H. Mattsson

Enterochromaffin-Like Cell Carcinoids in the Rat Gastric Mucosa following Long-Term Administration of Ranitidine

Long-term administration of some long-acting inhibitors of gastric acid secretion has been associated with the development of gastric enterochromaffin-like (ECL)-cell carcinoids in the rat. It has been argued that short-acting, surmountable histamine H2-receptor blockers such as ranitidine do not cause carcinoids. In this study, female rats (n = 100) were treated for 2 years with the histamine H2-receptor blocker ranitidine, 2 g/kg/day in the diet. Specimens from the stomachs of all rats, including 50 controls, were stained for argyrophil cells. Plasma gastrin and ranitidine levels were measured in separate groups of rats at different times during the study. The mean plasma level of ranitidine was 37.5 mumol/l, measured at midnight when the maximal level after food intake was expected. The resulting acid inhibition was associated with an approximately 3-fold increase in plasma gastrin which persisted throughout the whole period of the study. The ranitidine treatment resulted in a pronounced hyperplasia of gastric ECL cells. In 19 rats carcinoids were found, 4 of which were micro-invasive. No carcinoids were found in the control animals. The results provide further support for the gastrin mechanism, i.e. that the development of ECL-cell carcinoids in the rat gastric mucosa is a consequence of prolonged hypergastrinaemia and is not a unique effect of any individual acid-inhibiting drug.

Gastric acid secretion after depletion of enterochromaffin-like cell histamine. A study with a-fluoromethylhistidine in rats

Background: Histamine is thought to play a central role in the regulation of gastric acid secretion. In the rat oxyntic mucosa most of the histamine is synthesized and stored in enterochromaffin-like (ECL) cells, and the rest resides in mast cells. The present study examines the role of ECL-cell histamine in the control of acid secretion in the intact, conscious rat. Methods: Rats were treated with α-fluoromethylhistidine (α-FMH) to inhibit histamine synthesis. α-FMH was given by continuous subcutaneous infusion (3 mg/kg/h) for up to 9 days. An additional oral dose of α-FMH (50 mg/kg) was given 2 h before each acid secretion test. Acid secretion was studied in pylorus-ligated rats and in chronic gastric fistula rats stimulated with histamine, gastrin-17, or insulin after 2–6 days of α-FMH infusion. Results: Treatment with α-FMH lowered oxyntic mucosal histamine synthesis by 80%. From previous observations this is thought to reflect depletion of histamine from the ECL cells. The remaining 20% resides in mu...

Time-dependent changes in enterochromaffinlike cell kinetics in stomach of hypergastrinemic rats

BACKGROUND Hypergastrinemia has been claimed to cause first hyperplasia and then dysplasia/neoplasia of enterochromaffin-like (ECL) cells in rat stomach. The growth is thought to reflect an accelerated self replication rate of mature ECL cells. The cytokinetics and the histidine decarboxylase (HDC) activity of the ECL cells were investigated during sustained hypergastrinemia. METHODS Hypergastrinemia was evoked by omeprazole (400 mumol.kg-1 x day-1 orally) for up to 1 year. Immunocytochemistry for histamine was used to determine the ECL cell density and combined with [H3]-thymidine autoradiography to establish the labeling index (LI), i.e., the proportion of the ECL cells that has incorporated [H3]thymidine. RESULTS The ECL cell density increased progressively for 10-20 weeks in response to the hypergastrinemia and remained at a plateau for the remainder of the study. The hyperplasia was diffuse with additional micronodules at 52 weeks. The ECL cell Ll was maximally elevated after 1-2 weeks and declined to control values after 10-20 weeks of treatment. In contrast, the HDC activity remained elevated for the duration of the study. CONCLUSIONS The ECL cell hyperplasia reflects the transiently elevated ECL cell Ll during the early phase but is not associated with an accelerated rate of mitosis during the 10-52 weeks period. Even though with time gastrin seems to loose its ability to sustain a high ECL cell Ll it retains its ability to maintain a high HDC activity.

Hypergastrinemia after Blockade of Acid Secretion in the Rat: Trophic Effects

The availability of potent and long-acting blockers of acid secretion, such as omeprazole, has paved the way for experimental studies on the long-term effects of permanently raised levels of circulating gastrin without the complication of surgical intervention. We have examined rats given high doses of the antisecretagogues omeprazole and ranitidine during 10 or 20 weeks for general trophic effects on the gastrointestinal tract and pancreas and for the effects on endocrine cells such as the somatostatin cells and the enterochromaffin-like (ECL) cells, which are present in the oxyntic mucosa. The ECL cells, which in the rat produce and store histamine (in addition to an as yet unidentified peptide hormone), are known to be activated by gastrin. In rats given high doses of omeprazole, the serum gastrin levels rose about 10-fold. General trophic effects were restricted to the stomach; the weight was increased, as was the thickness of the oxyntic mucosa. Omeprazole treatment resulted in a 3- to 5-fold increase in the ECL cell density. A close correlation was found between plasma gastrin levels and the ECL cell density as well as the levels of histidine decarboxylase and histamine in the oxyntic mucosa. The somatostatin cell density was unaffected by the hypergastrinemia. During a 10-week recovery period after discontinuation of the omeprazole treatment, the ECL cell density diminished, but was still significantly higher than in age-matched control rats. Plasma gastrin levels and gastric histidine decarboxylase activity rapidly returned to control values. The results suggest that the observed general trophic effects on the oxyntic mucosa and on the ECL cells are related to the plasma gastrin levels and not to an action of the antisecretagogues per se.

