Inhibition Of Acid Secretion Research Articles

A Novel Antioxidant and Antiapoptotic Role of Omeprazole to Block Gastric Ulcer through Scavenging of Hydroxyl Radical

The mechanism of the antiulcer effect of omeprazole was studied placing emphasis on its role to block oxidative damage and apoptosis during ulceration. Dose-response studies on gastroprotection in stress and indomethacin-induced ulcer and inhibition of pylorus ligation-induced acid secretion indicate that omeprazole significantly blocks gastric lesions at lower dose (2.5 mg/kg) without inhibiting acid secretion, suggesting an independent mechanism for its antiulcer effect. Time course studies on gastroprotection and acid reduction also indicate that omeprazole almost completely blocks lesions at 1 h when acid inhibition is partial. The severity of lesions correlates well with the increased level of endogenous hydroxyl radical (*OH), which when scavenged by dimethyl sulfoxide causes around 90% reduction of the lesions, indicating that *OH plays a major role in gastric damage. Omeprazole blocks stress-induced increased generation of *OH and associated lipid peroxidation and protein oxidation, indicating that its antioxidant role plays a major part in preventing oxidative damage. Omeprazole also prevents stress-induced DNA fragmentation, suggesting its antiapoptotic role to block cell death during ulceration. The oxidative damage of DNA by *OH generated in vitro is also protected by omeprazole or its analogue, lansoprazole. Lansoprazole when incubated in a *OH-generating system scavenges *OH to produce four oxidation products of which the major one in mass spectroscopy shows a molecular ion peak at m/z 385, which is 16 mass units higher than that of lansoprazole (m/z 369). The product shows no additional aromatic proton signal for aromatic hydroxylation in (1)H NMR. The product absorbing at 278 nm shows no alkaline shift for phenols, thereby excluding the formation of hydroxylansoprazole. The product is assigned to lansoprazole sulfone formed by the addition of one oxygen atom at the sulfur center following attack by the *OH. Thus, omeprazole plays a significant role in gastroprotection by acting as a potent antioxidant and antiapoptotic molecule.

Review article: Esomeprazole--enhanced bio-availability, specificity for the proton pump and inhibition of acid secretion.

Esomeprazole, the S-isomer of omeprazole, is the first proton pump inhibitor available for clinical use as a single isomer. It demonstrates pharmacological and clinical benefits beyond those seen with the racemic omeprazole. Esomeprazole has higher and more consistent bio-availability than omeprazole, which results in a greater area under the plasma concentration-time curve. It is the area under the plasma concentration-time curve of omeprazole and esomeprazole that determines how much of each reaches the parietal cell, and thus the control of gastric acid secretion that is achieved. Esomeprazole, like other proton pump inhibitors, has a high specificity for the acidic environment of the parietal cell, where it is accumulated, activated and covalently inhibits the proton pump. Proton pumps elsewhere in the body do not achieve the level of acidity needed for accumulation and activation. Esomeprazole, 40 mg once daily, provides more effective control of gastric acid secretion than omeprazole, 20 or 40 mg once daily, and all other proton pump inhibitors given at their standard doses. This translates into greater clinical effect compared with omeprazole, 20 mg once daily, and lansoprazole, 30 mg once daily, in the management of reflux disease. Esomeprazole therapy is well tolerated, with a low adverse events profile, similar to that seen with omeprazole.

Lack of association between pro-inflammatory genotypes of the interleukin-1 (IL-1B -31 C/+ and IL-1RN *2/*2) and gastric cancer/duodenal ulcer in Korean population.

