Stimulation Of Gastric Acid Secretion Research Articles

Neuroendocrine mechanism of gastric acid secretion: Historical perspectives and recent developments in physiology and pharmacology.

The physiology of gastric acid secretion is one of the earliest subjects in medical literature and has been continuously studied since 1833. Starting with the notion that neural stimulation alone drives acid secretion, progress in understanding the physiology and pathophysiology of this process has led to the development of therapeutic strategies for patients with acid-related diseases. For instance, understanding the physiology of parietal cells led to the developments of histamine 2 receptor blockers, proton pump inhibitors (PPIs), and recently, potassium-competitive acid blockers. Furthermore, understanding the physiology and pathophysiology of gastrin has led to the development of gastrin/CCK2 receptor (CCK2 R) antagonists. The need for refinement of existing drugs in patients have led to second and third generation drugs with better efficacy at blocking acid secretion. Further understanding of the mechanism of acid secretion by gene targeting in mice has enabled us to dissect the unique role for each regulator to leverage and justify the development of new targeted therapeutics for acid-related disorders. Further research on the mechanism of stimulation of gastric acid secretion and the physiological significances of gastric acidity in gut microbiome is needed in the future.

Effect of Date (Phoenix Dactylifera L.) on Stimulated Gastric Acid Secretion in Wistar rats

Background: Peptic ulcer disease (PUD), encompassing gastric and duodenal ulcers is the most prevalent gastrointestinal disorder. The pathophysiology of PUD involves an imbalance between offensive factors like acid, pepsin and defensive factors such as nitric oxide and growth factors. The clinical evaluation of antiulcer drugs showed tolerance, incidence of relapses and side effects that make their efficacy arguable. Local folklore claims showed that Date (Phoenix Dactylifera L.) has a gastric beneficial role in humans. This study was therefore carried out to examine the effects of Dates on stimulated gastric acid secretion (GAS) in the Wister rats. Materials/Methods: Three groups of rats consisting of 5 rats (180- 200g) each were treated with aqueous undialyzed extract of Dates (1.5mg/kg, 2.5mg/kg and 4.0mg/kg) orally for 21 days, while the fourth group were given distilled water for the same number of days. At the last day of the treatment, the rats were fasted for 24 hours, anaesthetized with ketamine. GAS (mEq/l) induced by histamine, carbachol and pentagastrin administration was assessed by continuous perfusion technique. Data were analyzed using student's T-test and ANOVA at p≤ 0.05. Results: The aqueous extract of undialyzed Dates significantly decreased (p≤ 0.05) GAS induced by the histamine, carbachol and pentagastrin in a dose-dependent manner over 80 minutes period in all the treated groups. Conclusion: Date extract exhibited a graded dose-dependent decrease in gastric acid secretion. Keywords: Date, Gastric, Pentagastrin, Histamine and Carbachol

Effects of Coffee on the Gastro-Intestinal Tract: A Narrative Review and Literature Update.

The objective of the present research was to review the state of the art on the consequences of drinking coffee at the different levels of the gastrointestinal tract. At some steps of the digestive process, the effects of coffee consumption seem rather clear. This is the case for the stimulation of gastric acid secretion, the stimulation of biliary and pancreatic secretion, the reduction of gallstone risk, the stimulation of colic motility, and changes in the composition of gut microbiota. Other aspects are still controversial, such as the possibility for coffee to affect gastro-esophageal reflux, peptic ulcers, and intestinal inflammatory diseases. This review also includes a brief summary on the lack of association between coffee consumption and cancer of the different digestive organs, and points to the powerful protective effect of coffee against the risk of hepatocellular carcinoma. This review reports the available evidence on different topics and identifies the areas that would most benefit from additional studies.

