Gastrin Cells Research Articles

Rabeprazole for the prevention of pathologic and symptomatic relapse of erosive or ulcerative gastroesophageal reflux disease

OBJECTIVE: We evaluated the effectiveness and safety profile of 10 and 20 mg of rabeprazole, a new proton pump inhibitor, once daily versus placebo in preventing endoscopic and symptomatic relapse for up to 1 yr among patients with healed erosive or ulcerative gastroesophageal reflux disease (GERD). METHODS: The 52-wk trial used a multicenter, randomized, double-blind, parallel-group design in which 209 men and women were assigned to 10 or 20 mg of rabeprazole once daily in the morning or placebo. RESULTS: Both rabeprazole doses were significantly superior to placebo in preventing endoscopic relapse ( p < 0.001), and 20 mg was significantly more effective than 10 mg ( p < 0.04). Both doses were also significantly superior to placebo in reducing the frequency and severity of heartburn relapse ( p < 0.001). When adjusted for differences in exposure to study medication, no significant differences were found in the incidence of adverse events. No clinically significant changes were found regarding clinical laboratory parameters, vital signs, electrocardiograms, ophthalmological evaluations, body weight, serum gastrin, and enterochromaffin-like cell histology. CONCLUSIONS: Once-daily therapy with 10 or 20 mg of rabeprazole effectively prevents pathological and symptomatic GERD relapse. The 20-mg dose is significantly more effective than the 10-mg dose in preventing endoscopic recurrence. Treatment was well tolerated, and no clinically significant safety findings emerged. Our findings support rabeprazole’s efficacy in preventing GERD recurrence with excellent tolerability and a short-term favorable safety profile.

Rabeprazole for the prevention of pathologic and symptomatic relapse of erosive or ulcerative gastroesophageal reflux disease

We evaluated the effectiveness and safety profile of 10 and 20 mg of rabeprazole, a new proton pump inhibitor, once daily versus placebo in preventing endoscopic and symptomatic relapse for up to 1 yr among patients with healed erosive or ulcerative gastroesophageal reflux disease (GERD). The 52-wk trial used a multicenter, randomized, double-blind, parallel-group design in which 209 men and women were assigned to 10 or 20 mg of rabeprazole once daily in the morning or placebo. Both rabeprazole doses were significantly superior to placebo in preventing endoscopic relapse (p < 0.001), and 20 mg was significantly more effective than 10 mg (p < 0.04). Both doses were also significantly superior to placebo in reducing the frequency and severity of heartburn relapse (p < 0.001). When adjusted for differences in exposure to study medication, no significant differences were found in the incidence of adverse events. No clinically significant changes were found regarding clinical laboratory parameters, vital signs, electrocardiograms, ophthalmological evaluations, body weight, serum gastrin, and enterochromaffin-like cell histology. Once-daily therapy with 10 or 20 mg of rabeprazole effectively prevents pathological and symptomatic GERD relapse. The 20-mg dose is significantly more effective than the 10-mg dose in preventing endoscopic recurrence. Treatment was well tolerated, and no clinically significant safety findings emerged. Our findings support rabeprazole's efficacy in preventing GERD recurrence with excellent tolerability and a short-term favorable safety profile.

Effect of a histamine H1 receptor antagonist on gastric endocrine cell proliferation induced by chronic acid suppression in rats.

The effect of histamine on gastrin cells and enterochromaffin-like cells has not yet been clarified. We investigated the influence of pyrilamine (a histamine H1 receptor antagonist) on serum gastrin level, gastrin cells, and enterochromaffin-like cells in rats with or without 4 weeks of famotidine treatment. The rats were divided into six groups: a control group, two pyrilamine groups (2mg/kg, or 20mg/kg, p.o.), a famotidine group (20mg/kg twice/daily i.m.), and two pyrilamine + famotidine groups. The serum gastrin concentration was determined, and gastrin cells and enterochromaffin-like cells were identified by the labeled streptavidin biotin complex method and counted. Hypergastrinemia, gastrin cell hyperplasia, and enterochromaffin-like cell hyperplasia were found after 4 weeks of famotidine treatment. Four weeks of treatment with pyrilamine alone did not affect the gastrin level, gastrin cells, or enterochromaffin-like cells in the rat stomach. When combined with famotidine, pyrilamine enhanced famotidine-induced hypergastrinemia, but it did not affect gastrin cell hyperplasia, and it significantly inhibited enterochromaffin-like cell hyperplasia. These results suggest that gastrin secretion and enterochromaffin-like cell proliferation may be regulated by histamine via the H1 receptor during acid suppression.