IL-1beta is a pro-inflammatory cytokine with multiple biological effects and is a potent inhibitor of gastric acid secretion, and IL-1RN has been shown to be associated with enhanced IL-1beta production in vitro. Recently, it was reported that the pro-inflammatory genotypes, IL-1B -31 C/+ and IL-1RN *2/*2, were associated with an increased risk of gastric cancer in a Caucasian population. We tested the association between the polymorphisms and 190 gastric cancer, 117 duodenal ulcer, and 172 healthy subjects as controls in the Korean population. The allele frequency of IL-1B -31 C was more prevalent in Korean (51%) than in Caucasian (30%), while the frequency of IL-1RN *2 allele was less in Korean (6%) than in Caucasian (27%). Using the IL-1B TT genotype as a reference group, the CC genotype was not associated with an increased risk of gastric cancer or duodenal ulcer in the Korean population (odds ratios (OR)=0.90, 95% confidence interval (CI)=0.50-1.64; OR=0.72, 95% CI=0.36-1.46, respectively). Similarly, IL-1RN*2 was not a risk genotype for either gastric cancer or duodenal ulcer. No association was recognized on the haplotype analysis of the two genes, either. Our results did not support the previous report that IL-1B -31 C/IL-1RN*2 polymorphisms were associated with an increased risk of gastric cancer. The lack of association with duodenal ulcer also suggested that the polymorphisms were not directly related to the acid-secreting capability.

Evidence on the presence of secretin cells in the gastric antral and oxyntic mucosa

Secretin is released from upper small intestinal mucosa to drive pancreatic secretion of fluid and bicarbonate and inhibit gastric acid secretion. Recently, we found that, in isolated, vascularly perfused rat stomach model, the inhibition of acid secretion by pituitary adenylate cyclase activating polypeptide (PACAP) was mediated in part via local release of secretin. However, the presence of secretin-producing cells and mRNA in gastric mucosa, particularly in oxyntic mucosa, has not been established. The present study was carried out to establish the presence of secretin cells by immunohistochemical and mRNA by biochemical methods in gastric mucosa. Secretin cells were identified in antral mucosa (27.8±2.0 cells/mm 2) and corpus (4.7±0.5 cells/mm 2). They were distinguishable, through double immunostaining, from gastrin and somatostatin cells in the antrum and from somatostatin cells in the corpus. The results of reverse transcription (RT)-PCR and Southern blot indicated that a secretin gene transcript of 454 bp was present in the mRNA extracts of both antral and corpus mucosae. The results indicated that secretin mRNA is present in gastric mucosa. In conclusion, secretin-producing cells and mRNA are present in gastric mucosa and the locally released secretin may exert a paracrine effect to inhibit acid secretion.

On the mechanisms underlying histamine induction of gastric mucosal lesions in rats with partial gastric vascular occlusion.

Although it is well known that histamine induces gastric mucosal lesions in laboratory animals, the fundamental mechanisms remain unclear. In order to further analyze the vascular mechanisms underlying histamine-induced lesions, a new model was developed in the glandular stomach via administration of histamine (40 mg/kg, s.c.) twice to rats with partial gastric vascular occlusion (ligated left gastric artery and vein) also subjected to pylorus ligation. Both antagonists of histamine H(2)-receptors (roxatidine and famotidine) and H(1)-receptors (epinastine and tripelennamine) significantly inhibited lesion formation at doses that did not inhibit acid secretion. Combined treatment of tripelennamine and famotidine synergistically inhibited lesion formation. Nitro L-arginine methyl ester inhibited lesion development; inhibition was reversed by concomitantly administered L-arginine. Indomethacin, diclofenac, and SC-560 (a selective COX-1 inhibitor), but not rofecoxib (a selective COX-2 inhibitor), significantly inhibited lesion formation. In addition, sodium bicarbonate, pirenzepine, S-0509 (a gastrin/CCK(2) inhibitor), omeprazole, sucralfate, and a prostaglandin analog also significantly inhibited lesion formation. It was concluded that the mechanism by which histamine induces gastric lesions in rats with partial gastric vascular occlusion appears to involve extensive vasodilation resulting from histamine acting on microvasculature histamine H(1)- and H(2)-receptors, generation of endogenous nitric oxide and prostaglandins, with the presence of gastric acid.

Neutrophil-derived hydroxyl radicals mediate interleukin-8-induced increases in tetragastrin-stimulated acid secretion in rats.

