Role of gastrin/CCK-B receptor in the regulation of gastric acid secretion in rat

The aim of this study was to investigate whether gastrin regulates morphological changes and alpha-subunit gene expression in parietal cells through the gastrin/CCK-B receptor on enterochromaffin-like cells by histamine release. Treatment with 100 mg/kg of YM022, a potent and selective gastrin/CCK-B receptor antagonist, for one week in rats did not alter mRNA levels of histidine decarboxylase or H+, K+-ATPase. However, parietal cell morphology predominantly changed to the resting form, although the serum gastrin concentration was significantly increased. Additional treatment with YM022 and oral omeprazole, 100 mg/kg, for one week markedly suppressed the increases of mRNA levels of histidine decarboxylase and H+, K+-ATPase and completely blocked the morphological transformation of the parietal cells to a stimulated form induced by treatment with omeprazole alone. This indicates that the morphological transformation of parietal cells to an activated form with a subsequent increase in H+, K+-ATPase synthesis caused by hypergastrinemia is mediated by increased histidine decarboxylase gene expression in enterochromaffin-like cells via gastrin/CCK-B receptors.     

Magnesium and gastric acid secretion

This study examined the modifications of acid gastric secretion caused by magnesium oxide, peroxide, silicate and sulphate in 805 patients with duodenal ulcers; The calcium-magnesium antagonism on the one hand and the acetazolamide - magnesium synergia on the other, were also investigated. Our results show that administration of magnesium, either oral or parenteral, does not significantly modify gastric acid secretion, either basal or stimulated by maximal histamine. Administration of un infusion of calcium gluconate 15 mg/kg body weight, significantly increases gastric acid secretion as compared to basal secretion. Addition of a dose of magnesium sulphate to the infusion antagonises the effect of gastric acid secretion caused by calcium. Administration of 1.5 gr magnesium oxide along with 25 mg acetazolamide per kg/body weight, strengthens the inhibitory effect of acetazolamide upon gastric acid secretion, increasing the proportion of significant inhibitory effects up to 98% of the cases under investigation. Addition of magnesium to the classical therapy antagonises the noxious effects of calcium compounds; the presence of magnesium in the composition of antacid powders proves necessary.     

Postprandial biliary and pancreatic secretion during profound inhibition of gastric secretion in humans

This study assessed the effect of profound inhibition of gastric secretion by an H2 antagonist on postprandial gastric emptying of acid and chyme, and on bile acid and pancreatic enzyme secretion under physiological conditions in humans. Six subjects were studied before and while they were given famotidine (40 mg). This study combined a continuous intestinal perfusion technique using 14C-polyethylene glycol (14C-PEG) as duodenal recovery marker, with intermittent sampling of gastric content using PEG 4000 as meal marker. During the three hour study, the area under the curve for gastric acid output decreased from mean (SEM) 88.9 (7.6) mmol for those not receiving treatment, to 21.2 (2.7) mmol for subjects receiving famotidine (p < 0.01). The corresponding values for the rate of acid delivery into the duodenum decreased from 65.2 (11.9) to 16.6 (2.9) mmol (p < 0.05), and those for the rate of gastric emptying of chyme remained unchanged for the group receiving no treatment and during famotidine (1040 (200) v 985 (160) ml respectively, NS). Duodenal bile acid and trypsin output remained unchanged (area under the curve, 457 (128) v 373 (86) umol/kg and 5022 (565) v 5058 (400) IU/kg respectively, NS) receiving no treatment and during famotidine. It is concluded that profound inhibition of postprandial gastric acid secretion by anti-secretory drugs is not accompanied by changes in biliary and pancreatic secretion, mainly because the gastric emptying of chyme is unaffected.     

A gastric acid secretion model

A theory of gastric acid production and self-protection is formulated mathematically and examined for clinical and experimental correlations, implications, and predictions using analytic and numerical techniques. In our model, gastric acid secretion in the stomach, as represented by an archetypal gastron, consists of two chambers, circulatory and luminal, connected by two different regions of ion exchange. The capillary circulation of the gastric mucosa is arranged in arterial-venous arcades which pass from the gastric glands up to the surface epithelial lining of the lumen; therefore the upstream region of the capillary chamber communicates with oxyntic cells, while the downstream region communicates with epithelial cells. Both cell types abut the gastric lumen. Ion currents across the upstream region are calculated from a steady-state oxyntic cell model with active ion transport, while the downstream ion fluxes are (facilitated) diffusion driven or secondarily active. Water transport is considered iso-osmotic. The steady-state model is solved in closed form for low gastric lumen pH. A wide variety of previously performed static and dynamic experiments on ion and CO2 transport in the gastric lumen and gastric blood supply are for the first time correlated with each other for an (at least) semiquantitative test of current concepts of gastric acid secretion and for the purpose of model verification. Agreement with the data is reported with a few outstanding and instructive exceptions. Model predictions and implications are also discussed.     

