Gastric Acid Secretion In Humans Research Articles

Loxiglumide inhibits cholecystokinin stimulated somatostatin secretion and simultaneously enhances gastric acid secretion in humans

In vitro studies have demonstrated that cholecystokinin releases somatostatin from the gastric mucosa. To date, there is no information about the in vivo significance of this finding in man. Therefore, we have studied the effect of infusion of cholecystokinin resulting in plasma concentrations within the range found after meal-stimulation, on somatostatin release and on gastric acid secretion. In addition we have studied these functions during infusion of the type A cholecystokinin receptor antagonist loxiglumide. In eight healthy subjects, basal gastric acid secretion was distinctly stimulated by cholecystokinin. The effect of cholecystokinin on gastric acid secretion was markedly enhanced by loxiglumide. Cholecystokinin also significantly stimulated somatostatin output into the gastric lumen, but not into the systemic circulation. Somatostatin output into the gastric lumen during infusion of cholecystokinin was abolished by loxiglumide. The data indicate that on the one hand circulating cholecystokinin, like gastrin, stimulates gastric acid secretion probably by binding to less specific type B receptors on parietal cells that are not blocked by loxiglumide, but on the other hand that cholecystokinin, in contrast to gastrin, also inhibits gastric acid secretion probably by binding to specific type A receptors present on somatostatin producing D-cells in the gastric mucosa, that are blocked by loxiglumide.

Cholecystokinin in the control of gastric acid secretion in humans.

This study was designed to determine the involvement of cholecystokinin (CCK) in the control of gastric acid secretion in men using loxiglumide, a specific CCK-receptor antagonist. Two groups of healthy subjects (A and B) were used: group A for studies of postprandial gastric secretion and group B for studies with exogenous gastric secretagogues. The cephalic phase activated by modified sham feeding (MSF) in group A subjects increased gastric acid secretion to about 36% of pentagastrin maximum, but treatment with loxiglumide in a standard dose (20 mumol/kg i.v. loading dose plus infusion of 20 mumol/kg/h afterwards) failed to affect this secretion. A 5% peptone meal instilled i.g. (to mimic the gastrointestinal phase) greatly enhanced gastric acid secretion and plasma gastrin concentration, but the addition of loxiglumide in a standard dose resulted in a further increase in both gastric acid and plasma gastrin responses to the peptone meal. Plasma somatostatin response to the peptone meal was significantly reduced by loxiglumide. Infusion of cerulein in gradually increasing doses (15-120 pmol/kg/h) and gastrin-releasing peptide (GRP) (25-200 pmol/kg/h) resulted in dose-dependent stimulation of gastric acid secretion, reaching about 35 and 25% of the maximum attained with pentagastrin. When loxiglumide was added the acid responses to cerulein and GRP were further increased by two- to threefold, attaining a peak similar to the pentagastrin maximum. Administration of loxiglumide resulted in a significant increase in plasma gastrin response to GRP, whereas plasma somatostatin was not significantly altered by loxiglumide.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of endoscopic biopsies and microelectrodes to study human gastric acid secretion in vitro

We have investigated the possibility of measuring acid secretion from human gastric mucosa in vitro as a potential pharmacological preparation. We used open-ended 10 μm-tip, lix-based glass microelectrodes to measure the pH of the mucus layer of gastric biopsies superfused with a HEPES buffered solution in an organ bath. With no drugs added the pH of the mucus layer of biopsies from the body of the stomach stayed constant but the pH of antral biopsies fell slightly by a median of 0.12 pH units over 80 min (P < 0.05). Stimulation of the biopsies with 1–100 μM histamine produced a dose-dependent decrease in pH which was significantly greater in biopsies from the gastric body than from the antrum. 500 pM pentagastrin produced a median fall in pH of 1.20 (P < 0.01) which was prevented by the prior addition of 100 μM omeprazole or 10 μM ranitidine. Omeprazole or ranitidine alone produced slight rises in the median pH of 0.47 (P < 0.05) and 0.26 (P < 0.05) units respectively. Those biopsies which were infected with Helicobacter pylori had a slightly elevated initial pH of about 0.2 of a pH unit (P < 0.05). This novel system provides a means to study human gastric acid secretion in vitro and may be valuable in the testing of new drugs on the stomach.

