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Biomedical subjects

S Okabe

Publications and source records attributed to S Okabe.

At least 451 records · Page 25Linked to original sources
PubMed1986

Cytoprotective action of mast cell stabilizers against ethanol-induced gastric lesions in rats.

We examined the effects of FPL-52694 and disodium cromoglycate (DSCG), mast cell stabilizers, on HCl X ethanol-induced gastric lesions in rats and investigated the factors involved in their protection. Oral (p.o.) administration of 1 ml of HCl X ethanol (60% in 150 mM HCl) induced linear hemorrhagic lesions in the gastric mucosa within 1 hr. FPL-52694 (1-30 mg/kg), given both p.o. and intraperitoneally (i.p.), prevented these lesions in a dose-related manner. DSCG (3-30 mg/kg) also dose-dependently reduced the formation of these lesions when this agent was given i.p. The protective effects of these drugs on HCl X ethanol-induced lesions were significantly attenuated by pretreatment with indomethacin (5 mg/kg, s.c.). Both gastric acid secretion and transmucosal potential difference were significantly reduced by topical application of FPL-52694 (greater than 10 mg/kg), but were not affected by i.p. administration of FPL-52694 and DSCG. On the other hand, gastric motor activity measured as intraluminal pressure recordings was significantly inhibited for 2 hr by both FPL-52694 (p.o. and i.p.) and DSCG (i.p.), and these effects were also significantly antagonized with prior administration of indomethacin. A significant relationship was found between the effects of these two drugs on the lesion index and the motility index (r: 0.9214, P less than 0.01), but not other factors. These results suggest that mast cell stabilizers such as FPL-52694 and DSCG protect the gastric mucosa against HCl X ethanol through a systemic action, probably mediated with endogenous prostaglandins. Although the mechanism of cytoprotection remains unknown, this property may be related to their inhibitory effects on gastric motor activity.

Animals↗
PubMed1986

Pathogenic mechanisms involved in mepirizole-induced duodenal damage in the rat.

Mepirizole (60 and 200 mg/kg) administered s.c. induced damage in the surface epithelial cells of the rat proximal duodenum as early as 2 hr after the treatment. 16,16-Dimethyl prostaglandin E2 (dmPGE2, 30 micrograms/kg) administered s.c. significantly protected the duodenal mucosa against mepirizole-induced damage for up to 6 hr. Gastric acid secretion in acute fistula preparations was significantly reduced 1 hr after administration of mepirizole (60 and 200 mg/kg). The secretion reverted to the control level 2 hr later. In the 60 mg/kg-treated group, however, there was a significant increase in the acid output for up to 6 hr. Duodenal HCO3- secretion, stimulated with 10 mM HCl was significantly inhibited with mepirizole (60 and 200 mg/kg). Mepirizole (60 and 200 mg/kg) significantly increased the amount of acid in the duodenum for 2 to 6 hr after the treatment. dmPGE2 (30 micrograms/kg) significantly inhibited gastric acid secretion, stimulated duodenal HCO3- secretion, and reduced the increased amount of acid in the duodenum in response to mepirizole. Endogenous prostaglandin E2 and 6-keto prostaglandin F1 alpha in the duodenal mucosa were significantly reduced by mepirizole (200 mg/kg) 1 to 2 hr later. Mepirizole-induced duodenal damage appears to be caused by the increased amount of acid in the duodenum.

16,16-Dimethylprostaglandin E2↗
PubMed1986

Effects of indomethacin on the duodenal mucosa of rats: comparative study with cysteamine.

Effects of indomethacin and cysteamine on the duodenal mucosa of rats were studied microscopically (using scanning electron microscopy) and also functionally. Indomethacin (5 mg/kg, s.c.) induced no microscopic damage to the duodenal epithelium for up to 6 hr after administration. Indomethacin had no effects on gastric H+ output and the amount of H+ in the duodenum, but did reduce the duodenal HCO3- secretion (both basal and 10 mM-HCl stimulated). PGE2 contents in the duodenal mucosa were markedly reduced by indomethacin for 6 hr. These results suggest that reductions of duodenal HCO3- secretion and endogenous prostaglandins per se do not impair the H+ disposal system of the duodenum and so do not damage the epithelial cells. In contrast, cysteamine (100 mg/kg, s.c.) produced microscopic damage to the duodenal epithelium as early as 2 hr later. Cysteamine significantly increased gastric H+ output and reduced duodenal HCO3- secretion, resulting in an increased amount of H+ in the duodenum 3 hr later. Cysteamine had no effect on PGE2 contents in the duodenum. The time lag between damage formation and functional changes suggests that the earliest damage caused by cysteamine occurs by mechanisms other than erosive action of H+ emptied by the stomach. The increased amount of H+ may contribute to an enhancement of the initial damage.

