The aetiology of gastric ulceration induced by electrical vagal stimulation in rats

Histamine and serotonin levels in gastric secretion and the effects of pharmacological antagonists were studied in rats in which stomach ulceration was induced by electrical vagal stimulation. Electrical vagal stimulation (2 and 5 V) produced a graded increase in haemorrhagic glandular mucosal ulcers. NaHCO3 perfusion completely neutralised the increased acid output but failed to prevent ulceration. Atropine inhibited gastric mast cell degranulation as well as histamine and serotonin release. Diphenhydramine, atropine and sub-diaphragmatic vagotomy antagonised the increase in intragastric pressure. Diphenhydramine, cimetidine, atropine or vagotomy but not methysergide reduced ulcer severity. It is concluded that gastric acid and serotonin do not play an important role in glandular ulceration induced by electrical vagal stimulation. The lesions probably result from increased intragastric pressure and release of gastric histamine which stimulates H1 and H2 receptors in the stomach. The similarities between the aetiologies of glandular ulcers due to electrical vagal stimulation and to stress are also discussed.     

The effects of metiamide on gastric secretion and stress ulceration in rats.

The effects of metiamide, a histamine H2 blocker, on gastric secretion and ulcer formation in stressed pylorus-occluded rats were investigated. Metiamide, like atropine, significantly reduced the volume of gastric secretion and total acid output in unrestrained pylorus-occluded rats. Both drugs produced greater decreases in the volumes of gastric secretion in stressed rats than in their corresponding unrestrained groups. Stress itself reduced both parameters. Metiamide, like atropine, significantly reduced the incidence of gastric stress ulcers. When given together these two drugs did not provide greater protection. The results obtained with metiamide indicate that histamine plays a role in basal gastric secretion and in the pathogenesis of stress ulcers. As no correlation between gastric acid secretion and ulcer formation was demonstrated in this study, it is suggested that H2 receptors may also be involved in gastric motility. However, the possibility that metiamide could exert its ulcer-protecting effects through other mechanisms cannot yet be excluded.     

The influence of cimetidine,a histamine H2-receptor antagonist,on the gastric effects of reserpine in rats

The effects of the graded doses of cimetidine on both resting and reserpine-evoked gastric acid secretion were examined in relation to their influence on reserpine-induced ulceration, mast cell degranulation and mucosal microcirculatory changes in rat stomachs. Cimetidine 10 mg/kg or above reduced resting or reserpine-provoked gastric acid secretion as well as rumenal and glandular ulceration. However, non-acid-inhibiting doses, 5 mg/kg or below, continued to prevent glandular ulceration. Reserpine-evoked gastric glandular mucosal mast cell degranulation was unaffected by both acid-inhibiting and non-acid-inhibiting doses of cimetidine which dose-dependently blocked the superficial glandular mucosal microcirculatory volume changes. These results suggest that cimetidine prevents reserpine-induced glandular ulceration largely by blocking the ulcerogenic effect of histamine H₂-receptor-mediated mucosal microcirculatory congestion, in contrast to antagonising rumenal lesions through acid inhibition; they also support the idea that reserpine may release histamine mainly from the glandular mucosal mast cells. The possibility of another antiulcer mechanism, due to cytoprotection, is discussed.     

The lack of effects of somatostatin on gastric responses induced by electrical vagal stimulation

The effects of somatostatin on ulcer formation, gastric acid secretion and histamine release were assessed during vagus nerve stimulation in rats. Direct electrical vagal stimulation significantly increased histamine release and acid output in gastric secretion but decreased mast cell counts in gastric glandular mucosa. Hemorrhagic ulceration on the gastric glandular mucosa was also observed. Somatostatin pretreatment (10 micrograms/kg) did not inhibit gastric ulcer formation, gastric acid secretion or histamine release induced by vagal stimulation. Cimetidine (an H2 blocker) pretreatment, however, significantly decreased gastric acid secretion as well as ulcer formation. The present study indicates the direct vagal stimulation increases gastric acid secretion and ulcer formation. These effects are partially histamine dependent. Somatostatin did not inhibit histamine release induced by vagal stimulation and reflects the inability of the drug to prevent ulcer formation and gastric output under these conditions in rats. However, the inhibition of basal gastric acid secretion produced by somatostatin might be useful clinically in humans.     