The role of endogenous acid in the development of acute gastric ulcer induced by ischemia-reperfusion in the rat

We investigated the role of endogenous gastric acid in the development of gastric ulcer from erosion induced by ischemia-reperfusion of the celiac artery in the rat. A half-hour clamping of the celiac artery (ischemia) caused acute gastric erosions 1 hour after reperfusion and such acute injuries progressed to ulcers 48-72 hours after reperfusion without any necrotizing agents. Gastric acid secretion decreased immediately after ischemia and didn't recover until 12 hours after reperfusion. Intraperitoneal administrations of cimetidine (100 mg/kg, every 12 hours) or omeprazole (30 mg/kg, every 24 hours) were started at 1, 6, or 12 hours after reperfusion. When administrations were started 1 hour after reperfusion, both drugs significantly decreased the total damaged area and prevented the progression of gastric erosions to ulcers. However, administrations started 6 or 12 hours after reperfusion failed to inhibit the total damaged area and to prevent ulcer formation. These results suggest that endogenous gastric acid may play an important role in the progression of gastric erosions to ulcers although ischemia itself reduces acid secretion. Furthermore, treatment with anti-acid-secretory drugs in the early stage of mucosal damage may be important for the prevention of ulcer.     

Hypoxia inhibits gastric emptying and gastric acid secretion in conscious rats

This study examines the effects of hypoxia in the gastric function in conscious rats which adapted to a meal-feeding schedule, that allowed free access to a high protein (HP) diet (550 g casein/kg diet, Exp.1,2 and 4), a normal protein (NP) diet (200 g casein/kg diet, Exp.3) or a nonpurified rat (NPR) diet (Exp. 5 and 6) for 4 h every day for 2 wk. In Exp. 1, after 4 h of consuming the HP diet, rats were exposed to 7.6 or 10.5% O2 normobaric hypoxia. Hypoxia delayed the excretion of urinary urea for 12 h. In Exp.2 and 3, when rats were exposed to 7.6%O2 after 4 h of consuming the HP diet and exposed to 10.5% O2 after 4 h of consuming the NP diet, respectively, a significant delay in gastric emptying was found in the hypoxic rats. In Exp. 4, when rats were exposed to 7.6 O2 hypoxia after 4 hr of eating the HP diet, the plasma gastrin concentration in the 7.6% O2 hypoxic rats was 2.3-fold that of the normoxic rats after 6 h of hypoxia. Furthermore, when rats that did not consume any HP diet on the day of the experiment were exposed to 7.6 or 10.5% O2 hypoxia, the plasma gastrin concentration was higher in both hypoxic groups than in the normoxic group after 3 and 6 of hypoxia. In Exp. 5, rats that were not fed the NPR diet on the day of study were exposed to 7.6 or 10.5% O2 hypoxia for 3 h after pylorus ligation. Hypoxia inhibited the secretion of gastric acid and elevated the plasma gastrin concentration. In Exp. 6, unfed rats that had been consuming the NPR diet were exposed to 7.6% O2 hypoxia for 3 h after pylorus ligation and were orally administered HCl. The rise of the gastrin concentration due to hypoxia was completely inhibited by oral HCl. These results demonstrate that hypoxia inhibits gastric emptying and gastric acid secretion and that the inhibitory effect of hypoxia on gastric acid secretion stimulates gastrin release through positive feedback regulation.     

Role of GABA in the control of thyrotropin secretion in the rat

Various doses of GABA from 0.25 to 5 mumol injected into the third ventricle decrease serum TSH rapidly. The same effect was observed with GABOB (10 mumol), the hydroxylated form of GABA. The inhibitory effect of both of these drugs was prevented by picrotoxin injection (1 microgram). Peripheral injection of GABAergic drugs such as GABOB or AOAA also decreased serum TSH. In vitro, the addition of GABA (from 6.7 . 10(-6) to 6.7 . 10(-4) M) to the incubation medium of hemi-anterior pituitary did not modify the liberation of TSH. To test the physiological role of GABA in the regulation of thyrotropin function the circadian TSH rhythm was used as a model. Both GABAergic inhibitors, picrotoxin (10 microgram/kg b.w.) as well as semicarbazide (150 mg/kg b.w.), induced an increase of the low basal nocturnal level of TSH (centered on the 02.00 h time point) without altering the diurnal peak of TSH. We conclude that GABA has an inhibitory effect on central thyrotropin control via an inhibition of TRH release from the hypothalamus and might be, at least partly, responsible for the low nocturnal levels of serum TSH observed during the circadian physiological rhythm.     

