The influence of a histamine2-receptor antagonist on the healing of an experimentally induced gastric mucosal lesion.

The effect of an H2-receptor antagonist (ranitidine) on the healing of gastric mucosal lesions was studied. Mucosal lesions were induced by a standardized thermo-mechanical technique. The healing process was assessed by macro- and light microscopical examination. It was further evaluated by measurements of the tissue contents of hydroxyproline, a chemical compound reflecting collagen, and of DNA and RNA, reflecting cell frequency and protein synthesis respectively, in the gastric wall from both injured and wound-free areas. The healing process was more rapid in ranitidine-treated animals than in controls. After four weeks, however, the lesion in nine out of ten animals had healed in the ranitidine-treated group and seven of nine rats in the control group. At that time the amounts of hydroxyproline, DNA and RNA did not differ between the two groups. These findings may be taken as an indication that the tissue components of the healed lesions were similar in ranitidine-treated rats and in the saline controls, i.e. the different speeds of the healing process did not seem to influence the components of the scar tissue.     

Inhibition of gastric acid secretion in the dog by the histamine H2-receptor antagonists ranitidine and cimetidine

The H₂-receptor antagonists ranitidine and cimetidine inhibit gastric acid secretion elicited by a test meal in the dog. Ranitidine is approximately 10 times more potent than cimetidine in this respect.     

Cholinergic-like effects of the new histamine H2-receptor antagonist ranitidine

The new H₂-receptor blocker ranitidine, together with the effect on histamine H₂-receptors, possesses a series of cholinergic-like actions: it provokes atropine-sensitive contractions of several isolated smooth muscle preparations from different animal species and it potentiates the stimulant effect of acetylcholine. Moreover it contracts human lower esophageal sphincterin vivo, an effect which is completely prevented by small doses of atropine. Finally, ranitidine potentiates the stimulant effect of bethanechol and of carbachol on salivary glands of the rat while leaving unaffected the secretagogue effect of physalaemin which is known to be completely independent of the cholinergic system. In thein vivo experiments the doses of ranitidine capable of eliciting cholinergic-like effects were of the same order of magnitude as those necessary to cause the H₂-receptor blockade.     

In vitro actions of ranitidine,a new histamine H2-receptor antagonist

Ranitidine has been tested on isolated guinea-pig right atrium and rat uterine horn, tissues known to possess histamine H₂-receptors; and on isolated guinea-pig ileum a tissue containing histamine H₁-receptors. These experiments have shown ranitidine to be a potent competitive antagonist of histamine at H₂-receptor sites in vitro. This action is selective since high concentrations of ranitidine do not affect -adrenoceptor, histamine H₁-receptor and muscarinic receptor mediated responses.     

The value of a histamine H2-receptor antagonist in the management of patients with the Zollinger-Ellison syndrome.

Inhibition of acid secretion by an H2-receptor antagonist (metiamide) was assessed in three patients with the Zollinger-Ellison syndrome. Metiamide (200 or 300 mg) inhibited acid secretion transiently (2 1/2 hours) by 85 to 100 per cent in all patients. Although anticholinergic drugs alone inhibited acid secretion by only 0 to 35 per cent in these patients, the combination of metiamide and anticholinergic markedly prolonged the inhibitory effect of metiamide. Total gastrectomy was refused by one patient, and was impossible in another; both were treated with metiamide and anticholinergic for five and 10 months. A third patient was treated with metiamide and anticholinergic for three weeks in preparation for total gastrectomy. Ulcer pain and diarrhea disappeared, and each gained weight. H2-receptor antagonists may be useful in the treatment of some patients with the Zollinger-Ellison syndrome.     

Acid secretion and mobilization of gastric mucosal histamine on combined cholinergic and pentagastrin stimulation

Acid secretion and urinary excretion of histamine in response to vagus excitation, infusion of methacholine or pentagastrin and to various combinations of these stimuli, were concomitantly studied in rats with Pavlov pouches. Vagus excitation (2-deoxy-d-glucose) enhanced the secretory response to pentgastrin, the effect being most conspicuous with small doses of pentagastrin, probably corresponding to the physiological dose-range of gastrin. Vagus excitation marginally increased excretion of histamine but did not seemingly encreased excretion of histamine but did not seemingly enhance excretion of histamine in response to pentagastrin. Methacholine substantially enhanced the secretory response to all doses of pentagastrin studied, but did not further increase histamine excretion. The secretory effect of a maximal dose of pentagastrin or histamine was about the same when combined with methacholine. The site of interaction between cholinergic stimuli, pentagastrin and gastric mucosal histamine is discussed.     