Parameters of blood short-chain peptides and digestive hydrolases in patients with chronic hepatitis B virus infection

The aim of the study was to examine specifics of changes in the level of stomach- and pancreas-released blood hydrolases in chronic viral hepatitis B and analyze the mechanisms underlying such changes. We assessed serum markers of HBV infection, liver enzymes tests as well as gastric and pancreatic hydrolase level. The patients examined were divided into three groups: control (healthy) and two study groups — HBV post-infection and chronic HBV infection. Patients with HBV post-infection had no significant deviations from normal range for blood level of gastric and pancreatic hydrolases. Patients with chronic HBV infection were found to contain increased blood level of amylase and lipase, which may evidence about increasing pancreatic functional activity and development of covert pancreatitis. At the same time, decline in the concentration of serum pepsinogen-1 below 40 μg/l could indicate about prominently decreased secretion of hydrochloric acid and development of atrophic gastritis, and it was found that the major factor contributing to development of such disorders was the short-chain peptide CCK-8, which utilization declines in patients with chronic HBV infection. CCK-8 can play a pivotal role in inhibiting stimulation of gastric acid secretion and controls gastric acid, plasma gastrin and somatostatin secretion. Cholecystokinin has been found to inhibit acid secretion by activating CCK type A receptors as well as via somatostatin-involving mechanism. The secretion of gastric somatostatin-14 increased by fivefold due to CCK-8 alone, but was blocked by the CCK-A receptor blocker loxiglumide. These data show that CCK-8 directly inhibits acid reactions by stimulating the release of gastric somatostatin indirectly through the CCK-A receptor. Thus, it can be assumed that normally CCK-8 is mainly utilized by the liver, which is altered during chronic hepatitis B resulting in elevated blood CCK-8 concentration. As a consequence, it enhances pancreatic secretion resulting in developing pancreatitis that is paralleled with inhibited gastric secretion and emerged atrophic gastritis.

Analysis of Capsicum annuum L. Methanolic Extract and Its Potential as a Hepatoprotector

ThinLayerChromatography(TLC) method performed to purify capsaicin compound in C. annum L. and test the bioactive component of Capsicum Annum L on MAPK1 target proteins using the Immunohistochemistry (IHC) method to determine the reactions between receptor-ligand (antigen-antibody) complexes formed and become a reference in vivo tests. Natural ingredients need to be extracted to get some or all of the active ingredients used to synthesize the right dosage, easily stored, and maintain for a long time. The active ingredient of capsaicin is efficacious as a stimulant of gastric acid secretion and prevents infections in the digestive system.The immunohistochemical examination is intended to determine the expression of MAPK1 (ERK) on cells of mice hepatocytes (Mus musculus). MAPK 1 (ERK) expression score data were obtained using the modified Remmele method is the result of multiplying the percentage score of immunoreactive cells with the color intensity score on immunoreactive cells. The abnormal target protein signaling pathway contributes to cell proliferation, differentiation, survival, and uncontrolled cell apoptosis.Analysis of amino acid residues, Capsaicin to MAPK1haverelativelysimilarresiduessothatitcanbeconcludedthat the binding sites of the two compounds are close to similarities and affect receptors at relatively similar sites, namely oncogenicreceptors/ proteins. Concluded that the ethanol extract of Capsicum. annum L. had a greater in the powder form , TLC method showed the capsaicin standard was 1020 µg/ml, that capsaicin in chilies (Capsicum Annum L.) can synergistically inhibit cell through reactions in the anti-apoptotic MAPK 1 potentiates the antiproliferative action that can promote hepatoprotector, a finding that demands further clinicaltesting.

Effects of Bambara Nut (Vigna subterranean) on Basal and Stimulated Gastric Acid Secretion due to Histamine, Pentagastrin and Carbachol in rats

