Gastrin Response Research Articles

Active immunization against somatostatin alters regulation of gastrin in response to gastric acid secretagogues.

We have examined the coupling between somatostatin, gastrin, and gastric acidity, using sheep chronically immunized against somatostatin. All immunized sheep had high-titer (3.2 x 10(5) +/- 1.1 x 10(4) M), high-affinity (1.5 x 10(11) +/- 1.2 x 10(10) l/mol) antibodies. However, basal gastrin and gastric acidity were similar to those in control animals, indicating that an inhibitory somatostatin tone was not required for the maintenance of normal basal gastrin and gastric acidity. Omeprazole (a proton pump inhibitor) increased gastric pH to a similar extent in both the control and immunized groups but resulted in a smaller increase in plasma gastrin in the immunized sheep, thus calling into question the assumption that hypergastrinemia associated with hypochlorhydria is the result of somatostatin withdrawal. Pentagastrin- or histamine-stimulated somatostatin secretion reversed or attenuated the omeprazole-induced hypergastrinemia in control but not immunized sheep, demonstrating a functional role for somatostatin and the biological efficacy of the somatostatin immunization. In a separate series of omeprazole-treated sheep, restoration of an acidic gastric pH with intragastric HCl reversed the hypergastrinemia in both control and immunized animals. We conclude that somatostatin is not essential for the acid-mediated regulation of gastrin. The use of a chronically immunized model as opposed to the acute administration of somatostatin antibodies has important advantages in determining the steady-state regulatory role of somatostatin.

Carboxypeptidase e (CPE) deficiency in mice with the fat mutation have reduced stomach function

An obese mouse model (Cpefat/Cpefat) that has hyperproinsulinemia and late onset obesity has been described. Cpefat/Cpefat mice have a missense mutation in carboxypeptidase E (CPE), a processing enzyme essential for production of biologically active endocrine and neuroendocrine peptides. We have reported previously that CPE activity was absent in the antrum of the stomach and that processing of progastrin to the amidated biologically active form of gastrin is reduced. Since gastrin is a major secretagogue for gastric acid secretion, the purpose of the present experiments was to examine gastric acid secretion in Cpefat/Cpefat mice. In addition, secretion of amidated gastrin in response to inhibition of acid secretion was tested in Cpefat/Cpefat. Both gastric acid and challenged gastrin secretion are reduced in Cpefat/Cpefat mice. We conclude that stomach CPE activity is essential for gastric secretory activity and for challenged gastrin release.

Somatostatin type 2 receptor (SSTR2) inhibition of histidine decarboxylase (HDC) transcription is not mediated through a phosphatase pathway in the human gastric cancer cell line AGS-B

Background: Somatostatin (SS) inhibits both basal and gastrin stimulated histamine release from ECL cells in gastric mucosa. This is mediated through the SSTR2 receptor in human and rat antral mucosal strips. Histidine decarboxylase (HDC) is the enzyme responsible for histamine production in ECL cells and has previously been shown to be transcriptionally regulated through a gastrin response element. We postulated that SS may regulate the HDC promoter. The mechanisms through which SS may alter HDC transcription have not been elucidated. Methods: AGS-B cells were transfected with a plasmid containing 1.8 kb of the 5' promoter region of hHDC upsteam of the firefly luciferase reporter (1.8 kb hHDC-luc). Plasmids containing the cDNA of either human or rat SSTR2 were co-transfected. The cells were stimulated with 10 -7 M of gastrin, phothol ester (PMA) and dose responses with SS or octreotide were done. In addition overexpression of phosphatase SHP-1 and the G protein subunits Gictl and Gict3 were done using plasmids with the respective cDNA. Results.: Overexpression of both human and rat SSTR2 resulted in a dose dependent inhibition of hHDC transcription as measured by a luminometer. Maximal inhibition caused a 80% reduction in HDC transcription. This was seen in basal conditions, as well as with gastrin and PMA stimulated cells. Co-transfection with SHP-1 or its mutant did not block this effect. This inhibitory effect was not overcome with the phosphatase inhibitors sodium orthovanadate or okadaic acid. Addition of receptor agonists SS or octreotide resulted in a dose dependent 2-3 fold stimulation of HDC-Iuc activity. SS mediated stimulation in stably transfected cells was not altered by overexpression of GiQtl and Gia 3, suggesting that this paradoxical effect was not due to a lack of these subunits in AGS-B cells. Conclusions: SSTR2 has an inhibitory effect on HDC transcription in basal and stimulated AGS-B cells. This inhibition by the receptor is not mediated through a phosphatase pathway. Addition of agonists SS and octreotide produces a dose dependent stimulation in transcription of HDC. This is not due to a lack of the appropiate G i subunits in AGS-B cells. SS stimulates HDC transcription independently of G i pathway in AGS-B cells.