Octreotide inhibits the enterochromaffin-like cell but not peroxisome proliferator-induced hypergastrinemia.

The peroxisome proliferator ciprofibrate induces hypergastrinemia and as a consequence, enterochromaffin-like (ECL) cell hyperplasia. The mechanism for the gastrin cell stimulation is unknown. The somatostatin analog octreotide LAR (long-acting release) was used to see if the stimulating effects of ciprofibrate could be attenuated. Female Fischer rats were dosed with ciprofibrate (50 mg/kg body weight per day) alone or combined with octreotide LAR (10 mg/30 days) for 60 days. Plasma gastrin and histamine, gastric endocrine cell densities and mRNA abundances were measured. Ciprofibrate increased gastrin mRNA abundance (P<0.05), gastrin cell number (P<0. 001) and cell area (P<0.01), and induced hypergastrinemia (P<0.001). These rats had profound ECL cell hyperplasia, confirmed by an increase in chromogranin A (CgA) and histidine decarboxylase (HDC) mRNA, density of neuroendocrine and ECL cells and plasma histamine levels (all P<0.001). Octreotide LAR did not affect ciprofibrate stimulation of gastrin cells, but all parameters of ECL cell hyperplasia were reduced (P<0.001). Octreotide LAR also significantly inhibited basal ECL cell function and growth. Ciprofibrate stimulates gastrin cell activity by a mechanism unaffected by octreotide, but octreotide does inhibit basal and gastrin-stimulated ECL cell function and growth.

Immunocytochemical evidence suggesting that diamine oxidase catalyzes biosynthesis of gamma-aminobutyric acid in antropyloric gastrin cells.

gamma-Aminobutyric acid (GABA) is a neurotransmitter that also occurs in a few non-neuronal cell types, where it may serve as a paracrine modulator. GABA is biosynthesized from glutamate by glutamate decarboxylase (GAD) and from putrescine via diamine oxidase (DAO). GAD is demonstrable in several GABA-positive cell types but is undetectable in the GABA-containing gastrin cells and somatostatin cells of the antropyloric mucosa of the stomach. Using two antisera raised against synthetic peptides corresponding to two different regions of rat DAO, we now demonstrate strong reactivity for DAO in gastrin-positive cells of the rat antropyloric mucosa, whereas somatostatin-positive cells as well as other structures of the antrum are unreactive. Western blotting analysis of antrum and colon demonstrate that both antisera react with a single band of 85 kD, consistent with the predicted molecular weight of DAO. Expression of DAO mRNA in the antrum is demonstrated by reverse transcriptase polymerase chain reaction (RT-PCR). Our results strongly indicate that gastrin cells produce GABA via DAO-catalyzed oxidation of putrescine, and experimental data moreover suggest that the biosynthesis of GABA is regulated by the prandial state. Because GABA modulates release of somatostatin, these results point to a new mechanism of paracrine interaction between gastrin cells and somatostatin cells.

Histomorphological characteristics of gastric mucosa in patients with Zollinger-Ellison syndrome or autoimmune gastric atrophy: role of gastrin and atrophying gastritis.

The role of gastrin in the pathophysiology of two diseases affecting the human stomach, the Zollinger Ellison syndrome (ZES) and the pernicious anemia (PA), is reviewed. Both diseases present chronic hypergastrinemia but from different origins. The ZES is characterized by the occurrence of ectopic endocrine gastrin-secreting tumors and PA by a fundic atrophic gastritis leading to complete atrophy of fundus and resulting in achlorhydria. In PA, the lack of acid induces continuous gastrin cell activation and is responsible for the subsequent gastrin hypersynthesis and secretion. In ZES, hypergastrinemia causes hypertrophy of the oxyntic mucosa, which, in addition, displays hyperplasia of parietal and mucus cells. In both diseases, hypergastrinemia also induces the hyperproliferation of enterochromaffin-like endocrine cells in the fundic mucosa, which can offer all aspects from hyperplasia, then dysplasia, until true carcinoid tumor. The influence of antisecretory treatments and MEN 1 in the ZES as well as that of several other factors and antrectomy in PA on the behavior of the different gastric cells is evoked. Finally, the role that gastrin and its receptor play in the maintenance of the normal development of gastric mucosa and gastric acid secretion is emphasized by results observed in gene knockout models.

