Disodium cromoglycate: a novel gastric antiulcer agent?

The influence of oral pretreatment with disodium cromoglycate (2.5 or 5 mg/kg X 9 doses) on the 4-h gastric effects of i.p. injected reserpine (5 mg/kg) was examined in rats. Disodium cromoglycate markedly prevented reserpine-induced ulceration, mucosal mast cell degranulation and superficial mucosal microcirculatory changes in the glandular portion of the stomach wall. These interesting results points to the possibility that disodium cromoglycate may also have gastric antiulcer effects in man.     

Cholinergic-mediated gastric mast cell degranulation with subsequent histamine H1-and H2-receptor activation in stress ulceration in rats.

The effects of atropine, mepyramine, metiamide or NaHCO3 on gastric ulceration, gastric secretion and gastric mast cell degranulation were studied in stressed pylorus-occluded rats. The influence of dexamethasone pretreatment on stress ulcers in animals without pylorus occlusion (intact rats) was also examined. Stress produced a high glandular lesion incidence and ulcer index, and markedly lowered gastric secretion and glandular wall mast cell counts. Injected 0.5 h before stress, atropine, mepyramine or metiamide strongly antagonised ulceration. Atropine or metiamide, but not mepyramine, reduced gastric secretion. Only atropine prevented stress-induced mast cell changes. NaHCO3, given intragastrically before stress, did not prevent ulceration or mast cell degranulation despite complete neutralisation of gastric acid. Dexamethasone-induced gastric mucosal mast cell depletion could reduce stress ulceration. The findings show that stress degranulates stomach mast cells via a cholinergic pathway; released histamine from this source is largely responsbile for gastric ulceration through H1- and H2-receptor effects. Histamine H2-receptor-mediated gastric acid may play only a small contributory role in stress ulcers in rats. The antiulcer mechanisms of histamine H1- and H2-receptor blockade are discussed.     

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.     

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 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.     

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.     

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.     

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.     

Effects of nicotine on activity and stress-induced gastric ulcers in rats.

Nicotine is known to influence locomotor activity. The alkaloid also intensifies gastric ulcer formation in stressed rats. The effects of nicotine on locomotor activity in relation to gastric lesions induced by restraint at 4 degrees C for 2 h (stress) were, therefore, studied. Ten-day treatment with nicotine 25 or 50 micrograms/ml drinking water potentiated stress-evoked ulceration and mast cell degranulation. These same doses of nicotine increased vertical motor activity; only the higher dose of the alkaloid enhanced horizontal movements. Phenobarbitone (12.5, 25, or 50 mg/kg, SC) dose dependently reduced vertical activity, as well as stress-induced gastric ulceration and mucosal mast cell degranulation. The drug also lessened the potentiating effects of nicotine on motor activity and stress-evoked gastric lesion formation. It is concluded that the ability of chronic nicotine treatment to intensify stress-induced gastric ulceration most likely owes part of its action to a mechanism evoking increased activity, which possibly reflects an influence on the CNS, as well as to enhancement of mast cell degranulation in the stomach glandular mucosa.     

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.     

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 chronic or acute nicotine pretreatment on ethanol-induced gastric ulceration in the rat

The effects in rats of chronic or acute nicotine pretreatment were studied on three gastric parameters: ethanol-induced ulceration, gastric wall mucus content and gastric acid secretion, under basal or histamine-stimulated conditions. Oral administration of ethanol (40%, 10 ml kg-1) depleted gastric wall mucus and produced ulceration in the gastric glandular mucosa. Ten-day nicotine pretreatment (15 or 25 micrograms ml-1 drinking water) worsened the adverse effects of ethanol on mucosal ulceration and mucus content, potentiated the gastric secretory action of histamine, but did not affect basal acid secretion. Single oral doses of nicotine (2 or 4 mg kg-1, given 1 h beforehand) prevented ulceration and mucus depletion in ethanol-treated animals; however, they did not influence either basal or histamine-stimulated gastric acid output. It is concluded that chronic nicotine administration aggravates ethanol ulceration, possibly by decreasing gastric wall mucus content and sensitizing the stomach to the acid secretory action of histamine. On the other hand, an acute oral dose of nicotine preserves the mucus content and prevents ethanol-induced ulcer formation.     

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.     

Ethacrynic acid and sulphasalazine inhibit the generation of leukotriene C4 in rat stomachs: a possible gastric anti-ulcer mechanism in cold-restraint-stressed rats.

The role of gastric glandular mucosal leukotriene C4 in gastric ulceration, produced by restraint at 4 degrees C (stress) for 2 h in rats, was studied in relation to the ulcer-preventing effects of ethacrynic acid, sulphasalazine and its constituents (sulphapyridine and 5-aminosalicylic acid), AA-861 and ONO-1078. Stress itself significantly raised mucosal leukotriene C4 levels; pretreatment with ethacrynic acid, sulphasalazine, sulphapyridine or AA-861 antagonised these changes and reduced the severity of gastric ulceration. Mucosal mast cell degranulation was prevented by ethacrynic acid, sulphasalazine, 5-aminosalicylic acid, AA-861 or ONO-1078; the mucus-depleting effect of stress was also reversed by all these drugs, except for 5-aminosalicylic acid. The anti-ulcer effect of ethacrynic acid and sulphasalazine appears to be related to their influence on glandular mucosal leukotriene C4 levels.     