A marked high response of serum gastrin concentrations to the test meal may contribute to the pathogenesis of duodenal ulcer

Recent studies have indicated that Helicobacter pylori (17-1. py!ori) infection is associated with duodenal ulcer (DU). However, most of H. pylori-infected subjects do not develop DU. The AIM of this study was to clarify the pathogenesis of DU though investigating the meal-stimulated serum gastrin response in asymptomatic volunteers with or without tl. pylori infection and DU subjects. S_UBJECTS AND METHODS: The study population consisted of 31 H. pylori negative volunteers (27 males, mean age 26 yrs), 10 H. pylori positive volunteers (6 males, mean age 29 yrs), and 15 subjects with DU (13 males, mean age 29 yrs). After an overnight fast, blood samples were taken before and 15, 30, and 60 min after eating the test meal, which consisted of 100g rice, 130g chicken, and 1 egg (374 Kcal, 37.5 g carbohydrate, 41.5 g protein, and 11.6 g fat). The H. pylori infection status was determined by histology, serology, and the 13C-urea breath test. Serum gastrin concentrations were measured by radioimmunoassay. RESULTS: Results were expressed as the mean -+ standard error.

Inhibition of sham feeding-stimulated acid secretion in dogs by immunoneutralization of gastrin.

A monoclonal antibody to gastrin was used to study the role of circulating gastrin in mediating acid secretion stimulated by sham feeding in dogs. On separate days, four conscious, fasted, adult mongrel dogs with esophageal and gastric fistulae were pretreated intravenously with either 7 mg of gastrin monoclonal antibody (MAb 28.2), 7 mg of keyhole limpet hemocyanin monoclonal antibody as control, or 12.5 micrograms/kg atropine sulfate. Thirty minutes later, acid secretion was stimulated first by sham feeding for 5 min, then, 60 min later, by an intravenous infusion of a maximum stimulatory dose of histamine (40 micrograms/kg) for 60 min, and after returning to basal, by intravenous infusion of a submaximal stimulatory dose of gastrin (200 pmol.kg-1.h-1) for 60 min. Acid output from secretions collected every 15 min by gravity drainage was determined by titration to pH 7.0 with 0.2 N NaOH. Sham feeding-stimulated acid output (17.7 +/- 5.5 mmol/h) was significantly inhibited by administration of either MAb 28.2 (0 mmol/h) or atropine (1.7 +/- 1.1 mmol/h). Histamine-stimulated acid output (19.6 +/- 3.4 mmol/h) was not reduced by either pretreatment. Gastrin-stimulated acid output (3.9 +/- 0.6 mmol/h) was significantly reduced only by pretreatment with MAb 28.2 (0.1 +/- 0.1 mmol/h) and not by atropine (2.2 +/- 1.4 mmol/h). A background intravenous infusion of pentagastrin (0.5 microgram.kg-1.h-1) restored sham feeding-stimulated acid output blocked by administration of MAb 28.2, although the intrinsic acid response to sham feeding could not be seen with the background pentagastrin infusion. Furthermore, the plasma gastrin response to sham feeding was not blocked by atropine pretreatment. Because immunoneutralization of both gastrin and cholinergic blockade significantly inhibited acid output during sham feeding, circulating gastrin and cholinergic pathways are involved in mediating the cephalic phase of gastric acid secretion in dogs.

Perturbations in gastric physiology in Helicobacter pylori duodenal ulcer: are they all epiphenomena?

