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The role of gastrin in the pathophysiology of two diseases affecting the human stomach, the Zollinger Ellison syndrome (ZES) and the pernicious anemia (PA), is reviewed. Both diseases present chronic hypergastrinemia but from different origins. The ZES is characterized by the occurrence of ectopic endocrine gastrin-secreting tumors and PA by a fundic atrophic gastritis leading to complete atrophy of fundus and resulting in achlorhydria. In PA, the lack of acid induces continuous gastrin cell activation and is responsible for the subsequent gastrin hypersynthesis and secretion. In ZES, hypergastrinemia causes hypertrophy of the oxyntic mucosa, which, in addition, displays hyperplasia of parietal and mucus cells. In both diseases, hypergastrinemia also induces the hyperproliferation of enterochromaffin-like endocrine cells in the fundic mucosa, which can offer all aspects from hyperplasia, then dysplasia, until true carcinoid tumor. The influence of antisecretory treatments and MEN 1 in the ZES as well as that of several other factors and antrectomy in PA on the behavior of the different gastric cells is evoked. Finally, the role that gastrin and its receptor play in the maintenance of the normal development of gastric mucosa and gastric acid secretion is emphasized by results observed in gene knockout models., (Copyright 2000 Wiley-Liss, Inc.)

We report the case of a 45-yr-old white man, investigated for chronic diarrhea, malabsorption and weight loss associated with sicca syndrome. Endoscopic and x-ray examinations showed normal macroscopic mucosa in gastrointestinal tract (GIT). Immunohistochemistry showed diffuse polyclonal T cell lymphocytes infiltrating either epithelium and lamina propria in GIT. There was no villous atrophy in the jejunum and ileum. Corticosteroids, azathioprine, and cyclosporine failed to improve symptoms. Monthly intravenous cyclophosphamide administered over 1 yr, stopped the diarrhea and weight loss. The patient is free of symptoms up to a 5-yr follow-up.

Platelet activating factor (PAF) is a phospholipid mediator known as potent ulcerogenic agent but its physiological role is still unknown in the gastrointestinal tract. Lyso PAF the immediate PAF procursor has no deleterious effect in the gastrointestinal tract. We have previously reported that lyso PAF is produced by gastric mucosa in basal condition and in response to gastrin in healthy men. Helicobacter pylori metabolises lyso PAF to produce PAF. The aim was to study the effect of PAF on the gastric acid secretion. Isolated rabbit glands were used as a model and acid secretion was assessed by (14C) Aminopyrine (AP) uptake. PAF and histamine stimulated AP accumulation time- and dose-dependently. PAF-induced AP accumulation was supressed by omeprazole and Fura 2. BN50727 a specific PAF antagonist inhibited PAF-induced AP accumulation. The presence of a PAF receptor transcript was investigated by reverse transcriptase polymerase chain reaction (RT-PCR) from total mRNA using two primers in which oligonucleotides were synthetized from the human leucocyte PAF receptor cDNA. A single RT-PCR band of the transcript with expected size was detected in the crude isolated cell fraction. These results and others from our laboratory suggest that PAF stimulates gastric acid secretion via specific receptor on the parietal cells and H. pylori produces PAF which may induce mucosal injury directly or indirectly via acid pathway.

We assessed the effects of pirenzepine (2 mg/kg per os) on gastric secretion and gastrin and histamine release in response to food and histamine dihydrochloride infusion in four dogs during 24 weeks of treatment and for 15 weeks after the end of treatment. The results were compared to those obtained in the same animals in control experiments, before treatment, and in four untreated dogs. Pirenzepine absorption was checked by measuring plasma concentrations. Pirenzepine led to a significant reduction in acid and pepsin secretion in response to histamine. In response to food, the reduction in secretion was concomitant with a reduction in gastrin and histamine release. Baseline concentrations of gastrin were reduced, while those of histamine were unchanged. No side effects were observed. After treatment, a long time lapse (about 15 weeks) was required for acid and pepsin secretion and gastrinemia to return to control levels, while histamine release in response to food normalized rapidly. Pirenzepine fixes selectively to M1 muscarinic receptors of the synaptic ganglion, thus inhibiting the effect of vagal stimulation, especially on pepsin secretion. Our data suggest that it might also fix to M1 receptors located on ECL cells, thereby reducing histamine release. In addition, pirenzepine probably fixes to other muscarinic receptors inhibiting gastrin release and resulting in a G and secretory cell mass reduction, probably by increasing somatostatin release.

