Stomach gastrin is regulated by sodium via PPAR-α and dopamine D1 receptor.

Gastrin, secreted by stomach G cells in response to ingested sodium, stimulates the renal cholecystokinin B receptor (CCKBR) to increase renal sodium excretion. It is not known how dietary sodium, independent of food, can increase gastrin secretion in human G cells. However, fenofibrate (FFB), a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, increases gastrin secretion in rodents and several human gastrin-secreting cells, via a gastrin transcriptional promoter. We tested the following hypotheses: (1.) the sodium sensor in G cells plays a critical role in the sodium-mediated increase in gastrin expression/secretion, and (2.) dopamine, via the D1R and PPAR-α, is involved. Intact human stomach antrum and G cells were compared with human gastrin-secreting gastric and ovarian adenocarcinoma cells. When extra- or intracellular sodium was increased in human antrum, human G cells, and adenocarcinoma cells, gastrin mRNA and protein expression/secretion were increased. In human G cells, the PPAR-α agonist FFB increased gastrin protein expression that was blocked by GW6471, a PPAR-α antagonist, and LE300, a D1-like receptor antagonist. LE300 prevented the ability of FFB to increase gastrin protein expression in human G cells via the D1R, because the D5R, the other D1-like receptor, is not expressed in human G cells. Human G cells also express tyrosine hydroxylase and DOPA decarboxylase, enzymes needed to synthesize dopamine. G cells in the stomach may be the sodium sensor that stimulates gastrin secretion, which enables the kidney to eliminate acutely an oral sodium load. Dopamine, via the D1R, by interacting with PPAR-α, is involved in this process.

Proton pump inhibitors: impact on glucose metabolism.

Diabetes mellitus is a complex chronic disease associated with an absolute insulin deficiency in type 1 diabetes (T1D) and a progressive deterioration of ß-cell function in type 2 diabetes (T2D). T2D pathophysiology has numerous defects including incretin deficiency/resistance. Gastrin has demonstrated to be an islet growth factor (like glucagon-like peptide-1, epidermal growth factor, transforming growth factor-α,…) and be able to restore a functional ß-cell mass in diabetic animals. This hormone is likely to stimulate insulin secretion during an ordinary protein-rich meal, this is, to have an incretin-like effect. Proton pump inhibitors (PPIs) can raise serum gastrin concentration significantly and therefore, affect to glucose metabolism through promoting ß-cell regeneration/expansion and also enhancing insulin secretion. The present paper aims to review studies concerning the effect of PPIs on glucose metabolism. Several research groups have recently explored the potential role of this class of drugs on glycemic control, mainly in T2D. The results show antidiabetic properties for the PPIs with a global glucose-lowering power around 0.6-0.7 % points of HbA1c, but the level of evidence for the available literature is still not high. If these data start to become demonstrated in the ongoing clinical trials, PPIs could become a new antidiabetic agent with a good and safe profile for T2D and even useful for T1D, particularly in the area of islet transplantation to preserve ß-cell mass.

Oxytocin and dopamine stimulate ghrelin secretion by the ghrelin-producing cell line, MGN3-1 in vitro.

To understand the physiological role of ghrelin, it is crucial to study both the actions of ghrelin and the regulation of ghrelin secretion. Although ghrelin actions have been extensively revealed, the direct factors regulating ghrelin secretion by ghrelin-producing cells (X/A-like cells), however, is not fully understood. In this study, we examined the effects of peptide hormones and neurotransmitters on in vitro ghrelin secretion by the recently developed ghrelin-producing cell line MGN3-1. Oxytocin and vasopressin significantly stimulated ghrelin secretion by MGN3-1 cells. Because MGN3-1 cells express only oxytocin receptor mRNA, not vasopressin receptor mRNA, oxytocin is the likely regulator, with the effect of vasopressin mediated by a cross-reaction. We also discovered that dopamine stimulates ghrelin secretion from MGN3-1 cells in a similar manner to the previously known ghrelin stimulators, epinephrine and norepinephrine. MGN3-1 cells expressed mRNA encoding dopamine receptors D1a and D2. The dopamine receptor D1 agonist fenoldopam stimulated ghrelin secretion, whereas the D2, D3 agonist bromocriptine did not. Furthermore, the D1 receptor antagonist SKF83566 attenuated the stimulatory effect of dopamine. These results indicate that the stimulatory effect of dopamine on ghrelin secretion is mediated by the D1a receptor. In conclusion, we identified two direct regulators of ghrelin, oxytocin and dopamine. These findings will provide new direction for further studies seeking to further understand the regulation of ghrelin secretion, which will in turn lead to greater understanding of the physiological role of ghrelin.