Developmental biology of gastrin and somatostatin cells in the antropyloric mucosa of the stomach.

Gastrin is a hormone regulating gastric acid secretion and the growth of the gastrointestinal epithelium. It is expressed by endocrine tumors and by adenocarcinomas of the gastroenteropancreatic region and may represent an autocrine tumor growth factor. Gastrin is also implicated in the genesis of peptic ulcer disease both in conjunction with H. pylori infections and with gastrin-producing tumors. The secretion and expression of gastrin are under the paracrine control of somatostatin, produced by D cells situated in close contact with gastrin-producing G cells. D cells also contain neuronal nitric oxide synthase and appear to regulate apoptosis of G cells by paracrine release of nitric oxide. Both G and D cells are derived from a common multihormonal precursor cell present in the regenerative (isthmus) region of the gastric units. The precursor cells have been suggested to undergo asymmetrical divisions resulting in gastrin- and somatostatin-producing daughter cells that remain in paracrine contact during their migration into the glands. The precursor cells also give rise to the third main antropyloric endocrine cell type; the serotonin-producing EC cell. The maturation of all of these cell types is regulated by a number of transcription factors containing homeobox motifs (Pdx-1, Pax 4 and 6, Isl-1, Nkx6.1). Many of these also regulate the development of the central nervous system and the pancreas. The use of different combinations of these factors for regulating the expression of different hormones may explain the phenomenon of abberant hormone expression during development and carcinogenesis and the occurrence of multihormonal cells.

Innervation of the gastric mucosa.

A plethora of neuronal messengers ("classical" transmitters, gaseous messengers, amino acid transmitters, and neuropeptides) are capable of mediating or modulating gastric functions. Accordingly, the stomach is richly innervated. Gastric nerves are either intrinsic to the gastric wall, i.e., they have their cell bodies in the intramural ganglia and thus belong to the enteric nervous system, or they reach the stomach from outside, originating in the brainstem, in sympathetic ganglia, or in sensory ganglia. Topographically, the nerve fibers in the stomach reach all layers from the most superficial portions of the gastric glands to the outer smooth muscle layer. This wide distribution implies that virtually all different cell types may be reached by neuronal messengers. Within the gastric mucosa endocrine and paracrine cells (e.g., gastrin cells, ECL cells, somatostatin cells), exocrine cells (parietal cells, chief cells, mucous cells), smooth muscle cells, and stromal cells are regulated by neuronal messengers. The sensory innervation, responding to capsaicin, plays an important role in mucosal protection, and in ulcer healing. Presumably also other nerves are involved and a plasticity in the neuropeptide expression has been demonstrated at the margin of gastric ulcers. Taken together, available data indicate a complex interplay between hormones, paracrine messengers and neuronal messengers, growth factors and cytokines in the regulation of gastric mucosal activities such as secretion, local blood flow, growth, and restitution after damage.

Cellular expression of the neurokinin 1 receptor in the human antrum

The localization of the neurokinin 1 receptor in rat and guinea pig gastrointestinal tract has been extensively studied but not in human tissues. The present study used antibodies to characterize the cellular expression of neurokinin 1 receptors in human antrum. Cryostat sections (40–80 μm) were immunostained for the neurokinin 1 receptor double labeled with substance P, von Willebrand’s factor, c-kit, fibronectin, S-100, serotonin, gastrin and somatostatin. Neurokinin 1 receptor-immunoreactivity was observed on neurons within the myenteric and submucosal plexuses surrounded by substance P-immunoreactive fibers and on von Willebrand’s factor-immunoreactive endothelial cells lining blood vessels throughout the antral wall. c-Kit-immunoreactive interstitial cells of Cajal and gastrin cells were co-stained by the monoclonal neurokinin 1 receptor antibody. Finally, there was no evidence for the presence of the neurokinin 1 receptor on fibroblasts, Schwann, somatostatin, serotonin or smooth muscle cells. This study clearly demonstrates an expanded cellular expression of the neurokinin 1 receptor in the human antrum.

Serum gastrin and gastrin-immunoreactive cells in the antral mucosa of patients with alcoholic liver disease.