The Holy Grail of physiological studies in acid secretion has been to identify a specific abnormality in gastroduodenal physiology responsible for the development of duodenal ulcer disease. We review the available data relating duodenal ulcer and Helicobacter pylori infection to perturbations in gastric physiology, especially acid secretion. It is known now that elevated serum pepsinogen levels, reduced inhibition of acid secretion with antral acidification or distention, exaggerated gastrin response to meals or infusion of bombesin or gastric-releasing peptide, exaggerated acid output in response to gastric-releasing peptide, and abnormalities in duodenal bicarbonate secretion in response to instillation of acid are reversible epiphenomena related to the H. pylori infection and are not in themselves responsible for duodenal ulcer disease. H. pylori is inhibited by bile, yet can thrive in the duodenal bulb of duodenal ulcer patients. Glycine-conjugated bile acids are precipitated by acid; thus, any mechanism that would increase the duodenal acid load may remove the inhibitory bile and allow unrestrained growth of H. pylori. These data and speculations offer one possible explanation for why duodenal ulcer occurs in only some people--those with high acid secretion--and suggest that the combination of high duodenal acid load and H. pylori infection is sufficient to result in duodenal ulcer disease.

The effect of gastrin-releasing peptide on gastrin and somatostatin messenger RNAs in humans infected with Helicobacter pylori

BACKGROUND & AIMS: Gastrin-releasing peptide stimulates gastrin secretion but also inhibits its release via somatostatin. Exogenous gastrin-releasing peptide stimulates a greater increase in plasma gastrin concentrations in patients infected with Helicobacter pylori than in uninfected controls. Because this infection suppressed gastric mucosal somatostatin, we studied whether the increased gastrin response was a result of an abnormal response of the somatostatin cell. METHODS: Patients without dyspeptic ulcers received an infusion of either gastrin-releasing peptide or saline on separate occasions. Acid secretion was measured, and gastric biopsy specimens were taken for gastrin and somatostatin messenger RNA (mRNA) analysis and H. pylori diagnosis. RESULTS: In response to gastrin-releasing peptide, the increase in plasma gastrin concentrations in the infected patients was significantly higher than in the uninfected. Antral gastrin mRNA also increased significantly in the infected group but decreased significantly in the uninfected group. Basal somatostatin was lower in the infected group; gastrin-releasing peptide produced a significant increase in antral somatostatin mRNA concentration in infected, but not uninfected, patients. CONCLUSIONS: The somatostatin cell responds to gastrin-releasing peptide in H. pylori infection. Gastrin-releasing peptide normally inhibits gastrin mRNA expression, but inhibition is deficient in H. pylori infection, possibly because of low stimulated somatostatin levels. (Gastroenterology 1997 Jun;112(6):1940-7)

Role of gastrin/CCK-B receptors in meal-stimulated acid secretion in rats.

Gastrin is the principal hormonal mediator of gastric acid secretion. Using an in vivo, intact, anesthetized rat model, we studied the role of gastrin/cholecystokinin (CCK)-B receptors in regulating the release of histamine and somatostatin during intragastric stimulation of acid secretion during a peptone meal. In pylorusligated, adult male rats (each implanted with a gastric cannula and portal venous and splenic artery catheters), after a 30-min basal period, gastric acid secretion was stimulated for 90 min either by an intravenous infusion of gastrin-17 (15 micrograms.kg-1.h-1) or by extragastric titration of 5 ml 8% peptone meal at pH 5.5. Basal and stimulated acid outputs and portal venous plasma gastrin, histamine, and somatostatin concentrations were measured before and after close-arterial injection of a new, relatively selective, gastrin/CCK-B receptor antagonist GR143330X. GR143330X reduced basal acid output by 50% but not basal plasma gastrin, histamine, or somatostatin concentrations. GR143330X reduced gastrin-stimulated acid output by 80%, plasma histamine by 70%, and plasma somatostatin by 34%. During intragastric peptone meal stimulation GR143330X reduced the acid response by 42% during the 30- to 60-min period but not during the 60- to 90-min period. GR143330X reduced the plasma histamine response by 72 and 68%, and the plasma somatostatin response by 32 and 54% during the 30- to 60- and 60- to 90-min periods, respectively. GR143330X did not block the gastrin response to peptone at any time. These results indicate that GR143330X is an effective agent for blocking gastrin-stimulated acid secretion and histamine and somatostatin release in rats. Furthermore, we show for the first time in an intact, in vivo, anesthetized rat model that meal-stimulated activation of gastrin/CCK-B receptors stimulates acid secretion in part by regulating the release of histamine and somatostatin.

Effect of cimetidine on basal and postprandial plasma concentrations of cholecystokinin and gastrin in humans.