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.     

A study on the aetiology of reserpine ulceration and the antiulcer action of solcoseryl in rat stomach

The aetiology of reserpine-induced gastric ulcer formation and the antiulcer effects of solcoseryl were studied in rats. Intraperitoneal injection of reserpine produced severe ulceration, as well as mast cell and histamine depletion, in the gastric glandular mucosa. Mepyramine and Cimetidine markedly antagonized the gastric lesions, but did not influence the reduced mast cell count; atropine pretreatment significantly inhibited both parameters. Intramuscular injection of solcoseryl lessened ulcer severity and prevented the decreased mast cell counts and histamine levels in reserpine-treated rats. However, the same dose of solcoseryl injected intraperitoneally was ineffective. Solcoseryl, irrespective of the route of administration, did not influence the gastric secretory activities of reserpine. It is concluded that resperine ulceration is both cholinergic- and histamine-mediated, and that the antiulcer effects of solcoseryl appear to be due to prevention of histamine depletion in the gastric mucosa.     

Effects of the new anti-ulcer agent KB-5492 on experimental gastric mucosal lesions and gastric mucosal defensive factors, as compared to those of teprenone and cimetidine.

Effects of KB-5492, a new anti-ulcer agent, on various experimental gastric mucosal lesions and mucosal defensive factors in rats were compared with those of teprenone and cimetidine. KB-5492 administered orally at 12.5-200 mg/kg inhibited water-immersion stress- and indomethacin-induced gastric mucosal lesions in a dose-dependent manner with ED50 values of 46 and 27 mg/kg, respectively, indicating that KB-5492 was more potent than teprenone but less potent than cimetidine. KB-5492, administered orally at 12.5-100 mg/kg, also inhibited ethanol-induced gastric mucosal lesions in a dose-dependent manner with an ED50 of 23 mg/kg, so KB-5492 was 3 times more potent than teprenone, whereas cimetidine produced no obvious inhibition. In addition, KB-5492, administered orally at 25 and 50 mg/kg twice daily for 10 consecutive days, significantly accelerated the healing of acetic acid-induced gastric ulcers more potently than teprenone and cimetidine. KB-5492 at anti-ulcer doses significantly increased gastric mucosal blood flow in normal anesthetized rats and inhibited the reduction of gastric mucosal hexosamine content induced by aspirin, but did not affect gastric acid secretion in pylorus-ligated rats. These results indicate that KB-5492 has potent and broad anti-ulcer properties, which are probably exerted by its enhancement of gastric mucosal defensive factors through increasing gastric mucosal blood flow and/or retaining gastric mucus, and not by its inhibition of gastric acid secretion.     

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.     

Effect of DS-4574, a novel peptidoleukotriene antagonist with mast cell stabilizing action, on acute gastric lesions and gastric secretion in rats.

DS-4574 is a peptidoleukotriene antagonist with mast cell stabilizing activity. In the present study, we studied the effects of this compound on gastric secretion and various acute gastric lesions in rats. Intraduodenal administration of DS-4574 at doses of 5 to 10 mg/kg significantly and dose-dependently inhibited gastric acid secretion in pylorus-ligated rats, but a further increase in the dose up to 50 mg/kg did not cause any further inhibition. Shay ulceration in response to pylorus ligation was dose-dependently prevented by DS-4574 (10-25 mg/kg, i.d.). Water-immersion restraint stress- and aspirin-induced gastric ulcers were also significantly prevented in a dose-related manner by oral pretreatment with DS-4574 (10-50 mg/kg). The lower doses of DS-4574 (1-10 mg/kg, p.o.) significantly and dose-dependently protected the gastric mucosa against the necrotizing action of either absolute ethanol or concentrated hydrochloric acid, indicating that this compound possesses a potent gastroprotective activity. These antiulcer and gastric protective effects of DS-4574 were more potent than those of cimetidine used as a reference drug. These findings suggest that DS-4574 is useful for peptic ulcer therapy, as well as for the therapy of various allergic diseases, including asthma.     

Prostaglandin E2 and the stimulation of rat gastric acid secretion by dibutyryl cyclic 3',5'-AMP

In the anaesthetised rat, i.v. injection of dibutyryl cyclic 3′,5′-AMP (dbcAMP) caused a dose-dependent increase in gastric acid secretion during pentagastrin, histamine or carachol stimulation. This was accompanied by a rise in gastric mucosal blood flow. During basal secretion, dbcAMP caused by a relatively small stimulation, atlhough this response was greatly enhanced by threshold doses of pentagastrin or histamine. Cyclic AMP (cAMP) did not stimulate acid secretion, but increased mucosal blood flow and decreased blood pressure. Theophylline had no consistent effect on acid secretion. Prostaglandin E₂, administered i.v. or perfused through the gastric lumen, reduced basal acid secretion but failed to inhibit the secretory response to dbcAMP. These results in the rat support the role of cAMP in gastric acid secretion and suggest that prostaglandins inhibit other secretogogues at a stage prior to cAMP.