Stimulation Of Acid Secretion Research Articles

A new neonatal gastro-intestinal physiology-and pyloric stenosis of infancy a hypothesis

The outside world carries many dangers for the new-born baby especially in primitive societies. One danger undoubtedly is the risk of serious early enteric infections. Neonatal gastric acid is the principal defense.This author proposes that this acid defense is increased in two main ways;1. An immediate temporary acidity created by maternal gastrin transfer during spontaneous labor.2. A progressively rising acidity which culminates in a temporary peak acidity at approximately 3 weeks and is due to a late maturation of the negative feed-back between gastrin and gastric acidity.The author contends that there is an immature negative-feed-back between neonatal gastrin and gastric acidity at birth which matures around 3 weeks of life. Until maturity, both gastrin and acid secretion rise without restraint.In this way rising gastrin will stimulate acid secretion as well as enhance the development of gastric parietal cells to allow them, after feed-back matures, to independently provide an acid defense.One consequence of this new physiology is that it allows us to simply explain why pyloric stenosis of infancy occurs--the most common and hitherto unexplainable cause of milk vomiting in the neonate.

Marginal Ulcer Incidence and the Population of Gastrin Producing G cells Retained in the Gastric Pouch after Roux-en-Y Gastric Bypass: Is There a Relationship?

Marginal ulcers are the most prevalent endoscopic abnormality after RYGB. The etiology is still poorly understood; however, an increase in acid secretion has been strongly implicated as a causal agent. Although gastrin is the greatest stimulant of acid secretion, to date, the presence of gastrin producing G cells retained in the gastric pouch, related to the occurrence of marginal ulcers, has not been evaluated. Evaluate the density of G cells and parietal cells in the gastric pouch of RYGB patients with a diagnosis of marginal ulcer on the post-op EGD. We retrospectively evaluated 1104 gastric bypasses performed between 2010 and 2020. Patients with marginal ulcer who met the inclusion criteria and controls were selected from this same population. Endoscopic gastric pouch biopsies were evaluated using immunohistochemical study and HE staining to assess G cell and parietal cell density. In total, 572 (51.8%) of the patients performed endoscopic follow-up after RYGB. The incidence of marginal ulcer was 23/572 (4%), and 3 patients required revision surgery due to a recalcitrant ulcer. The mean time for ulcer identification was 24.3months (2-62). G cell count per high-power field (× 400) was statistically higher in the ulcer group (p < 0.05). There was no statistical difference in parietal cell density between groups (p 0.251). Patients with a marginal ulcer after gastric bypass present a higher density of gastrin-producing G cells retained in the gastric pouch.

Blastocyst-Derived Lactic Acid May Regulate S100A6 Expression and Function in Mouse Decidualization via Stimulation of Uterine Epithelial Arachidonic Acid Secretion.

(1) Background: Inflammatory responses are implicated in embryo implantation, decidualization, pregnancy maintenance and labor. Both embryo implantation and decidualization are essential to successful pregnancy in rodents and primates. S100A6 is involved in inflammation, tumor development, apoptosis and calcium homeostasis. S100A6 is strongly expressed in mouse decidua, but the underlying mechanisms of how S100A6 regulates implantation and decidualization are poorly defined. (2) Methods: Mouse endometrial stromal and epithelial cells are isolated from day 4 pseudopregnant mouse uteri. Both immunofluorescence and Western blotting are used to analyze the expression and localization of proteins. The molecular mechanism is verified in vitro by Western blotting and the quantitative polymerase chain reaction. (3) Results: From days 4 to 8 of pregnancy, S100A6 is specifically expressed in mouse subluminal stromal cells. Blastocyst-derived lactic acid induces AA secretion by activating the luminal epithelial p-cPLA2. The epithelial AA induces stromal S100A6 expression through the COX2/PGI2/PPAR δ pathway. Progesterone regulates S100A6 expression through the progesterone receptor (PR). S100A6/RAGE signaling can regulate decidualization via EGFR/ERK1/2 in vitro. (4) Conclusions: S100A6, as an inflammatory mediator, is important for mouse implantation and decidualization.