Hypergastrinaemia has been reported in liver cirrhosis; meanwhile, it is unclear whether it is associated with an increase in gastrin cell function. The serum gastrin concentration and the number of gastrin cells in antral biopsies were studied in patients with alcoholic liver disease. Immunocytochemical and quantification techniques were used to localize and determine the number of gastrin cells. Slight non-significantly higher serum gastrin values were observed in the alcoholic liver disease patients compared with controls, but the individual variation within the groups was considerable. The frequency of gastrin cells did not differ between groups. However, the size of the gastrin cell nuclei was larger in patients with liver disease than in controls, indicating increased cellular activity. Alcoholic liver disease, with a disturbed liver function, influences the gastrin cells. The observed alterations may reflect the effect of alcohol and/or malnutrition, or may be secondary to the influence of liver disease on other regulatory peptides.

Serotonin and gastrin cells in rat gastrointestinal tract after thyroparathyroidectomy and induced hyperthyroidism.

Thyroidectomy appears to reduce the serotonin content in the rat brain, whereas hyperthyroidism has the opposite effect. As it is not known whether the serotonin-producing cells of the gastrointestinal tract are influenced by these conditions, the effects of thyroparathyroidectomy and induced hyperthyroidism were studied experimentally, particularly as regards the serotonin- and gastrin-immunoreactive cells of the gastrointestinal tract. Immunocytochemical and quantification techniques were used to localize and determine the numbers of serotonin and gastrin cells. In thyroparathyroidectomized rats the intestine was significantly shorter and the mucosa thinner than in sham-operated and untreated controls, whereas the converse was found in the hyperthyroid rats. Following thyroparathyroidectomy, there were fewer gastrin-immunoreactive cells in antrum and the serotonin-immunoreactive cells were significantly less dense throughout the gastrointestinal tract. In hyperthyroid rats, gastrin-immunoreactive cells were more numerous, as were the serotonin-immunoreactive cells in the small intestine, whereas these cells were fewer in antrum and caecum. In conclusion, the thyroid gland exerts a significant influence on the gastrointestinal tract and on the serotonin-and gastrin-immunoreactive cells. The observed alterations may reflect a direct effect of the thyroid hormones, although indirect factors must also be considered.

Expression of Islet Amyloid Polypeptide. Localization and regulation in the pancreatic islets, gastrointestinal tract and sensory nervous system

Islet amyloid polypeptide (IAPP; also named ”amylin”) is a member of the calcitonin superfamily of peptides, displaying the closest structural relationship to the neuropeptide calcitonin gene-related peptide (CGRP). It is expressed in islet beta-cells and forms islet amyloid in type 2 diabetic patients. IAPP may restrain release and peripheral actions of insulin. Thus, IAPP has been implicated in the pathogenesis of type 2 diabetes. By examinations of tissue-specific expression of IAPP and its regulation under normal and experimental conditions, we aimed to illuminate a possible role of IAPP. IAPP was expressed in islet beta-cells in nearly all species examined; in some species IAPP occurred also in delta-cells. IAPP expression was of early onset during embryonic islet development. In vivo, we found a parallel regulation of IAPP and insulin expression by administration of glucose. These findings agree with a role for IAPP in glucose homeostasis by autocrine/paracrine regulation of islet function as well as by endocrine secretion. Following dexamethasone treatment of rats, a model for type 2 diabetes, we found a non-parallel expression of IAPP and insulin; in relative terms, IAPP was over-expressed compared with insulin. In rodents given streptozotocin or alloxan, conferring beta-cell depletion reminiscent of type 1 diabetes, IAPP expression was consistently less impaired than that of insulin. These studies show that IAPP and insulin gene expression are differentially regulated. Apparently, beta-cell stress, regardless of ethiology, results in over-expression of IAPP. IAPP was also found to be expressed in the gastrointestinal tract in a region- and species-dependent manner; when present, IAPP expression was most abundant proximally, occurring in somatostatin and gastrin cells. Also gastrointestinal IAPP expression was of early embryonic onset. In vitro, IAPP relaxed pre-contracted gut musculature. In the sensory nervous system IAPP was expressed in CGRP neurons and displayed a distribution typical of sensory neuropeptides. Upon sciatic axotomy, IAPP and CGRP expression were co-ordinately downregulated. In contrast, following adjuvant-induced rat paw inflammation, IAPP expression was upregulated in innervating neurons, indicating that IAPP may play a role in neurogenic inflammation. In conclusion, our studies have expanded the view of IAPP as an exclusive islet hormone to become a ”classical” neurohormonal peptide, with several endocrine and neuronal expression sites. The studies on the regulation of islet IAPP and insulin expression in response to glucose and in experimental diabetes may form the basis for an understanding of the role of IAPP in diabetes. Provided that the amyloidogenic mechanisms and metabolic effects of IAPP are elucidated, an over-expression of IAPP may prove to be relevant for diabetes development.