The seed extracts of V. subterranean (Bambara nuts) have many therapeutic applications in folkloric medicine owing to their effective secondary metabolites such as alkaloids, flavonoids, saponins, resins, and glycosides (Andzouana et al., 2014). The infusions and decoctions of the seeds are used to treat venereal diseases, diarrhoea, cataract, beriberi and polymenorrhea (Brink and Belay, 2006; Basu et al., 2007). The raw seeds are chewed to alleviate nausea and vomiting in pregnant women. V. Subterranea seed extracts have been shown to possess some biological properties such as antioxidant and hepatoprotective (Nyau et al., 2015; Iweala and Elekwa, 2001). In spite of multi‐functional properties of V. subterranea, its gastroprotective effect has not been fully explored. This study was carried out to examine the effects of V. Subterranea on basal and stimulated gastric acid secretion (GAS) in the Wistar rats. Each group of rats consisting of 5 rats (180–210g) was treated with aqueous extract of V. Subterranea (150 mg/kg, 250mg/kg and 400mg/kg) orally for 21 days. The animals were handled in accordance with guide for the care and use of laboratory animals (NIH, 2011). At the last day of the treatment, the rats were fasted for 24 hours, anaesthetized with ketamine. GAS (mEq/l) induced by histamine, carbachol and pentagastrin administration were assessed by the continuous perfusion technique using phenolphthalein as indicator. Data obtained were expressed as the Mean ± SEM) and analyzed using one way Analysis of Variance (ANOVA) and Graph Pad prism 5. The differences in mean were considered significant at p≤ 0.05. The aqueous extract of V. Subterranea significantly decreased (p<0.05) GAS induced by the histamine, carbachol and pentagastrin in a dose‐dependent manner over 80 minutes period in all the treated groups, although at varying rates. The gastroprotective action of V. Subterranea may be multifactorial that may include an anti‐secretory action.Support or Funding InformationWe wish to thank Usmanu Danfodiyo University, Sokoto, Nigeria for their support.Effect of Histamine on BambaraFigure 1Effect of Carbachol on BambaraFigure 2Effect of Pentagastrin on BambaraFigure 3

Gastrin, Cholecystokinin, Signaling, and Biological Activities in Cellular Processes

The structurally-related peptides, gastrin and cholecystokinin (CCK), were originally discovered as humoral stimulants of gastric acid secretion and pancreatic enzyme release, respectively. With the aid of methodological advances in biochemistry, immunochemistry, and molecular biology in the past several decades, our concept of gastrin and CCK as simple gastrointestinal hormones has changed considerably. Extensive in vitro and in vivo studies have shown that gastrin and CCK play important roles in several cellular processes including maintenance of gastric mucosa and pancreatic islet integrity, neurogenesis, and neoplastic transformation. Indeed, gastrin and CCK, as well as their receptors, are expressed in a variety of tumor cell lines, animal models, and human samples, and might contribute to certain carcinogenesis. In this review, we will briefly introduce the gastrin and CCK system and highlight the effects of gastrin and CCK in the regulation of cell proliferation and apoptosis in both normal and abnormal conditions. The potential imaging and therapeutic use of these peptides and their derivatives are also summarized.

Disruption of mesothelial connections to the spleen inhibits splenic anti‐inflammatory responses and protects from the development of insulin resistance in rats

We have recently reported that stimulation of gastric acid secretion with NaHCO3 promotes an anti‐inflammatory response in both rats and healthy human subjects. Importantly, disruption of ‘neuronal like’ mesothelial cell connections to spleen abolished this response. The Dahl salt‐sensitive (SS) rat model develops insulin resistance when fed a high salt diet. As low grade inflammation is thought to promote insulin resistance, we hypothesized that ‘Ingestion of NaHCO3 would prevent the development of insulin resistance in Dahl SS rats and that this protection would be lost following surgical disruption of mesothelial connections to the spleen’.9 week old male Dahl salt‐sensitive rats were anesthetized with isoflurane, an abdominal incision performed and either; mesothelial connections to the spleen physically disrupted (DISRUPTED) or; the spleen left untouched (SHAM). Following 1 wk of recovery from surgery, all rats were placed on an 8% high salt (HS) diet for 3 weeks. Upon starting the HS diet, the drinking water was replaced with either 0.1M NaHCO3 (n=12 sham, n=10 disrupted) or equimolar NaCl solutions (n=11 sham, n=9 disrupted). An insulin tolerance test as performed at day 17 of HS feeding. Following 21 days of HS the spleen was harvested for flow cytometry analysis (n=6 each group).Ingestion of NaHCO3 in SHAM rats resulted in significantly fewer splenic pro‐inflammatory M1 macrophages when compared to SHAM rats drinking NaCl (4.8±0.3 vs 7±0.5% splenocytes, ANOVA p=0.01, respectively) and this difference was abolished following mesothelial disruption (NaHCO3 + DISRUPTED =7.2±0.5%, p=N.S). Insulin administration resulted in a decrease in blood glucose in all groups, however the decrease in blood glucose was significantly greater in the DISRUPTED + NaHCO3 group when compared to all other groups (p=0.02). The % of splenic cells identified as myeloid dendritic cells mirrored the development of insulin resistance, with myeloid dendritic cells being significantly lower (p=0.02) only in the DISRUPTED + NaHCO3 group.In agreement with our previous studies, ingestion of NaHCO3 promoted an anti‐inflammatory response in the spleen which was abolished by surgical disruption of splenic mesothelial connections. Protection from the development of insulin resistance however, did not correlate with this anti‐inflammatory effect. Rather, the degree of insulin resistance was mirrored by differences in splenic myeloid dendritic cells. These data are important as they demonstrate that, despite promoting an inflammatory phenotype, disruption of mesothelial connections to the spleen can contribute to protection from the development of insulin resistance. As both NaHCO3 ingestion and vagal nerve stimulation promote gastric acid secretion, and the anti‐inflammatory response to both stimuli can be inhibited by a nicotinic receptor antagonist, we speculate that these mesothelial connections mediate the anti‐inflammatory response to efferent vagal stimulation. Our data indicate however, that multiple signals are received by the spleen and that these act in combination to modulate immune responses resulting in varied functional effects.Support or Funding InformationDK099548, P01HL134604This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Complexes of gastrin with In3+, Ru3+ or Ga3+ ions are not recognised by the cholecystokinin 2 receptor.