Effect of EDDS on the rhizosphere ecology and microbial regulation of the Cd-Cr contaminated soil remediation using king grass combined with Piriformospora indica

The negative impacts of soil heavy metals composite pollution on agricultural production and human health are becoming increasingly prevalent. The applications of green chelating agents and microorganisms have emerged as promising alternate methods for enhancing phytoremediation. The regulatory effects of root secretion composition, microbial carbon source utilization, key gene expression, and soil microbial community structure were comprehensively analyzed through a combination of HPLC, Biolog EcoPlates, qPCR, and high-throughput screening techniques. The application of EDDS resulted in a favorable rhizosphere ecological environment for the king grass Piriformospora indica, characterized by a decrease in soil pH by 0.41 units, stimulation of succinic acid and fumaric acid secretion, and an increase in carbon source metabolic activity of amino acids and carbohydrates. Consequently, this improvement enhanced the bioavailability of Cd/Cr and increased the biomass of king grass by 25.7%. The expression of dissimilatory iron-reducing bacteria was significantly upregulated by 99.2%, while there was no significant difference in Clostridium abundance. Furthermore, the richness of the soil rhizosphere fungal community (Ascomycota: 45.8%, Rozellomycota: 16.7%) significantly increased to regulate the proportion of tolerant microbial dominant groups, promoting the improvement of Cd/Cr removal efficiency (Cd: 23.4%, Cr: 18.7%). These findings provide a theoretical basis for the sustainable development of chelating agent-assisted plants-microorganisms combined remediation of heavy metals in soil.

Seven-Month Vitamin D Deficiency Inhibits Gastric Epithelial Cell Proliferation, Stimulates Acid Secretion, and Differentially Alters Cell Lineages in the Gastric Glands.

Vitamin D (VD) deficiency can result from insufficiency of either light exposure or VD intake. We investigated the biological effects of VD deficiency for 7 months on the mouse gastric glands. Varying degrees of VD deficiency were induced in C57BL/6 mice by keeping them on standard diet with constant-dark conditions (SDD) or VD deficient diet with constant-dark conditions (VDD). Samples of serum, glandular stomach, and gastric contents were collected for LCMS/MS, RT-PCR, immunohistochemistry, and acid content measurements. Both SDD and VDD mice had a significant decline in 25OHVD metabolite, gastric epithelial cell proliferation, and mucin 6 gene expression. These effects were enhanced with the severity of VD deficiency from SDD to VDD. Besides and compared to the control group, SDD mice only displayed a significant increase in the number of zymogenic cells (p ≤ 0.0001) and high expression of the adiponectin (p ≤ 0.05), gastrin (p ≤ 0.0001), mucin 5AC (*** p ≤ 0.001) and the Cyclin-dependent kinase inhibitor 1A (**** p ≤ 0.0001). These phenotypes were unique to SDD gastric samples and not seen in the VDD or control groups. This study suggests that the body reacts differently to diverse VD deficiency sources, light or diet.