Diurnal secretory patterns and tolerance during individually titrated infusions of ranitidine

Background: Gastric acid secretion in humans shows chronobiological patterns that modify the efficacy of antisecretory agents. The ability of individually titrated ranitidine infusions to overcome circadian patterns of gastric acidity and tolerance during prolonged dosing was assessed. Methods: Eleven healthy subjects were randomized to receive ranitidine infusions of up to 600 mg/24 hours by a pH feedback-regulated pump before and after 9 days of oral dosing with ranitidine, 300 mg four times daily, beginning either in the evening or in the morning in a cross-over, third party-blinded and placebo-controlled study design. Results: Mean 24hour intravenous ranitidine doses given to attain the target pH of 4 were greater after 9 days of treatment with oral ranitidine than before in the morning and evening studies (P < 0.01). The median 24-hour pH decreased from 5.1 before to 3.6 after oral dosing in the morning study (P < 0.001) and from 4.4 to 2.8 in the evening study (P < 0.001). Before oral dosing of ranitidine, the time of pH > 4 in the evening and morning fasting periods was 71% and 84%, respectively (P < 0.05). After 9 days oral ranitidine, the respective results were 20% and 53% (P < 0.05). Conclusions: The reduced responsiveness to ranitidine in the evening and the tolerance to ranitidine with repeated dosing were not overcome by individually titrated, high intravenous doses of ranitidine.

Alcohol and gastric acid secretion in humans.

The secretory response of gastric acid to pure ethanol and alcoholic beverages may be different because the action of the non-ethanolic contents of the beverage may overwhelm that of ethanol. Pure ethanol in low concentrations (< 5% vol/vol) is a mild stimulant of acid secretion whereas at higher concentrations it has either no effect or a mildly inhibitory one. Pure ethanol given by any route does not cause release of gastrin in humans. Alcoholic beverages with low ethanol content (beer and wine) are strong stimulants of gastric acid secretion and gastrin release, the effect of beer being equal to the maximal acid output. Beverages with a higher ethanol content (whisky, gin, cognac) do not stimulate gastric acid secretion or release of gastrin. The powerful stimulants of gastric acid secretion present in beer, which are yet to be identified, are thermostable and anionic polar substances. The effect of chronic alcohol abuse on gastric acid secretion is not as predictable. Chronic alcoholic patients may have normal, enhanced, or diminished acid secretory capacity; hypochlorhydria being associated histologically with atrophic gastritis. There are no studies on the acute effect of alcohol intake on gastric acid secretion in chronic alcoholic patients. The acid stimulatory component of beer and wine needs to be characterised and its possible role in the causation of alcohol induced gastrointestinal diseases needs to be investigated.

Single-dose oral omeprazole for reduction of gastric residual acidity in adults for outpatient surgery

Omeprazole is a substituted benzimidazole that causes dose-dependent intracellular inhibition of gastric acid secretion in humans. This double-blind study examined the effect of omeprazole in decreasing gastric acidity and gastric residual volume in outpatient adults. Unpremedicated outpatients, ASA I-III, 18 years or older (n = 17), were randomly assigned to receive omeprazole 80 mg, or placebo by mouth the night before scheduled elective outpatient surgery. The patients were fasted for 8 h prior to surgery. After the patient was anesthetized, an orogastric tube was inserted with proper placement verified by auscultation for gastric sounds. Gastric residual contents were withdrawn into a Luken's trap, and pH was then determined and gastric volume indexed to weight (ml.kg-1). Data were analyzed by a t-test, with P less than 0.05 considered statistically significant. Patient characteristics of both groups were similar. There was a statistically significant difference between the two groups for pH (P = 0.02), but not between the two groups for gastric volume indexed to weight (P = 0.07).

