titration to pH 5.5) with either continuous CGRP 8-37 (1000 pmol/kg/hr) or saline (control). Additionally, intravenous bombesin (75-600 ng/kg/hr) and bethanechol (12.5-100 micrograms/kg/hr) was tested in the presence of the antagonist. Plasma gastrin levels also were measured via radioimmunoassay (RIA) in control and CGRP 8-37-stimulated animals. Gastric acid secretion increased by 100% with infusion of 1000 pmol/kg/hr CGRP 8-37 when compared to the control. Acid output increased 98% with both intravenous antagonist and 600 ng/kg/hr bombesin when compared to bombesin alone. However, no augmentation of acid secretion by CGRP 8-37 was shown with 25 micrograms/kg/hr bethanechol. RIA of plasma gastrin demonstrated no effect with the antagonist when given alone and did not increase bombesin-stimulated gastrin release. We conclude that CGRP 8-37 blocks native CGRP inhibitory effects on gastric acid secretion. Our findings of potentiation of acid secretion by bombesin as well as no change in gastrin levels in the presence of the antagonist is likely due to a blockage in a noncholinergic neuron to the somatostatin cell. Furthermore, CGRP 8-37 did not increase bethanechol-stimulated acid secretion, most likely due to bethanechol's (acetylcholine) nearly ubiquitous positive effects on acid secretion.

Role of α2-adrenoceptors on gastrin release in the dog

Role of α2-adrenoceptors on gastrin release in the dog

Effect of Helicobacter pylori eradication on G-cell and D-cell density in children

Helicobacter pylori infection is associated with abnormalities in serum gastrin concentration, antral gastrin and somatostatin content, and D-cell density in adults. We have studied the effects of H pylori infection in children. We studied 13 children positive for H pylori and 7 negative children. The median antral somatostatin content was significantly lower in the positive than in the negative group (0 69 [range 0 35-0 91] vs 1 31 [0 73-1 67] ng/mg, p=0 007). Both antral and serum gastrin concentrations were significantly higher in the positive group (30·1 [15·3-83 6] vs 14·8 [13·8-28·8] ng/mg, p=0·008; and 89 9 [59 4-313·2] vs 29·5 [13·9-71·1] pg/mL, p=0·006). Treatment to eradicate H pylori was successful in 11 of the 13 positive patients. With eradication antral somatostatin increased to within the normal range (by a median of 0 41 [0 21-0 86] ng/mg to 1 10 [0 81-1·55] ng/mg, p=0 016). Serum and antral gastrin decreased (by 37 1 [5 5-265 2] pg/mL to 52 8 [21 4-267 5] ng/mg, p=0 001; and by 8·0 [2·0-47 2] ng/mg to 22 1 [10·9-37 5] ng/mg, p=0·001). Eradication of H pylori also significantly increased antral D-cell density (8 [5-22] to 15 [9-22] cells per mm, p=0 031) and decreased G-cell density (138 [89-161] to 88 [33-121] cells per mm, p=0 016). The hypergastrinaemia in children positive for H pylori may be due to a deficiency of antral somatostatin, which inhibits gastrin synthesis and release.