Role of spinal neurotransmitter receptors in itch: new insights into therapies and drug development.

Targets for antipruritic therapies are now expanding from the skin to the central nervous system. Recent studies demonstrate that various neuronal receptors in the spinal cord are involved in pruritus. The spinal opioid receptor is one of the best-known examples. Spinal administration of morphine is frequently accompanied by segmental pruritus. In addition to µ-opioid receptor antagonists, κ-opioid receptor agonists have recently come into usage as novel antipruritic drugs, and are expected to suppress certain subtypes of itch such as hemodialysis- and cholestasis-associated itch that are difficult to treat with antihistamines. The gastrin-releasing peptide receptor in the superficial dorsal horn of the spinal cord has also received recent attention as a novel pathway of itch-selective neural transmission. The NMDA glutamate receptor appears to be another potential target for the treatment of itch, especially in terms of central sensitization. The development of NMDA receptor antagonists with less undesirable side effects on the central nervous system might be beneficial for antipruritic therapies. Drugs suppressing presynaptic glutamate-release such as gabapentin and pregabalin also reportedly inhibit certain subtypes of itch such as brachioradial pruritus. Spinal receptors of other neuromediators such as bradykinin, substance P, serotonin, and histamine may also be potential targets for antipruritic therapies, given that most of these molecules interfere not only with pain, but also with itch transmission or regulation. Thus, the identification of itch-specific receptors and understanding itch-related circuits in the spinal cord may be innovative strategies for the development of novel antipruritic drugs.

Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion.

The calcium-sensing receptor (CaR) is the major sensor and regulator of extracellular Ca(2+), whose activity is allosterically regulated by amino acids and pH. Recently, CaR has been identified in the stomach and intestinal tract, where it has been proposed to function in a non-Ca(2+) homeostatic capacity. Luminal nutrients, such as Ca(2+) and amino acids, have been recognized for decades as potent stimulants for gastrin and acid secretion, although the molecular basis for their recognition remains unknown. The expression of CaR on gastrin-secreting G cells in the stomach and their shared activation by Ca(2+), amino acids, and elevated pH suggest that CaR may function as the elusive physiologic sensor regulating gastrin and acid secretion. The genetic and pharmacologic studies presented here comparing CaR-null mice and wild-type littermates support this hypothesis. Gavage of Ca(2+), peptone, phenylalanine, Hepes buffer (pH 7.4), and CaR-specific calcimimetic, cinacalcet, stimulated gastrin and acid secretion, whereas the calcilytic, NPS 2143, inhibited secretion only in the wild-type mouse. Consistent with known growth and developmental functions of CaR, G-cell number was progressively reduced between 30 and 90 d of age by more than 65% in CaR-null mice. These studies of nutrient-regulated G-cell gastrin secretion and growth provide definitive evidence that CaR functions as a physiologically relevant multimodal sensor. Medicinals targeting diseases of Ca(2+) homeostasis should be reviewed for effects outside traditional Ca(2+)-regulating tissues in view of the broader distribution and function of CaR.

Gastrin: an acid-releasing, proliferative and immunomodulatory peptide?

Gastrin release is affected by gastric inflammatory conditions. Antral G cells respond to inflammatory mediators by increasing gastrin secretion. Accumulating experimental evidence suggests that gastrin exerts immunomodulatory and proinflammatory effects. Gastrin could be a contributing factor to these pathologies, which may constitute a new justification for pharmacological blockade of gastrin action.

Delineation of the chemomechanosensory regulation of gastrin secretion using pure rodent G cells.