Cimetidine reduces the appetite and weight in healthy overweight subjects. Gastrointestinal regulatory peptides such as cholecystokinin (CCK) have been proposed to mediate the satiety signal from gut to brain. Therefore, the effect of cimetidine on basal and postprandial plasma concentrations of cholecystokinin and gastrin was studied. After an overnight fast, 12 healthy volunteers were given cimetidine (400 mg) on day 1, breakfast on day 2, and cimetidine 20 min before breakfast on day 3. Plasma concentrations of cholecystokinin and gastrin were measured by radioimmunoassay. Plasma cholecystokinin concentration increased with one major peak observed 30 min and one smaller peak observed 120 min after intake of cimetidine. The meal induced an increase in the plasma concentration of cholecystokinin, while cimetidine prior to the meal elicited a sustained postprandial cholecystokinin response. Cimetidine had no effect on the basal plasma concentration of gastrin. The meal induced an increase in the plasma concentration of gastrin, while cimetidine prior to the meal elicited a sustained postprandial gastrin response. In conclusion, cimetidine increases the basal concentration of plasma cholecystokinin and elicits a sustained postprandial response of both cholecystokinin and gastrin. At least the cholecystokinin response may be one mechanism by which cimetidine reduces the appetite.

Gastrin regulates the human histidine decarboxylase promoter through an AP-1-dependent mechanism.

The histidine decarboxylase (HDC) gene is regulated transcriptionally by gastrin and phorbol 12-myristate 13-acetate (PMA) through a protein kinase C (PKC)-related pathway. To determine the role of AP-1 (fos/jun) in the regulation of the HDC promoter, gastric cancer (AGS-B) cells stably expressing the cholecystokinin-B/ gastrin receptor and the 1.8-kb human (h) HDC-luciferase (luc) construct were cotransfected with constructs expressing c-fos and c-jun. Overexpression of c-fos and c-jun activated the HDC promoter in a dose-dependent fashion in 1.8-kb hHDC-luc/AGS-B cells as well as in transfected F9 embryonal carcinoma cells, which lack endogenous AP-1 activity. PMA was unable to activate the HDC promoter in F9 cells, which were not transfected with c-fos and c-jun. Gastrin stimulation increased c-fos and c-jun mRNA abundance and AP-1-dependent transcriptional activity, as assessed by a reporter construct in which the CAT reporter gene is under the control of a 12-O-tetradecanoylphorbol-13-acetate response element multimer. Gastrin-stimulated HDC promoter activity was blocked by transfection of c-fos antisense and dominant negative c-jun expression constructs. Finally, overexpression of c-fos and c-jun activated the hHDC promoter through a downstream cis-acting element (gastrin response element), which does not bind AP-1. In conclusion, activation of AP-1 is essential for gastrin-stimulated HDC transcription, but the mechanism appears to be indirect.

Role of vagal fibers and bombesin/gastrin-releasing peptide-neurons in distention-induced gastrin release in rats

In the rat the exact role of vagal fibers and the interaction between the extrinsic and intrinsic neural system in distention-induced gastrin release are still a matter of debate. Accordingly, the aim of the present study was to examine the contribution of afferent and efferent vagal fibers as well as intrinsic neurons on gastrin response to gastric distention. In anesthetized rats graded gastric distention by 5, 10 and 15 ml saline for 20 min caused a significant volume-dependent increase of plasma gastrin levels by 12±6 pg/ml (5 ml saline, n=8, P=0.05), 26±7 pg/ml (10 ml saline, n=10, P<0.05) and 37±7 pg/ml (15 ml saline, n=8, P<0.01), respectively. To examine the role of the extrinsic vagal innervation, gastrin response to distention was studied in anesthetized rats after bilateral truncal vagotomy ( n=9) or selective afferent vagotomy following pretreatment with capsaicin ( n=6). Stimulation of gastrin release by 10 ml distention in sham-operated control rats was reversed to an inhibition after truncal vagotomy (26±7 vs. −11±4 pg/ml; P<0.05) and capsaicin-treatment (37±18 vs. −34±11 pg/ml; P<0.05). A contribution of cholinergic mechanisms to this vagovagal-mediated stimulation of distention-induced gastrin release was excluded, since atropine (100 μg/kg/h; n=8) further augmented distention-stimulated gastrin release. Since bombesin/gastrin-releasing peptide (GRP)-neurons contribute to vagally stimulated gastrin secretion, we have examined gastrin response to distention in the presence of the specific bombesin-receptor antagonist d-Phe 6-BN(6-13)OMe (400 μg/kg/h; n=10). This bombesin-antagonist completely reduced distention-stimulated gastrin release in vivo. In contrast, distention of the isolated, extrinsically denervated stomach significantly decreased gastrin release by 13±5 pg/min (5 ml saline, n=8, P<0.05), 28±8 pg/min (10 ml saline, n=11, P<0.05) and 35±10 pg/min (15 ml saline, n=8, P<0.01), respectively, without changing the activity of bombesin/GRP-neurons. Distention-induced decrease of gastrin release was attenuated to 50 percent by atropine (10 −7 M; n=10) or tetrodotoxin (TTX) (10 −6 M; n=10), respectively. These data demonstrate, that in anesthetized rats distention-stimulated gastrin secretion depends on the activation of a vagovagal reflex and intrinsic bombesin/ GRP-neurons. In contrast distention of the isolated rat stomach inhibits gastrin release in part via intrinsic cholinergic pathways and other as yet unknown mechanisms.