The peptide hormone gastrin (Gamide) binds trivalent metal ions, including indium (In), ruthenium (Ru) and gallium (Ga), with high affinity. Complexes of gastrin with chelated isotopes of In and Ga have previously been used for the location of tumours expressing the cholecystokinin 2 receptor (CCK2R). The aim of the present study was to purify the complexes of Gamide with radioactive isotopes of In, Ru or Ga and to investigate their ability to bind to the CCK2R. The radioactive Gamide complexes were purified on Sep-Pak C18 cartridges or by anion exchange HPLC. Binding to the CCK2R was assessed with a stably transfected clone of the gastric carcinoma cell line AGS. The 106Ru-Gamide complex could be eluted from the C18 cartridge; the 111In-Gamide and 68Ga-Gamide complexes bound irreversibly. All three complexes were successfully purified by anion exchange HPLC. The failure to detect binding of the 111In-Gamide, 106Ru-Gamide and 68Ga-Gamide complexes to the CCK2R suggests that formation of these complexes will not be useful for the detection of tumours expressing this receptor, but may instead provide alternative ways to block the actions of Gamide as a growth factor or a stimulant of gastric acid secretion. The complexes between the hormone gastrin and radioactive 111In, 106Ru or 68Ga ions were purified by anion exchange HPLC using a NaCl gradient. The failure to detect binding of the complexes to the cholecystokinin 2 receptor suggests that metal ion treatment may provide novel approaches to block the biological actions of gastrin.

Caffeine induces gastric acid secretion via bitter taste signaling in gastric parietal cells

Caffeine, generally known as a stimulant of gastric acid secretion (GAS), is a bitter-tasting compound that activates several taste type 2 bitter receptors (TAS2Rs). TAS2Rs are expressed in the mouth and in several extraoral sites, e.g., in the gastrointestinal tract, in which their functional role still needs to be clarified. We hypothesized that caffeine evokes effects on GAS by activation of oral and gastric TAS2Rs and demonstrate that caffeine, when administered encapsulated, stimulates GAS, whereas oral administration of a caffeine solution delays GAS in healthy human subjects. Correlation analysis of data obtained from ingestion of the caffeine solution revealed an association between the magnitude of the GAS response and the perceived bitterness, suggesting a functional role of oral TAS2Rs in GAS. Expression of TAS2Rs, including cognate TAS2Rs for caffeine, was shown in human gastric epithelial cells of the corpus/fundus and in HGT-1 cells, a model for the study of GAS. In HGT-1 cells, various bitter compounds as well as caffeine stimulated proton secretion, whereby the caffeine-evoked effect was (i) shown to depend on one of its cognate receptor, TAS2R43, and adenylyl cyclase; and (ii) reduced by homoeriodictyol (HED), a known inhibitor of caffeine's bitter taste. This inhibitory effect of HED on caffeine-induced GAS was verified in healthy human subjects. These findings (i) demonstrate that bitter taste receptors in the stomach and the oral cavity are involved in the regulation of GAS and (ii) suggest that bitter tastants and bitter-masking compounds could be potentially useful therapeutics to regulate gastric pH.

