Basal Acid Secretion Research Articles

Role of somatostatin receptors on gastric acid secretion in wild-type and somatostatin receptor type 2 knockout mice

Somatostatin, probably acting through somatostatin type 2 receptors (SSTR2), is the main inhibitor of gastric acid secretion. We characterized gastric acid secretion in SSTR2 knockout mice, and used preferential somatostatin receptor agonists to assess the relative role of SSTR1, 2, 3, 4, and 5 on gastric acid secretion. Basal gastric acid secretion and the secretory response to a meal were similar in conscious wild-type and knockout mice. However, under urethane anesthesia, which releases endogenous somatostatin, SSTR2 knockout mice had a basal secretion 11-15-fold higher than wild-type animals (micromol/10 min:1.40+/-0.09 vs. 0.10+/-0.01, p<0.05). Gastrin immunoneutralization or H(2) receptors blockade (cimetidine), but not cholinergic blockade (atropine), reduced the high basal secretion in SSTR2 knockout mice. In SSTR2 knockout mice, gastrin and histamine stimulated acid secretion with similar efficacy, while in wild-type mice histamine was more effective than gastrin. SSTR2 knockout mice showed also a hypersecretory response to pylorus ligation compared with wild-type animals. In wild-type mice, somatostatin-14, SMS 201-995, and the SSTR2-preferential agonist, DC 32-87, inhibited gastrin-stimulated acid secretion with an order of potency SMS 201-995>DC 32-87>somatostatin-14. Preferential agonists for the SSTR1, 3, 4, and 5 were devoid of any effect. None of the compounds tested affected the high basal secretion observed under urethane anesthesia in SSTR2 knockout mice. These results show that gastric antisecretory effects of peripheral somatostatin are mediated solely through SSTR2. In the absence of functional SSTR2 other somatostatin receptors do not compensate for the lack somatostatin-SSTR2-mediated inhibition. Basal acid secretion and the response to a meal are normal in conscious SSTR2 knockout mice, suggesting the presence of somatostatin-independent mechanisms that compensate for the lack of somatostatin-SSTR2-mediated inhibitory responses.

THE POTENTIAL OF DEXTOFISOPAM FOR TREATMENT OF IRRITABLE BOWEL SYNDROME AND INFLAMMATORY BOWEL DISEASE

Purpose: A series of nonclinical and clinical studies were conducted to determine the potential of dextofisopam, the R-enantiomer of the homophthalazine tofisopam, for treating irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Methods: We tested dextofisopam in animal models of IBS and IBD, including the glass bead expulsion test (IBS), the balloon distension test (IBS), and the dextran sodium sulfate (DSS)-induced colitis test (IBD). We also tested the effects of dextofisopam on various aspects of GI function, including basal upper (the charcoal meal test) and lower (fecal output) GI motility, basal gastric acid secretion, and gastric irritancy. Dextofisopam was also tested in randomized, placebo-controlled, double-blind, single- and multiple-dose Phase 1 clinical trials in healthy human volunteers, and is currently under investigation in a double-blind, placebo-controlled Phase 2 clinical trial in male and female patients with diarrhea-predominant or alternating IBS. Results: In animal models, dextofisopam attenuated distension-induced contractile activity in the glass bead expulsion test and reduced abdominal contractions in the balloon distension test. In contrast, dextofisopam had little or no effect on basal upper or lower GI motility. Dextofisopam, administered orally, intraperitoneally, or intracolonically, also reduced the signs and symptoms of colitis in the DSS-induced colitis test. At pharmacologically relevant doses, dextofisopam had little or no effect on basal gastric acid secretion and did not cause gastric irritation. In the two Phase 1 studies in healthy volunteers, single oral doses of up to 400 mg dextofisopam and multiple oral doses of up to 600 mg BID for 7 days were well tolerated, with no serious or severe adverse events and minimal impact on cognitive or motor function. Preliminary, blinded safety data from the ongoing Phase 2 study of dextofisopam in patients with IBS continue to support a favorable safety profile for the drug. Conclusions: Preclinical data support the potential utility of dextofisopam for the treatment of IBS and IBD. Results from completed Phase 1 studies indicate dextofisopam is well tolerated at daily doses of up to 600 mg BID. Data from an ongoing trial of dextofisopam in patients with IBS continue to support a favorable safety profile for the drug. Additional clinical studies are planned.

