Pathogenic Mechanisms Involved in Mepirizole-lnduced Duodenal Damage in the Rat

Tanaka, Hironori; Ueki, Shigeru; Ohno, Tomochika; Takeuchi, Koji; Okabe, Susumu

doi:10.1254/jjp.42.383

Cited by 22 publications

(11 citation statements)

References 16 publications

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“…Yet, the acid-in duced HCO3 secretion was significantly inhib ited even by the third injection of DDC, sug gesting that HCO3 secretory disorders may be more important in the pathogenesis of DDC induced duodenal ulcers. This is consistent with the previous observation showing that the impairment of acid-induced HCO3 secretion is more closely associated with the pathogen esis of duodenal ulcers as induced by cys teamine, mepirizole, or indomethacin plus his tamine (4)(5)(6)(7)20). Certainly, acid is essential to the development of duodenal ulcers in duced by DDC, since they were significantly prevented by cimetidine which inhibits acid secretion without any effect on HCO3 secre tion (5).…”

Section: Discussionsupporting

confidence: 91%

“…Since the anti oxidative system including SOD may play a role in maintaining the functional integrity of these organs, the pathogenesis of DDC-in duced toxicity might involve the functional dis orders related to the insufficiency of this sys tem. We have previously shown that the im pairment of alkaline secretion is commonly in volved in the mechanism of experimental pro duction of duodenal ulcers as induced by mepirizole, antiinflammatory drugs or digi toxin (4)(5)(6)(7). Thus, it is of interest to study the relationship between the antioxidative system and duodenal alkaline secretion.…”

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confidence: 99%

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Duodenal Ulcers Induced by Diethyldithiocarbamate, a Superoxide Dismutase Inhibitor, in the Rat: Role of Antioxidative System in the Pathogenesis.

et al. 1991

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ABSTRACT-Pathogenesis of duodenal ulcers induced by diethyldithiocarbamate (DDC), a superoxide dismutase (SOD) inhibitor, was investigated in the rat. Repeat ed s.c. administration of DDC (750 mg/kg) every 12 hr induced duodenal ulcers in the fed rats, and the severity of the ulcers reached the maximum after three injections. DDC not only reduced basal acid output but also impaired duodenal alkaline secre tion. These ulcers were significantly prevented by antioxidative agents such as SOD (50000 units/kg, s.c.), allopurinol (50 mg/kg, s.c.) or glutathione (200 mg/kg, s.c.) as well as the antisecretory agent cimetidine (100 mg/kg, s.c.). The impaired HCO3 re sponse caused by DDC was partially but significantly reversed by either SOD (15000 units/kg/hr, i.v.), allopurinol or glutathione; and SOD by itself significantly elevated the rate of basal alkaline secretion. 16,16-Dimethyl prostaglandin E2 (10 ,ug/kg, s.c.) increased duodenal HCO3 output in the presence of DDC and significantly prevented the development of duodenal ulcers in response to DDC. These results suggest that the mucosal antioxidative system including SOD may play a role in the regulatory process of alkaline secretion and contribute to the mucosal defensive ability in the duodenum. The insufficiency of this system may be involved in the pathogenesis of DDC-induced duodenal ulcers. Diethyldithiocarbamate (DDC), a potent metal chelator, is known to induce damage in the gastrointestinal mucosa in rats (1, 2). Re cently, we found that repeated administration of DDC to fed rats produced penetrating ulcers in the duodenum with a high incidence (3). Although inhibition of copper modulated cytosolic superoxide dismutase (SOD) is thought to be a significant factor in the pathogenesis of this toxicity, the precise mechanism remains unknown. Since the anti oxidative system including SOD may play a role in maintaining the functional integrity of these organs, the pathogenesis of DDC-in duced toxicity might involve the functional dis orders related to the insufficiency of this sys tem. We have previously shown that the im pairment of alkaline secretion is commonly in volved in the mechanism of experimental pro duction of duodenal ulcers as induced by mepirizole, antiinflammatory drugs or digi toxin (4-7). Thus, it is of interest to study the relationship between the antioxidative system and duodenal alkaline secretion.In the present study, we examined the effects of DDC and antioxidative drugs on duodenal alkaline secretion in the rat to in vestigate (a) the pathogenesis of DDC-induced duodenal ulcers and (b) the role of the anti oxidative system in duodenal alkaline secretion.