The release of platelet activating factor (PAF-ACETHER or PAF) and its precursors in the gastric lumen was assessed in 13 normal subjects in basal condition and after stimulation by gastrin. Acid, pepsin, and sialic acid outputs were determined under the same conditions. Gastric juice was collected using a nasogastric tube after overnight fast in basal condition for 60 minutes, then under pentagastrin infusion (6 micrograms/kg/hr for 60 minutes). Platelet activating factor was detected at low concentration in 4/13 subjects under basal condition (mean (SEM) 1.2 (0.6) pg/hr) while high concentrations of lyso platelet activating factor (6.1 (1.8) microgram/hr) and of alkyl-acyl-glycerophosphocholine (AAGPC) (11.5 (3) micrograms/hr) were found in 13 and 11 subjects, respectively. Platelet activating factor was not detected during pentagastrin infusion, while lyso platelet activating factor and alkyl-acyl-glycerophosphocholine were detected in 13 and in 12 subjects, respectively. Compared with the basal condition these platelet activating factor precursors increased significantly (p < 0.001) going up to fivefold baseline (31.8 (6.8) micrograms/hr and 53 (9.3) micrograms/hr respectively) in response to pentagastrin. There was a positive correlation between platelet activating factor precursors and acid or pepsin output but not between platelet activating factor precursors and sialic acid. As sialic acid may be considered an index of mucus glycoprotein degradation, it seems that gastrin stimulation of gastric epithelial cells results in a concomittant secretion of platelet activating factor precursors, acid, and pepsin irrespective of mucus glycoprotein degradation.

In light of evidence that certain aluminum-based antacids adhere to the gastric mucosa, we modified our previously described "artificial stomach" (AS) model by including a piece of hog stomach and compared the antacid activity of six aluminum-containing antacid products in the model with and without gastric mucosa. The activity of three of these, Maalox, Riopan and Supralox, was not significantly different in the two systems. In contrast, the activity of the other three, Aludrox, Phosphalugel and Simeco, was significantly greater with mucosa. Antacid activity of one product from each set (Supralox, Phosphalugel) was evaluated in two in vivo methods in human volunteers. For both antacids, results in vivo were similar to those obtained with the AS-containing mucosa. Without mucosa, in vivo and in vitro results were dissimilar for Phosphalugel, thus validating the modified AS. The difference between the two sets of antacids can be explained by 1) the fact that the Al:Mg ratio in the set affected by mucosa is greater than that of unaffected antacids, and 2) a weaker antacid load than in unaffected Supralox. We suggest that in an acid milieu, aluminum ions in antacids like Aludrox, Phosphalugel and Simeco are bound to sialic acid residues in mucus glycoproteins, thus retarding the transit of these antacids through both the AS and the real stomach and prolonging their activity in both situations. When the Al:Mg ratio is low or when the amount of antacid salts is large, aluminum ions tend to be buried in complexes, giving them less chance to interact with gastric mucus, so they transit the stomach more quickly.

Platelet-activating factor (PAF) has been implicated in the pathogenesis of acute inflammatory and ulcerative diseases of the upper gastrointestinal tract. In the present study, we compared the gastric output of PAF and its precursors with gastric acid output, in patients with various upper gastrointestinal tract diseases and healthy controls. PAF and precursors were also extracted from gastric biopsies from subjects with chronic gastritis and/or gastric colonization by Helicobacter pylori. Under basal conditions, hourly gastric PAF output increased in esophagitis and erosive gastritis, but not in duodenal ulcer or Zollinger-Ellison syndrome. In the gastric juice of duodenal ulcer patients, PAF output rose after secretin, but in patients with Zollinger-Ellison syndrome, PAF was only detected when gastric acid secretion had been reduced by antisecretory drugs and no concurrent changes were observed in serum gastrin levels. After pentagastrin, patients and controls exhibited a significant decrease in PAF output and a negative correlation was found between PAF and acid outputs (r = -0.57, p < 0.01). When PAF was incubated with gastric juice in vitro, it underwent degradation irrespective of the medium pH. We found no relation between the outputs of PAF and precursors and the severity of gastritis or gastric colonization by H. pylori. Overall, these results suggest that PAF might be released in the stomach by gastric epithelial cells and could be responsible for mucosal injury of the upper gastrointestinal tract.