The healing effect of TGF-$alpha; on gastric ulcer induced by acetylsalicylic acid in rats

The present study was designed to investigate the effects of microemulsion and aqueous solution containing transforming growth factor alpha (TGF-α) and/or aprotinin administered intragastrically (i.g.) on healing of acute gastric ulcers induced by acetylsalicylic acid (ASA). The microemulsion was prepared by modification of the microemulsion formulation described in our previous study. Acute gastric lesions were induced by the application of ASA (150 mg/kg in 1.5 ml of 0.2 N HCl i.g.). TGF-α in solution or microemulsion formulations were administered at a dose of 10 μg/kg per 24 h i.g. for 2 days. The effects of TGF-α on the healing was evaluated with the measurement of ulcer score, basal gastric acid secretion, total protein content of gastric fluid, gastric mucus level and histological analysis. The results indicated that the highest decrease in ulcer area was observed in group treated with microemulsion containing TGF-α plus aprotinin (TA-ME). TGF-α in microemulsion formulation was more effective than TGF-α in solution formulation in the increase of gastric mucus secretion, in the decrease of gastric acid secretions and ulcer scores. Histological evaluation of the gastric mucosa samples revealed that, best recovery was obtained in the TA-ME treated group.

The effect of insulin-dependent diabetes mellitus on basal and distention-induced acid and pepsin secretion in rat

Background: Diabetes mellitus is one of the most common endocrine diseases and affects most body organs. It affects gastric acid secretion, but this effect has not been fully understood. As the effects of diabetes on gastric pepsin secretion has not been proved yet, in this experimental study basal and distension-stimulated acid and pepsin secretions of diabetic and non-diabetic rats have been compared. Material and methods: Female N-Mari rats weighing 200–250 g were used. Diabetic state was induced by intraperitoneal injection of 75 mg/kg streptozotocin. Animals were anaesthetized by the interaperitoneal injection of 60 mg/kg thiopental sodium. Then tracheostomy and laparotomy were done and gastric secretions were collected by a cannula entered via duodenum. Gastric distention induce by 1.5 ml normal saline per each 100 g of body weight in stomach. Acid and pepsin were measured by titration and Anson’s method, respectively. Results: Basal gastric secretions were similar in diabetic and non-diabetic animals. Distention-stimulated acid secretions in diabetic and non-diabetic rats were 3.24±0.16 and 8.05±0.21 μmol/15 min, respectively, which were significantly different ( P=0.00001). Distention-induced pepsin secretion in diabetic and non diabetic rats were 3.16±0.13 and 5.24±0.16 μg/15 min, respectively, which were significantly different ( P=0.00001). Conclusion: In this study the stomach of diabetic animals showed less reaction to distention, which may be due to the reduction of acid and pepsin secretary cells, reduction of the function of the cells, gastric atrophy or gastric vagus neuropathy. These probabilities need to be examined.

Pantoprazole treatment does not invoke anti-inflammatory properties in vivo

Background and aims: Proton pump inhibitors (PPIs) are antiulcer agents that have gastric antisecretory and mucosal protective actions. The antisecretory effect of these agents derives from the inhibition of gastric parietal cell proton pump H +/K + ATPase. The exact mechanism of PPI-induced gastric mucosal protection is not known though. It has been suggested that PPI may accumulate, modulating the functions of neutrophils and, thus, may be useful in reducing the gastric mucosal injury caused by these cells. However, these same mechanisms may not be desirable when PPIs are prescribed in prophylaxis and pre-operatively for ill or immunodepressed patients. The present study was designed to examine a possible anti-neutrophil activity of pantoprazole in vivo. A short study with omeprazole and lanzoprazole was also performed. Methods: Dosages of PPIs able to inhibit basal acid secretion (10 and 100 mg kg −1) were administered intraperitoneally (i.p.) to rats for 7 or 28 days. Cimetidine (100 mg kg −1) and dexamethasone (0.75 mg kg −1) were used as controls for antisecretory and anti-inflammatory activity, respectively. Air pouches were then developed in these animals, and Helicobacter pylori suspension or carrageenan was used as inflammatory stimulus. Exudate formation and leukocyte migration to air pouches were assessed. Results: Neither short nor long treatment with pantoprazole modified the ability of neutrophils to migrate in response to carrageenan or H. pylori. The same results were obtained when omeprazole or lanzoprazole was used. Dexamethasone, alone, a potent anti-inflammatory drug, was able to reduce polymorphonuclear and mononuclear cell migration. Conclusion: Based on these observations, pantoprazole and other PPIs seem to have no anti-inflammatory properties in vivo.