BACKGROUND & AIMS: Gastrin is a key regulator of gastric acid secretion. We aimed to isolate pure G cells to identify the mechanistic basis of luminal- and strain-mediated regulation. METHODS: Using gradient centrifugation and fluorescence-activated cell sorting, rat G cells were prepared and luminal, neural, hormonal, and mechanical activation of secretion and signaling pathways studied. RESULTS: Pure G-cell preparations (>97%) were isolated. Reverse-transcription polymerase chain reaction identified neural, hormonal, bacterial, and luminal G protein-coupled receptors, and immunostaining visualized specific sweet/bitter receptors and the tastant-associated G protein alpha-gustducin. Gastrin release was stimulated by forskolin (adenosine 3',5'-cyclic monophosphate [cAMP] inducer, 10 micromol/L; >3-fold), potentiated by 3-isobutyl-1-methylxanthine (IBMX; phosphodiesterase type 5 inhibitor and adenosine antagonist, 10 micromol/L) and phorbol myristate acetate (phorbol ester, 10 micromol/L), and inhibited by H-89 (protein kinase A inhibitor, 10 micromol/L), PD98059 (MEK1 inhibitor, 0.1 micromol/L), and wortmannin (phosphatidylinositol 3-kinase inhibitor, 1 nmol/L). Gastrin release was stimulated by neuronal G protein-coupled receptor ligands, pituitary adenylate cyclase-activating protein (20 pmol/L, >8-fold) and bombesin (0.1 micromol/L, 8-fold) through cAMP signaling. The tastants sucralose, glucose, caffeine, denatonium, and the vanilloid receptor activator capsaicin all stimulated secretion (>3-fold), as did bacterial lipopolysaccharides Salmonella enteritidis (0.24 nmol/L, 5-fold) greater than Helicobacter pylori (0.57 micromol/L, 3-fold). Secretion was associated with elevated cAMP levels (approximately 2-fold) and could be inhibited by H-89 and PD98059 and potentiated by IBMX and cholera toxin (250 microg/mL). Bacterially mediated secretion also involved activation of nuclear factor kappaB and the c-Jun-N-terminal kinase pathway. Mechanical strain stimulated (2-fold to 8-fold) gastrin release, and decreasing pH from 7.4 to 5.5 inhibited release. The adenosine receptor 2B antagonist MRS1754 inhibited mechanically induced gastrin release. CONCLUSIONS: G cells are luminal sampling chemomechanosensory cells whose secretion is regulated by neural, hormonal, luminal, and mechanical factors through protein kinase A activation, cAMP signaling, and mitogen-activated protein kinase phosphorylation.

Regulated expression of the human gastrin gene in mice.

Gastrin is secreted from neuroendocrine cells residing in the adult antrum called G cells, but constitutively low levels are also expressed in the duodenum and fetal pancreas. Gastrin normally regulates gastric acid secretion by stimulating the proliferation of enterochromaffin-like cells and the release of histamine. Gastrin and progastrin forms are expressed in a number of pathological conditions and malignancies. However, the DNA regulatory elements in the human versus the mouse gastrin promoters differ suggesting differences in their transcriptional control. Thus, we describe here the expression of the human gastrin gene using a bacterial artificial chromosome (BAC) in the antral and duodenal cells of gastrin null mice. All 5 founder lines expressed the 253 kb human gastrin BAC. hGasBAC transgenic mice were bred onto a gastrin null background so that the levels of human gastrin peptide could be analyzed by immunohistochemistry and radioimmunoassay without detecting endogenous mouse gastrin. We have shown previously that chronically elevated gastrin levels suppress somatostatin. Indeed, infusion of amidated rat gastrin depressed somatostatin levels, stimulated gastric acid secretion and an increase in the numbers of G cells in the antrum and duodenum. In conclusion, human gastrin was expressed in mouse enteroendocrine cells and was regulated by somatostatin. This mouse model provides a unique opportunity to study regulation of the human gastrin promoter in vivo by somatostatin and possibly other extracellular regulators contributing to our understanding of the mechanisms involved in transcriptional control of the human gene.

G cells and gastrin in chronic alcohol-treated rats.