Reduced meal-related gastrointestinal hormone response to adrenocorticotropic hormone stimulation test in female athletes

This study was undertaken to elucidate the impact of hypercortisolism in meal-related gastrointestinal hormone secretion and appetite in female endurance athletes. Thirteen elite runners and seven sedentary women participated on two occasions, either receiving intravenous injection of 250 μg synthetic adrenocorticotropic hormone (ACTH) 1-24 or saline. Blood samples were collected before and after the injection, and then in connection with a standardized meal. Serum concentrations of Cortisol, cholecystokinin (CCK), gastrin, insulin and glucose were analyzed. Self-ratings of appetite were assessed by visual analog scales. Elevated basal levels of Cortisol and glucose were found in the athletes. ACTH-induced Cortisol response was comparable between groups, but a negative correlation between basal Cortisol levels and the ACTH-induced response was found. In sedentary women, ACTH challenge enhanced meal-related CCK and gastrin responses, whereas athletes showed a blunted response of these hormones combined with decreased satiety and reduced levels of insulin. Blunted meal-related response of gastrointestinal hormones and decreased satiety in female runners after ACTH stimulation compared to sedentary women are probably due to differences in the effect of Cortisol, which could be explained by Cortisol insensitivity as a result of basal hypercortisolism in the athletes. Decreased CCK response and satiety in female athletes may reflect increased nutritional requirements.

Association between serum gastrin levels, gastric acid secretion and age in early gastric cancer.

This study evaluated the effect of gastric acid secretion and serum gastrin response on tumor differentiation for early gastric cancer according to patients' age. We investigated the association between serum gastrin levels, gastric acid secretion and the histologic types of 335 early gastric carcinomas limited to the mucosal and submucosal layers in comparison with 450 gastric and 197 duodenal ulcers. The preoperatively examined basal acid output, maximal acid output and peak acid output after administration of tetragastrin and serum gastrin levels before and after ingestion of a test meal were determined. Patients with differentiated cancer and duodenal ulcer showed a significant negative correlation between gastric acid secretion and age, while the former group also had a significant positive correlation between serum gastrin levels and age. On the other hand, patients with undifferentiated cancer did not show any such correlation between gastric acid and age, but showed a significant positive correlation between serum gastrin, integrated gastrin response and age. Patients with gastric ulcer did not show any such correlations. These data suggest that both low acid secretion and endogenous hypergastrinemia, especially in the elderly, may play an important role in differentiated and undifferentiated gastric carcinomas.

Adaptive Gastrointestinal Hormone Changes after Gastric Resection

Circulating alimentary hormones were measured following a standardized meal in 10 patients after partial distal gastrectomy and 12 patients after total gastrectomy, both groups reconstructed by Billroth-II anastomosis, and in 9 age-matched healthy controls. Patients underwent resection for gastric cancer and were studied 45 ± 10 months after surgery. At the time of study, the patients had adapted well to surgery and no longer exhibited the symptoms of dumping seen immediately postoperatively. In contrast, the total gastrectomy patients exhibited severe symptoms of reflux esophagitis. The nutritional states of the patients, evaluated by measurement of rapid turnover proteins in serum, was impaired in proportion to the degree of gastric resection. Basal gastrin levels were reduced by partial (p < 0.05) and total gastrectomy (p < 0.01). Postprandial responses of both gastrin and pancreatic polypeptide were abolished following either partial gastrectomy or total gastrectomy (all p < 0.001). Glucose-dependent insulinotropic peptide and motilin were relatively normal after both procedures. In contrast, early cholecystokinin responses were increased 2-fold after partial gastrectomy (p < 0.05) and 3-fold after total gastrectomy (p < 0.001). Postprandially, a large increase in neurotensin levels and a moderate increase in peptide YY were seen after both partial and total gastrectomy (all p < 0.01). Fasting peptide YY levels were also increased after total gastrectomy (p < 0.01). The late adaptive changes in alimentary hormone secretion may help to compensate for loss of gastric motor function which accompanies gastric resection. On the other hand these hormonal changes may exacerbate the esophageal reflux seen following gastrectomy.