The effect of insulin-dependent diabetes mellitus on basal and distention-induced acid and pepsin secretion in rat

The effect of insulin-dependent diabetes mellitus on basal and distention-induced acid and pepsin secretion in rat

The healing effect of TGF-α on gastric ulcer induced by acetylsalicylic acid in rats

The present study was designed to investigate the effects of microemulsion and aqueous solution containing transforming growth factor alpha (TGF-α) and/or aprotinin administered intragastrically (i.g.) on healing of acute gastric ulcers induced by acetylsalicylic acid (ASA). The microemulsion was prepared by modification of the microemulsion formulation described in our previous study. Acute gastric lesions were induced by the application of ASA (150 mg/kg in 1.5 ml of 0.2 N HCl i.g.). TGF-α in solution or microemulsion formulations were administered at a dose of 10 μg/kg per 24 h i.g. for 2 days. The effects of TGF-α on the healing was evaluated with the measurement of ulcer score, basal gastric acid secretion, total protein content of gastric fluid, gastric mucus level and histological analysis. The results indicated that the highest decrease in ulcer area was observed in group treated with microemulsion containing TGF-α plus aprotinin (TA-ME). TGF-α in microemulsion formulation was more effective than TGF-α in solution formulation in the increase of gastric mucus secretion, in the decrease of gastric acid secretions and ulcer scores. Histological evaluation of the gastric mucosa samples revealed that, best recovery was obtained in the TA-ME treated group.

Lipopolysaccharide-induced changes in rat gastric H/K-ATPase expression.

To evaluate lipopolysaccharide (LPS)-induced inhibition of gastric acid secretion. Endotoxemia from LPS inhibits gastric acid secretion by an unknown mechanism. Bacterial overgrowth in the stomach caused by decreased acid secretion could be responsible for nosocomial pneumonia developing in critically ill intensive care unit patients. Because acid secretion is via the H/K-ATPase and the effects of LPS on this enzyme are unknown, we hypothesized that LPS causes inhibition of gastric acid secretion by down-regulating the H/K-ATPase. A rat model to study gastric acid secretion was created. Saline or LPS (0.05-20 mg/kg IP) was given for 1 hour, after which basal acid secretion was determined for 1 hour. Pentagastrin (PG; 10 microg/kg IV) or saline was then given and gastric acid output collected for another 2 hours. LPS dose dependently inhibited basal and PG stimulated acid secretion. LPS increased alpha- and beta-H/K-ATPase subunit mRNA expression (Northern blot) in the absence of PG compared with saline. In the presence of PG, LPS did not have this effect. Western blot analysis did not show any difference in alpha- or beta-subunit immunoreactivity. Immunofluorescence analysis demonstrated that PG increased staining in the secretory membranes for H/K-ATPase subunits whereas in all LPS-treated rats, it appeared that H/K-ATPase subunits remained within the tubulovesicles. Furthermore, changes in H/K-ATPase mRNA expression may not be related to changes in NF-kappaB activity. These data suggest that inhibition of gastric acid secretion by LPS is due to inhibition of H/K-ATPase enzymatic function or changes in cytoskeletal rearrangements in H/K-ATPase subunits rather than by down-regulation of transcriptional or translational events.