Until recently, the secretion of gastric acid, which plays an important role in the pathogenesis of peptic ulcer, was thought to be controlled by diet, the autonomic nerves and gut hormones. However, peptic ulcer is now known to be caused by the infection with Helicobacter pylori (H. pylori), so it is possible that inflammation modifies the secretion of gastric acid. We used gastric-lumen-perfused rats to first examine the effect of interleukin-8 (IL-8) on acid secretion and then the involvement of free radicals and neutrophils in the action of IL-8. IL-8 enhanced tetragastrin-stimulated acid secretion and free radical scavengers or inhibitors and the pretreatment with anti-rat neutrophil serum inhibited this effect, which indicates that IL-8 enhances gastrin-stimulated acid secretion and that neutrophil-derived hydroxyl radicals mediate the IL-8-induced increase in acid secretion.

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Efficacy of Omeprazole for the Prevention of Exercise-Induced Gastritis in Racing Alaskan Sled Dogs

Exercise-induced gastritis and gastric ulcers are common in humans and horses, and recently have been described in racing sled dogs. The cause of exercise-induced gastric disease is not completely understood in any species, but pharmacologic suppression of acid secretion is an effective treatment in humans and horses. Thus, we tested the hypothesis that omeprazole, a proton-pump inhibitor shown to reduce gastric acid secretion in dogs, would reduce the severity of exercise-induced gastric disease. Three teams of 16 dogs each competing in the 2002 Iditarod Sled Dog Race were recruited for participation. Within each team, dogs were randomly assigned to either treatment (20 mg omeprazole PO q24h) or placebo. Treatments were administered until either completion of the race or withdrawal of an individual dog from competition. Gastric endoscopy was performed in all dogs 24 hours after completion or withdrawal, and the gastric mucosa was scored by using a subjective severity score (0 = normal, 3 = numerous bleeding ulcers). Treatment with omeprazole significantly reduced mean gastric severity score compared to placebo (omeprazole: 0.65 ± 0.17, placebo: 1.09 ± 0.18; P= .028), but also was associated with increased frequency of diarrhea during the race (omeprazole 54%, placebo 21%; P= .017). Examination of our data suggests that omeprazole may be an effective treatment for exercise-induced gastric disease in racing sled dogs. However, further investigation regarding the cause and clinical relevance of diarrhea associated with omeprazole treatment must be conducted before omeprazole can be recommended for routine prophylactic treatment in these athletes.

Gastric ulcers

Abstract Gastric ulceration is a common cause of economic loss and a source of welfare concern in the pig industry worldwide. Stomach lesions tend to be restricted to the non-glandular area surrounding the oesophageal opening. Tissue damage occurs when acid, bile and digestive enzymes come in contact with this relatively unprotected area because of a breakdown in the normal pH gradient of the pig's stomach. The stomach contents become fluid and mixing occurs when finely ground feed is consumed or if the pig has not eaten for 12 to 24 hours. Helicobacter-like organisms are often found in the glandular region of the stomach but it seems unlikely that these bacteria play a major role in the development of lesions in the pars oesophagea , but more research is needed before this possibility is ruled out. Prevention of ulcers needs to be directed at ensuring pigs have feed in their stomachs, and that very fine feed particle size is avoided. Treatment is generally aimed at encouraging pigs to eat, and under exceptional circumstances acid secretion inhibitors can be used but generally economic circumstances prohibit their use.

Polarized distribution of IQGAP proteins in gastric parietal cells and their roles in regulated epithelial cell secretion.

Actin cytoskeleton plays an important role in the establishment of epithelial cell polarity. Cdc42, a member of Rho GTPase family, modulates actin dynamics via its regulators, such as IQGAP proteins. Gastric parietal cells are polarized epithelial cells in which regulated acid secretion occurs in the apical membrane upon stimulation. We have previously shown that actin isoforms are polarized to different membrane domains and that the integrity of the actin cytoskeleton is essential for acid secretion. Herein, we show that Cdc42 is preferentially distributed to the apical membrane of gastric parietal cells. In addition, we revealed that two Cdc42 regulators, IQGAP1 and IQGAP2, are present in gastric parietal cells. Interestingly, IQGAP2 is polarized to the apical membrane of the parietal cells, whereas IQGAP1 is mainly distributed to the basolateral membrane. An IQGAP peptide that competes with full-length IQGAP proteins for Cdc42-binding in vitro also inhibits acid secretion in streptolysin-O-permeabilized gastric glands. Furthermore, this peptide disrupts the association of IQGAP and Cdc42 with the apical actin cytoskeleton and prevents the apical membrane remodeling upon stimulation. We propose that IQGAP2 forms a link that associates Cdc42 with the apical cytoskeleton and thus allows for activation of polarized secretion in gastric parietal cells.

