Effect of long-term cimetidine on gastric acid secretion, serum gastrin, and gastric emptying.

Gastric acid secretion, gastric emptying, fasting serum gastrin and the serum gastrin response to a meal were measured in duodenal ulcer patients before, and at least five days after completing prolonged treatment with cimetidine (1 or 2 g/day for four or eight weeks followed by 600 mg twice daily for six months). Fasting serum gastrin and the gastrin response were also measured during treatment. Compared with pretreatment values, fasting serum gastrin concentrations were raised both during and five to 31 days after stopping treatment (P less than or equal to 0.02). The integrated gastrin response and the rate of gastric emptying of the solid component of the meal were increased during treatment (P less than 0.001 and P less than 0.002 respectively) but returned to pretreatment levels after stopping therapy. No significant changes were observed in the basal or maximal acid outputs or the rate of emptying of the liquid component of the meal. The results imply that the hypergastrinaemia associated with long-term cimetidine therapy does not result in increased gastric acid secretion.     

Effect of naloxone on met-enkephalin-induced gastric acid secretion and serum gastrin in man.

It has previously been demonstrated that met-enkephalin, and endogenous opiate, stimulates gastric acid secretion in man, while naloxone inhibits meal-stimulated acid secretion. In seven healthy subjects the opiate receptor antagonist naloxone was infused in a dose of 10 microgram/kg/h during stimulation of gastric acid secretion with pentagastrin 100 ng/kg/h and met-enkephalin 0.1 microgram/kg/h. Naloxone had no effect on pentagastrin-induced acid secretion, whereas met-enkephalin-induced acid secretion was completely abolished in both studies without affecting serum gastrin levels, suggesting that the acid inhibitory effect of naloxone is specifically directed towards met-enkephalin-induced acid secretion. The results support the assumption that met-enkephalin participates in the physiological stimulation of gastric acid secretion.     

Effect of food consistency on gastric emptying in man.

The gastric emptying of two radiolabelled pancake meals of identical composition, but different consistency, was compared with the rates at which they could be broken down in vitro by mechanical agitation in a solution of either acid-pepsin or saline. Neither of the pancake meals were broken up within 150 minutes by mechanical agitation in a normal saline medium, but both were disrupted in the presence of acid-pepsin, the light consistency pancake being broken up more rapidly than the heavy consistency pancake (0.5 +/- 0.1 v 0.2 +/- 0.1% radioactivity appearing in the bathing medium per minute, p less than 0.01). Under normal conditions, the pattern and rate of gastric emptying of both meals was similar. Stimulating acid secretion with pentagastrin (6 micrograms/kg bodyweight sc) delayed the onset of emptying of both pancakes and tended to increase the slope of emptying. Under these conditions, the denser pancake was emptied more slowly than the lighter pancake because of an increase in the lag period. Thus the data did not confirm the hypothesis that the rate of emptying of disruptible solid food from the stomach under normal conditions of acid secretion is influenced by the ease with which it can be broken down by mechanical agitation in an acid-pepsin medium. The trend for an accelerated rate of emptying after administration of pentagastrin, however, may well be explained by the increased rate of disruption of the food in the presence of acid, but the longer lag periods are more compatible with inhibition of gastric emptying caused by free acid in the duodenum.     

Effect of small bowel bypass on serum gastrin levels and gastric acid secretion in man.

In animals massive resection of the small intestine is followed by increased gastric acid secretion and an increase in serum gastrin levels. Whether hypersecretion occurs in man after intestinal resections or intestinal bypass is unclear, but an increase in fasting gastrin levels has been reported after intestinal resection. In this series a significant increase in basal gastric acid secretion and fasting serum gastrin levels has been demonstrated after intestinal bypass. However, none of the patients developed peptic ulcer or clinical symptoms of hypersecretion after the bypass operation. Whether the increase in basal secretion and the serum gastrin concentration are interrelated or of any clinical importance is uncertain.     

Effect of cimetidine on lower esophageal sphincter pressure, intragastric pH and serum levels of immunoreactive gastrin in man.

The influence of cimetidine on the lower esophageal sphincter, the intragastric pH and the serum levels of immunoreactive gastrin was investigated in eight volunteers and compared with a control group. After oral application of 400 mg cimetidine, the intragastric pH rose from 1.7 +/- 0.13 to 6.2 +/- 0.4 and the lower esophageal sphincter pressure increased slightly but significantly from 15.6 +/- 1.1 to 22.7 +/- 1.8 mm Hg after 20 min and to 25.8 +/- 2.0 after 30 min, respectively. At the same time the serum immunoreactive gastrin levels did not change. A direct effect of cimetinidine on the lower esophageal sphincter or an indirect effect via gastric alkalinization is discussed.     

Effect of cimetidine on pentagastrin-stimulated gastric secretion in healthy man.