Helicobacter pylori eradication releases prolonged increased acid secretion following omeprazole treatment

Background & Aims : Rebound increased acid secretion has been observed at 2 weeks after discontinuing omeprazole treatment in Helicobacter pylori-negative, but not H. pylori-positive, subjects. It is unknown whether this is a prolonged phenomenon or whether a similar phenomenon appears later in H. pylori positives or is released by eradication therapy. The aims of this study were to answer these 3 questions. Methods : Twelve H. pylori-negative and 20 H. pylori-positive subjects were studied. Each had a basal, submaximal, and maximal pentagastrin-stimulated acid secretion study before, during, and at 7, 14, 28, 42, and 56 days after a 56-day course of omeprazole 40 mg/day. Ten of the H. pylori-positive subjects had their infection eradicated during the last week of treatment. Results : In the H. pylori-negative subjects, there was rebound secretion of submaximal ( P < 0.003) and maximal ( P < 0.003) acid output, which persisted until at least 56 days after discontinuing omeprazole. The H. pylori-uneradicated subjects had no rebound increased secretion other than in maximal acid output at 28 ( P < 0.01) and at 42 days after treatment ( P < 0.02). In those eradicated of H. pylori close to the end of omeprazole, there was rebound increased secretion of submaximal acid output ( P < 0.04) lasting until 56 days and of maximal acid output ( P < 0.01) lasting until 28 days after treatment. Conclusions : Rebound increased acid secretion following omeprazole is a prolonged phenomenon in H. pylori-negative subjects. There is little evidence of it in H. pylori-infected subjects, but eradicating the infection releases the phenomenon. The accentuated H. pylori-related oxyntic gastritis induced by omeprazole is likely to protect against the rebound phenomenon.

Fluoxetine and sertraline stimulate gastric acid secretion via a vagal pathway in anaesthetised rats

The effect of the selective serotonin reuptake inhibitors, fluoxetine and sertraline on basal, secretagogues (histamine or bethanechol)- and distention-stimulated gastric acid secretion was investigated in the urethane-anaesthetised acute gastric fistula rat. Gastric acid secretion was measured by flushing of the gastric contents with saline every 15 min. Fluoxetine (10 or 20 mg kg −1, i.p.) produced a dose-dependent increase in basal gastric acid secretion. These stimulatory effects were abolished by vagotomy. Intraperitoneally administered sertraline also stimulated gastric acid secretion. The stimulatory effect of lower doses (5 mg kg −1) of sertraline was similar to that of the higher (30 mg kg −1) doses. The gastric secretory response to i.p. sertraline was long lasting (greater than 60 min), and blocked by vagotomy. Intraperitoneally administered fluoxetine (10 or 20 mg kg −1) or sertraline (5 mg kg −1) also increased gastric secretion induced by histamine, bethanechol or distention. The fluoxetine or sertraline stimulatory effects of histamine-induced acid secretion were abolished by vagotomy. Data indicate a stimulatory effect for fluoxetine and sertraline mediated by vagal nerve on gastric acid secretion in urethane-anaesthetised rats.

A lyophilized aqueous extract of Maytenus ilicifolia leaves inhibits histamine-mediated acid secretion in isolated frog gastric mucosa.

Lyophilized aqueous extract of Maytenus ilicifolia leaves (LAEMIL) is commonly used in Brazilian folk medicine in the treatment of dyspepsia as well as gastric ulcers. We have investigated the effect and the possible mechanism of action of the LAEMIL on acid secretion in isolated frog gastric mucosa incubated in an Ussing chamber. It was observed that LAEMIL (7-28 mg%) as well as cimetidine (125-4,000 microM), a well-known histamine H2 receptor antagonist, decreased basal acid secretion in a concentration-dependent manner. Similarly to cimetidine (190 microM), LAEMIL (21 mg%) also inhibited gastric acid secretion induced by increasing concentrations of histamine (50-800 microM). The EC50 values for histamine alone and histamine in the presence of LAEMIL or cimetidine were 94.6 microM (71.1-125.9 microM), 244.9 microM (209.4-286.4 microM) and 142.2 microM (23.6-855.0 microM), respectively. LAEMIL, histamine and cimetidine were effective on acid secretion only when added to the serosal surface of the mucosa. Furthermore, simultaneous addition of LAEMIL and cimetidine at concentrations, per se, ineffective, caused a 16% reduction in the basal acid secretion [from 8.3 +/- 0.3 to 6.9 +/- 0.2 microEq g(-1) (15 min)(-1), n=4]. Although effects such as inhibition of histamine biosynthesis and/or histamine release can not be ruled out, our data suggest that LAEMIL, like cimetidine, reduces acid secretion in the isolated frog gastric mucosa by antagonising histamine H2 receptors.