Basal and pentagastrin- or insulin- stimulated secretion was studied in 72 non ulcer dyspectic patients (NUD), in 289 non operated duodenal ulcer patients (DU), and in 30 DU, before and after highly selective vagotomy (HSV). Acidity, proteolytic activity, choline indicating the presence of duodenogastric refluxed material and sialic acid bound to mucus glycoprotein, marker of mucus erosion, were measured. Basal and pentagastrin-stimulated acid and pepsin secretions in NUD were significantly reduced with regard to those in DU. Sialic acid content was weak in basal secretion and markedly increased in response to pentagastrin reaching the values observed in DU. DU basal secretions of acid and of pepsin were modulated according to the stimulating secretory mechanism. Mucus glycoprotein erosion was related to pepsin mucolytic activity and/or to the presence in gastric juice of refluxed material. In DU the increase of peptic mucolysis corresponded to a biological signal of the ulcer attack when no duodenogastric reflux was identified. High values pepsin output in basal secretion and in response to insulin and of basal sialic acid content combined with a pepsin/acid basal output ratio higher than 80 were biological arguments anticipating the efficacy of HSV in DU. Multiparametric analysis of gastric secretion allows to evaluate the ratio between aggressive factors and mucosal defense corresponding to an equilibrium in NUD and to greater aggressivity in DU whose intensity is related to the course of disease.

The quantification of mucus glycoproteins (GPs) faces paramount difficulties in terms of methods and interpretation. Mucus glycoprotein erosion, however, might be quantified in gastric juice by measurement of GP-bound sialic acid. Basal sialic acid content was low in normal healthy subjects (N) and in nonulcer dyspepsia (NUD) patients. They were five to six times higher in duodenal ulcer (DU), or more in Zollinger-Ellison patients. Pentagastrin stimulation induced a five- to sixfold rise in N and NUD patients although it did not affect DU patient sialic acid contents. Relationships between sialic acid content and pepsin output in DU indicate that pepsin exerts a variable mucolytic activity depending on disease evolution. In addition to pepsin, duodenogastric reflux exerts a potent mucolytic effect. Therapeutically, highly selective vagotomy without recurrent ulcer markedly reduced mucus erosion. The reduction of mucus erosion by protective drugs has been observed in some cases but in other cases sialic acid measurement did not allow to verify a protective effect. Adherent mucus analysis by high-performance liquid chromatography (HPLC) should allow one to appreciate GP fractions qualitatively. Combination of both methods should allow further determination of the mucus protective role, simultaneously investigating the adherent mucus quality and eroded GPs.

Different surgical models are used in the dog for studying gastric secretion: gastric fistula, denervated Heidenhain pouch, innervated Amdrup pouch and cervical esophagostomy. The surgical procedures are described as well as the care and the monitoring allowing long-term survival of the animals. The association of gastric fistula - Heidenhain pouch has been assessed 30 times and 8 times with cervical esophagostomy. The death-rate was been 7% and the morbidity 24%. Three dogs were provided with an Amdrup pouch. Calibration of the animals allowed the acid and pepsin secreting dose-response to be platted and translation according to lineweaver-Burk or Dowd and Riggs is used to calculate the efficient dose (ED 50) and the maximal response (maxR). Pharmacological or physiological effects might be analyzed in regard to the modification of these parameters in response to a pharmacological agonist or antagonist substance. Some physiological studies could be made using sham-feeding on dogs fitted with a cervical esophagostomy.