Influence of nicotine on gastrin and peptide YY in the rat

The objective of this study was to examine the effects of nicotine and high-fat diets on gastrin and peptide YY (PYY) homeostasis in the rat. Antral levels of gastrin mRNA and peptide and ileal and colonic levels of PYY mRNA and peptide were examined. Serum levels of gastrin in response to food were also measured. Control rats were ad-lib fed or pair-fed according to the daily food intake of nicotine-treated rats. The results of this study indicate that nicotine treatment and fat diets can influence gastrin and PYY gene expression in the gastrointestinal tract.

Evidence that endogenous GRP in rat stomach mediates omeprazole-induced hypergastrinemia.

To investigate the physiological role of endogenous gastrin-releasing peptide (GRP) in regulating the release of gastrin, we evaluated the response of intragastric pH, gastrin, and GRP after omeprazole treatment in rats. A significant elevation of the plasma level of GRP (P < 0.01) and a significant reduction of the antral content of GRP (P < 0.05) were observed after the administration of 100 mg/kg omeprazole. The antral content of GRP was significantly decreased 12 h after omeprazole administration and thereafter gradually returned to control levels. Peak values for intragastric pH and plasma GRP were observed 3 h after omeprazole administration and before the peak of serum gastrin. The bombesin antagonist [D-Phe6]-bombesin-(6,13)-methyl ester significantly inhibited gastrin release after omeprazole treatment (P < 0.05). These observations indicate that omeprazole-induced inhibition of acid secretion stimulates the release of GRP and suggest that the secretion of GRP induced by omeprazole may stimulate the secretion of gastrin, at least in the early phase.

The effect of ethanol, beer, and wine on histamine release from the dog stomach

The mediator for the action of ethanol on the parietal cell of the stomach is not known. However, because the action the ethanol on gastric acid secretion was proposed to involve the release of histamine, we decided to investigate the effects of ethanol and some alcoholic beverages (red wine and beer) on histamine release from the dog stomach. After performing a splenectomy in anaesthetized beagle dogs, the gastrosplenic vein draining the corpus of the stomach was cannulated for blood withdrawal to evaluate the local release of gastrin and histamine by RIA. Intragastric administration of 200 ml of beer (4.8% ethanol) or red wine (12.5% ethanol) caused a significant enhancement in gastric and histamine concentrations in venous blood from the stomach. By contrast, intragastric administration of pure ethanol in distilled water at the same concentrations of wine or beer did not significantly modify gastrin and histamine release. Integrated histamine responses for 20 min to beer and wine paralleled gastrin concentrations and were of the same magnitude of those induced by intravenous infusion of pentagastrin at 1 and 6 μg/kg/h, respectively. We conclude that: 1) beer and red wine, but not pure ethanol, are potent releasers of histamine; 2) histamine release seems to be related to the gastrin response and probably occurs at the level of enterochromaffin-like (ECL) cells; 3) the ethanol content of these drinks is not important for their stimulant effect, indicating that some other components of beer and wine are responsible for gastrin and histamine release from the dog stomach.

Gastrin processing and secretion in patients with end-stage renal failure.