Impaired gastric secretion and lack of trophic responses to hypergastrinemia in M 3 muscarinic receptor knockout mice

Background & Aims : The physiologic significance of the M 3 muscarinic receptor is unclear due to an absence of specific ligand. In the present study, M 3 receptor knockout (KO) mice were used to elucidate the role of M 3 receptors in gastric acid secretion and gastric mucosal integrity. Methods : M 3 KO versus wild-type mice aged 1 month to 2 years were included. Gastric acid secretion was assessed by both direct intragastric pH measurement and pylorus ligation. Serum gastrin and gastric mucosal histamine levels were determined by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. Morphologic analysis was performed by both immunohistochemistry and transmission electron microscopy. Results : Fasted M 3 KO mice exhibited higher intragastric pH, lower acid output after pylorus ligation, a lower proportion of active parietal cells, and higher serum gastrin levels than fasted wild-type mice. Acid secretion in response to carbachol, histamine, gastrin 17, and 2-deoxy- d-glucose was impaired in the mutant mice. Although carbachol was still able to cause ∼30% acid output in M 3 KO mice, the acid secretion was inhibited by pirenzepine or famotidine. Despite remarkable hypergastrinemia in M 3 KO mice, there were no trophic responses in the oxyntic mucosa with respect to the mucosal thickness, proliferation rate, and numbers of parietal and enterochromaffin-like cells. Cholecystokinin type 2 receptor antagonist YM022 was without the effect in M 3 KO mice. Conclusions : The present study shows that M 3 receptors are essential for basal acid secretion, a fully acid secretory response to histamine and gastrin, and the trophic responses of oxyntic mucosa to gastrin.

Effects of Azadirachta indica extract on gastric ulceration and acid secretion in rats

The effect of Azadirachta indica extract on gastric ulceration was studied in albino rats. Azadirachta indica extract (100–800 mg/kg p.o., 100–250 mg/kg i.p.) significantly inhibited gastric ulceration induced by indomethacin (40 mg/kg). Administration of 800 mg/kg p.o. and 250 mg/kg i.p. caused 100% cytoprotection against indomethacin (40 mg/kg, i.p.)-induced gastric ulceration. This action was accompanied by a dose-dependent decrease in total gastric acidity. In order to investigate the probable mechanism of Azadirachta indica antiulcer activity, the effect of the extract alone and in combination with histamine (1 mg/kg) and cimetidine (0.12 mg/kg) on gastric acid secretion in situ was studied. Azadirachta indica (250 mg/kg) significantly inhibited the basal and histamine-induced gastric acid secretion. Cimetidine seemed to augment Azadirachta indica inhibition of gastric acid secretion. The results suggest that the stem bark extract of Azadirachta indica possesses antiulcer agents, which probably act via histamine H 2 receptor.

History of acid suppression: focus on the hospital setting.

In the hospital setting, prophylactic acid suppression is an important part of care for many critically ill patients. It may also prevent rebleeding in patients admitted with acute upper gastrointestinal tract bleeding. Effective treatments for these conditions stemmed from our increased understanding of the gastric acid secretory pathway and target pH values. The late 1970s saw the introduction of histamine2-receptor antagonists (H2RAs), which partially suppress basal and meal-stimulated acid secretion. Some of these agents can induce an intragastric pH greater than 3, lasting for approximately 10 hours/day when given twice/day at recommended doses. This level of acid suppression can facilitate healing of duodenal ulcers but has limited efficacy for other indications (e.g., gastrointestinal bleed). In the late 1980s a more potent class of acid-suppressing agents was developed, proton pump inhibitors (PPIs). The PPIs can induce an intragastric pH above 3 lasting for approximately 17 hours/day, and an intragastric pH above 5 for approximately 9 hours/day after once-daily oral administration of recommended doses. It is possible to attain even higher target pH values with large doses and with continuous intravenous infusion. Thus, PPIs are agents of choice for treatment of many acid-related disorders including peptic ulcer disease and moderate-to-severe gastroesophageal reflux disease, and for prevention of rebleeding in patients with upper gastrointestinal bleeding. Availability of an intravenous formulation, pantoprazole, enables hospitalized patients for whom oral administration is not feasible to benefit from the superior potency of PPIs. Preliminary data suggest that intravenous PPIs may be more effective than H2RA prophylaxis against stress-related ulcer bleeding for intensive care patients and should facilitate healing in those with bleeding ulcers of the upper gastrointestinal tract.

