L. Olbe

Relationship between reduction of gastric acid secretion and plasma gastrin concentration during omeprazole treatment.

We have studied the relationship between reduction of gastric acid secretion and fasting plasma gastrin concentrations during once daily omeprazole treatment. Healthy subjects were given omeprazole for 5 days in daily doses of 5, 10, 20, 40, or 80 mg. Acid secretion and fasting gastrin concentration were measured 6 h (maximal omeprazole effect) and 24 h (minimal omeprazole effect) after the fifth omeprazole dose. Omeprazole in doses lower than 20 mg daily did not suppress pentagastrin-stimulated acid secretion in all subjects 6 h after dosing on the 5th day. Doses of 20-80 mg omeprazole, however, significantly reduced acid secretion 24 h after the fifth dose, the range being 36-76%. A relationship between degree of acid inhibition and fasting gastrin concentration was observed. However, acid secretion needed to be reduced by more than 80% before gastrin levels were clearly affected. This degree of acid inhibition was only achieved 6 h after administration of omeprazole in doses of 20 mg and higher. The inhibitory effect of omeprazole on acid secretion decreased 24 h after dosing. Thus, fasting gastrin concentrations were moderately increased in the beginning and normalized at the end of each 24-h period during treatment with daily doses of 20-80 mg omeprazole.

Fat Inhibition of Gastric Acid Secretion in Man and Plasma Concentrations of Neurotensin-Like Immunoreactivity

The effects of intraduodenal administration of oleic acid (5, 10, 20, and 40 ml) on gastric acid secretion stimulated by a submaximal intravenous pentagastrin infusion and on plasma concentrations on neurotensin-like plasma immunoreactivity (NTLI) were studied in 18 healthy subjects. Each volume of oleic acid or saline (controls) was tested in six subjects except the volume of 20 ml, which was given to ten subjects. Gastric acid secretion was studied for a 2-h period at 15-min intervals after intraduodenal infusion. Five milliliters oleic acid evoked a significant inhibition (29%) of gastric acid secretion. Maximal inhibition by oleic acid appeared after 20 ml (43%), which was significantly greater than after 10 ml. In seven duodenal ulcer (DU) patients 20 ml oleic acid evoked an inhibition of 20%, which was significantly lower than in the healthy subjects. Proximal gastric vagotomy (PGV) abolished the fat inhibition in DU patients. Basal and peak NTLI concentrations after 20 ml oleic acid were significantly lower in DU patients than in health subjects. In DU patients there was no significant difference in the integrated response of NTLI before and after PGV. The 2-h integrated NTLI response was dependent on the administered volume of oleic acid in healthy subjects. There was a correlation between acid inhibition and the integrated response ot NTLI in healthy subjects. This suggests that immunoreactive neurotensin may be involved in the oleic-acid-induced inhibition of gastric acid secretion. Neurotensin, or a neurotensin metabolite, apparently exerts its inhibitory effect at a synaptic level, which explains the finding that oleic acid did not inhibit gastric acid secretion after PGV. Neurotensin may have a physiological role as a hormone with enterogastrone functions.

Continuous computerized determination of gastric bicarbonate secretion in man.

A method for continuous determination of gastric bicarbonate secretion in man has been developed. A computer-based system calculated the total bicarbonate secretion every 30 sec throughout the experiment on the basis of the continuously recorded pH and Pco2 measurements. A high gastric perfusion rate facilitated the identification of duodenogastric reflux, which was observed as rather short-lived spikes on the curves. The contribution of alkaline saliva to the measured gastric bicarbonate secretion was minimized by continuous salivary suction and was corrected for after determining amylase in the gastric aspirate. Validation of the measuring system, by introducing bicarbonate in the range of 50-400 mumol into the stomach, demonstrated a correlation value of 0.91 (p less than 0.001) between added and recovered bicarbonate. Basal gastric bicarbonate output in seven healthy subjects was 379 +/- 105 mumol/h (mean +/- SEM). Intragastric instillation of 16,16-dimethyl prostaglandin E2 in five subjects resulted in a fourfold increase in gastric bicarbonate output.