Paracetamol potentiates stress-induced gastric ulceration in rats

The effect of paracetamol on gastric ulcers produced by restraint at 4 degrees C for 2 h (stress) was studied in rats. Paracetamol treatment s.c. or p.o., with a dose as high as 250 mg kg-1, did not produce any haemorrhagic lesions in the glandular mucosa. Oral administration with 250 mg kg-1, however, significantly reduced the mast cell count in the gastric glandular mucosa and potentiated haemorrhagic ulceration but not mast cell degranulation caused by stress. The potentiating action was maximum when paracetamol was given between 15 and 30 min before stress. Ranitidine, astemizole, dimethylsulphoxide, sucralfate and verapamil did not protect against the adverse action of paracetamol on stress-evoked lesions. This study suggests that paracetamol worsens stress-induced stomach ulceration by an action which appears not to be due to histamine release, free radical production or intracellular calcium disturbance in the gastric mucosa.     

Effects of propranolol and alprenolol on intra-atrial conduction in the dog

The relationship to gastric secretion of 2 types of gastric ulcer produced in pylorus-occluded rats was evaluated. Exposure to stress for 2 hr produced a high incidence of lesions in the glandular part of the stomach. Both the volume and total acid output of gastric secretion were significantly decreased. Stress ulceration was prevented only by atropine, but not by antacids or adrenoreptor blocking agents. Increase in gastric motility during stress appears to cause these ulcers. The second type of gastric ulcer, produced during a 5 hr period following pyloric occlusion, was located only in the rumenal part of the stomach. Both atropine and antacids prevented its development, indicating causation mainly by accumulation of gastric juice.It is concluded that rats with experimentally induced rumenal ulcers may be a more logical model for assessing the activity of anti-ulcer agents in preventing peptic ulceration associated with accumulation of gastric acid.     

Nifedipine versus cimetidine in prevention of stress-induced gastric ulcers in rats

The effects of nifedipine and cimetidine on cold/restraint stress-induced gastric ulcers and glandular wall mast cell count were studied in rats. Two hours of restraint at 4 degrees C resulted in 90% ulceration rate in the glandular stomach with a decrease in glandular wall mast cell count in the mucosa, submucosa and muscle layer. Nifedipine in three doses (1, 5 and 10 mg/kg) administered i.p. 30 min before stress significantly and dose dependently prevented gastric ulceration and mast cell degranulation. Cimetidine, in doses of 50, 100 and 150 mg/kg, again administered 30 min before stress prevented only gastric ulceration dose dependently without a significant change in mast cell count. The results indicate that both nifedipine and cimetidine are equally effective to reduce gastric mucosal ulceration in response to stress. However, the unique effect of nifedipine to inhibit mast cell degranulation which was now clearly demonstrated may favour the potential value of this drug in the management of peptic ulcer disease in humans.     

A correlative study of the antiulcer effects of zinc sulphate in stressed rats

The effects on zinc sulphate pretreatment of rats on stress-induced gastric ulcers and on changes in mast cell counts were studied and correlated with changes in gastric mucosal microcirculation. The effects on zinc sulphate on blood pressure responses and on growth were also examined. Stress (2 h restraint at 4 degrees C) produced marked glandular mucosal ulceration, lowered the stomach wall mast cell counts and increased the microcirculatory blood volume in the superficial glandular mucosa. Zinc sulphate (22, 44 or 88 mg/kg; injected i.p. 48 h before stress) reversed all these changes in a dose-related manner. Blood pressure responses to i.v. acetylcholine, adrenaline or histamine were unaffected and growth of the rats as observed for 7 days after injection was not impaired. On the basis of these findings the mechanism of the antiulcer action of zinc sulphate is the following: inhibition of the stress-induced release of vasoactive agents from gastric mast cells and thus prevention of the subsequent microciculatory changes known to produce mucosal ulceration. Interference with vascular responses through direct blockade or toxicity is unlikely.     