РОЛЬ ГІСТАМІНУ У ШЛУНКОВІЙ СЕКРЕЦІЇ В НОВОМУ: ВІД ВІДКРИТТЯ ДО КЛІНІЧНОГО ЗНАЧЕННЯ (НА ЧЕСТЬ 150 РІЧЧЯ З ДНЯ НАРОДЖЕННЯ ЛЕОНА ПОПЕЛЬСЬКОГО)

Professor of Lviv National Medical University (formerly known as Jan Kazimierz Lemberg University), Ukraine, Leon Popielski was the fi rst to recognize that histamine stimulated gastric acid secretion 100 years ago, at 1916. He produced over one hundred publications and founded Lviv’s experimental gastroenterology school (Koskowski, 1931), and strong pharmacology tradition. He is less well known today than he deserves to be. Popielski began his scientifi c career at the Military Medical Academy in St Petersburg, then dominated by I. Pavlov. In 1901, he published work indicating the existence of a peripheral ‘refl ex center’ controlling gastric secretion (Popielski, 1901). His fi ndings contradicted the prevailing ‘nervism’ theory of Pavlov, who had supervised Popielski’s PhD thesis. Perhaps not surprisingly this caused friction between them. Pavlov then started a process to verify Popielski’s results, which was later described in Boris Babkin’s memoirs. The results were confi rmed thereby establishing the idea that processes other than conditional-refl exes, and in particular peripheral mechanisms, also controlled gastric secretion. Popielski’s work on histamine was carried out in Lviv during the World War I period, although published only later. He clearly showed that histamine was a strong stimulant of gastric acid secretion. His PhD student W. Koskowski subsequently introduced the histamine test for gastric secretion in patients, which in a somewhat modifi ed form, was used clinically for many decades in Poland at 1930’s. In the 1960’s and early 1970’s, Professor Sir James Black, at what was then Smith, Kline and French, brilliantly extended Popielski’s model of the role of histamine in gastric secretion through the development and use of a new class of antisecretory drug – the H2 receptor antagonists (Black et al., 1972). These proved the essential role of histamine in stimulating acid secretion. An early example, cimetidine, became the fi rst truly blockbuster drug, and revolutionised the treatment of peptic ulcer disease. At 21st century the novel gastric acid blockers – inhibitors of proton pump (PPI) were included in standard protocols for treatment several acid-related diseases. Long-term gastric acid suppression has been associated with different complications in gastric mucosa. Moreover, the roles of gastric acid inhibition in extragastral damage manifestation and several groups have reported abnormal proliferation in gastrointestinal tract during long-term treatment by IPP or H2 receptor antagonists. In the past 10 years due to these side effects, there is a need to study dual actions of histamine on gastrointestinal mucosa. Progress of scientifi c thought allowed to identify numerous histamine receptors (H1-H4) and their multifunctional meaning, and in that way to facilitate appearing of new medicine, which have totally changed treatment tactic of gastroenterological and neurogical diseases. Popielski’s work provides a clear example of how basic physiological research can be translated into the clinic for patient benefi t. Scientifi c portrait of L. Popielski doesn’t limit in his scientifi c and studying publications, he is an author of numerous publications, dedicated to the healthy way of life. Intellectual courage, belief in the reliability of obtained results and incredible assiduity of L. Popielski, deserve to be respected nowadays.

Activation of Muscarinic Acetylcholine Receptor Subtype 4 Is Essential for Cholinergic Stimulation of Gastric Acid Secretion: Relation to D Cell/Somatostatin.