Apoptosis in rat gastric antrum: evidence that regulation by food intake depends on nitric oxide synthase.

The turnover of the epithelium of the gastrointestinal tract is regulated by a balance between cell multiplication and cell loss. We examined the effects of starvation on apoptosis in endocrine and other epithelial cells of rat antropyloric mucosa. Apoptosis was determined by the TUNEL reaction combined with immunocytochemical staining for gastrin and somatostatin. Apoptotic cell morphology was determined by bisbenzimide staining for DNA. Both gastrin and somatostatin cells showed a significantly lower apoptotic index than the general epithelium. This agrees with the longer turnover kinetics of gastric endocrine cells. On starvation, the apoptotic index of the general epithelium and of the gastrin but not of the somatostatin, cells increased significantly. This was prevented by the nitric oxide synthase (NOS) inhibitor L-NAME but not by its inactive stereoisomer D-NAME. Immunoreactive neuronal NOS was present in somatostatin cells, in nonendocrine cells predominating in the surface and pit epithelium, and in rare nerve fibers. Endothelial cell NOS was present in vessels, whereas the inducible isoform was barely detectable. Thus, endogenous NOS isoforms participate in regulating antropyloric epithelial apoptosis during starvation. The close paracrine relation between somatostatin cells and gastrin cells suggests that the former regulates apoptosis of the latter through release of NO.

Use of flow cytometry to quantify mouse gastric epithelial cell populations.

Flow cytometry provides the opportunity to quantify cell populations within a total cell suspension. The quality of flow cytometry is strongly dependent on the isolation of intact viable cells. However, techniques to isolate mouse gastric cells for flow cytometry have not been evaluated. The objective of this study was to develop an effective method for isolating intact viable cells from mouse gastric tissue for flow cytometry. Cells were isolated from mouse stomach and spleen by either enzymatic separation or mechanical dissociation. A Percoll density gradient was used to separate viable cells from cellular debris. Cells were labeled with fluorescently tagged ligand or antibody and analyzed by flow cytometry. According to propidium iodide staining, there was a higher percentage of viable cells after mechanical dissociation (10-20%) compared to enzymatic separation (1%). After Percoll centrifugation there was a further increase in the percent of viable cells (50-80%). Gastrin (G), somatostatin (D), and parietal cells represented 0.6%, 3%, and 8% of the total epithelial cell population, respectively. T and B lymphocytes made up 4% and 2% in the gastric mucosa. Dissociated splenocytes were comprised of 20% T cells and 14% B cells. The ability to reliably resolve a cellular fraction that comprises only 0.6% of the input marks a substantial improvement over morphometric methods. Therefore, mechanical dissociation of the stomach followed by use of a Percoll gradient is the preferred method for isolating viable intact gastric epithelial cells for flow cytometry.

Immunocytochemical identification and localization of APUD cells in the gut of seven stomachless teleost fishes.