Ammonia and gastric acid secretion: a key to understanding activity and regulation of the H+,K+-ATPase

Ammonia is a cytotoxic substance liberated during Helicobacter pylori infection that may be responsible, in part, for the significant reduction in gastric acid secretion in human patients. However, it is not clear how ammonia blocks acid secretion. Here, we investigate several potential pathways for ammonia blockade in gastric oxyntic cells.___TAGSTART___BR___TAGEND___ Methods: Stomachs from the bullfrog, Rana catesbeiana, were stripped and mounted in Ussing chambers. Four possible pathways of blockade were investigated: (1) blockade of basolateral K+-channel activity, (2) blockade of ion transport activity, (3) neutralization of secreted H+ or (4) ATP depletion.___TAGSTART___BR___TAGEND___ Results: Addition of nutrient 10 mM NH4Cl at pH 7.4, yielding 92.5 μM NH3 and 9.91 mM NH4+, abolished acid secretion within 30 min. Inhibition of acid secretion did not occur by blockade of basolateral K+-channel activity or ion transport activity, nor did NH4+ enter cells by substituting for Na+ or K+ on individual ion transporters. Furthermore, neutralization of the luminal solution by NH3 and/or ATP depletion cannot account for the total reduction in acid secretion. We demonstrate that NH4Cl acts specifically on stimulated tissues.___TAGSTART___BR___TAGEND___ Conclusions: We show that small concentrations of ammonia completely block gastric acid secretion. We propose that inhibition of acid secretion occurs by blockade of an apical K+-channel, specifically inwardly rectifying K+-channels. Our data suggest that apical K+-channel activity may be essential for the regulation of acid secretion and could be a new therapeutic target for acid inhibitory drugs.

Helicobacter pylori attenuates the delay in ulcer healing induced by aspirin and selective COX-2 inhibitor

Helicobacter pylori (H. pylori) and NSAIDs are recognized as major pathogenic factors in peptic ulcer disease. However, whether these two factors exert synergistic or antagonistic effects on ulcer healing has not yet been fully explained. In this study, the effects of aspirin (ASA) alone and rofecoxib, a specific prostaglandin cyclooxygenase (COX)-2 inhibitor, were compared with that of ASA and rofecoxib applied in combination with H. pylori on gastric acid secretion and healing of acetic acid ulcers in rats. The H. pylori colonization of gastric mucosa was determined by viable bacterial culture and histology. The area of ulcers was determined by planimetry, the gastric blood flow (GBF) was measured using the H2-gas clearance method and the gastric mucosal generation of PGE2 and plasma gastrin levels were assessed by radioimmunoassay. ASA or rofecoxib applied alone delayed significantly the healing of chronic gastric ulcers and this effect was accompanied by a marked decrease in the GBF at the ulcer margin and gastric mucosal PGE2 generation without significant influence of gastric acid output. H. pylori that produced moderate gastric inflammation at the ulcer margin as confirmed by bacterial culture, prolonged significantly the healing of these ulcers and decreased the GBF at the ulcer margin and gastric acid output while elevating significantly the gastric mucosal PGE2 generation and plasma gastrin levels. H. pylori attenuated significantly the ASA- and rofecoxib-induced inhibition of ulcer healing and accompanying fall in the GBF at the ulcer margin and reversed, in part, the ASA- and rofecoxib-induced alterations in PGE2 generation. We conclude that H. pylori attenuates the delay in ulcer healing induced by ASA and rofecoxib due to enhancement in the generation of endogenous PGE2 and gastrin release, as well as suppression of acid secretion which may limit deleterious influence of NSAID on ulcer healing.