Cholecystokinin in the control of gastric acid secretion in humans

Cholecystokinin in the control of gastric acid secretion in humans

Cholecystokinin (CCK) inhibits gastric acid secretion in humans via a CCK-A receptor mediated mechanism

Cholecystokinin (CCK) inhibits gastric acid secretion in humans via a CCK-A receptor mediated mechanism

Role of prostaglandins in oleic acid and secretin mediated inhibition of human gastric acid secretion

Role of prostaglandins in oleic acid and secretin mediated inhibition of human gastric acid secretion

Continuous gastric pH monitoring in children: The effect of gastric emptying on the measurement of gastric acid secretion

Continuous gastric pH monitoring offers the opportunity to evaluate gastric acid secretion in humans without the need for collection of gastric aspirates. However, gastric emptying may be an important variable for the accurate measurement of gastric acid secretion using continuous gastric pH monitoring. We conducted an in vitro study (phase I) to evaluate the effect of gastric emptying on gastric pH. The in vitro study used a laboratory model in which continuous pH monitoring of a standard formula (Nutramigen, 100 mL) in a reservoir was performed while varying both the reservoir emptying rate (10% to 80%) over 1 hour and the amount of added acid (2 to 15 mEq/h: in vivo equivalent of 6 to 45 mEq/m2 BSA/h). An in vivo study (phase II) was then performed in 28 infants less than 6 months of age who had gastroesophageal reflux (GER) documented by 18- to 24-hour esophageal pH monitoring. At the end of esophageal pH monitoring, the pH electrode was advanced into the stomach for measurement of gastric pH continuously for 2 hours after a feeding of Nutramigen formula (300 mL/m2 BSA). Each patient also had a radionuclide gastric emptying study performed with the same volume of Nutramigen formula. In the in vitro model, the reservoir pH (% time pH less than 4) was proportional to the reservoir emptying rate only when acid was added at less than 15 mEq/h (less than 45 mEq/m2 BSA/h). Reservoir pH was independent of reservoir emptying rate when acid was added at 15 mEq/h (45 mEq/m2 BSA/h).(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction of omeprazole with DNA in rat tissues.

There has been concern recently over the possible genotoxicity of omeprazole, a potent inhibitor of gastric acid secretion in humans. In order to investigate its possible DNA binding activity in vivo, 14C-labelled omeprazole was administered to male PVG rats, 8-10 weeks old, orally by gavage at a dose of 30 mg/kg. At various times after treatment, animals were killed and DNA isolated from the fundic and antral regions of the glandular stomach, and from the duodenum, ileum and colon. Scintillation counting of the DNA samples revealed a reproducible association of 14C that was not extractable with organic solvents and could not be removed from the DNA by column cartridge chromatography. DNA samples were digested enzymically to deoxyribonucleosides and analysed by reversed-phase high performance liquid chromatography (HPLC). With DNA from each tissue, most of the radioactivity eluted in a peak that was chromatographically distinct from normal nucleosides and from omeprazole itself. Chromatography following partial digestion of DNA gave rise to the same radioactivity elution profiles, whilst chromatography on hydroxyapatite resulted in retention of most of the radioactivity on the column using conditions under which DNA was eluted. These findings suggest either the formation in rat tissues of chemically-labile covalent omeprazole-DNA adducts or, more likely, a strong non-covalent interaction. The apparent DNA binding occurs rapidly in vivo and is short-lived, the maximum levels of radioactive incorporation (equivalent of up to 36 pmol omeprazole/mg DNA) occurring at 0.5 h in fundus, 0.5-1 h in antrum, 1 h in duodenum, 2 h in ileum and at 4-8 h in colon.

Effect of age on gastric acid secretion and serum gastrin concentrations in healthy men and women

The effects of age on basal, meal-stimulated, and human gastrin-17-stimulated gastric acid secretion rates and serum pepsinogen concentrations were evaluated in 41 healthy men and women. Older subjects (ages 44–71 years; mean, 57 years) had higher mean basal, meal-stimulated, and gastrin-17-stimulated acid secretory rates and basal serum pepsinogen I and II concentrations than younger subjects (ages 23–42 years; mean, 33 years). Age-related differences in acid secretion were especially prominent in men, and age-related differences in serum pepsinogen I and II concentrations were more prominent in women. Higher gastric acid secretion rates in older subjects could not be explained by body size (height, weight, body surface area, or fat-free body mass) or by the higher incidence of infection with Helicobacter pylori. Using a multivariate linear regression model, age had an independent positive effect on acid secretion, and H. pylori infection had an independent negative effect. It was concluded that aging is associated with an increase in gastric acid secretion in humans, especially in men, while infection with H. pylori is associated with lower acid secretion rates.