History and Pharmacological Mechanism of Gastric Acid-suppressive Drugs

Gastric acid-related disorders are commonly encountered in clinical practice. Acetylcholine, gastrin, and histamine are physiological agonists that stimulate acid secretion from parietal cells. Histamine plays a decisive role in the transformation of parietal cells into acid-secreting forms. The H&lt;sup&gt;+&lt;/sup&gt;, K&lt;sup&gt;+&lt;/sup&gt;- ATPase proton pump, which represents the final step of acid secretion, translocates from cytoplasmic tubulovesicles to secretory canaliculi upon parietal cell stimulation and facilitates exchange of intracellular H&lt;sup&gt;+&lt;/sup&gt; with extracellular K&lt;sup&gt;+&lt;/sup&gt; in a 1:1 ratio. Histamine-2 receptor antagonists and proton pump inhibitors (PPIs) are widely used in clinical practice, and potassium-competitive acid blockers (P-CABs) have gained attention in recent times. P-CABs address the unmet needs of patients who receive conventional PPIs and have broadened the spectrum of drug choices; however, further research is warranted to confirm long-term safety of these drugs. Comprehensive understanding of the mechanisms of actions, characteristics, advantages and disadvantages, and the adverse effect profile is essential for appropriate prescription of gastric acid-suppressive drugs. In this review, we provide a developing history and outline the pharmacological mechanisms underlying various gastric acid-suppressive drugs used in clinical settings.

Glucose- and Bile Acid-Stimulated Secretion of Gut Hormones in the Isolated Perfused Intestine Is Not Impaired in Diet-Induced Obese Mice.

PurposeDecreased circulating levels of food-intake-regulating gut hormones have been observed in type 2 diabetes and obesity. However, it is still unknown if this is due to decreased secretion from the gut mucosal cells or due to extra-intestinal processing of hormones.MethodsWe measured intestinal hormone content and assessed morphological differences in the intestinal mucosa by histology and immunohistochemistry. Secretion of hormones and absorption of glucose and bile acids (BA) were assessed in isolated perfused mouse intestine.ResultsGIP (glucose-dependent insulinotropic polypeptide) and SS (somatostatin) contents were higher in the duodenum of control mice (p < 0.001, and <0.01). Duodenal GLP-1 (glucagon-like peptide-1) content (p < 0.01) and distal ileum PYY content were higher in DIO mice (p < 0.05). Villus height in the jejunum, crypt depth, and villus height in the ileum were increased in DIO mice (p < 0.05 and p = 0.001). In the distal ileum of DIO mice, more immunoreactive GLP-1 and PYY cells were observed (p = 0.01 and 0.007). There was no difference in the absorption of glucose and bile acids. Distal secretion of SS tended to be higher in DIO mice (p < 0.058), whereas no difference was observed for the other hormones in response to glucose or bile acids.ConclusionOur data suggest that differences regarding production and secretion are unlikely to be responsible for the altered circulating gut hormone levels in obesity, since enteroendocrine morphology and hormone secretion capacity were largely unaffected in DIO mice.

Sham Feeding Induced Gastric Acid Secretion in Patients with Caustic Induced Esophageal Stricture.

Caustic ingestion can lead to structural changes in the upper gastro-intestinal tract. However, there is limited data on the effect of caustic ingestion on gastric secretion. This study was planned to determine changes in gastric acid output after sham feeding in patients with caustic induced esophageal stricture and to compare it with healthy controls. It was a prospective study done at tertiary care center in North India. Consecutive patients with caustic induced esophageal stricture were evaluated for the study. Gastric secretory function was estimated in the basal state and after modified sham feeding. These results were compared withage-matched controls. The mean age of the included patients (n = 18) was 30.11 ± 9.19years and 13 patients were male. 16 (88%) patients had history of acid ingestion. Patients with caustic sequelae had significantly lower basal and stimulated acid secretion compared to controls (n = 10) (5.84 ± 2.44mmol/hr; p < 0.01 and 17.16 ± 7.53mmol/hr; p < 0.01; respectively). Patients with lower esophageal stricture (n = 8) had significantly lower increase in acid output compared to patients with stricture elsewhere in esophagus (0.20 ± 0.3 vs. 2.31 ± 1.74mmol/hr, p < 0.01). Patients with lower esophageal involvement had significantly lower stimulated acid secretion and increase in acid secretion compared to controls (4.74 ± 4.67 vs. 17.16 ± 7.53mmol/hr; p < 0.01 and 20 ± 0.3 vs. 2.09 ± 0.88mmol/hr; p < 0.01; respectively).