Numerous reports have described gastric mucosal injury in rats treated with high ethanol concentrations. However, to the best of our knowledge, ultrastructural characteristics of G cells and antral gastrin levels have not been previously reported, either in rats that chronically consumed alcohol or in human alcoholics. The goal of this study was to examine the effect of ethanol consumption (8.5 g/kg) over a 4-month period, under controlled nutritional conditions, on antral and plasma levels of gastrin, ultrastructure of G cells, morphometric characteristics of G cells by stereological methods, and analysis of endocrine cells in the gastric mucosa by immunohistochemistry. The chronic alcohol consumption resulted in a nonsignificant decrease in gastrin plasma levels and unchanged antral gastrin concentrations. A slightly damaged glandular portion of the gastric mucosa and dilatation of small blood vessels detected by histological analysis, suggests that ethanol has a toxic effect on the mucosal surface. Chronic alcohol treatment significantly decreased the number of antral G cells per unit area, and increased their cellular, nuclear, and cytoplasmatic profile areas. In addition, the volume density and diameter of G-cell granules, predominantly the pale and lucent types, were increased, indicating inhibition of gastrin release. Ethanol treatment also decreased the number of gastric somatostatin-, serotonin-, and histamine-immunoreactive cells, except the somatostatin cells in the pyloric mucosa, as well as both G: D: enterochromaffin cells (EC) cell ratios in the antrum and D: ECL cell ratios in the fundus. These results indicate that the change of morphometric parameters in G cells may be related to cellular dysfunction. Our findings also suggest that regulation of G-cell secretion was not mediated by locally produced somatostatin in ethanol-consuming rats, but may involve gastric luminal content and/or neurotransmitters of gastric nerve fibers.

Effect of mica monomer powder on chief and parietal cells as well as G and D cells in gastric mucosa of chronic atrophic gastritis in rats.

OBJECTIVE: To study the regulative action of mica monomer powder preparation on the chief and parietal cells as well as G and D cells in the gastric mucosa of the experimental atrophic gastritis (CAG) rats. METHODS: Intervention therapy was given to the experimental CAG rats at three different doses of mica monomer powder preparation to evaluate the changes of chief and parietal cells as well as G and D cells in the gastric mucosa and the histopathological changes of gastric mucosa. RESULTS: Mica monomer powder preparation at three different doses could increase the amount of chief and parietal cells as well as G and D cells in gastric mucosa of the experimental CAG rats and alleviate and control the inflammation of gastric mucosa and the atrophy of gastric mucosa glands. Especially, better effects were shown in the mid and high dose groups. CONCLUSION: Mica has the pharmacological action of protecting the gastric mucosa, enhancing blood flow of the gastric mucosa, and consequently improving the inflammatory responses of the gastric mucosa. One of the mechanisms is associated with promoting the secretion of gastric acid and gastric pepsin and regulating the neuroendocrine mechanism including gut hormone secretion (gastrin and somatostatin) by increasing the number of chief and parietal cells as well as G and D cells.

Ciprofibrate stimulates the gastrin-producing cell by acting luminally on antral PPAR-alpha.

The lipid-lowering drug ciprofibrate stimulates gastrin-producing cells in the rat stomach without lowering gastric acidity. Although suggested to be a luminal action on antral peroxisome proliferator-activated receptor-alpha (PPAR-alpha), the mechanism is still not fully elucidated. Gastric bypass was surgically prepared in male Sprague-Dawley rats. Gastric-bypassed and sham-operated rats were either given ciprofibrate (50 mg.kg(-1).day(-1) in methocel) or vehicle alone for 7 wk. PPAR-alpha knockout (KO) and wild-type (WT) mice were either given ciprofibrate (500 mg.kg(-1).day(-1) in methocel) or vehicle alone for 2 wk. The concentration of gastrin in blood was analyzed. Antral G cell density and gastrin mRNA abundance were determined by using immunostaining and Northern blot analysis. Ciprofibrate did not raise plasma gastrin or G cell density in gastric-bypassed rats, although the gastrin mRNA level was slightly increased. In contrast, ciprofibrate induced hypergastrinemia, a 50% increase in G cell density, and a threefold increase in gastrin mRNA in sham-operated rats. In PPAR-alpha KO mice, ciprofibrate did not raise G cell density or the gastrin mRNA level. The serum gastrin level was reduced by ciprofibrate. In WT mice, ciprofibrate induced hypergastrinemia, a doubling of G cell density, and a threefold increase in gastrin mRNA. Comparing animals dosed with vehicle only, PPAR-alpha KO mice had higher serum gastrin concentration than WT mice. We conclude that the main effects of ciprofibrate on G cells are mediated from the antrum lumen, and the mechanism is dependent on PPAR-alpha. The results indicate that PPAR-alpha may have a role in the physiological regulation of gastrin release.