The Effects of Secretagogues on Isolated Human Gastric Glands

The function of isolated human gastric glands has been studied in vitro by measuring the 14C-aminopyrine accumulation (RAP) in basal, unstimulated, conditions and after stimulation with different secretagogues. A microscale technique was used which enabled determinations of RAP in tissue obtained as gastroscopic biopsies. In addition, oxyntic-gland-containing mucosa was obtained at gastric resections for gastric or prepyloric ulcer disease. Histamine and cAMP derivative both induced maximal stimulation; RAP was approximately three times larger than in basal states. Carbachol induced a smaller but still significant stimulation. Pentagastrin did not increase RAP above the unstimulated level. Combinations of histamine and carbachol or pentagastrin did not induce a larger response than carbachol alone. The peak acid response to pentagastrin or betazole in vivo did not correlate with the maximum RAP in vitro.

Effect of Omeprazole on Gastric Acid Secretion and Plasma Gastrin in Man

Single doses of omeprazole inhibit pentagastrin-stimulated gastric acid secretion and almost complete inhibition can be achieved for 4-6 hours with a single dose of 80 mg. Acid secretion then slowly returns and reaches normal levels after 3-4 days. Omeprazole also dose-dependently inhibits basal acid secretion as well as acid secretion stimulated with histamine, peptone and modified sham feeding, with similar efficiency. During repeated once-daily dosing with an enteric-coated granule capsule formulation, inhibition of acid secretion increased initially, and stabilized within about 4 days. Dose-response studies in patients with duodenal ulcers and healthy subjects have shown that 20-40 mg/day results in a peak reduction (80-100%) of pentagastrin-stimulated acid secretion 6 hours after dose. Studies of 24-hour intragastric acidity in duodenal ulcer patients have shown that 4 weeks of treatment with omeprazole, 20 mg once daily, resulted in a reduction of median intragastric acidity by 97%, which was superior to the 57% median reduction achieved with ranitidine, 150 mg b.d., for 4 weeks in the same patients. During omeprazole treatment, fasting plasma gastrin increased in relation to the degree of inhibition of acid secretion. After discontinuation of treatment, plasma gastrin normalized. Treatment with omeprazole, 20 mg, increased 24-hour plasma gastrin to the same extent as after highly selective vagotomy. Long-term treatment with omeprazole, 20-40 mg, for up to 2 years has not been associated with any progressive rise in fasting plasma gastrin.

Inhibitory action of omeprazole on acid formation in gastric glands and on H+,K+-ATPase isolated from human gastric mucosa.

The inhibitory effect of omeprazole on acid formation has been studied in vitro in gastric glands and partly purified H+,K+-ATPase, prepared from mucosa obtained either from healthy subjects by gastroscopic biopsy or from gastric ulcer patients during antrectomy. The effect of omeprazole was compared with the inhibitory pattern of the H2-antagonist cimetidine. Acid production in the glands was determined by measuring the accumulation of 14C-aminopyrine. In glands isolated from patients, omeprazole inhibited acid production maximally stimulated by histamine, db-cAMP, and potassium in a dose-dependent manner, with an IC50 value of about 50 nM irrespective of the agonist used. In contrast, cimetidine inhibited only histamine-induced aminopyrine accumulation, with an IC50 of about 30 micron. The inhibitory effect of omeprazole in db-cAMP-stimulated glands from healthy volunteers was of the same magnitude as seen in glands from gastric ulcer patients. Basal aminopyrine accumulation in glands from both patients and healthy volunteers was almost totally inhibited by omeprazole, whereas cimetidine was without effect. Omeprazole also concentration-dependently inhibited the H+,K+-ATPase activity in isolated gastric membrane vesicles. The estimated IC50 value was 4 micron.

24-Hour Intragastric Acidity and Plasma Gastrin during Long-Term Treatment with Omeprazole or Ranitidine in Patients with Reflux Esophagitis

The reduction in intragastric acidity and the subsequent increase in plasma gastrin were compared during long-term treatment with either omeprazole or ranitidine in 19 patients with erosive reflux esophagitis. The patients received 40 mg omeprazole in the morning or 300 mg ranitidine twice daily. After healing, half the dose was given as maintenance treatment for 1 year. Intragastric acidity and plasma gastrin were measured 24 h before entry and monthly with the high dose and after 1, 6, and 12 months with the low dose. Omeprazole reduced intragastric acidity more effectively than ranitidine (p less than 0.001). This difference in efficacy was more pronounced during the daytime. Plasma gastrin increased more after omeprazole than after ranitidine (p less than 0.01), and both drugs showed a normal postprandial response and approached fasting levels before the next dose. During long-term treatment with 20 mg omeprazole in the morning no progressive alterations were observed in 24-h intragastric acidity or plasma gastrin.

