The relationship of gastric hypermotility to mucosal hemodynamics, lipid peroxidation and vascular permeability changes was investigated in the pathogenesis of indomethacin-induced gastric lesions in rats. Subcutaneous administration of indomethacin (25 mg/kg) produced an increase in both the amplitude and frequency of stomach contraction from 30 min after treatment, resulting in hemorrhagic damage 2 h later. Gastric mucosal blood flow measured by a Laser flowmetry showed oscillatory fluctuations under hypercontractile states: a decrease during contraction followed by an increase during relaxation. Mucosal lipid peroxidation and vascular permeability were significantly increased with time after indomethacin treatment, and these changes preceded the appearance of hemorrhagic damage. All these events were prevented when gastric hypermotility was inhibited by atropine or 16,16-dimethyl prostaglandin E2. Pretreatment of the animals with allopurinol and hydroxyurea or continuous infusion of superoxide dismutase and dimethyl sulfoxide during a test period also attenuated these functional changes and mucosal lesions induced by indomethacin, without affecting the motility response. We conclude that oxygen free radicals may play a role in the development of mucosal lesions associated with gastric hypermotility in indomethacin-treated rats.
Healing of duodenal ulcers induced by indomethacin + histamine was investigated in rats. Animals were treated with indomethacin (5 mg/kg, s.c, once daily) and histamine (40 mg/kg, s.c, 3 times every 2.5 h after indomethacin treatment) for 2 days under fasting conditions, and they were fed normally thereafter. The duodenal ulcers so induced were confined to the proximal part of the duodenum and penetrated to the muscular mucosa with an incidence of over 80% when determined 32 h after the first injection of indomethacin (day 1). The ulcers became smaller and shallower within 7 days with granulation from the ulcer base, the mucosa grew in from the edges over the surface of granulation tissue, and they had healed almost completely after 15 days with epithelial regeneration from the edge of the ulcers. The healing of ulcers was significantly promoted by a 5-day treatment with an antacid (Al(OH)3) as well as antisecretory agents (omeprazole, cimetidine, propantheline bromide) and 16,16-dimethyl prostaglandin E2 at the dose which produced a potent inhibition of acid output and a marked increase in duodenal alkaline secretion. These results suggest that the duodenal ulcers induced in rats by indomethacin + histamine may provide a useful model for studying the healing process of duodenal ulcers and for the evaluation of the drugs with possible effects on ulcer healing.
Healing processes of duodenal ulcers induced by mepirizole and effects of several drugs on the ulcer healing were studied in rats. Mepirizole-induced duodenal ulcers, except for the perforated ones within 3 days after ulceration, gradually diminished in size and depth by the 15th day. Several ulcers persisted for up to 40 days, but complete healing in all rats occurred by the 60th day after ulceration. Oral cimetidine and YM-11170 (both histamine H2-receptor antagonists), at 200 and 30 mg/kg twice daily for 10 days, respectively, significantly accelerated the healing of duodenal ulcers. Oral Maalox (antacid) at 1,000 mg/kg thrice daily and propantheline (anticholinergic agent) at 30 mg/kg twice daily tended to accelerate the healing of the ulcers. Oral 16,16-dimethyl PGE2, at 0.03 and 0.1 mg/kg twice daily, resulted in a delayed healing of the ulcers. Mepirizole-induced duodenal ulcers appear to be a useful model for the study of ulcer healing and for screening of antiulcer drugs.
Gastric ulcers induced in dogs by transserosal injection of 1 ml of 40% acetic acid healed completely by the 7th week after ulceration and never reulcerated during the observation period up to 12 weeks. Acetic acid ulcers in the active (at 1 week), quiescent (3 weeks) or healed (at 7 weeks) stages were not influenced by the daily administration of aspirin 2 g/dog/day for 5 consecutive weeks. All examinations were done by gastroscopy in addition to macroscopical and histological observations at autopsy.
We used capsaicin as a selective probe for sensory neuronal mechanisms and examined in rats whether defunctionalization of the sensory nerves caused duodenal ulcers in the presence of acid hypersecretion. Chemical deafferentation was performed by subcutaneous injection of capsaicin for 3 days (total dose: 100 mg/kg) 2 weeks before the experiment. This treatment did not cause by itself any damage in the duodenum. However, intravenous infusion of histamine (4, 8 and 16 mg/kg/h) in these animals caused hemorrhagic lesions in the proximal duodenum within 6 h in a dose-dependent manner with an incidence of 100%. Histamine alone in the control animals did not induce macroscopically visible lesions at lower doses and caused only slight damage at the highest dose (16 mg/kg/h), although acid secretion was stimulated to the maximal degree at 8 mg/kg/h. Ablation of capsaicin-sensitive sensory neurons did not have any effect on acid secretion induced by histamine (8 mg/kg/h), but significantly inhibited the increase in duodenal HCO3- secretion in response to mucosal acidification. We conclude that functional ablation of capsaicin-sensitive sensory nerves impairs duodenal HCO3- secretory response to acid and results in duodenal ulcers if acid hypersecretion is present. These sensory nerves may be important in the defense mechanism of the duodenum against luminal acid.
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