Background/Aim: Muscarinic acetylcholine receptors exist in five subtypes (M1∼M5), and they are widely expressed in various tissues to mediate diverse autonomic functions, including gastric secretion. In the present study, we demonstrated, using M1∼M5 KO mice, the importance of M4 receptors in carbachol (CCh) stimulation of acid secretion and investigated how the secretion is modulated by the activation of M4 receptors.Methods: C57BL/6J mice of wild-type (WT) and M1–M5 KO were used. Under urethane anesthesia, acid secretion was measured in the stomach equipped with an acute fistula. CCh (30 μg/kg) was given subcutaneously (s.c.) to stimulate acid secretion. Atropine or octreotide (a somatostatin analog) was given s.c. 20 min before the administration of CCh. CYN154806 (a somatostatin SST2 receptor antagonist) was given i.p. 20 min before the administration of octreotide or CCh.Results: CCh caused an increase of acid secretion in WT mice, and the effect was totally inhibited by prior administration of atropine. The effect of CCh was similarly observed in the animals lacking M1, M2 or M5 receptors but significantly decreased in M3 or M4 KO mice. CYN154806, the SST2 receptor antagonist, dose-dependently and significantly reversed the decreased acid response to CCh in M4 but not M3 KO mice. Octreotide, the somatostatin analog, inhibited the secretion of acid under CCh-stimulated conditions in WT mice. The immunohistochemical study showed the localization of M4 receptors on D cells in the stomach. Serum somatostatin levels in M4 KO mice were higher than WT mice under basal conditions, while those in WT mice were significantly decreased in response to CCh.Conclusions: These results suggest that under cholinergic stimulation the acid secretion is directly mediated by M3 receptors and indirectly modified by M4 receptors. It is assumed that the activation of M4 receptors inhibits the release of somatostatin from D cells and minimizes the acid inhibitory effect of somatostatin through SST2 receptors, resulting in enhancement of the acid response mediated by M3 receptors on parietal cells.

Stimulation of gastric acid secretion by rabbit parietal cell A2B adenosine receptor activation

Adenosine modulates different functional activities in many cells of the gastrointestinal tract; some of them are believed to be mediated by interaction with its four G protein-coupled receptors. The renewed interest in the adenosine A2B receptor (A2BR) subtype can be traced by studies in which the introduction of new genetic and chemical tools has widened the pharmacological and structural knowledge of this receptor as well as its potential therapeutic use in cancer and inflammation- or hypoxia-related pathologies. In the acid-secreting parietal cells of the gastric mucosa, the use of various radioligands for adenosine receptors suggested the presence of the A2 adenosine receptor subtype(s) on the cell surface. Recently, we confirmed A2BR expression in native, nontransformed parietal cells at rest by using flow cytometry and confocal microscopy. In this study, we show that A2BR is functional in primary rabbit gastric parietal cells, as indicated by the fact that agonist binding to A2BR increased adenylate cyclase activity and acid production. In addition, both acid production and radioligand binding of adenosine analogs to isolated cell membranes were potently blocked by selective A2BR antagonists, whereas ligands for A1, A2A, and A3 adenosine receptors failed to abolish activation. We conclude that rabbit gastric parietal cells possess functional A2BR proteins that are coupled to Gs and stimulate HCl production upon activation. Whether adenosine- and A2BR-mediated functional responses play a role in human gastric pathophysiology is yet to be elucidated.

Identification of Catechin, Syringic Acid, and Procyanidin B2 in Wine as Stimulants of Gastric Acid Secretion.

Organic acids of wine, in addition to ethanol, have been identified as stimulants of gastric acid secretion. This study characterized the influence of other wine compounds, particularly phenolic compounds, on proton secretion. Forty wine parameters were determined in four red wines and six white wines, including the contents of organic acids and phenolic compounds. The secretory activity of the wines was determined in a gastric cell culture model (HGT-1 cells) by means of a pH-sensitive fluorescent dye. Red wines stimulated proton secretion more than white wines. Lactic acid and the phenolic compounds syringic acid, catechin, and procyanidin B2 stimulated proton secretion and correlated with the pro-secretory effect of the wines. Addition of the phenolic compounds to the least active white wine sample enhanced its proton secretory effect by 65 ± 21% (p < 0.05). These results indicate that not only malic and lactic acid but also bitter and astringent tasting phenolic compounds in wine contribute to its stimulatory effect on gastric acid secretion.