Pharmacokinetic Models to Characterize the Absorption Phase and the Influence of a Proton Pump Inhibitor on the Overall Exposure of Dacomitinib

Introduction: Dacomitinib is an epidermal growth factor receptor (EGFR) inhibitor approved for the treatment of metastatic non-small cell lung cancer (NSCLC) in the first line in patients with EGFR activating mutations. Dacomitinib is taken orally once daily at 45 mg with or without food, until disease progression or unacceptable toxicity occurs. Oncology patients often can develop gastroesophageal reflux disease (GERD), which may require management with an acid-reducing agent. Proton pump inhibitors (PPIs), such as rabeprazole, inhibit sodium-potassium adenosine triphosphatase (H+/K+-ATPase) pumps that stimulate acid secretion in the stomach and have a prolonged pharmacodynamic effect that extends beyond 24 h post-administration. The aim of this work was to characterize the absorption of dacomitinib via modeling with a particular interest in quantifying the impact of rabeprazole on the pharmacokinetics (PK) of dacomitinib. Materials and Methods: The pooled dataset consisted of five clinical pharmacology healthy volunteer studies, which collected serial pharmacokinetic concentration-time profiles of dacomitinib. Non-linear mixed effects modeling was carried out to characterize dacomitinib pharmacokinetics in the presence and absence of the concomitant use of a PPI, rabeprazole. Several absorption models, some more empirical, and some more physiologically based, were tested: transit compartment, first-order absorption with and without lag time, and variations of combined zero- and first-order absorption kinetics models. Results: The presence of a PPI was a significant covariate affecting the extent (F) and rate (ka) of dacomitinib absorption, as previously reported in the dedicated clinical study. A transit compartment model was able to best describe the absorption phase of dacomitinib.

Influence of the Novel Histamine H3 Receptor Antagonist/Inverse Agonist M39 on Gastroprotection and PGE2 Production Induced by (R)-Alpha-Methylhistamine in C57BL/6 Mice.

The role of histamine H3 receptors (H3Rs) in the regulation of gastroprotection and production of prostaglandin E2 (PGE2) as well as somatostatin remains contradictory. Therefore, the effects of the H3R antagonist/inverse agonist M39 on in vivo acidified ethanol-induced gastric ulcers and gastric acid secretion in the C57BL/6 mice were assessed. Results showed that acute systemic administration of H3R agonist (R)-α-methylhistamine (RAMH, 100 mg/kg, i.g.) significantly reduced the severity of ulcer index, increased gastric acid output, and increased mucosal PGE2 production without any alteration of somatostatin concentration in gastric juice. However, only acute systemic administration of the H2R agonist dimaprit (DIM, 10 mg/kg, p.o.) significantly decreased the level of somatostatin measured in gastric juice. Moreover, acute systemic administration of M39 (0.3 mg/kg, i.g.) abrogated the RAMH-induced increase of acid output as well as PGE2 production, but not the DIM (10 mg/kg, i.g.)-stimulated acid secretion, indicating that RAMH as well as M39 modulate the gastroprotective effects through interactions with histamine H3Rs. The present findings indicate that agonistic interaction with H3Rs is profoundly involved in the maintenance of gastric mucosal integrity by modulating PGE2 as well as gastric acid secretion, with no apparent role in the regulation of the inhibitory influence of somatostatin.

Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass

BackgroundThe mechanism by which Roux-en-Y Gastric Bypass (RYGB) increases the secretion of glucagon-like peptide-1 (GLP-1) remains incompletely defined. Here we investigated whether TGR5-mTORC1 signaling mediates the RYGB-induced alteration in GLP-1 production in mice and human beings. MethodsCirculating bile acids, TGR5-mTORC1 signaling, GLP-1 synthesis and secretion were determined in lean or obese male C57BL/6 mice with or without RYGB operation, as well as in normal glycemic subjects, obese patients with type 2 diabetes before and after RYGB. ResultsPositive relationships were observed among circulating bile acids, ileal mechanistic target of rapamycin complex 1 (mTORC1) signaling and GLP-1 during changes in energy status in the present study. RYGB increased circulating bile acids, ileal Takeda G protein-coupled receptor 5 (TGR5) and mTORC1 signaling activity, as well as GLP-1 production in both mice and human subjects. Inhibition of ileal mTORC1 signaling by rapamycin significantly attenuated the stimulation of bile acid secretion, TGR5 expression and GLP-1 synthesis induced by RYGB in lean and diet-induced obese mice. GLP-1 production and ileal TGR5-mTORC1 signaling were positively correlated with plasma deoxycholic acid (DCA) in mice. Treatment of STC-1 cells with DCA stimulated the production of GLP-1. This effect was associated with a significant enhancement of TGR5-mTORC1 signaling. siRNA knockdown of mTORC1 or TGR5 abolished the enhancement of GLP-1 synthesis induced by DCA. DCA increased interaction between mTOR-regulatory-associated protein of mechanistic target of rapamycin (Raptor) and TGR5 in STC-1 cells. InterpretationDeoxycholic acid-TGR5-mTORC1 signaling contributes to the up-regulation of GLP-1 production after RYGB.

Physiologic, pathophysiologic, and pharmacologic regulation of gastric acid secretion.

The present review summarizes the past year's literature, both clinical and basic science, regarding physiologic and pharmacologic regulation of gastric acid secretion in health and disease. Gastric acid kills microorganisms, assists digestion, and facilitates absorption of iron, calcium, and vitamin B12. The main stimulants of acid secretion are the hormone gastrin, released from antral G cells; paracrine agent histamine, released from oxyntic enterochromaffin-like cells; and neuropeptide acetylcholine, released from antral and oxyntic intramural neurons. Gastrin is also a trophic hormone that participates in carcinogenesis. Helicobacter pylori may increase or decrease acid secretion depending upon the acuity and predominant anatomic focus of infection; most patients manifest hypochlorhydria. Despite the fact that proton pump inhibitors (PPIs) are amongst the most widely prescribed drugs, they are underutilized in patients at high risk for UGI bleeding. Although generally considered well tolerated, concerns have been raised regarding associations between PPI use and dementia, kidney disease, myocardial infarction, pneumonia, osteoporosis, dysbiosis, small bowel injury, micronutrient deficiency, and fundic gland polyps. Our understanding of the physiologic, pathophysiologic, and pharmacologic regulation of gastric secretion continues to advance. Such knowledge is crucial for improved and safe management of acid-peptic disorders.

Acute effects of N-terminal progastrin fragments on gastric acid secretion in man.

We previously identified an N‐terminal fragment of progastrin in human antrum and plasma, where it circulates in high concentrations. In this study, we examined the effects of N‐terminal progastrin fragments on gastric acid secretion by infusion in healthy individuals. Increasing doses of progastrin fragment 1‐35 were infused intravenously during constant gastric acid stimulation by gastrin‐17. In addition, the effects of progastrin fragment 1‐35, fragment 6‐35, and fragment 1‐19 on gastrin‐17 stimulated acid secretion were tested. The gastrin‐17 stimulated acid secretion decreased 30% after administration of a high dose of progastrin fragment 1‐35 (P < 0.05). In extension, a 1‐h infusion of fragment 1‐35 also decreased gastric acid output. In contrast, fragment 6‐35 did not affect acid secretion, and a single infusion of gastrin‐17 alone did not reveal fading of gastric acid output during the time course of the experiments. The results show that N‐terminal fragments of progastrin may acutely affect gastrin‐stimulated gastric acid secretion in vivo. Structure‐function analysis suggests that the N‐terminal pentapeptide of progastrin is required for the effect.

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.

Gastric acid secretion.