Expression of UreI is required for intragastric transit and colonization of gerbil gastric mucosa by Helicobacter pylori

Helicobacter pylori colonizes the antral mucosa of the human stomach. There is a controversy as to whether the microorganism is exposed to acidity in its ecological niche. In vitro, the microorganism requires urease for gastric colonization and survival at pH < 4.0. UreI encodes an acid activated urea channel enabling urea access to intrabacterial urease at acidic pH. UreI is also necessary for survival at pH < 4.0. However, the role of UreI for both intragastric transit and colonization of the epithelial gastric mucosa has never been analyzed in detail. We therefore infected gerbils, whose intragastric pH and response to infection resemble those of man, with H. pylori G1.1 wild type bacteria and their corresponding isogenic ureI mutants. Inhibitors of gastric acid secretion and colonization were used for manipulation of gastric pH. Gastric colonization was determined by urease assay and PCR. Gastric pH was measured with pH electrodes. Whereas H. pylori wild type or ureI complemented ureI knockout bacteria colonized the antrum, ureI deletion mutants were unable to colonize. However, continuous inhibition of acid secretion resulted in gastric colonization by the ureI mutants, as also observed with the wild type strain. Restoration of acid secretion resulted in eradication of ureI mutants but not wild type bacteria. The data show that ureI is essential for both gastric transit after inoculation and mucosal colonization in the untreated stomach. The eradication of ureI mutants following restoration of acid secretion suggests that the organism is exposed to pH < 4.0 at the surface of the antral mucosa and that UreI provides a target for specific monotherapy of H. pylori infections.

Gastric secretion

Overlapping neural, hormonal, and paracrine pathways finely regulate gastric acid secretion. In rats and guinea pigs, most of the intrinsic neural innervation to the gastric mucosa originates in the myenteric plexus. In contrast, human stomachs have a clearly defined submucosal plexus that contains a variety of transmitters including nitric oxide, vasoactive intestinal peptide (VIP), gastrin-releasing peptide (GRP), substance P, and calcitonin gene-related peptide (CGRP). Although GRP is known to participate in meal-stimulated acid secretion by releasing gastrin in a variety of laboratory animals, recent studies were unable to demonstrate a role for endogenous GRP in meal-stimulated gastrin secretion in humans. Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the secretin-glucagon-VIP family, has been localized to gastric mucosal neurons and may participate in vagally mediated acid secretion. Two novel peptides, ghrelin and leptin, have been localized to the stomach. Peripheral administration of ghrelin stimulates and of leptin inhibits acid secretion. The binding of secretagogues to parietal cells generates changes in second messengers that regulate the translocation and activation of the proton pump, HK-ATPase. In resting cells, HK-ATPase is contained within cytoplasmic tubulovesicles in an inactive form. At stimulation, the tubulovesicles fuse with the apical canaliculi and the HK-ATPase is incorporated into the apical membrane where it actively pumps H ions in exchange for K. Acute infection with Helicobacter pylori results in hypochlorhydria, whereas chronic infection can cause either hypo- or hyperchlorhydria, depending on the distribution of the infection and the degree of corpus gastritis. Recent studies suggest that inflammatory cytokines, produced in response to the organism, can play a role in the perturbations in acid and gastrin secretion induced by H. pylori.

Adrenomedullin stimulates somatostatin and thus inhibits histamine and acid secretion in the fundus of the stomach

Adrenomedullin has recently been localized to enterochromaffin-like (ECL) and chief cells in the gastric fundus. It has been proposed that adrenomedullin may play a role in gastric mucosal defense and repair. In the present study, we have used the isolated, luminally perfused mouse stomach and superfused rat fundic segments to examine the effect of adrenomedullin on exocrine and endocrine secretion in this region of the stomach. Addition of adrenomedullin (1 pM to 1 μM) to the isolated mouse stomach caused a concentration-dependent decrease in acid secretion. The EC 50 value was 1.4×10 −9 and maximal inhibition of acid secretion was obtained at a concentration of 1 μM (31±4% below basal level, P<0.001). In rat fundic segments, superfusion with adrenomedullin (0.1 pM to 0.1 μM) caused a concentration-dependent increase in somatostatin secretion (EC 50, 1×10 −10) that was accompanied by a reciprocal decrease in histamine secretion (EC 50, 1.2×10 −11). Maximal stimulation of somatostatin secretion (60±5% above basal level, P<0.001) and inhibition of histamine secretion (50±5% below basal level, P<0.01) was obtained at a concentration of 0.1 μM. Changes in acid and histamine secretion induced by adrenomedullin reflected changes in somatostatin secretion and could be abolished by addition of somatostatin antibody. The axonal blocker, tetrodotoxin, also abolished the somatostatin and, consequently, the acid and histamine responses to adrenomedullin, implying that the effect of adrenomedullin on somatostatin secretion was mediated via activation of intramural neurons. We conclude that adrenomedullin, acting via intramural fundic neurons, stimulates somatostatin and thus inhibits histamine and acid secretion. This represents one mechanism by which adrenomedullin might enhance mucosal defense and repair.