Two series of experiments were carried out in three healthy volunteers. In one series increasing doses of cimetidine were tested on a constant background stimulation with 0.15 microgram-kg-1h-1 of pentagastrin. In the other series of experiments increasing doses of pentagastrin were given either alone or in combination with a fixed dose of cimetidine (1.2 mg-kg-1h-1). Pentagastrin and cimetidine were given as continuous intravenous infusions, the various doses tested on separate days. The inhibition of acid output in response to pentagastrin stimulation increased almost linearly with the log dose of cimetidine. Fifty per cent inhibition of the response to 0.15 microgram-kg-1h-1 of pentagastrin was achieved by about 0.6 mg-kg-1h-1 of cimetidine. 2.4 mg-kg-1h-1 of cimetidine gave on average 90% inhibition. The inhibition caused by cimetidine decreased to a minimum of 57% and could not be overcome by increasing the doses of pentagastrin. The results suggest a mixture of competitive and noncompetitive interaction. The effect of cimetidine on pepsin secretion was less regular. Generally, pepsin output was less inhibited than acid output.     

Effect of gastrin on gastric mucosal cell proliferation in man.

The effect of short-term infusion of a large dose of pentagastrin and a small dose of synthetic human gastrin I (SHG) on the rate of cell proliferation in gastric mucosa was studied in normal human subjects. Moreover, the kinetic parameters were compared with the serum gastrin concentrations in fasting patients. Endoscopic biopsies were labelled in vitro with 3H-thymidine and autoradiographs were prepared. The percentage of DNA-synthesising cells in the progenitor cell region was estimated. In healthy volunteers infusion of a large dose of pentagastrin (10 mug/kg per hour) was followed by a marked increase in the labelling index in fundic mucosa. The antral mucosa was not responsive to this effect. In the same subjects, infusion of a low dose of SHG (8 ng/kg per min) did not affect the rate of cell proliferation, either in fundic or in antral mucosa. In 46 patients with different gastric diseases no correlation between the serum gastrin concentrations and the labelling indices was found. The results suggest that human fundic mucosa is responsive to a trophic action of pentagastrin. If it exists, however, a physiological action of gastrin as a trophic hormone for human gastric mucosa must be considerably more complex than previously believed.     

Effect of prolonged cimetidine therapy on gastric acid secretion in man.

In a double blind trial, 23 patients with endoscopically confirmed duodenal ulceration received cimetidine (300 mg four times daily in six patients, or 400 mg four times daily in 10 patients) or placebo (seven patients) for six weeks. Before entry into the trial, pentagastrin (6 microgram.kg-1.h-1)--stimulated gastric acid secretion after a single oral dose of 300 or 400 mg cimetidine was lowered by 82.1% and 81.0%, respectively, while no significant inhibition was recorded in the patients receiving placebo (8.8%). The same test repeated after six weeks of continuous treatment showed that the effect of the drug was maintained, the percentage inhibition of acid secretion being of the same order as in the first test.     

Effect of meal temperature on gastric emptying of liquids in man.

Serial studies were carried out on six healthy volunteers (19-24 years) to investigate the effect of meal temperature [either 4 degrees C (cold), 37 degrees C (control) or 50 degrees C (warm)] on the rate of gastric emptying of a radiolabelled isosmotic drink of orange juice. The mean maximum intragastric temperature occurred 60 seconds after the onset of ingestion of the warm drink and reached 43.0 degrees C (0.4) mean (SD) while the mean minimum intragastric temperature occurred 45 seconds after the onset of ingestion of the cold drink and reached 21.2 degrees C (1.9). Intragastric temperature then returned to body temperature within 20-30 minutes of ingestion of the warm and cold drinks. Warm and cold drinks appeared to empty from the stomach more slowly than the control drink. The initial rate of gastric emptying of the cold drink was significantly slower than the control drink (p less than 0.05) and the difference in emptying rates between cold and control drinks were significantly correlated with the differences in intragastric temperatures (p less than 0.01). The difference in the initial emptying rates between warm and control drinks were not statistically significant.     

Effect of cimetidine on gastric mucosal cell proliferation in man

Seven duodenal ulcer patients were treated for 3 months with cimetidine. Before and after treatment endoscopic biopsy specimens were taken for autoradiographic estimation of cell proliferation in the gastric mucosa in the antral and fundic part of the stomach and from the duodenum. In all three areas the estimated labeling index was increased during medication with cimetidine. The increase in epithelial cell renewal may participate in the ulcer healing effect of cimetidine.     

Effect of calcitonin on serum gastrin concentration and component pattern in man.

Synthetic salmon calcitonin (sCT, doses of 0.7 Medical Research Council U per kg) was injected into nine normal subjects and three patients with hypergastrinemia (pemicious anemia). sCT depressed basal as well as food-stimulated serum gastrin concentrations without concomitant changes in total and ultrafiltrable concentrations of calcium in serum. Gel filtration of sera revealed that sCT reduced mainly the small components, III (gastrin-17 or "little" gastrin) and IV (gastrin-13 or "mini"-gastrin).     