277 Effect of acute heroin on basal and electrical vagal stimulation acid and pepsin secretion in rat

We have reported that rats given 10–20 mmol/kg of propionate develop hyperammomemia in response to amino acid loads. Ethanol in doses of 0.1–5 mmoles/kg attenuates or prevents this hyperammonemia. Liver ATP, glutamate and aspartate levels are unaffected, but the fall in acetyl CoA and secondarily in N-acetylglutamate caused by propionate alone is much reduced. As a result of this effect, mitochondrial carbamoyl phosphate synthetase activity is restored nearly to normal. Thus low-dose ethanol combats this form of hyperammonemia by augmenting hepatic acetyl CoA.

Crucial role of histamine for regulation of gastric acid secretion ascertained by histidine decarboxylase-knockout mice.

Histidine decarboxylase (HDC) represents the sole enzyme that produces histamine in the body. The present work investigated the role of endogenous histamine in carbachol- and gastrin-induced gastric acid secretion with HDC-knockout (HDC-/-) mice. Acid secretion was measured in either mice subjected to acute fistula production under urethane anesthesia or conscious mice that had previously undergone pylorus ligation. In wild-type mice, carbachol and gastrin significantly stimulated acid secretion, increasing gastric mucosal histamine. In contrast, in HDC-/- mice, carbachol and gastrin had little impact when either delivered alone or together. Nonetheless, the two agents achieved a synergistic effect when delivered together with exogenous histamine, stimulating acid secretion in HDC-/- mice. Such synergism was abolished by the histamine H2-receptor antagonist famotidine. cAMP involvement in acid secretion was also examined with theophylline, a phosphodiesterase inhibitor, and forskolin, an adenylate cyclase activator. In wild-type mice, theophylline significantly increased acid secretion, enhancing carbachol- and gastrin-stimulated acid secretion. In contrast, in HDC-/- mice, theophylline failed to exert an effect on basal acid secretion, as well as carbachol- and gastrin-stimulated acid secretion. Although forskolin interacted with carbachol, allowing acid secretion in HDC-/- mice, similar results were not achieved with gastrin. Such results suggest that 1) histamine is essential for carbachol- and gastrin-stimulated gastric acid secretion in mice; and 2) histamine-induced cAMP production contributes to the in vivo response to carbachol or gastrin.

Effects of lipopolysaccharide and phenylbutazone on gastric contents in the horse

Endotoxaemia causes a disruption of gastrointestinal motility in the horse but there is no information on its effects on gastric secretion. Lipopolysaccharide (LPS) administration is known to affect gastric secretion in other species. That LPS, a toxic component of Gram-negative bacteria, would reduce gastric acid secretion and that pretreatment with phenylbutazone (PBZ) would block the effects of LPS. The effects of LPS and PBZ on gastric contents were investigated in fasted, mature horses, with permanent gastric cannulae. Horses were pretreated with either saline or PBZ 15 mins before a 60 min infusion of either LPS or saline. Gastric contents were collected at 15 min intervals for 3 h, beginning 15 mins after the start of the LPS or saline infusion. Lipopolysaccharide significantly decreased gastric acid output, [K+] and potassium output and increased [Na+] and sodium output. Phenylbutazone did not affect basal gastric acid secretion but decreased LPS-induced changes in the secreted volume, [Na+] and sodium output. This study provides evidence that LPS affects gastric acid secretion in the horse and that these LPS-induced changes are mediated, in part, by prostaglandins. Lipopolysaccharide administration can induce changes in the composition of gastric contents in the horse but further work is needed to determine the source of these changes.