AIM:To study the cell types, localization, distribution density and morphology of APUD cells in the intestinal mucosa of stomachless teleost fishes.METHOD:By using the peroxidase antiperoxidase complex (PAP) immunocytochemical staining technique the identification, localization and morphology of immunoreactive (IR) endocrine cells seattered in the intestinal mucosa of grass carp (Cyenopharyngodon idellus), black carp ( Mylopharyngodon piceus ) and common carp (Cyprinus carpio) were investigated with 20 kinds of antisera prepared against mammalian peptide hormones of APUD cells, and likewise by using avidin-biotin-peroxidase complex (ABC) method those of silver carp (Hypophthalmichthys molitrix), bighead (Aristichthys nobilis), silver crucian carp (Carassius gibelio) and bluntnose black bream (Megalobrama amblyocephala ) were also studied with 5 different antisera. The replacement of the first antiserum by phosphate buffered saline (PBS) was employed as a control. IR endocrine cells were counted with a square-mesh ocular micrometer from 10 fields selected randomly in every section of each part of the intestine specimen. The average number of IR endocrine cells per mm(2) was counted to quantify their distribution density.RESULT:Gastrin (GAS), Gastric inhibitory peptide (GIP), glucagon (GLU), glucagons like immunorea-ctants (GLI), bovine pancreatic polypeptide (BPP), leucine-enkephalin (ENK) and substance P (SP)-IR endocrine cells were found in the gut of grass carp, black carp and common carp, and somatostatin (SOM) IR endocrine cells were only seen in common carp. GAS, GIP and GLU-IR endocrine cells were found in the intestinal mucosa of silver carp, bighead, silver crucian carp and bluntnose black bream. Most of IR endocrine cells had the higher distribution density in the foregut and midgut, and were longer in shape. They had a long apical cytoplasmic process extended to the gut lumen and a basal process extended to adjacent cells or basement membrane and touched with it. Sometimes, the basal cytoplasmic process formed an enlarged synapse-like structure in the contiguous part with basement membrane. This phenomenon provided new morpho-logical evidence for neuroendocrine and paracrine secretory function of these enteroendocrine cells.CONCLUTION:At least 8 kinds of IR endocrine cells were found in the gut of stomachless teleost species for the first time in China. These IR endocrine cells scattering in the gut mucosa belong to the APUD system. Among them, the hormones secreted by SP-, ENK-, SOM- and GLU-IR endocrine cells belong to the peptides of dual distribution in the brain and gut. This provided new evidence for the concept of brain-gut peptide. According to the cell types, distribution density, morphological characteristics and variety in shape of APUD cells in the gut of stomachless teleost fishes, it is deemed that the digestive tract of fishes is also an endocrine organ of great importance and complexity.

Nalpha-methyl histamine and histamine stimulate gastrin release from rabbit G-cells via histamine H2-receptors.

Gastrin release by Helicobacter pylori may be an important step in the pathway leading to duodenal ulceration. A histamine H3-receptor agonist was found to release gastrin from antral mucosal fragments; this was interpreted as being due to suppression of somatostatin release. H. pylori is reported to produce Nalpha-methyl histamine (NalphaMH), which is an agonist of H3 as well as other histamine receptors. H. pylori infection also recruits mast cells, which release histamine. To determine the direct effects of histamine receptor agonists on isolated gastrin cells. Rabbit G-cells were prepared by countercurrent elutriation and cultured on 24-well plates. NalphaMH (10-6-10-4 M) caused a dose-dependent increase in gastrin release from a basal level of 2.3 +/- 0.2% total cell content (TCC; mean +/- S.E.M.) to a maximum of 5.1 +/- 0.7%, an increase of 117% (P < 0. 005) above basal. This was abolished by the H2-antagonist ranitidine (10-5 M), but not by immunoblockade with anti-somatostatin antibody, the H1-antagonist chlorpheniramine (10-5 M) or the H3-antagonist thioperamide (10-4 M). The histamine H2-receptor agonist dimaprit (10-6-10-4 M) increased gastrin release from 2.4 +/- 0.2% to 3.6 +/- 0.2% TCC (P < 0.001). Gastrin release was also stimulated by histamine (10-7-10-4 M) from a basal value of 3.0 +/- 0.3% to 5.4 +/- 0.5% TCC (P < 0.001). This also was inhibited by ranitidine (10-5 M) (P < 0.01). NalphaMH and histamine release gastrin from G-cells via H2-receptors; this might contribute to H. pylori-associated hypergastrinaemia.

Regulation of gastric acid secretion

This paper summarizes important developments, published over the past year, that improve our understanding of the regulation of gastric acid secretion at the central, peripheral, and intracellular levels and mechanisms by which various neurotransmitters, paracrine agents, and hormones regulate gastric secretion and are themselves regulated. The main stimulants of acid secretion from the parietal cell are histamine, gastrin, and acetylcholine. Histamine, released from fundic enterochromaffin-like cells, interacts with H(2) receptors on parietal cells that are coupled via separate G proteins to activation of adenylate cyclase and phospholipase C. The antral hormone gastrin, released by activation of cholinergic and bombesin/gastrin-releasing peptide neurons, acts mainly by release of histamine from enterochromaffin-like cells. Acetylcholine, released from gastric intramural neurons, interacts with muscarinic M(3) receptors on parietal cells and has little, if any, effect on histamine secretion. The main inhibitor of acid secretion is somatostatin, which, acting via sst(2) receptors, exerts a tonic restraint on parietal, enterochromaffin-like, and gastrin cells. In patients with duodenal ulcer, infection with Helicobacter pylori is associated with increased basal and stimulated plasma gastrin concentrations and acid outputs. The precise mechanisms mediating the effects are not known, but evidence suggests that both products of the bacteria and the inflammatory infiltrate are capable of stimulating gastrin and acid secretion.