Inhibition of in vitro stimulated gastric acid secretion by a histamine H2-receptor antagonist, metiamide

The effect of a specific histamine H₂-receptor antagonist, metiamide, on gastric acid secretion induced by histamine or pentagastrin was studied in the isolated frog gastric mucosa and the isolated rat stomach. Histamine or pentagastrin approximately doubled acid secretion by the frog gastric mucosa; metiamide markedly inhibited acid secretion induced by these two stimulants. Consistent and significant stimulation of acid secretion by histamine and pentagastrin could be obtained in the isolated rat stomach provided that stomach preparations with initial low basal secretion were selected and that suitable concentrations of stimulants were used. Acid secretion induced by histamine or pentagastrin in these rat stomach preparations was strongly antagonised by metiamide. These results suggest that the basic effect of the H₂-receptor antagonist is exerted directly on the acid secretory mechanisms in the gastric mucosa, although these in vitro findings do not rule out an additional in vivo effect of metiamide on gastric mucosal blood flow.     

Synergistic effect of irsogladine maleate and histamine H2-receptor antagonists on experimental gastric ulcers in rats

Effects of irsogladine maleate (IM), in combination with histamine H2-receptor antagonists or a muscarinic receptor antagonist, on the formation of stress ulcer were investigated in rats. The ED50 of IM and that of cimetidine for suppressing stress ulceration were remarkably reduced when these drugs were used in combination. ED50s in this case were less than the theoretical values calculated on the basis of additive action, thereby suggesting the synergistic effect of IM and cimetidine. The synergistic effect of IM and ranitidine or famotidine in suppressing stress ulceration was also observed, while IM and pirenzepine did not always produce a synergistic effect. In addition, for acetic acid-induced gastric ulcers, combined administration of IM and cimetidine also markedly potentiated ulcer healing. The marked synergistic potentiation of IM and histamine H2-receptor antagonists may be due to compensatory coordination of both drugs on the gastric secretion and mucosal microcirculation. These results suggest that the combination of IM and histamine H2-receptor antagonists may be beneficial in clinical gastric ulcer therapy.     

Central histaminergic stimulation of hyperlipemic response in rats under stress

In rats subjected to a mild stress of immobilization histamine, the H1-receptor agonist 2-pyridylethylamine (PEA), and the H2-receptor agonists 4-methyl histamine (4-MeHA) and impromidine administered intracerebroventricularly (i.c.v.) 1 h prior to stress, intensified the stress-induced increase in serum free fatty acid (FFA) levels. Impromidine was far more potent than histamine and its agonists in increasing hyperlipemia in stressed rats. The hyperlipemic response to histamine was abolished by i.c.v. pretreatment of rats with mepyramine, a H1-receptor antagonist, but was unchanged in rats pretreated with cimetidine or metiamide, H2-receptor antagonists. The increase in serum FFA levels induced in stressed rats by PEA was abolished by mepyramine but the hyperlipemic responses to 4-MeHA and impromidine were not antagonized by cimetidine. These results suggest that central H1-receptor mediate the histamine-stimulated hyperlipemic response in stressed rats.     