Effect of Helicobacter pylori on delay in ulcer healing induced by aspirin in rats

Helicobacter pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) are major pathogenic factors in peptic ulcer disease but whether these two factors exert synergistic or antagonistic effects on ulcer healing has been a subject of controversy. We compared the effect of aspirin alone with that of aspirin combined with H. pylori on gastric acid secretion and healing of acetic acid gastric ulcers in rats. The H. pylori colonization of gastric mucosa was determined by viable H. pylori culture, histology and assessment of bacterial DNA using polymerase chain reaction (PCR). The area of ulcers, gastric blood flow, mucosal generation of prostaglandin E 2 and plasma gastrin levels and expression of cyclooxygenase-1, cyclooxygenase-2 and growth factors was determined. Aspirin delayed significantly the healing of chronic gastric ulcers, decreased the gastric blood flow at the ulcer margin and gastric mucosal prostaglandin E 2 generation being without significant influence on gastric acid output. H. pylori acquisition that produced moderate gastric inflammation at the ulcer margin delayed significantly the healing of gastric ulcers, decreased significantly both the gastric blood flow at the ulcer margin and the gastric secretion while raising significantly the gastric mucosal prostaglandin E 2 generation and plasma gastrin levels. H. pylori infection attenuated the aspirin-induced inhibition of ulcer healing and accompanying fall in the gastric blood flow. Both aspirin and H. pylori up-regulated significantly cyclooxygenase-2 messenger RNA (mRNA) and protein but not that of cyclooxygenase-1 at the ulcer margin. Aspirin reduced significantly the transforming growth factor alpha- and vascular endothelial growth factor mRNAs, but these effects were significantly attenuated by H. pylori. We conclude that H. pylori antagonizes, in part, aspirin-induced delay of ulcer healing due to suppression of acid secretion, the enhancement in prostaglandin E 2 possibly derived from cyclooxygenase-2 and the overexpression of transforming growth factor alpha and vascular endothelial growth factor in the ulcer area.

Comparison of oral omeprazole and endoscopic ethanol injection therapy for prevention of recurrent bleeding from peptic ulcers with nonbleeding visible vessels or fresh adherent clots

OBJECTIVES: Omeprazole is a potent inhibitor of gastric acid secretion. Recently it was reported that p.o. omeprazole therapy reduced the rebleeding rate in patients with nonbleeding visible vessels or adherent clots. The aim of this study was to ascertain whether p.o. administration of omeprazole can be an effective alternative to endoscopic injection therapy in peptic ulcers with stigmata of recent hemorrhage. METHODS: A total of 101 patients who had peptic ulcer bleeding based on endoscopic findings of nonbleeding visible vessels or fresh adherent clots were randomly assigned to receive omeprazole (40 mg p.o. every 12 h) or endoscopic ethanol injection therapy. RESULTS: Rebleeding rates were 22.9% (11 of 48) in the omeprazole group and 20.8% (11 of 53) in the endoscopic injection therapy group. The rebleeding rates of clinical significance were 14.6% and 13.2%, respectively. There was no significance difference in the rebleeding rate, requirement for surgery, total units of blood transfused, or mortality between the two groups. CONCLUSIONS: Oral omeprazole administration is comparable to endoscopic ethanol injection therapy for prevention of rebleeding in patients with nonbleeding visible vessels or adherent clots.

Different actions of protein kinase C isoforms alpha and epsilon on gastric acid secretion.