Actions of crude hydroalcoholic extract of Pfaffia sp on gastrointestinal tract

The plants that compound the Pfaffia genus are used in folk medicine to treat gastric disturbances. This study examined the effects of a crude hydroalcoholic extract of Pfaffia sp on the gastrointestinal tract. Female Wistar rats were pretreated orally (p.o.) with the hydroalcoholic extract of Pfaffia (0.5, 1 and 2 g.kg-1) before the induction of ulcer with hypothermic restraint stress (HRS), ethanol (ET) or indomethacin (IND). Control animals received water (C) or ranitidine (60mg/kg) p.o. The hydroalcoholic extract of Pfaffia (0.5, 1 and 2 mg.kg-1) protected rats against HRS and ET - induced ulcers, but was not able to protect the gastric mucosa against IND - induced ulcers. When injected into the duodenal lumen, the hydroalcoholic extract of Pfaffia inhibited basal and stimulated acid secretion in pylorus-ligated rats. These results indicate that this plant has a protective action against gastric lesions of the mucosa involving the reduction of gastric acid secretion.

Somatostatin receptor type 2 mediates bombesin-induced inhibition of gastric acid secretion in mice.

Studies in isolated mouse stomach showed that bombesin releases somatostatin. We characterized the effects of exogenous bombesin on gastric acid secretion in mice and determined the involvement of somatostatin and somatostatin receptor type 2 (SSTR2) by using somatostatin immunoneutralization, the SSTR2 antagonist, PRL-2903, and SSTR2 knockout mice. Gastric acid secretion was monitored under basal and pentagastrin-, histamine- or bethanechol-stimulated conditions in urethane-anaesthetized mice. Bombesin (10-40 micro g kg-1 h-1) and somatostatin-14 (20 micro g kg-1 h-1) were infused I.V. 10 and 30 min after PRL-2903 or somatostatin antibody pretreatment, respectively. Urethane-anaesthetized wild-type mice had low basal acid secretion (0.12 +/- 0.01 micro mol (10 min)-1) compared with SSTR2 knockout mice (1.43 +/- 0.10 micro mol (10 min)-1). Somatostatin antibody and PRL-2903 increased basal secretion in wild-type mice but not in SSTR2 knockout animals. In wild-type mice, bombesin inhibited secretagogue-stimulated acid secretion in a dose-dependent manner, and somatostatin-14 inhibited pentagastrin-stimulated secretion. In wild-type mice pretreated with somatostatin antibody or PRL-2903 and in SSTR2 knockout mice, bombesin and somatostatin-14 I.V. infusion did not alter the increased gastric acid secretion. These results indicate that, in mice, bombesin inhibits gastric acid secretion through the release of somatostatin and the activation of SSTR2. These observations strengthen the important role of SSTR2 in mediating somatostatin inhibitory actions on gastric acid secretion.

Expanded Parietal Cell Pool in Transgenic Mice Unable to Synthesize Histamine

Background: The histidine decarboxylase enzyme (HDC) is responsible for the synthesis of histamine in mammals. Histidine decarboxylase-deficient (HDC −/− ) mice have recently been developed by targeted mutation of the HDC gene. Methods: The impact of prolonged histamine deficiency was studied on gastric morphology (by immunohistochemistry and morphometry), gastric acid secretion (by a wash-through method for basal gastric acid secretion and by pylorus ligation for stimulated gastric acid secretion) and gastrin levels (by radioimmunoassay) in homozygous HDC −/− mice kept on a low-histamine diet. Results: A double maximal gastric acid secretory response was found in knockouts after exogenous histamine administration. In contrast, the gastric acid secretion was significantly reduced after gastrinergic and cholinergic stimulation in the absence of histamine. The oxynthic gland area of HDC −/− mice was thickened with an increased parietal cell count compared to wild types. Substantially elevated serum and antral tissue gastrin levels of HDC −/− mice could be possible indications of both an expanded parietal cell mass and/or an increased histamine-induced maximal gastric acid secretory capacity of this genotype. Conclusions: These data suggest that not enough compensatory mechanisms develop in HDC −/− mice during a prolonged low-histamine diet to maintain/restore normal gastric acid secretion. An expanded parietal cell pool was also demonstrated in HDC −/− mice kept on a low-histamine diet, probably caused by a trophic effect of sustained hypergastrinaemia. The HDC −/− strain is a suitable model for studying the effects of achlorhydria and consequent hypergastrinaemia as an approach to human conditions such as atrophic gastritis or long-term antisecretory therapies.