Gastrin circulates at higher than normal concentrations in patients with end-stage renal failure (ESRF). However, it remains unclear which forms of gastrin are elevated and whether there is also an alteration in the secretory profile after stimulation. In the present study all processed and partially processed forms of circulating gastrin were measured in plasma before and after meal stimulation in ESRF patients and control subjects. Since Helicobacter pylori (HP) infection affects gastrin secretion, HP status was determined. Fasting gastrin-amide (36 +/- 8 pmol/L), gastrin-Gly (55 +/- 16 pmol/L), and total gastrin (218 +/- 32 pmol/L) measured in ESRF/HP-patients were all significantly greater than those in the control group (10 +/- 1, 15 +/- 3, and 17 +/- 2 pmol/L, respectively; P < 0.01). Plasma gastrin-amide (126 +/- 67 pmol/L) and total gastrin (397 +/- 164 pmol/L) were highest in the ESRF/HP+ patients. The proportion of nonamidated gastrin products was 4-fold higher in ESRF patients than in control subjects, suggesting structure-specific changes in gastrin secretion and metabolism, and this was confirmed by chromatography. The meal-stimulated increments in control/HP- and ESRF/HP-groups were similar. However, the ESRF/HP+ group had a markedly potentiated gastrin response. Fasting plasma somatostatin, an inhibitor of gastrin secretion, was also measured and was significantly lower in the ESRF patients than that in the control group. These studies show that the hypergastrinemia associated with renal failure has been underestimated. This is because only amidated products were measured. The potentiated gastrin meal response in ESRF attributed previously to changes in gastrin metabolism are in part explained by the effect of HP infection. The observed diminished somatostatin response suggests that the increase in circulating gastrin in ESRF is the result of loss of inhibition of secretion as well as decreased metabolism. As both amidated and nonamidated gastrin are now considered to have trophic and secretory effects, these findings may explain the gastrointestinal tract hypertrophy often associated with ESRF.

Selective ligand-induced intracellular calcium changes in a population of rat isolated gastric endocrine cells

BACKGROUND & AIMS: Peripheral regulation of acid secretion depends mainly on stimulation or inhibition of the three major gastric endocrine cells (enterochromaffin-like, gastrin, and somatostatin). The aim of this paper was to define physiological responses of enterochromaffin-like, gastrin, and somatostatin cells in a mixed endocrine cell population by measuring ligand-selective changes of intracellular calcium ([Ca2+]i) in individual cells. METHODS: Endocrine cells were enriched from a rat gastric cell suspension by elutriation, a density-gradient fractionation, and a 48-hour short-term culture. [Ca2+]i responses of individual cells to various ligands such as gastrin/carboxy-terminal cholecystokinin octapeptide and selective cholecystokinin antagonists, carbachol, and gastrin-releasing peptide were monitored using video imaging in a perfusion chamber. Characteristic [Ca2+]i changes distinguished the three cell types, confirmed by immunostaining. RESULTS: All enterochromaffin-like cells respond to cholecystokinin-B receptor stimulation, but only a few respond to carbachol. Gastrin cells respond to both gastrin-releasing peptide and carbachol but not to cholecystokinin-receptor agonists. Somatostatin cells have both stimulatory cholecystokinin-A and cholecystokinin-B receptors and inhibitory muscarinic receptors. All cells have inhibitory somatostatin receptors. CONCLUSIONS: Calcium- signaling responses of gastric endocrine cells are distinctive. This allows individual cell types in a mixed population to be characterized and permits an analysis of the hormones and transmitters that act directly on a specific cell type. (Gastroenterology 1996 Jun;110(6):1835-46)

The Human Histidine Decarboxylase Promoter Is Regulated by Gastrin and Phorbol 12-Myristate 13-Acetate through a Downstream cis-Acting Element

Transcriptional regulation of the human histidine decarboxylase (HDC) gene by gastrin and the phorbol ester phorbol 12-myristate 13-acetate (PMA) was studied using transient transfection of human HDC promoter-luciferase constructs in a human gastric carcinoma cell line (AGS-B) that expresses the human cholecystokinin-B/gastrin receptor. The transcriptional activity of the human HDC promoter was stimulated 3-4-fold by gastrin and 13-fold by PMA, effects that could be blocked by down-regulation or antagonism of protein kinase C. 5'- and 3'-deletion analysis demonstrated that the sequence responsible for gastrin- and PMA-stimulated transactivation (gastrin response element (GAS-RE)) was located in a region (+2 to +24) downstream of the transcriptional start site (+1) in the human HDC promoter and contained a palindrome (5'-CCCTTTAAATAAAGGG-3'). When ligated upstream of the herpes simplex virus 1 thymidine kinase promoter, a single copy of the GAS-RE was sufficient to confer responsiveness to gastrin and PMA. Electrophoretic mobility shift assays with specific competitors and factor-specific antibody supershifts showed that the labeled GAS-RE bound a novel nuclear factor(s). In addition, both gastrin and PMA increased binding of this factor to the GAS-RE. Hence, the palindromic GAS-RE site is sufficient to explain the gastrin/PMA responsiveness of the human HDC promoter and appears to bind a novel transcription factor.