Stress ulceration in the intensive care unit: use of H2‐receptor antagonists

H2-receptor antagonist drug therapy is the mainstay of peptic ulcer treatment in the USA. About 75% of patients in intensive care units receive parenteral H2-antagonists. The rationale for their use is that parenteral H2-antagonists offer about a four-fold protective effect compared with placebo against significant upper gastrointestinal haemorrhage. Parenteral administration of H2-receptor antagonists appears to be preferred to oral antacid or sucralfate regimens because of ease of administration and, perhaps, lower treatment costs. Recommended dosage schedules for intravenously administered H2-receptor antagonists are at fixed intervals, 6- to 8-h intervals for cimetidine and ranitidine and 12-h intervals for famotidine. These dosage schedules assume a fixed dose-response relationship (i.e. a given dose of H2-antagonist results in equivalent acid suppression throughout the circadian, or 24-h, period). However, human basal gastric acid secretion exhibits circadian variation, with peak rates occurring during the evening hours. Recent evidence from 24-h continuous intragastric pH studies in fasting patients with healed duodenal ulcer suggests that larger doses of intravenous H2-antagonists are required in the evening than in the morning to achieve equivalent acid suppression. These findings are consistent with a changing H2-antagonist dose/acid-inhibiting response over the circadian period. Continuous infusion has the advantage of providing consistent and sustained suppression of gastric acid secretion in patients at risk for stress ulceration. Results of a double-blind, randomized, crossover study indicated that equally effective suppression of acidity and time-to-onset of pharmacological effect can be achieved with and without priming bolus doses of ranitidine, and presumably other H2-receptor antagonists as well.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of Human Gastric Acid Secretion by Peptide YY and Secretin

In 6 healthy volunteers we investigated the effect of secretin and peptide YY (PYY) on gastric acid secretion stimulated by pentagastrin (100 ng/kg/h). Secretin (0.05 CU/kg/h) and PYY (10.0 pmol/kg/h) were given intravenously either alone or in combination. Given alone secretin and PYY inhibited gastric acid output by 25 and 21%, respectively. The combined infusion of secretin and PYY inhibited acid output by 38% indicating an additive effect. The infusion of one hormone did not influence release of the other. It is suggested that the interaction of PYY and secretin on pentagastrin-stimulated gastric acid secretion in normal man is of the additive type.

Pentagastrin-stimulated gastric acid secretion: does desensitization exist?

The existence of tachyphylaxis to pentagastrin-stimulated gastric acid secretion in humans is controversial. To study this, we determined gastric acid output in 19 duodenal ulcer patients following the administration of two successive intramuscular injections of pentagastrin (6 micrograms/kg body weight). In 18 of 19 patients, the maximal acid output decreased by 33.73 +/- 3.25% (mean +/- SE) following the second pentagastrin administration when compared with the maximal acid output following the first injection. This study indicates the existence of tolerance to pentagastrin-induced gastric acid secretion in humans, which may be due to a receptor-mediated phenomenon of "down-regulation."

A model study of the regulation of gastric acid secretion.

A computer simulation model is presented of the gastric phase regulation of gastric acid secretion in humans. The model is based on experimental data from the literature and includes terms representing gastric pH and gastric volume-dependent gastrin secretion, gastrin-dependent acid secretion, food storage in the stomach, and gastric emptying. We have explored the predictive value of the model in assessing the relative importance of gastric pH-dependent and gastric volume-dependent acid secretion mechanisms under various conditions. Similarly we have studied the role of gastric acid deregulation in achlorhydria, the Zollinger-Ellison syndrome, and duodenal ulcer, and the influence of the antacid drugs cimetidine and ranitidine under duodenal ulcer conditions. Model analysis of normal gastric acid regulation suggests that gastric volume-controlled acid secretion is of major importance during eating and predicts that pH-dependent gastrin secretion is of major importance in preventing excessively low pH levels between meals and during the night.