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

Duodenal Ulcers Induced by Diethyldithiocarbamate, a Superoxide Dismutase Inhibitor, in the Rat: Role of Antioxidative System in the Pathogenesis.

et al. 1991

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“…Gallagher and Szabo (19) and Tanaka et al (20) showed a marked increase of acid load in the duodenum following administration of cys teamine and mepirizole in rats, and they sug gested that the increased amount of acid in the duodenum may be directly associated with formation of duodenal lesions. Water immersion stress also impaired acid neutralizing capacity and produced damage in the rat duodenum when acid hypersecretion was concomitantly present (21).…”

Section: Discussionmentioning

confidence: 96%

“…The cause-effect relationship between the acid neutralizing capacity and duodenal lesions has been suggested by several experi mental ulcer models (7,(19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

Impairment of Acid-Neutralizing Capacity and Lesion Formation in the Rat Duodenum during Hemorrhagic Shock: Comparative Study with Indomethacin

Takeuchi

Furukawa

Tanaka

et al. 1987

Japanese Journal of Pharmacology

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Abstract-The effects of hemorrhagic shock (HE) on duodenal pH, acid-neutralizing capacity and mucosal tolerance to acid were investigated in anesthetized rats, and they were compared with those of indomethacin. HE was performed by bleeding from the carotid artery to reduce arterial blood pressure to about 55 mmHg (3 ml of bleeding per 200 g of body weight), and indomethacin was given s.c. in a dose of 5 mg/kg. Duodenal pH was determined in the outflow from the proximal duodenum (1.7 cm) which was perfused with 10-4 M HCI, and acid-neutralizing capacity was measured by back-titration of the perfusate to pH 4.0 with 10 mM HCI. Under these conditions, duodenal pH was kept at around 6.0 as the result of neutralization in the loop (-8 ,uEq/hr). Both HE and indomethacin significantly decreased the pH and acid-neutralizing capacity. Administration of 16,16 dimethyl prostaglandin E2 (16-dmPGE2: 30 ,ag/kg, s.c.) significantly increased both pH and acid-neutralizing capacity in normal and indomethacin-treated rats, but failed to affect these parameters in rats under HE conditions. When the duodenal loop was perfused with 50 mM HCI for 1.5 hr, both HE and indomethacin induced extensive damage in the mucosa. Pretreatment with 16-dmPGE2 sig nificantly reduced the formation of duodenal lesions induced by indomethacin but not by HE. These results suggest that HE as well as indomethacin impaired duodenal acid-neutralizing capacity to reduce the tolerance to acid of the mucosa. The deleterious effects of H E on the mucosa may be mainly due to a decreased mucosal blood flow, but not due to a deficiency of endogenous prostaglandins.

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“…It is most likely that the accumulation of gastric juice for longer periods might be caused by delayed gastric emptying. This accumulated gastric juice gradually empties into the duodenum which has an attenuated neutralizing capacity due to reduced HC03 secretion (4,12). The corrosive action of gastric acid on the duo denal mucosa results in villous damage, and finally, in penetrating ulcers.…”

Section: Discussionmentioning

confidence: 99%

Histamine-induced villous damage in the rat duodenum.

1989

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Abstract-A single s.c. administration of histamine dose-dependently (5-20 mg/ kg) induced villous damage of the proximal duodenum in 24-hr fasting rats. Time course studies indicate that histamine (20 mg/kg) induced severe exfoliation of the epithelial cells at the villous tips of the duodenal mucosa 0.5 hr after administration. The damage, however, tended to heal with time, and recovery was nearly complete 8 hr later. This villous damage was significantly inhibited by pretreatment with sodium bicarbonate given orally or cimetidine, omeprazole and NC-1300 given subcutaneously.Histamine (20 mg/kg) significantly stimulated gastric acid secretion and lowered the intraduodenal pH for 1 hr. Gastric content was sig nificantly greater than that in the control group for 1 hr after histamine administration, probably due to stimulated gastric secretion and delayed emptying.We conclude that a single administration of histamine induces microscopical duodenal damage by stimulation of gastric acid secretion, but the damage heals with time, probably as a result of the short periods of acid stimulation and delayed emptying.

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Pathogenic Mechanisms Involved in Mepirizole-lnduced Duodenal Damage in the Rat

Cited by 22 publications

References 16 publications

Duodenal Ulcers Induced by Diethyldithiocarbamate, a Superoxide Dismutase Inhibitor, in the Rat: Role of Antioxidative System in the Pathogenesis.

Duodenal Ulcers Induced by Diethyldithiocarbamate, a Superoxide Dismutase Inhibitor, in the Rat: Role of Antioxidative System in the Pathogenesis.

Impairment of Acid-Neutralizing Capacity and Lesion Formation in the Rat Duodenum during Hemorrhagic Shock: Comparative Study with Indomethacin

Histamine-induced villous damage in the rat duodenum.

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