Animals↗
PubMed1986

Functional and morphological alterations in the rat stomach following exposure to hypertonic NaCl solution.

We examined the effects of 1 M NaCl as a mild irritant on gastric potential difference (PD), acid secretion, mucosal blood flow (MBF), and DNA synthetic activity in anesthetized rat stomachs and compared these effects with those of 4 M NaCl as a strong irritant. Both 1 M and 4 M NaCl produced a PD reduction (mucosal injury), but the reduced PD recovered faster in the mucosa exposed to 1 M NaCl as compared to 4 M NaCl. Acid secretion ceased after exposure to these hypertonic NaCl solutions, but histamine infusion (8 mg/kg/hr) stimulated acid secretion only in the mucosa exposed to 1 M NaCl. The MBF was significantly increased in response to 1 M NaCl, while exposure to 4 M NaCl had no effect on the MBF. These changes in acid secretion and MBF induced by 1 M NaCl were significantly antagonized by pretreatment with indomethacin (5 mg/kg, s.c.). The levels of PGE2 and 6-keto PGF1 alpha in the corpus mucosa were significantly increased in the stomach exposed to both 1 M and 4 M NaCl, and these increases disappeared in the presence of indomethacin. The rate of [3H]-thymidine incorporation was significantly reduced in the mucosa after exposure to 4 M NaCl, but remained unaltered in the stomach exposed to 1 M NaCl. These results suggest that although both 1 M and 4 M NaCl produced mucosal injury (PD reduction) and enhanced PGs formation, a variety of functional alterations mediated by PGs occurred in response to injury in the stomach exposed to 1 M NaCl. The presence or absence of these functional responses may be associated with the biphasic actions on the gastric mucosa of these hypertonic NaCl solutions as mild and strong irritants.

Adaptation, Physiological↗
PubMed1985

Role of luminal Ca2+ on normal and damaged gastric mucosa in the rat.

Influence of luminal Ca2+ on the integrity of normal mucosa and recovery of damaged mucosa in anesthetized rat stomachs was studied using a perfusion system. Changes in the mucosal integrity were monitored by measuring transmucosal potential difference (PD) and luminal pH. EDTA, a Ca2+ chelator, dose-dependently reduced PD and increased luminal pH. Five mM Ca2+ (CaCl2) alone produced no changes in either PD and luminal pH, but the PD which was reduced by 250 mM EDTA was significantly recovered. Ethanol or NaCl concentration-dependently reduced PD, but gradually reverted to baseline levels. While 5 mM Ca2+ or 5 mM EDTA did not influence the reduction in PD with 50% ethanol and 1 M NaCl, these agents either enhanced or delayed the recovery processes in reduced PD, respectively. Five mM Ca2+ enhanced the recovery of PD which was reduced by 50% ethanol plus 5 mM EDTA. Gastric damage induced by 50% ethanol plus 5 mM EDTA was much more severe than that induced by 50% ethanol alone or 50% ethanol plus 5 mM Ca2+. Both 50% ethanol and 1 M NaCl significantly increased Ca2+ contents in the gastric lumen. Luminal Ca2+ appears to play an important role in maintaining mucosal integrity, under normal physiological conditions, and in accelerating the recovery process of damaged mucosa in rat stomachs.

Action Potentials↗
PubMed1985

Characterization of FPL-52694 [5-(2-hydroxypropoxyl)-8-propyl-4-oxo-4H-benzopyran-2-carboxylic acid Na] on histamine release from rat peritoneal mast cells induced by antigen, compound 48/80 and A 23187.