17Beta-estradiol modulates gastroduodenal preneoplastic alterations in rats exposed to the carcinogen N-methyl-N'-nitro-nitrosoguanidine.

Gastric cancers are a significant cause of morbidity worldwide. Epidemiological studies and animal models show that males have higher incidences of gastric cancers compared with females, suggesting that sex hormones may modulate gastric cancer risk. An animal model of the initiation phase of gastric cancer was used to determine the effects of systemic estrogen administration on morphological progression of preneoplastic lesions and to define cell populations at which estrogens may act. Preneoplastic progression in antral and duodenal mucosa was examined in male rats that received the chemical carcinogen, N-methyl-N'-nitro-nitrosoguanidine (MNNG), during treatment with implants containing 17beta-estradiol or oil vehicle. Histopathological changes in antral and duodenal gland morphology, numbers of proliferating cells and apoptotic bodies, and antral gastrin cell numbers and protein storage levels were determined 4 weeks later. With MNNG treatment, duodenal villous heights were significantly decreased, and epithelial cells displayed histological features of hyperplasia and dysplasia. Antral glands showed epithelial hyperplasia and dysplasia, increased mucosal height, and decreased mucin levels. Antral gastrin storage protein levels were decreased by MNNG. Systemic treatment with 17beta-estradiol significantly reversed MNNG-induced alterations in duodenal gland heights while increasing mucin and gastrin levels in antral glands. Cell proliferation and apoptosis rates were not significantly different between groups. The present results indicate that systemic 17beta-estradiol treatment influences antral and duodenal gland differentiation during the initiation phase of chemical gastroduodenal carcinogenesis in male rats. These results explain, in part, a potential pathway through which protective effects of estrogens on chemical carcinogenesis are mediated in the upper gastrointestinal tract.

Gastric amylin expression. Cellular identity and lack of requirement for the homeobox protein PDX-1. A study in normal and PDX-1-deficient animals with a cautionary note on antiserum evaluation.

The gene encoding amylin is implicated in the generation of amyloid in the islets of Langerhans of diabetics and is believed to be regulated by the homeodomain transcription factor PDX-1. Although gastric mucosa also produces amylin, studies on its cellular site of production have yielded highly divergent results, localizing this peptide to either gastrin, serotonin, or somatostatin cells or to combinations thereof. Using region-specific amylin antisera in combination with reverse transcriptase-polymerase chain reaction, we now document that the majority of cells expressing amylin correspond to somatostatin cells. Only a small subpopulation of gastrin cells contained immunoreactive amylin. Studies of PDX-1-deficient mice, which fail to develop gastrin cells while possessing normal numbers of somatostatin cells, revealed no detectable change in gastric amylin expression. These data show that neither normal gastrin cell development nor PDX-1 expression is needed for gastric amylin expression.

The Role of Protein Kinase C Isozymes in Bombesin-stimulated Gastrin Release from Human Antral Gastrin Cells

Two of the most effective stimuli of gastrin release from human antral G cells are bombesin and phorbol esters. Both agonists result in activation of the protein kinase C family of isozymes, however, the exact contribution of protein kinase C to the resultant release of gastrin has been difficult to assess, possibly due to the presence of multiple protein kinase C isozymes in the G cells. The results of the present study demonstrated that the human antral G cells expressed 6 protein kinase C isozymes alpha, gamma, theta, epsilon, zeta, and mu. Of these protein kinase C, gamma and theta were translocated by stimulation of the cells by either 10 nM bombesin or 1 nM phorbol ester. Inhibition of protein kinase Cmu (localized to the Golgi complex) did not decrease bombesin-stimulated gastrin release indicating that this isozyme was not involved in the secretory process. The use of selective antagonists of the calcium-sensitive conventional protein kinase C subgroup resulted in an increase in bombesin-stimulated gastrin release and indicated that protein kinase Cgamma was involved in the desensitization of the bombesin response.