Effect of a histamine H2-receptor antagonist on immunologically induced mediator release in vitro

The histamine H₂-receptor has been implicated in the autoregulation of endogenous histamine release from actively sensitized human basophils. Consequently, the activity of metiamide (SK & F 92058), a specific histamine H₂-receptor antagonist, was investigated for its effect on immunologically-induced histamine release in several in vitro models of immediate hypersensitivity. Metiamide enhanced the release of histamine from passively sensitized fragmented Rhesus monkey lung and skin when these tissues were challenged in a reversed type anaphylactic reaction with antihuman IgE. The enhancing effect of metiamide on the release of ‘slow reacting substance of anaphylaxis, from monkey lung was considerably less pronounced. In contrast, metiamide failed to significantly enhance the antigen-induced release of histamine from fragmented rat lung which had been passively sensitized with rat anti-ovalbumin serum. The data supports a species-specific enhancement of immunologic histamine release in vitro, perhaps by H₂-receptor blockade on cells responsible for such release.     

Rapid induction of enterochromaffinlike cell tumors by histamine2-receptor blockade.

The effect of acid inhibition on gastric endocrine cells was investigated in Praomys (Mastomys) natalensis. Long-term treatment (1 to 32 weeks) with an irreversible histamine 2-receptor blocker (loxtidine) caused a sustained increase in plasma gastrin levels, which was accompanied by a gradual increase in histamine and histidine decarboxylase activity of the gastric oxyntic mucosa. The density of endocrine cells in the oxyntic mucosa increased gradually, doubled by 8 weeks, and was three times that of controls after 24 weeks of treatment. Hyperplastic changes in the endocrine cell population were evident after 2 to 8 weeks in all animals, whereas dysplastic or neoplastic lesions were observed in half the animals after 16, 24, and 32 weeks of treatment. Gross tumors in the oxyntic mucosa were observed in 1/4 of the animals treated for 24 or 32 weeks. Proliferating cells were identified as enterochromaffinlike cells because they were argyrophilic and immunopositive for chromogranin A and histamine. The results demonstrate that histamine 2-receptor blockade initiated by loxtidine promotes a rapid development of enterochromaffinlike cell tumors in Mastomys and suggest a critical role for gastrin in the formation of these tumors. However, the rate and frequency by which carcinoid tumors appeared in Mastomys after acid inhibition was much greater than that reported in other species, indicating that several factors, including hormonal and genetic factors, are important in the development of gastric endocrine tumors.     

H2-receptor antagonist and gastric acid antisecretory properties of Wy-45,662

Investigations were carried out to delineate the biological activity of Wy-45,662, a new H₂-receptor antagonist. In the pylorus-ligated rat after intraduodenal administration, total acid output (TAO) over 4 hours was inhibited by Wy-45,662 with an ED₅₀ of 0.3 mg/kg as compared to ranitidine (ED₅₀=7 mg/kg) and cimetidine (ED₅₀=12 mg/kg); i.v. or i.m. administration increased Wy-45,662's potency 10-fold. In dogs with innervated gastric pouches Wy-45,662 inhibited food-stimulated TAO with ED₅₀'s of 0.35 mg/kg (p.o.), 0.045 mg/kg (i.v.) and 0.065 mg/kg (i.m.); cimetidine (ED₅₀=6mg/kg p.o.) and ranitidine (ED₅₀=1 mg/kg p.o.) were less potent. Wy-45,662 also inhibited pentagastrin- or histaminestimulated acid secretion in the conscious fistula rat. In vitro, Wy-45,662 antagonized the histaminestimulated a) positive chronotropism in guinea pig atria and b) [¹⁴C]aminopyrine uptake by rat gastric mucosal cells, confirming its H₂-receptor antagonist properties.     