Lansoprazole and omeprazole have similar effects on plasma gastrin levels, enterochromaffin-like cells, gastrin cells and somatostatin cells in the rat stomach

This study compares the effects of lansoprazole and omeprazole on the activation and proliferation of enterochromaffin-like (ECL) cells in the rat stomach. Lansoprazole was given orally once daily for 10 weeks in two doses, 135 and 200 mumol/kg. Omeprazole was given by the same regimen in a dose of 400 mumol/kg, which is equipotent in terms of acid inhibition to the higher lansoprazole dose. Lansoprazole (both doses) as well as omeprazole raised the plasma gastrin levels about 11-fold 2 h after dosing and 8-to 10-fold 24 h after dosing, reflecting complete (2 h) and 70-80% (24 h) reductions of gastric acid secretion. Administration of either drug for 10 weeks increased the weight of the stomach and the oxyntic mucosa. The oxyntic mucosal histidine decarboxylase activity, histamine concentration and ECL cell density were increased to the same extent in the rats given either of the two lansoprazole doses or omeprazole. The numbers of antral gastrin cells were doubled and the numbers of antral somatostatin cells half that in the controls. These results show that long-standing lansoprazole-evoked hypergastrinemia affects the ECL cell similarly to omeprazole, ranitidine and other acid secretion inhibitors.

ECL Cells: Biology and Pathobiology

During recent years, the so-called ECL cells of the acid-producing part of the stomach have attracted much attention, mainly due to the fact that mice and rats were found to develop gastric carcinoids (ECL cell tumors) following life-long treatment with blockers of acid secretion. These observations touched off concern about the safety of the long-term clinical use of such drugs. The ECL cells are the predominant endocrine cell population in the oxyntic mucosa. They produce histamine, chromogranin A/pancreastatin and an as yet unidentified peptide hormone. They respond to gastrin by the release of secretory products; more long-term responses include adaptation to the gastrin stimulus, hypertrophy and hyperplasia. Intravenous infusion of maximally effective doses of gastrin promptly reduced the number of cytoplasmic vesicles in the ECL cells and their content of histamine and pancreastatin. Despite the ongoing infusion of gastrin, the number of vesicles and the content of histamine and pancreastatin were back to normal 4-6 h after the start of the infusion. The histidine decarboxylase (HDC) activity and HDC mRNA level increased progressively until plateaus were reached after 6-8 h of gastrin infusion. The size of the ECL cells started to increase about 4 days after the start of a subcutaneous gastrin infusion (resulting in half-maximally effective serum gastrin concentrations). The ECL cell size reached maximum after about 2 weeks and then remained at this level.The number of cytoplasmic vesicles was increased; this effect seemed to reach a maximum after 1-2 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Partial Resection of Acid-Secreting Mucosa on Plasma Gastrin and Enterochromaffin-Like Cells in the Rat Stomach

Female rats were subjected to various degrees (50, 75, 90 and 100%) of fundectomy, i.e. resection of the acid-producing part of the stomach, to compare the effects of different degrees of reduction of the amount of acid reaching the antrum. Plasma gastrin was monitored for 10 weeks after the operation. Histidine decarboxylase (HDC) activity, histamine concentration and density of enterochromaffin-like (ECL) cells in the remaining oxyntic mucosa were determined in the rats subjected to 50 or 75% fundectomy. There was a close correlation between the amount of acid-producing mucosa removed and the plasma gastrin levels, the highest gastrin level being observed in the rats subjected to 100% fundectomy. HDC activity, histamine concentration and ECL cell density seemed to reflect plasma gastrin concentration. These findings indicate that hypergastrinemia induced by surgical removal of acid-producing mucosa in the rat has the same effects on oxyntical mucosal HDC activity, histamine concentration and ECL cell density as hypergastrinemia induced by continuous gastrin infusion or by long-term treatment with effective antisecretagogues.

Effect of 7 Years’ Daily Oral Administration of Omeprazole to Beagle Dogs

Ten beagle dogs were given omeprazole orally at a dose of 0.17 mg/kg (0.5 mumol/kg) daily for 7 years. Six dogs served as controls. Regularly evaluated criteria were clinical signs, body weight, food consumption, rectal temperature, electrocardiography, hematology, blood chemistry, urinalysis, ophthalmoscopy, gastroscopic examination including gastric mucosal biopsy sampling for histological evaluation, pharmacokinetics of omeprazole, and plasma gastrin levels. After approximately 5 years, a quantitative gastric acid secretion test was performed. No treatment-related adverse clinical signs or effects were observed in the dogs, and all animals survived to term. The annual gastroscopy with histological examinations of gastric mucosa did not show any treatment-related changes. At all investigations and in all dogs, the parietal cells were morphologically normal, and there were no changes of pattern or any increase in the number of argyrophil enterochromaffin-like cells compared to the control animals. In the plasma samples collected 24 h after dosing, there were no significant differences in either basal or meal-stimulated gastrin levels between the controls and the omeprazole-treated animals. Peak plasma concentration of omeprazole occurred within 2 h of dosing. The area under the concentration curve (AUC) was not affected by dosing over 7 years and was in good agreement with the AUC in humans given a dose of 20 mg omeprazole daily. Acid secretion tests after 5 years of treatment showed that the mean inhibition of acid secretion by omeprazole 4-7 h after dosing was as expected--about 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Biopharmaceutics: Changes in Gastric Mucosal Permeability Induced by Haemorrhagic Shock in the Anaesthetized Rat: Modulation by Acid

Gastric mucosal damage induced by haemorrhagic shock in the anaesthetized rat has been evaluated by studying changes in capillary‐to‐lumen clearance of fluorescein isothiocyanate (FITC)‐labelled dextran.