Effects of IT-066, a new histamine H2-receptor antagonist, on gastric acid secretion and experimental gastric ulcers in rats and dogs

We examined the effects of a new histamine H2-receptor antagonist, 3-amino-4-(4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2- butenylamino)-3- cyclobutene-1,2-dione hydrochloride (IT-066), on gastric acid secretion and the healing process of experimental ulcers in rats and dogs. Famotidine, a well-established H2-receptor antagonist, was used as the reference drug. Male Donryu rats (240-260 g) and Beagle dogs of both sexes (8-10 kg), having Heidenhain pouches, were used. IT-066 dose-dependently inhibited the basal gastric acid secretion of rats, and this inhibition significantly persisted for 12 hr. In addition, the agent significantly inhibited histamine-stimulated acid secretion in both normal rats and rats with acetic acid ulcers. IT-066, given p.o. twice daily for 2 and 3 weeks after ulceration, significantly accelerated both spontaneous and delayed healing (with indomethacin) of acetic acid-induced gastric ulcers in rats. The effects of IT-066 on acid secretion and ulcer healing were almost the same or slightly more potent than those observed with famotidine. IT-066, when given i.v. or p.o., dose-dependently inhibited the gastric acid secretion stimulated by histamine, pentagastrin, or carbachol in dogs. The antisecretory effects of the agent on histamine-stimulated acid secretion significantly persisted for more than 6 hr. These results indicate that IT-066 appears to be a promising antisecretory and anti-ulcer agent.     

Effects of cimetidine and atropine sulfate on gastric secretion and healing of gastric and duodenal ulcers in rats.

Cimetidine, a new histamine H2-receptor antagonist (50 or 100 mg/kg) and atropine sulfate (15 mg/kg) given intraduodenally, markedly inhibited gastric secretion in pylorus-ligated rats. Cimetidine (100 or 200 mg/kg/day) given for 10 or 12 consecutive days orally in two divided doses, significantly promoted the healing rate of both gastric and duodenal ulcers induced in rats. Atropine (30 mg/kg/day) also significantly accelerated the healing of duodenal ulcers but failed to affect gastric ulcers.     

Effect of metiamide, a histamine H2-receptor antagonist on reserpine-induced gastric ulcers and acid secretion

The effect of metiamide on reserpine-induced gastric ulcers and on gastric secretion during 6 h after ip administration was investigated in conscious intact rats and in rats with chronic gastric fistula. Reserpine, 3 mg/kg ip increased substantially the concentration of gastric acid in the first 4 h. Metiamide given every 3 h in a low dose (0.01 mumol/kg) intensified reserpine-induced gastric ulcers and also significantly increased the reserpine-induced acid concentration and output. In larger doses, (50-100 mumol/kg) metiamide considerably diminished gastric ulcer development and decreased gastric acid concentration. Given every 2 h metiamide in doses of 50-100 mumol/kg almost completely abolished gastric ulcer formation and markedly reduced the secretion of gastric acid in reserpinized rats. Anti-ulcer effect of metiamide was stronger than its antisecretory action, suggesting also the antiulcer action of metiamide other than inhibition of acid secretion. The results suggest that in conscious rats histamine H2-receptors are involved in reserpine-induced gastric ulcer development and gastric acid secretion. The antiulcer effect of metiamide may in part depend on its antisecretory action.     

Inhibition of stress-induced gastric ulcers by sulphasalazine and its constituents (sulphapyridine and 5-aminosalicylic acid) in rats

The effects of sulphasalazine and of its major constituents, sulphapyridine and 5-aminosalicylic acid (5-ASA), on gastric ulceration as well as on changes in mast cell counts and mucus levels in the glandular mucosa were examined in restrained rats exposed to 4 degrees C (stress) for 2 h. Sulphasalazine (50, 100, 200 mg/kg), sulphapyridine (31.25, 62.5, 125 mg/kg) or 5-ASA (18.75, 37.5, 75 mg/kg) was injected subcutaneously 0.5 h before stress induction. Cold-restraint stress produced gastric glandular mucosal ulcers which were significantly reduced by all three doses of sulphasalazine and the higher doses of sulphapyridine and 5-ASA. Sulphasalazine prevented mast cell degranulation and increased the amount of mucus adhering to the mucosa. In contrast, the higher doses of sulphapyridine significantly increased only the mucus levels, whereas those of 5-ASA effectively prevented mast cell degranulation. The results show that the total effect of sulphasalazine is approximately equivalent to the summation of the actions of its component doses of sulphapyridine and 5-ASA. It is notable that sulphapyridine itself appears to be biologically active in reducing ulcer severity.     