Increased gastrin and calcitonin secretion after oral calcium or peptones administration in patients with hypercalciuria: a clue to an alteration in calcium-sensing receptor activity.

The calcium-sensing receptor (CaSR) has been detected in human antral gastrin-secreting cells, where, upon calcium and/or amino acid allosteric activation, it stimulates gastrin secretion. Patients with absorptive hypercalciuria (AH) display an enhanced gastric acid output; therefore, we evaluated the secretion of gastrin in subjects with AH (30 subjects vs. 30 healthy female controls, all postmenopausal) after oral calcium administration (1 g calcium gluconate) and, on a separate occasion, after peptone loading test (protein hydrolyzed, 10 g). Gastrin and monomeric calcitonin responses were higher in AH after both oral calcium administration (P < 0.01) and peptone loading (P < 0.01). Because the activation of CaSR by oral calcium and peptones directly induces gastrin release, the higher gastrin responses to these stimuli suggest an increased sensitivity of gastrin-secreting cells CaSR in patients with AH. A similar alteration in thyroid C cells might explain the enhanced calcitonin responses to both calcium and peptones. If the same alterations should in addition be present in the distal tubule (where CaSR is expressed as well), then a possible explanation for amino acid-induced hypercalciuria in AH would have been identified.

[Effect of mica monomer granule on gastrin, somatostatin and G cells as well as D cells of gastric mucosa in CAG rat].

OBJECTIVE: To study regulative action of mica monomer granule preparation on gastrin (GAS), somatostatin (SS) and G cells as well as D cells of gastric mucosa in experimental chronic atrophic gastritis (CAG) rat. METHOD: CAG rats were treated with mica monomer granule preparation with three different dosages--high, moderate and low level respectively. Changes of blood serum GAS, blood plasma SS and G cells as well as D cells of gastric mucosa in CAG rats were observed and detected with ELISA method, RIA method and immunocytochemistry method. RESULT: Mica monomer granule of three different dosages could increase the quantity of G cells as well as D cells of gastric mucosa and the concentration of blood serum GAS and decrease the content of blood plasma SS in CAG rat at different level respectively. It was more effective in high and moderate dosage groups. CONCLUSION: Mica has the pharmacological action of protecting gastric mucosa, promoting the palingenesis of gastric gland and enhancing blood stream of gastric mucosa consequently to abate the inflammation reaction of gastric mucosa. Its effective mechanism is associated with the neuroendocrine regulative mechanism of promoting the secretion of gastric acid and gastric pepsin by increasing the amount of G cells as well as D cells and the concentration of blood serum GAS, and reducing inhibiting action on GAS secretion and enhancing the secretion of GAS by decreasing the content of SS.

Tumour necrosis factor alpha antibody affects gastrin release in Crohn disease.

BACKGROUND: Gastrin plays an important role in the regulation of gastric acid secretion in humans. Tumour necrosis factor alpha (TNF-alpha) stimulates gastrin release from antral G cells in vitro. The aim was to determine whether gastrin release decreases in patients with Crohn disease treated with monoclonal antibody to TNF-alpha. METHODS: Twenty-five consecutive patients with Crohn disease (10 M, 15 F; 18 with fistulas) were treated with a single intravenous infusion of the monoclonal antibody to TNF-alpha, infliximab, at a dose of 5 mg/kg. Basal and bombesin stimulated gastrin was measured after an overnight fast immediately before and 2 weeks after infliximab. Helicobacter pylori status was determined by serology. RESULTS: Twenty-two patients were H. pylori-negative. Basal plasma gastrin was 21 (16-26) pmol/L before and 19 (15-25) pmol/L after infliximab (NS). Bombesin stimulated gastrin decreased from 49 (40-62) pmol/L before to 36 (33-59) pmol/L (P < 0.005) 2 weeks after infliximab. CONCLUSION: Gastrin release in response to bombesin decreases in patients with Crohn disease treated with infliximab.

Antral G cells in rats during dosing with a PPAR alpha agonist: a morphometric and immunocytochemical study.