The present review summarizes the past year's literature, both clinical and basic science, regarding neuroendocrine and intracellular regulation of gastric acid secretion and proper use of antisecretory medications. Gastric acid kills microorganisms, modulates the gut microbiome, assists in digestion of protein, and facilitates absorption of iron, calcium, and vitamin B12. The main stimulants of acid secretion are gastrin, released from antral G cells; histamine, released from oxyntic enterochromaffin-like cells; and acetylcholine, released from antral and oxyntic intramural neurons. Other stimulants include ghrelin, motilin, and hydrogen sulfide. The main inhibitor of acid secretion is somatostatin, released from oxyntic and antral D cells. Glucagon-like peptide-1 also inhibits acid secretion. Proton pump inhibitors (PPIs) reduce acid secretion and, as a result, decrease somatostatin and thus stimulate gastrin secretion. Although considered well tolerated drugs, concerns have been raised this past year regarding associations between PPI use and kidney disease, dementia, and myocardial infarction; the quality of evidence, however, is very low. Our understanding of the physiology of gastric secretion and proper use of PPIs continues to advance. Such knowledge is crucial for improved management of acid-peptic disorders.

Secretagogue-dependent and -independent transport of zinc hydration forms in rat parietal cells

Prolonged exposure to gastric acid is a leading cause of gastroesophageal reflux disease (GERD) and esophagitis. With the ever increasing number of patients showing insensitivity to proton-pump-inhibitor (PPI) therapy with recurrence of symptoms over time, alternative treatment options remain an important issue. Previous studies from our laboratory have shown that a zinc sulfate salt can inhibit HCl generation at the cellular level of the parietal cell. In this paper, we examine the difference between two hydration forms of ZnSO4 (monohydrate H2O and heptahydrate 7H2O) in their entry characteristics into the parietal cell under several physiological conditions associated with acid secretion. Using the Zn sensitive fluorochrome Newport Green, we examined the rate of Zn entry in Δfluorescent units/second (ΔFU/second), at two different concentrations for both hydration states on both fasted and non-fasted animals. In a separate series of studies, we examined the effects of secretagogues on the entry rates and transport mechanisms. Exposure of the secretagogue carbachol transformed the resting parietal cell to an activated state and represents a stimulated condition through the neuronal pathway. The hormonal activation of the parietal cell was achieved by using histamine. Non-fasted conditions were considered to be a state between hormonal and neuronal activation. To demonstrate that ZnSO4 enters the parietal cell through the NKCC1 co-transporter, the inhibitor bumetanide was applied during secretagogue-stimulated acid secretion. Both salts, monohydrate and heptahydrate ZnSO4, show a concentration-dependent cell entry under all conditions studied. During stimulated acid secretion, induced through either the neuronal or the hormonal pathway, heptahydrate ZnSO4 enters the parietal cell significantly faster than monohydrate ZnSO4, whereas monohydrate ZnSO4 exhibits faster entry during resting conditions in fasted animals. At 30μM following stimulation with histamine, heptahydrate ZnSO4 enters the cell faster than monohydrate ZnSO4 (ΔFU/second 30μM ZnSO4*7H2O+histamine=1.782, ΔFU/second 30μM ZnSO4*H2O+histamine=1.038, respectively). Three hundred micromolar, heptahydrate ZnSO4 shows a faster entry into the cells (ΔFU/second ZnSO4*7H2O300μM+carbachol=4.02407) compared to monohydrate ZnSO4 (ΔFU/second ZnSO4*H2O300μM+carbachol=3.225) following exposure to carbachol. The mechanism of entry of both salts was found to be predominantly via the basolateral NKCC1 transporter with the rate of zinc entry decreasing to minimal values (ΔFU/second=0.275) after application of bumetanide during stimulated conditions.

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.