Stimulation of gastric acid secretion by dimaprit in unanesthetized rats

In unanesthetized rats, dimaprit and histamine given by intravenous infusion were about equipotent in stimulating gastric acid secretion. The maximal rate of acid secretion in response to dimaprit was significantly greater than to histamine but not significantly different from the response to pentagastrin.     

Effect of electroacupuncture on gastric acid secretion and gut hormones

21 patients with mild type of chronic superficial gastritis were selected in this study. The effect of electroacupuncture in Zhongwan (RM12), Neiguan (P6) and Sanyinjiao (Sp6) on gastric acid secretion, serum gastrin, plasma somatostatin, plasma motilin concentration and erythrocyte acetylcholinesterase (AchE) activity were observed. The results were as follows: There were significant decreases in gastric acid output, serum gastrin concentration and AchE activity (P < 0.05), but no significant changes in plasma somatostatin and motilin concentration (P > 0.05) after simultaneous electroacupuncture in Zhongwan, Neiguan and Sanyinjiao.     

Role of gastric acid in the aetiology of dyspeptic disease and dyspepsia

The main diseases associated with dyspepsia are peptic ulcer disease, gastro-oesophageal reflux disease and non-ulcer dyspepsia. Increased gastric acid secretion is a characteristic of most duodenal ulcer patients and of a small minority of non-ulcer dyspepsia and gastro-oesophageal reflux disease patients. Although acid secretion is normal in most gastro-oesophageal reflux disease patients, the condition is mainly the result of excess exposure of the distal oesophagus to acid refluxing from the stomach. Increased mucosal sensitivity to acid is involved in the aetiology of dyspeptic symptoms in the majority of patients with peptic ulcer disease and gastro-oesophageal reflux disease, and in a minority of non-ulcer dyspepsia subjects. Gastric acid, therefore, plays an important role in both the aetiology of dyspeptic diseases and in the aetiology of dyspeptic symptoms.     

Role of nitric oxide in regulation of gastric acid secretion in rats: effects of NO donors and NO synthase inhibitor

1. The role of nitric oxide (NO) in the regulation of acid secretion was examined in the anaesthetized rat. 2. A rat stomach was mounted in an ex vivo chamber, instilled with 2 ml of saline every 15 min, and the recovered sample was titrated at pH 7.0 against 0.1 N NaOH by use of an automatic titrator for acid secretion. Gastric mucosal blood flow (GMBF) was measured simultaneously by laser Doppler flowmeter. 3. Intragastric application of NO donors such as FK409 (3 and 6 mg ml[-1]) and sodium nitroprusside (SNP; 6 and 12 mg ml[-1]) as well as i.p. administration of cimetidine (60 mg kg[-1]), a histamine H2-receptor antagonist, significantly inhibited the increase in acid secretion in response to pentagastrin (60 microg kg(-1) h(-1), i.v.), in doses that increased gastric mucosal blood flow (GMBF). 4. Intragastric application of FK409 (6 mg ml[-1]) increased both basal and stimulated acid secretion induced by YM-14673 (0.3 mg kg(-1), i.v.), an analogue of thyrotropin-releasing hormone (TRH), but had no effect on the acid secretory response induced by histamine (4 mg kg(-1) h(-1), i.v.). 5. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME; 10 mg kg(-1), i.v.) did not affect basal acid secretion, but significantly potentiated the increase in acid secretion induced by YM-14673 and slightly augmented the acid secretory response to pentagastrin. 6. Both pentagastrin and YM-14673 increased the release of nitrite plus nitrate (NOx), stable NO metabolites, into the gastric lumen, and these changes were completely inhibited by prior administration of L-NAME (10 mg kg(-1), i.v.). 7. Pentagastrin caused an increase in luminal release of histamine and this response was significantly suppressed by intragastric application of FK409 (6 mg ml[-1]). 8. These results suggest that either exogenous or endogenous NO has an inhibitory action on gastric acid secretion through suppression of histamine release from enterochromaffin-like (ECL) cells.     