The influence of verapamil on the gastric effects of stress in rats

The influence of verapamil on stress- or bethanechol-induced gastric effects was investigated in rats. Intraperitoneally injected verapamil (1, 2 or 4 mg/kg), given 30 min beforehand, dose-dependently prevented gastric glandular ulceration, mast cell degranulation and the increased stomach wall contractions evoked by restraint at 4 degrees C for 1 h. Gastric acid secretion, as well as ulceration in both the forestomach and glandular segment, produced by subcutaneously-injected bethanechol (3.2 mg/kg) were also inhibited. It is concluded that decreased amine release from the mast cells, stomach wall relaxation and reduced gastric acid were responsible for the ulcer-antagonising effects of the calcium-entry blocker. The possible antiulcer actions of verapamil are discussed in the light of present knowledge regarding calcium involvement in the various mechanisms thought to contribute to the pathophysiology of stress ulceration in rat stomachs.     

Protection by zinc sulphate against reserpine-induced ulceration and other gastric effects in the rat.

The effects of intraperitoneal pretreatment, 48 h beforehand, with zinc sulphate (22, 44 or 88 mg/kg) were studied on gastric ulceration, gastric secretion and changes in stomach wall mast cell counts induced after 4 h by reserpine (5 mg/kg) given intraperitoneally to intact (unoperated for pylorus occlusion) or pylorus-occluded rats. Zinc sulphate dose-dependently antagonised the gastric actions of reserpine by preventing ulceration in the ruminal and glandular segments of the stomach, reducing acid secretion, and inhibiting mast cell degranulation which occurred mainly in the glandular mucosal layer. The relationship between these findings and the action of zinc on gastric mast cell is discussed.     

The protective mechanism of FPL55712 against stress-induced gastric ulceration in rats

Cold-restraint stress produced stomach ulceration which was accompanied by a decreased glandular mucosal mast cell count and blood flow. Pretreatment with FPL55712, a leukotriene antagonist, dose-dependently prevented ulcer formation and mast cell depletion; however, it did not affect the reduced mucosal blood flow, nor did it significantly influence acid secretion and pepsin output. The role of the leukotrienes in stress ulceration is discussed in the light of the findings with FPL55712 on gastric glandular mucosal mast cell degranulation.     

Inhibitors of gastric lesions in the rat.

The production by stress of gastric lesions in rats was inhibited by metiamide and by mepyramine. Lesions induced by indomethacin treatment were inhibited by mepyramine but not by metiamide. Those induced by aspirin treatment in pylorus-ligated rats were not affected by either antihistamine drug. Oral glutamine inhibited lesion production in all three systems whereas aspirin orally markedly potentiated it. Sodium salicylate inhibited both indomethacin-induced lesions and those produced by aspirin in pylorus-ligated rats. On the other hand, copper salicylate inhibited stress-induced lesions and it, like copper aspirinate, also markedly reduced the extent of lesions produced by aspirin. On the basis of these results, stress-induced lesion production offers a suitable animal model for testing anti-ulcer drugs as it is, like most human gastric ulcers, inhibited by H2-receptor inhibitors like metiamide.     

Histamine H1- and H2-receptors in the gastric vasculature of the rabbit

The histamine receptors in the rabbit blood perfused gastric vasculature were analysed pharmacologically. Histamine elicited a monophasic increase in perfusion pressure which was antagonized by mepyramine and enhanced by metiamide. The maximum observed response was enhanced by metiamide to that produce by a specific H₁-receptor agonist. It is concluded that the gastric vasculature responds to histamine with an H₁-receptor mediated vasoconstriction and an H₂-receptor mediated dilation. In this preparation the H₁-effect predominates in response to injection of histamine.