Human gastric acid secretion following repeated doses of AG‐1749

The effect of increasing doses (15 mg, 30 mg and 60 mg) of the substituted benzimidazole, AG-1749, on gastric acid secretion and fasting serum gastrin concentration has been studied after repeated administration to healthy volunteers. AG-1749 produced a dose-dependent and profound decrease in basal and stimulated gastric acid secretion in all volunteers, with almost total suppression at the highest dose. The extent of inhibition increased between Day 2 and Day 8 with the 15 and 30 mg doses of AG-1749. The inhibitory effect of AG-1749 appears to be fully reversible as control levels of acid output were reached 7 days after drug withdrawal. Seven days' dosing with 60 mg AG-1749 induced a more than threefold increment of fasting serum gastrin concentration, but this increase was still within the normal range. Seven days after cessation of dosing, fasting serum gastrin concentration returned to a pre-dose level.

Effect of omeprazole treatment on feed intake and blood gastrin and pepsinogen levels in the calf

Previous work has shown blood gastrin levels to be elevated and appetite depressed in ostertagia-infected calves. A possible relationship between raised blood gastrin values and feed intake was investigated in worm-free animals using the human gastric acid secretion inhibitor, omeprazole. An initial dose-titration experiment established that administration of the drug by intravenous injection at 1.95 mg kg-1 (four times the recommended human dose rate) resulted in a marked (5.2-fold) increase in blood gastrin levels in the calf. Daily administration of omeprazole by intravenous injection at 2 mg kg-1 for four days in a subsequent experiment resulted in a significant depression in feed intake (up to 40.4 per cent) which was accompanied by a significant rise in blood gastrin levels (peak 940 pg ml-1; 6.5-fold increase over control values). It is suggested that such a rise in hormone levels would reduce reticuloruminal and abomasal motility, slow down the passage of ingesta and, in turn, lead to a reduction in appetite.

Calcitonin gene-related peptides I and II and calcitonin: Distinct effects on gastric acid secretion in humans

The human calcitonin gene-related peptides I and II (CGRP I and CGRP II) are two neuropeptides that have been recognized throughout the gastrointestinal system including the stomach. The present study was undertaken to compare in healthy volunteers the effects of intravenous infusions of CGRP I and CGRP II (79 pmol/kg · h) on pentagastrinstimulated acid secretion to those of calcitonin (88 pmol/kg · h). Calcitonin gene-related peptide I did not inhibit basal or pentagastrin-stimulated acid secretion. However, CGRP II and calcitonin inhibited pentagastrin-stimulated acid responses by 20% and 28%, respectively (p < 0.05 and p < 0.01), whereas basal acid output was only reduced with calcitonin (p < 0.05). These effects were recognized with low doses of pentagastrin, and absent with high doses suggesting competitive inhibition. Furthermore, step-doses of CGRP I and CGRP II (79–320 pmol/kg · h) were given intravenously on continuous pentagastrin stimulation and compared with calcitonin (88–352 pmol/kg h). Calcitonin gene-related peptide II and calcitonin induced a dose-dependent decrease of acid output, whereas CGRP I was ineffective. The inhibitory effects of CGRP II and calcitonin are not due to increased gastric alkaline secretion or to somatostatin release, as neither peptide stimulated gastric bicarbonate secretion or induced an increase in circulating somatostatin. In conclusion, CGRP II, unlike CGRP I, inhibits gastric acid secretion in humans. Inhibitory effects of CGRP II and of calcitonin were comparable. The results imply that CGRP I and II, at the level of the stomach, have distinct biological properties in humans.

Effect of low-dose exogenous secretin on pentagastrin- and meal-stimulated gastric acid secretion in humans

Intravenous infusion of secretin in a dose of 0.05 CU/kg/hr inhibited pentagastrin-stimulated (100 ng/kg/hr) acid secretion by 42% (P less than 0.05) abd meal-stimulated (10% peptone, pH 5.5) acid secretion by 33% (P less than 0.05) in 10 healthy subjects. Median serum gastrin concentration during peptone stimulation was reduced by 24% (P less than 0.05) during secretin infusion. Median plasma secretin concentrations were 6.0 and 5.2 pmol/liter, respectively. Since these secretin concentrations are of the same magnitude as those seen after duodenal acidification, it is concluded that secretin may participate in the physiological inhibition of gastric acid secretion.