Both gastrin and acid responses to antral stimulation by meat extracts (Oxo) were studied in 15 undialysed males with chronic renal failure (CRF). Eighteen sex and age-matched duodenal ulcers (DU) served as controls. Oxo increased acid and plasma gastrin in both groups. The rise in plasma gastrin was larger in CRF than in DU. The pattern of gastrin response in CRF suggests accumulation of gastrin in the plasma probably related to impaired renal inactivation of the hormone. Five CRF had large acid responses representing 40 to 90 percent of their maximal secretory capacity. Antral function should be measured in CRF before haemodialysis or renal transplantation.

Omeprazole, a powerful and long-lasting gastric anti-secretory benziimidazole derivative has been used to treat a particularly severe case of Zollinger-Ellison syndrome with familial type I multiple endocrine involvement. Before treatment with omeprazole, the patient's basal acid secretion, ranging from 50 to 100 mmol/h, had been poorly controlled by cimetidine (doses of up to 2,400 mg/d), ranitidine (doses of up to 1,200 mg/d) and even by ranitidine (1,200 mg/d) combined with pirenzepine (150 mg/d). Upon oral administration of four 20-mg capsules of omeprazole twice daily, rapid healing of the diffuse mucosal ulcerations of the upper GI tract as well as control of diarrhea were achieved. Clinical benefit accompagnied dramatic and sustained reductions in gastric acid secretion as demonstrated by repeated basal output measurements and 24-hour intragastric pH recording. The biodisponibility of omeprazole improved as gastric intraluminal acidity was reduced. The effects of omeprazole on pepsin output appeared to be mainly related to the reduction of gastric secretory volume. After more than one year of treatment, neither clinical nor biological side-effects were noted. However, repeated ultrastructural studies of fundic gastric mucosa revealed two types of alterations: a) a pattern of hyper-stimulated parietal cells with turgescent intra-cellular micro-canalicus invested by numerous microvilli; b) in about a fourth of the parietal cells, cytoplasmic modifications resembling auto-phagosomia and mitochondrial reduction in number and morphological transformation. Poorly understood to date, these alterations call for regular histological control of the gastric mucosa in patients with Zollinger-Ellison syndrome submitted to long-term administration of large doses of omeprazole.

Serum gastrin and gastric endocrine cell numerical densities were examined in 22 patients with long-standing Zollinger-Ellison syndrome who were receiving either ranitidine, omeprazole, or other antisecretory drugs (SMS 201-995 or pirenzepine with or without ranitidine) for long periods of time. Fifteen patients had iterative biopsies. Twenty-one subjects with normal endoscopy, serum gastrin, and acid secretion served as controls. Individual fundic argyrophil cell density was above the highest control value in 77% of the patients, whatever the treatment. Argyrophil cell densities tended to be higher in women than in men. During the survey, fundic carcinoids developed in one ranitidine- and in one omeprazole-treated patient. Fundic argyrophil cell densities were correlated with serum gastrin levels (r' = 0.730, p less than 0.001). Antral somatostatin cell density was not modified in any patients as compared with controls, nor was antral gastrin cell density except in omeprazole-treated patients. In these patients, gastrin cell density and gastrin to somatostatin cell ratio were significantly higher than in all other patients or controls. Such increases may indicate true gastrin cell hyperplasia in relation to drug-induced profound acid inhibition.

1 Ranitidine oral kinetics and plasma concentration-effect relationships upon meal-induced gastric secretion were investigated in normal subjects. Four oral doses of ranitidine (50, 100, 150 or 200 mg) and placebo were tested. 2 Oral ranitidine showed a terminal half-life of about 2 h 25 min. Maximal plasma level was about 240 ng/ml for a 100 mg dose, and occurred about 1 h after dose. From the range of 50 to 200 mg dose, no indication of non-linearity was observed in the drug kinetics. 3 Ranitidine administration resulted in a dose-related reduction in meal-stimulated acid secretion reaching, 46, 70, 82 and 92%, respectively. Mean ranitidine plasma concentrations producing 50 and 80% inhibition of acid secretion were 73 and 180 ng/ml, respectively, with great inter-individual variability. 150 and 200 mg ranitidine oral doses maintained IC50 for at least 4.5 and 5.5 h, respectively. Upon oral administration, ranitidine exerted no effect on gastric emptying of the meal but slightly decreased the gastrin response to the meal.