The effect of some gastrointestinal peptides on pentagastrin-stimulated acid secretion and oxyntic mucosal histamine in rats

Inflammation Research -     

The fade of gastrin-stimulated gastric acid secretion in the rat is due to depletion of releasable mucosal histamine

The present study examines the applicability of the isolated, acid-secreting vascularly perfused rat stomach for long-term physiological and pharmacological studies. The model was used to study the fade of acid secretion during gastrin stimulation. The stomachs were stimulated by exogenous gastrin or histamine alone or in succession. Acid secretion and venous histamine concentrations were measured. Gastrin and histamine potently stimulated acid output, histamine-stimulated acid secretion was sustained for 300 min while gastrin-stimulated secretion peaked at 120 min and declined towards basal output at 300 min. Stomachs rendered tachyphylactic to gastrin could be re-stimulated by exogenous histamine. Venous histamine output during gastrin stimulation decreased in parallel to acid secretion. Thus, the acid-secreting, isolated vascularly perfused rat stomach can be used for physiological and pharmacological studies with histamine as stimulant for at least 300 min. The present results strongly indicate that the effect of gastrin on acid secretion is mediated by histamine, and that fade of acid secretion during stimulation with gastrin is due to depletion of releasable mucosal histamine.     

H2-receptor antagonist reduces food intake and weight gain in rats by non-gastric acid secretory mechanisms

The H₂-receptor antagonist cimetidine reduces appetite and weight in overweight healthy subjects and in overweight subjects with type II diabetes mellitus. The aim of this study was to characterize the mechanisms of this effect in rodents. Drugs were administered three times a day, 30 min before 1 h periods of free access to food. In one group of rats (n=9), cimetidine (8 mg) treatment resulted in significantly lower cumulative food intake than in a control group (n=9). The total intakes of food during the observation period of 22 days were 325.3 ± 29.1 g and 346.3 ± 16.7 g in the cimetidine and control groups, respectively. During the observation period, the weight gain in the cimetidine group was 63.3 ± 15.8 g, which was significantly lower than the weight gain of 74.8 ± 14.2 g in the control group, i.e. the cimetidine induced a 15.4% reduction in the weight gain during the observation period of 22 days. The weight gained per weight of food ingested was 0.20 ± 0.04 (g/g) and 0.22 ± 0.04 (g/g) in the cimetidine and control groups, respectively (NS). In other experiments, ranitidine (3 mg) and famotidine (0.4 mg), but not omeprazole (0.4 mg), taken three times a day for 8 days reduced the weight gain when compared with a control group (n=7 in each group). We therefore conclude that the effects of the H₂-receptor antagonists are not mediated by inhibitory mechanisms on the gastric acid secretion.     

Specific immunotherapy stimulates the binding of histamine H2 receptor antagonist by lymphocytes.

The binding of antagonists of histamine receptors H1 (promethazine) and H2 (ranitidine) by peripheral blood lymphocytes from pollinotics was determined before and after the course of immunotherapy. We found that lymphocytes from atopic subjects showed significant decrease in the binding of H2 receptor antagonist as compared to control subjects. Specific immunotherapy induced statistically significant increase in H2 receptor antagonist binding, which correlated with the improvement of clinical symptoms.     

Effect of histamine H2-receptor antagonist,cimetidine, on hypothermia induced by an α-adrenergic agonist,clonidine, in the rat

Conclusion The present results indicate that in hypothermia induced by clonidine both -adrenergic and histamine H₂-receptors at some synapses subserve thermoregulatory pathways within the hypothalamus in the rat.     

Heterogeneity of histamine H2-receptor mediated responses in the rabbit aorta

Distribution and properties of histamine H₂-receptor mediated responses in segments of rabbit aorta was studied with histamine and H₂-receptor stimulating drugs, dimaprit and impromidine. All agonists produced concentration-dependent tonus decreased in precontracted vascular strips, which were antagonised by selective H₂-receptor antagonists, cimetidine and oxmetidine. Activities of the agonists were segment-dependent, and increased caudally along the aorta. A nonspecific smooth muscle relaxant, papaverine had homogeneous activity along the vessel, suggesting receptor specific nature of the observed heterogeneity.