Functional anatomy and physiology of gastric secretion

This review summarizes the past year's literature regarding the neuroendocrine and intracellular regulation of gastric acid secretion, discussing both basic and clinical aspects. Gastric acid facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B12, and certain medications. High acidity kills ingested microorganisms and limits bacterial overgrowth, enteric infection, and possibly spontaneous bacterial peritonitis. The main stimulants of acid secretion are gastrin, released from antral gastrin cells; histamine, released from oxyntic enterochromaffin-like cells; and acetylcholine, released from antral and oxyntic intramural neurons. Ghrelin and coffee also stimulate acid secretion whereas somatostatin, cholecystokinin, glucagon-like peptide-1, and atrial natriuretic peptide inhibit acid secretion. Although 95% of parietal cells are contained within the oxyntic mucosa (fundus and body), 50% of human antral glands contain parietal cells. Proton pump inhibitors are considered well tolerated drugs, but concerns have been raised regarding dysbiosis, atrophic gastritis, hypergastrinemia, hypomagnesemia, and enteritis/colitis. Our understanding of the functional anatomy and physiology of gastric secretion continues to advance. Such knowledge is crucial for improved management of acid-peptic disorders, prevention and management of neoplasia, and the development of novel medications.

Genetic Ablation of the ClC-2 Cl- Channel Disrupts Mouse Gastric Parietal Cell Acid Secretion.

The present studies were designed to examine the effects of ClC-2 ablation on cellular morphology, parietal cell abundance, H/K ATPase expression, parietal cell ultrastructure and acid secretion using WT and ClC-2-/- mouse stomachs. Cellular histology, morphology and proteins were examined using imaging techniques, electron microscopy and western blot. The effect of histamine on the pH of gastric contents was measured. Acid secretion was also measured using methods and secretagogues previously established to give maximal acid secretion and morphological change. Compared to WT, ClC-2-/- gastric mucosal histological organization appeared disrupted, including dilation of gastric glands, shortening of the gastric gland region and disorganization of all cell layers. Parietal cell numbers and H/K ATPase expression were significantly reduced by 34% (P<0.05) and 53% (P<0.001) respectively and cytoplasmic tubulovesicles appeared markedly reduced on electron microscopic evaluation without evidence of canalicular expansion. In WT parietal cells, ClC-2 was apparent in a similar cellular location as the H/K ATPase by immunofluorescence and appeared associated with tubulovesicles by immunogold electron microscopy. Histamine-stimulated [H+] of the gastric contents was significantly (P<0.025) lower by 9.4 fold (89%) in the ClC-2-/- mouse compared to WT. Histamine/carbachol stimulated gastric acid secretion was significantly reduced (range 84–95%, P<0.005) in ClC-2-/- compared to WT, while pepsinogen secretion was unaffected. Genetic ablation of ClC-2 resulted in reduced gastric gland region, reduced parietal cell number, reduced H/K ATPase, reduced tubulovesicles and reduced stimulated acid secretion.

Effects of crude extracted proteins from supernatant of BCF-P and EGF on acid secretion

In order to compare the in vitro effects of crude extracts of broth culture filtrate protein (BCF-P) from the supernatant of an H. pylori liquid culture and epidermal growth factor (EGF) on acid secretion by isolated rabbit gastric parietal cells. Isolated rabbit gastric parietal cells were incubated with BCF-P or EGF for 1 and 12 h. Morphological changes were assessed by electron microscopy, and 14C-aminopyrine (14C-AP) uptake and H+-K+ATP mRNA expression were measured. At 50 µg/mL, BCF-P stimulated acid secretion by parietal cells (P<0.05) at 1 h but not at 12 h. At 100 µg/mL, BCF-P significantly inhibited histamine-stimulated acid secretion (P<0.05) and decreased H+- K+ATP mRNA expression in parietal cells, but it was reversed after EGF exposure. Crude extracted proteins from BCF-P damaged the inner cell membrane structure of parietal cells, reduced H+-K+ATP gene expression, and inhibited acid secretion, activities that differed markedly from those of EGF.