Exendin Increases Gastric Acid Secretion in the Anesthetized Rat

The objective of the current study was to assess the effect of the anti‐diabetic peptide, exenatide (Byetta®), on gastric acid secretion in the rat. Fasted rats were anesthetized and cannulas placed in esophagus (timed stomach secretion sampling), femoral artery (blood pressure monitoring), carotid artery (timed blood sampling). Phenol red was injected via the esophageal cannula and recovered every 10 minutes. Stomach aspirates were assessed for phenol red content (gastric emptying), pH, and titrated to pH 7.0 to calculate umoles of acid recovered. Exendin (up to 150 ug/kg) or vehicle were administered as a subcutaneous bolus at time zero, and stomach contents and blood were collected every 10 minutes for the subsequent 90 minutes. At 90 minutes, a pentagastrin bolus (~250 ug SC) was administered to confirm integrity of parietal cell responsiveness to pharmacologic stimulation of acid secretion. Basal acid secretion rate in the anesthetized rat (~1‐3 umoles per 10 minutes) was confirmed as lower than acid secretion rates previously reported in conscious rats. Exendin increased gastric acid secretion several‐fold above basal secretion rate, with maximal effect at 20‐30 minutes post‐injection. The anesthetized rat is a suitable model for assessing acute effects of peptides on stimulation of gastric acid secretion. The low basal acid secretion provides a substantial margin to successfully observe stimulation of acid secretion above an unstimulated baseline for at least 90 minutes. This model also allows simultaneous evaluation of hemodynamics and blood samples for pharmacokinetics and biomarker analysis.

Sa1725 FFA2 Activation Suppresses Basal and Stimulated Gastric Acid Secretion via 5-HT3 Receptor Activation in Rats

Sa1725 FFA2 Activation Suppresses Basal and Stimulated Gastric Acid Secretion via 5-HT3 Receptor Activation in Rats

Effect of Cannabis sativa extract on gastric acid secretion, oxidative stress and gastric mucosal integrity in rats

Studies were conducted in pylorus-ligated rats to investigate the effect of Cannabis sativa extract on gastric acid secretion, experimental gastric ulcer and on oxidative stress and inflammatory markers in the gastric mucosa. C. sativa (5, 10 and 20 mg/kg, expressed as Δ9-tetrahydrocannabinol) was administered subcutaneously daily for 4 weeks prior to pylorus ligation and different treatments. Under basal conditions, pretreatment with cannabis extract at doses of 5 and 10 mg/kg increased gastric acid secretion and induced minimally visible gastric mucosal lesions in the 4 h pylorus-ligated rat. Malondialdehyde and nitric acid concentration increased, while reduced glutathione decreased by cannabis at doses of 5 and 10 mg/kg in gastric mucosa. TNF-α increased by cannabis extract at doses of 5 and 10 mg/kg but decreased following the high dose of 20 mg/kg. On the other hand, the gastric acid secretory responses stimulated by pentagastrin or carbachol (but not histamine) were inhibited in rats pretreated with cannabis extract. Under these conditions, cannabis decreased pepsin content after pentagastrin and carbachol but not histamine stimulation. Cannabis also decreased lipid peroxidation and nitric oxide content, and increased both reduced glutathione and catalase activity in mucosa. Moreover, cannabis decreased mucosal inflammation (level of TNF-α) and the development of gastric mucosal lesions. Cannabis administered for 1 month prior to pylorus-ligation and either acidified aspirin or ethanol (96 %) decreased the development of gastric mucosal damage in a dose-dependent manner, along with reduction in gastric acid output, gastric mucosal oxidative stress and inflammation (TNF-α). Sections of gastric mucosa stained with periodic acid Schiff showed increased mucus secretion by cannabis in basal conditions and after treatment with aspirin or ethanol. Results indicate that: (1) the effect of cannabis differs in basal conditions and after exposure of the gastric mucosa to high acid concentrations or other chemical noxious agents; (2) cannabis administered systemically exerts gastric mucosal protective effects against mucosal damage evoked by stimulation of gastric acid secretion, acidified aspirin or ethanol. These effects of cannabis are likely to involve inhibition of gastric acid and pepsin secretion, increased mucus, decreased oxidative stress and inflammation in gastric mucosa.