Association between serum gastrin levels, gastric acid secretion and age in early gastric cancer

This study evaluated the effect of gastric acid secretion and serum gastrin response on tumor differentiation for early gastric cancer according to patients' age. We investigated the association between serum gastrin levels, gastric acid secretion and the histologic types of 335 early gastric carcinomas limited to the mucosal and submucosal layers in comparison with 450 gastric and 197 duodenal ulcers. The preoperatively examined basal acid output, maximal acid output and peak acid output after administration of tetragastrin and serum gastrin levels before and after ingestion of a test meal were determined. Patients with differentiated cancer and duodenal ulcer showed a significant negative correlation between gastric acid secretion and age, while the former group also had a significant positive correlation between serum gastrin levels and age. On the other hand, patients with undifferentiated cancer did not show any such correlation between gastric acid and age, but showed a significant positive correlation between serum gastrin, integrated gastrin response and age. Patients with gastric ulcer did not show any such correlations. These data suggest that both low acid secretion and endogenous hypergastrinemia, especially in the elderly, may play an important role in differentiated and undifferentiated gastric carcinomas.     

Effect of calcium infusions of serum calcium and gastric acid secretion

37 patients were studied with calcium infusions. Of these, 20 had previously undergone truncal vagotomy and pyloroplasty for duodenal ulcer disease, and 17 were unoperated patients with duodenal ulcer disease. Calcium was given intravenously either at a dose of 5 mg/kg/h for 3 h, or 4 mg/kg/h for 4 h. Gastric juice was collected by continuous suction. Results showed the 3-hour infusion raised calcium more than the 4-hour infusion. Top serum calcium achieved, however, did not correlate with calcium-stimulated gastric acid output, either with or without vagotomy. Stimulated gastric acid secretion was markedly less with vagotomy than without. It is suggested that the level of gastric acid stimulated by infusions might discriminate complete, from incomplete, vagotomies better than insulin, and that the 4-hour infusion is safer.     

Site of alpha blockade in the demonstration of nonvagally mediated gastric acid secretion

Peroperative tinidazole and placebo treatment were compared with respect to incidence of postoperative infections in a double blind investigation on patients admitted for elective bowel surgery. Patients in the tinidazole group had a significantly reduced postoperative infection rate, compared with the placebo group (7.4% and 46%, respectively). Complications in general were fewer in the tinidazole group and costs for antibiotic treatment decreased. All tinidazole-treated patients had clinically effective blood concentrations of the drug at the time of the operation. In contrast with the placebo-treated subjects, the individuals who developed postoperative wound infections from the tinidazole group had no growth of anaerobic bacteria and no antibody response to Bacteroides sp. The use of tinidazole may therefore be recommended for the prevention of postoperative anaerobic infections in patients undergoing bowel surgery.     

Roles of gastrin and somatostatin in the regulation of gastric acid secretion in the fetal rabbit

In adult gastric epithelium, gastrin and somatostatin regulate parietal cell acid secretion; however, their expression and function in the fetus are largely unknown. We defined the developmental expression of gastrin and somatostatin in the fetal rabbit stomach and determined their effects on fetal acid secretion. To define peptide expression, fetuses from 12 time-mated New Zealand white rabbit does were analyzed at successive ages during the third trimester (term is 31 days). Peptides were extracted from fetal gastric tissue by boiling in water and then in acetic acid. Amidated gastrin and somatostatin levels were measured by radioimmunoassay using antisera 1296 for gastrin and 8402 for somatostatin. To determine the effects of gastrin and somatostatin, pentagastrin (64 microg/kg/hr) or octreotide (35 microg/kg/hr) were infused intravenously in conscious pregnant rabbits at 28 days of gestation for 3 hr. Fetuses (n = 45) were harvested and gastric acid was titrated with 0.02 N NaOH. Gastrin and somatostatin tissue content were 12 +/- 3 and 51 +/- 6 pmol/g at gestational day 20, respectively, and increased to 146 +/- 10 and 162 +/- 5 pmole/g by day 30 (P < 0.05). Between days 24 and 26, when gastric acid was first detectable, the molar ratio of somatostatin to gastrin decreased from 5.0 +/- 1.0 to 1.1 +/- 0.1 (P < 0.05). Fetal gastric acid content (micromole) was 28.5 +/- 1.7 in controls, 27.5 +/- 1.9 with pentagastrin treatment, and 15.8 +/- 1.4 micromole with octreotide (P < 0.05). In summary, 1) In fetal gastric tissue, gastrin increased 12-fold and somatostatin increased 3-fold between days 20 and 30 of gestation. 2) The decreased ratio of somatostatin to gastrin between days 24 and 26 of gestation coincides with the onset of fetal gastric acid secretion in the fetal rabbit. 3) Maternal administration of octreotide inhibited fetal gastric acid content; however, pentagastrin had no effect. We conclude that, in the fetal rabbit stomach, the relative expression of gastrin and somatostatin may regulate the onset of parietal cell acid secretion.