Effect of nifedipine on gastric emptying and gastrointestinal motility in man

Nifedipine, a calcium-blocking agent, inhibits smooth muscle contractions in various organs including gastric muscle in vitro. Despite this, nifedipine has been found to have no effect on gastric emptying in man. We have investigated the effect of nifedipine on gastric emptying of liquids and solids and on gastrointestinal motility in six healthy subjects. For this, isotopic techniques and manometric methods were used. We confirm that nifedipine 30 mg per os does not modify gastric emptying of liquids or solids. By contrast, antra motility was significantly inhibited (P<0.05) and duodenal motility increased. These results could be interpreted as (1) gastroduodenal motility changes are not severe enough to alter emptying or (2) isotopic techniques are not sensitive enough to detect subtle changes in gastric emptying.     

Effect of press stimulation applied to back skin on gastric emptying and serum gastrin response to solid food

We studied the effect of press stimulation applied to the back skin on gastric emptying and serum gastrin response to solid food in healthy subjects. Although gastric emptying and serum gastrin response were significantly suppressed by press stimulation of T6-9 dermatomes corresponding to the spinal levels which sympathetic outflow to the stomach arise, they were not affected by press stimulation of T10-L1 dermatomes. Plasma levels of ACTH, epinephrine and norepinephrine, which usually increase by stresses acting on the brain, did not change by press stimulation of T6-10 dermatomes. These results suggest that press stimulation applied to the back skin of T6-9 dermatomes suppress gastric emptying and gastrin response to solid food mainly through the spinal cord.     

Effects of oral calcium gluconate on gastric acid secretion and serum gastrin concentration in man.

A single oral dose of 4-46 mmol calcium gluconate at pH 5-6 was administered intragastrically to 15 male volunteers without gastrointestinal disease. There was a significant rise in acid output from 30-90 minutes after the calcium was given compared with the basal hourly collection. The serum gastrin level 30 minutes after calcium administration was significantly raised, but no correlation could be demonstrated between the acid and gastrin responses. Serum calcium levels were unchanged throughout. An equimolar dose of magnesium sulphate had no such effects. This study suggests that the intragastric administration of calcium results in independent release of gastric acid and gastrin from the gastric mucosa.     

Effect of age on gastric emptying of liquid-solid meals in man

A dual radioisotopic method was employed to study the rate of gastric emptying of meals in ten males with an average age of 31 years and 10 elderly males with an average age of 76.4 years. All study subjects were fed a standardized 900-g meal labeled with a liquid (111indium-DTPA) and solid (99mtechnetium-tagged liver) phase isotopic marker. There were no significant differences in solid food emptying rates between the young and aged men. A delay in liquid emptying, however, was observed in the aged men. The clinical significance of this observation is unknown.     

Effect of the histamine H2-receptor antagonist, cimetidine, on gastric secretion and serum gastrin during insulin infusion in Man.

Cimetidine infusion (100 mg h-1) reduced the acid secretory response to insulin infusion (0.03 units Kg-1h-1) when compared to paired control tests in 6 healthy volunteers. There was no significant difference between cimetidine and control tests in terms of pepsin output or serum gastrin concentrations. Cimetidine also reduced the acid secretory response when administered after 90 minutes of insulin had established a secretory response in extended tests in 3 additional volunteers. Cimetidine may have therapeutic potential in the peptic ulcer diathesis.     

Effect of human gastrin infusion on gastric potential difference in man

Human gastrin I heptadecapeptide, infused intravenously to healthy volunteers in a dose of 0.5 g/kg/hr, caused a prompt, significant reduction in gastric potential difference (decrease of mucosal negativity), with the peak change at 6 min. This decline in potential difference occurred at a time when the serum gastrin level was between 24 and 83 pg/ml; at the same time, scanning electron microscopic examination of fractographs of parietal cells demonstrated marked increase in canalicular membrane area. This study shows that the decrease in potential difference after gastrin occurs with serum gastrin levels which are in the physiologic range.This work was supported in part by the Medical Research Service of the Veterans Administration.     

Effect of nifedipine on gastric acid secretion and gastrin release in man

The role of nifedipine in inducing the blockage of calcium slow channels in the smooth muscle cell of the esophagus is well known. The aim of our study was to evaluate the action nifedipine exerts upon acid secretion and gastrin release stimulated by intragastric titration with a peptone meal (pH 5.5) in 7 healthy adult males. Percentage gastrin variations were constantly lower after oral administration of 20 mg nifedipine than with placebo. However, IGO values were shown to be not significantly different (9.3 +/- 1.8 vs 8.4 +/- 2.1 ng. min/ml). No variations in acid output were observed throughout the entire examination period (120 min). In our experience, therefore, nifedipine - under experimental conditions - proved unable to interfere with gastric secretion, probably due to the absence of specific receptors on the parietal and antral cell.