1. The phorbol ester TPA, an activator of protein kinase C (PKC), inhibits cholinergic stimulation of gastric acid secretion but increases basal H(+) secretion. 2. Since these contradictory findings suggest the action of different PKC isozymes we analysed the role of calcium-dependent PKC-alpha, and calcium-independent PKC-epsilon in gastric acid secretion. 3. Inhibition of PKC-alpha by the indolocarbazole Gö 6976 revealed that about 28% of carbachol-induced acid secretion was inhibited by PKC-alpha. In the presence of Gö 6976 approximately 64% of the carbachol-induced signal transduction is mediated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), and 14% is conveyed by PKC-epsilon as deduced from the inhibition with the bisindolylmaleimide Ro 31-8220. 4. Inhibition of carbachol-induced acid secretion by TPA was accompanied by a decrease in CaMKII activity. 5. The stimulation of basal acid secretion by TPA was biphasic with a peak at a very low concentration (10 pM), resulting in an activation of the calcium-sensor CaMKII. The activation was determined with a phosphospecific polyclonal antibody against active CaMKII. The TPA-induced increase of H(+) secretion was sensitive to the cell-permeable Ca(2+)-chelator BAPTA/AM, Ro 31-8220, and the CaMKII-inhibitor KN-62, but not to Gö 6976. 6. Since TPA induced the translocation of PKC-epsilon but not of PKC-alpha in resting parietal cells, PKC-epsilon seems to be at least responsible for an initial elevation of free intracellular calcium to initiate TPA-induced acid secretion. 7. Our data indicate the different roles of two PKC isoforms: PKC-epsilon activation appears to facilitate cholinergic stimulation of H(+)-secretion likely by increasing intracellular calcium. In contrast, PKC-alpha activation attenuates acid secretion accompanied by a down-regulation of CaMKII activity.

Suppression by protease-activated receptor-2 activation of gastric acid secretion in rats

Activation of protease-activated receptor-2 (PAR-2), a receptor activated by trypsin/tryptase, induces neurally mediated gastric mucus secretion accompanied by mucosal cytoprotection. In the present study, we investigated whether PAR-2 could modulate gastric acid secretion in rats. Messenger RNAs for PAR-2 and PAR-1 were detected in the gastric mucosa and smooth muscle. The PAR-2-activating peptide SLIGRL-NH 2, but not the inactive control peptide, when administered i.v., strongly suppressed gastric acid secretion in response to carbachol, pentagastrin or 2-deoxy- d-glucose in the rats with a pylorus ligation. The PAR-2-mediated suppression of acid secretion was resistant to cyclooxygenase inhibition or ablation of sensory neurons by capsaicin. Our results provide novel evidence that in addition to stimulating neurally mediated mucus secretion, activation of PAR-2 suppresses gastric acid secretion independently of prostanoid production or sensory neurons. These dual actions of PAR-2 would result in gastric mucosal cytoprotection.

Ulinastatin in the treatment of acute pancreatitis: A multicenter clinical trial

OBJECTIVE: Lansoprazole (Takepron; Takeda) is extensively used in the treatment of acid-related diseases. There are no prior studies of the effects of antisecretion drugs on parietal cells, but we recently developed a rabbit parietal cell model. This allowed us to compare the antisecretory effects of lansoprazole and cimetidine in vitro in the present study. METHODS: Parietal cells were isolated using cell elutriation and continuous density gradient centrifugation. The effect of cimetidine and lansoprazole on histamine-induced acid secretion in rabbit parietal cells was investigated by measuring the accumulation of 14C-aminopurine. RESULTS: The purity and viability of isolated parietal cells was >80 and 95%, respectively. Lansoprazole and cimetidine both significantly inhibited histamine-stimulated acid secretion (10−4 mol/L), but the 50% inhibition concentration (IC50) of the two treatments was quite different. The IC50 of cimetidine was 3.70 × 10−5 mol/L, and that of lansoprazole was 9.59 × 10−8 mol/L. CONCLUSIONS: Lansoprazole is much more effective than cimetidine in the in vitro inhibition of histamine-stimulated acid secretion in rabbit parietal cells. This study developed a model for the study of acid inhibition drugs.