Expression of protease-activated-receptor 2 (PAR-2) in human esophageal mucosa

Objective. The role of duodenal reflux in gastroesophageal reflux disease (GERD) containing bile salts and pancreatic enzymes (with special attention to trypsin) is still under discussion. Proteinase-activated receptors (PARs) are a novel family and PAR-2 is a unique member of this family because it is activated by trypsin. The aim of the present study was to examine the presence and the position of the PAR-2 receptor in human esophageal mucosa in different subgroups of GERD. Material and methods. Distal biopsies taken from healthy controls, patients with erosive reflux disease (ERD), patients with specialized intestinal metaplasia (SIM) and adenocarcinoma were analyzed for the PAR-2 receptor with reverse-transcription polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry. Results. Gene transcripts for the PAR-2 receptor were found in all groups, with increased levels in SIM patients compared to controls. However, this visual pattern was not seen for the protein expression of the PAR-2 receptor showing no apparent quantitative differences between the groups. Immunohistochemistry revealed distinct staining for the PAR-2 receptor in the luminal part of the esophageal epithelium. Conclusions. The localization of the PAR-2 receptor indicates that the receptor can be cleaved and activated by trypsin in duodenogastric esophageal refluxate. The data thus suggest that the trypsin-PAR-2 pathway may be involved in the pathogenesis of GERD.

Gastric output of IgA in man : relation to migrating motility complexes and sham feeding

BACKGROUND/AIMS The immunologic reactivity of the gastric mucosa is poorly understood. The origin and dynamics of immunoglobulin A (IgA) occurring in the gastric lumen were investigated in healthy, Helicobacter pylori-negative volunteers. METHODS Gastroduodenal manometric motility recordings were combined with gastric luminal perfusion, enabling calculation of gastric acid output and analysis of the total IgA output. RESULTS Acid output and total IgA correlated with the migrating motility complexes (MMC). The gastric IgA release showed maximal values in association with gastric motility phase III (maximal motor activity) and lowest values during phases I and II (none or irregular motor activity). The IgA output correlated with neither swallowed saliva (as indicated by amylase in the gastric perfusate) nor duodenogastric reflux (as indicated by gastric occurrence of bilirubin and/or duodenally infused PEG4000). Stimulation of gastric acid secretion by sham feeding during phase II-like motor activity (n = 6) induced a rapid and transient doubling of IgA output. There was no significant correlation between gastric acid secretion and gastric IgA release. CONCLUSION Substantial amounts of IgA are released into the human stomach, most likely originating from the gastric mucosa. The up-regulation of IgA release in association with the activity front of the MMC and anticipatory to food intake suggests a neuroendocrine control of gastric mucosal immune responses.

Comparison of Once-Daily Intravenous and Oral Omeprazole on Pentagastrin-Stimulated Acid Secretion in Duodenal Ulcer Patients

The effect of 5 days of once-daily dosing with 20 mg p.o. and 40 mg i.v. omeprazole on pentagastrin-stimulated acid secretion was studied in 8 patients with duodenal ulcer. In addition they also received a 10-mg i.v. dose on day 6 during the oral treatment period. The antisecretory effect was measured 6-7 h after dose at a time point when maximal inhibition during the dosing interval is anticipated. The median percent inhibition of peak acid output (PAO) markedly increased from 43% on day 1 to 100% on day 5 during treatment with 20 mg p.o. The first 40-mg i.v. dose produced a median inhibition of 98% of PAO already on day 1. After 5 days of dosing, the inhibition had increased to 100%. On the other hand, a 10-mg i.v. dose could essentially maintain the degree of PAO reduction reached after 5 days of oral treatment. Plasma omeprazole concentrations increased during repeated dosing both with 20 mg p.o. and 40 mg i.v.