Gastrin-producing G cells constitute one of the major populations of neuroendocrine cells in the antral mucosa of the stomach. The peroxisome proliferator-activated receptor (PPAR) alpha-agonist ciprofibrate is used as a lipid-lowering drug. Recently, ciprofibrate has been shown to induce hypergastrinemia in rats without reducing gastric acidity, which indicates a direct stimulatory effect on the G cell. Gastrin probably plays an important role in gastric tumorgenesis, and long-term dosing with ciprofibrate results in enterochromaffin-like (ECL) cell carcinoids in the oxyntic mucosa of rats. In this study, we aimed to examine changes of neuroendocrine granules in G cells following ciprofibrate dosing and relate them to changes induced by the proton pump inhibitor pantoprazole. Furthermore, we wanted to study peroxisomes in G cells. Rats received ciprofibrate 80 mg/kg/day or pantoprazole 200 mg/kg/day in 4 weeks. Antral mucosal specimens were processed for conventional staining procedures and immunocytochemistry for both the light and electron micro-scope. Specimens were immunolabeled for gastrin and peroxisome-specific proteins. Electron micrographs were analyzed planimetrically. This study shows that hypergastrinemia induced by ciprofibrate is accompanied by a decrease in granule number per cell and a relative increase in electron-dense granules. These changes were quite similar to those induced by pantoprazole, indicating signs of G-cell activation in general. However, distinctions concerning granule size and composition and both hypertrophy and hyperplasia of G cells are presented. Finally, demonstration of peroxisomes in G cells was only achieved by using the highly sensitive tyramide signal amplification technique in immunostaining for the peroxisome-specific protein PMP-70. Therefore, neither morphological nor quantitative changes of peroxisomes in G cells were detected.

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.

Helicobacter pylori increases gastrin release from cultured canine antral G-cells.

OBJECTIVE: To investigate the mechanisms underlying the hypergastrinaemia of Helicobacter pylori by examining the effects of H. pylori on basal and stimulated gastrin release from cultured canine G-cells. METHODS: Canine antral G-cells were prepared by collagenase-EDTA digestion and cultured for 40 h. G-cells were then cultured for a further 24 h with two different H. pylori sonicates before basal and bombesin-stimulated gastrin release were measured by radioimmunoassay. RESULTS: Treatment of G-cells with both H. pylori sonicates significantly enhanced basal gastrin release (by 17-27%) and bombesin-stimulated gastrin release (by 115-133%). This effect was independent of cagA and vacuolating cytotoxin status. Control treatment with Escherichia coli sonicate had no effect on gastrin release. There was no change in the cellular content of gastrin. CONCLUSIONS: Incubation of antral G-cells with H. pylori constituents enhances subsequent basal and bombesin-stimulated gastrin release. Direct contact between H. pylori and G-cells in the gastric antrum may be responsible for the hypergastrinaemia seen with the infection.

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

BACKGROUND: 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. AIM: To determine the direct effects of histamine receptor agonists on isolated gastrin cells. METHODS: Rabbit G-cells were prepared by countercurrent elutriation and cultured on 24-well plates. RESULTS: 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). CONCLUSION: NalphaMH and histamine release gastrin from G-cells via H2-receptors; this might contribute to H. pylori-associated hypergastrinaemia.

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.

Effect of pirenzepine on gastric endocrine cell kinetics during lansoprazole administration.

We studied the effect of pirenzepine on gastric secretion kinetics in rats in a hypochlorhydric state induced by lansoprazole, a proton pump inhibitor. Pirenzepine was administered intramuscularly at a dosage of 20 mg/kg twice daily; and lansorprazole, subcutaneously at 50 mg/kg once daily, both every day for 4 weeks. After the 4-week treatment, serum gastrin and plasma somatostatin levels were determined by radioimmunoassay. In addition, gastrin cells, somatostatin cells, and enterochromaffin-like cells were immunostained and counted. Serum gastrin levels were elevated, and gastrin and enterochromaffin-like cell numbers increased in the group on lansoprazole alone, compared with these values in the control group (which received distilled water). In the group on the lansoprazole and pirenzepine combination, serum gastrin levels decreased, and gastrin and enterochromaffin-like cell numbers were significantly decreased, compared with the respective variables in the group on lansoprazole alone, while the number of somatostatin cells increased in the group on the combination. Plasma somatostatin levels did not vary significantly in any group. It was thus demonstrated that pirenzepine corrects the abnormal gastric secretion kinetics resulting from treatment with lansoprazole alone, such as hypergastrinemia and gastrin and enterochromaffin-like cell hyperplasia.