New insights in endogenous modulation of ligand-gated ion channels: Histamine is an inverse agonist at strychnine sensitive glycine receptors

Histamine is involved in many physiological functions in the periphery and is an important neurotransmitter in the brain. It acts on metabotropic H1–H4 receptors mediating vasodilatation, bronchoconstriction and stimulation of gastric acid secretion. In the brain histamine is produced by neurons in the tuberomamillary nucleus (TMN), which controls arousal. Histamine is also a positive modulator of the inhibitory Cys-loop ligand-gated ion channel GABAA. We investigated now its effect on the second member of inhibitory Cys-loop ligand-gated ion channels, the strychnine sensitive glycine receptor. We expressed different human and rat glycine receptor subunits in Xenopus laevis oocytes and characterized the effect of histamine using the two electrode voltage clamp technique. Furthermore we investigated native glycine receptors in hypothalamic neurons using the patch-clamp technique. Histamine inhibited α1β glycine receptors with an IC50 of 5.2±0.3mM. In presence of 10mM histamine the glycine dose–response curve was shifted, increasing the EC50 for glycine from 25.5±1.4μM to 42.4±2.3μM. In addition, histamine blocked the spontaneous activity of RNA-edited α3β glycine receptors. Histamine inhibited glycine receptors expressed in hypothalamic TMN neurons with an IC50 of 4.6±0.3mM. Our results give strong evidence that histamine is acting on the same binding site as glycine, being an inverse agonist that competitively antagonizes glycine receptors. Thus, we revealed histamine as an endogenous modulator of glycine receptors.

Annexin 7 in the Regulation of Gastric Acid Secretion

Background/Aims: Glucocorticoids enhance gastric acid secretion and inhibit gastric cyclooxygenase, thus downregulating formation of PGE₂, an inhibitor of gastric acid secretion. In erythrocytes, PGE₂ formation is inhibited by annexin 7. The present study thus explored whether annexin 7 participates in the regulation of gastric acid secretion. Methods: Annexin 7 protein expression was determined by Western blotting, cytosolic pH (pHi) of parietal cells utilizing BCECF-fluorescence, and gastric acid secretion by determination of Na⁺-independent pHi recovery from an ammonium pulse (∆pHi/min). Experiments were performed in isolated glands from gene targeted mice lacking annexin 7 (anx7^-/-) and in respective wild type animals (anx7^+/+). Results: Prior to treatment pHi and ∆pHi/min were similar in isolated gastric glands from anx7^-/- and from anx7^+/+ mice. Aspirin (100 µM added to the glands 1 hr prior to the experiment) significantly increased ∆pHi/min to similar values in both genotypes. The administration of dexamethasone (10 µg/g BW subcutaneously for 4 consecutive days prior to the experiments) significantly increased ∆pH/min in anx7^+/+ mice but not in anx7^-/- mice. Following dexamethasone treatment, the luminal pH was significantly lower and the acid content significantly higher in anx7^+/+ mice than in anx7^-/- mice. An increase of extracellular K⁺ concentration to 35 mM (replacing Na⁺/NMDG⁺) significantly increased ∆pHi/min in both genotypes. In neither genotype dexamethasone increased ∆pH/min further in the presence of 35 mM K⁺ or presence of aspirin. Conclusions: Annexin 7 is required for the stimulation of gastric acid secretion by glucocorticoids.

Identification of a unique nsaid, fluoro-loxoprofen with gastroprotective activity

We previously proposed that direct cytotoxicity of NSAIDs due to their membrane permeabilization activity, together with their ability to decrease gastric prostaglandin E2, contributes to production of gastric lesions. Compared to loxoprofen (LOX), fluoro-loxoprofen (F-LOX) has much lower membrane permeabilization and gastric ulcerogenic activities but similar anti-inflammatory activity. In this study, we examined the mechanism for this low ulcerogenic activity in rats. Compared to LOX, the level of gastric mucosal cell death was lower following administration of F-LOX. However, the gastric level of prostaglandin E2 was similar in response to treatment with the two NSAIDs. Oral pre-administration of F-LOX conferred protection against the formation of gastric lesions produced by subsequent administration of LOX and orally administered F-LOX resulted in a higher gastric pH value and mucus content. In the presence of a stimulant of gastric acid secretion, the difference in the ulcerogenic activity of F-LOX and LOX was less apparent. Furthermore, an increase in the mucus was observed in gastric cells cultured in the presence of F-LOX in a manner dependent of increase in the cellular level of cAMP. These results suggest that low ulcerogenic activity of F-LOX involves its both low direct cytotoxicity and protective effect against the development of gastric lesions. This protective effect seems to be mediated through an increase in a protective factor (mucus) and a decrease in an aggressive factor (acid).