We studied the in vitro effects of FPL-52694 [5-(2-hydroxypropoxyl)-8-propyl-4-oxo-4H-benzopyran-2-carboxylic acid Na] on histamine release from rat peritoneal mast cells. These cells exposed to ascaris antigen, compound 48/80 or the ionophore A 23187 concentration-dependently released histamine. About a 30-40% histamine release was obtained by 1 X 10(-4) g/ml of antigen, 1 X 10(-7) g/ml of compound 48/80 and A 23187. FPL-52694 (10(-9)-10(-4) g/ml) concentration-dependently inhibited the histamine release from mast cells in response to antigen (1 X 10(-4) g/ml) and compound 48/80 (1 X 10(-7) g/ml), but only slightly inhibited the histamine release induced by A 23187 (1 X 10(-7) g/ml). Similar results were obtained with disodium cromoglycate (DSCG), in the same dose ranges. However, the inhibitory activity of FPL-52694 on histamine release by antigen and compound 48/80 was approximately 10 times more potent than that of DSCG at certain concentrations. Tachyphylaxis was observed when these two agents were preincubated with mast cells for 10 min. These results show FPL-52694 to be a novel mast cell stabilizer.

Animals↗
PubMed1985

Effects of 16,16-dimethyl prostaglandin E2 on ethanol-induced and aspirin-induced gastric damage in the rat. Scanning electron microscopic study.

Ethanol and aspirin were administered orally to fasted rats and the effects of 16,16-dimethyl prostaglandin E2 (given orally as a pretreatment) were studied using scanning electron microscopy. Gastric secretory studies (pylorus ligation for 2 h) showed that 3 and 30 micrograms/kg of 16,16-dimethyl prostaglandin E2 were nonantisecretory doses and that 100 micrograms/kg was an antisecretory dose. 16,16-Dimethyl prostaglandin E2, given orally at 3-100 micrograms/Kg, induced no appreciable changes in the gastric surface epithelial cells. Oral administration of 1 ml of 50% ethanol invariably induced, within 10 min, extensive exfoliation of surface epithelial cells throughout the corpus and antrum and exposed the lamina propria. 16,16-Dimethyl prostaglandin E2, given orally at 3, 30, and 100 micrograms/kg 30 min before ethanol treatment, had no protective effect. Aspirin, given orally at 30 or 100 mg/kg, also damaged the surface epithelium of both the corpus and the antrum within 10 min. This damage ranged from apical cellular erosions to widespread exposure of the lamina propria. 16,16-Dimethyl prostaglandin E2, given orally at 3 or 30 micrograms/kg 30 min before aspirin treatment, significantly inhibited the gastric damage induced by both 30 and 100 mg/kg of aspirin. The inhibition of damage index was about 50%-60% at either 30 or 100 micrograms/kg of 16,16-dimethyl prostaglandin E2. The mechanism of the protection seen with 16,16-dimethyl prostaglandin E2 remains to be determined.

16,16-Dimethylprostaglandin E2↗
PubMed1985

[Effects of gefarnate on acute gastric lesions in rats].

The effects of gefarnate on several acute gastric lesions were studied in rats. Gefarnate, given at either 100 approximately 1000 mg/kg orally or intraduodenally, dose-dependently inhibited the formation of gastric lesions induced by HCl-ethanol, HCl-taurocholate and aspirin. Cimetidine, given at 30 approximately 100 mg/kg as a reference drug, also significantly inhibited both HCl-ethanol and aspirin-induced lesions. The present study suggests that gefarnate, as well as cimetidine, is useful for the treatment of acute gastric lesions in man.

Acute Disease↗
PubMed1985

Effects of prolonged treatment with compound 48/80 on the gastric mucosa and mast cells in the rat.

Effects of prolonged administration of compound 48/80 (48/80) on the gastric mucosa, serotonin and histamine levels in serum, and mast cells of rats were studied. Daily administration of 48/80 (0.75 mg/kg, i.p.) for 2 or 4 days produced widespread gastric lesions. Further administration of the agent for up to 12 days did not aggravate the lesions which had developed in the early period of administration of the drug. There were only a few visible lesions and numerous healed ones. Almost the same phenomenon was observed with the daily administration of serotonin plus histamine (10 mg/kg each, i.p.) for 2 to 12 days. While 48/80 given for 2 or 4 days increased serotonin and histamine levels in serum, it induced no appreciable increase of these amines after 8 or 12 days of treatment. Serotonin and histamine levels in peritoneal mast cells significantly decreased after the treatment with 48/80 over a 4 day period. The decrease in gastric lesions after prolonged treatment with 48/80 is due to both the depletion of serotonin and histamine from mast cells and an increased resistance of the gastric mucosa with healed lesions.

Animals↗
PubMed1985

Effects of various agents on prednisolone-induced gastric lesions in rats.

We studied the effects of various agents on prednisolone-induced gastric lesions in rats. Gastric lesions were produced by subcutaneous administration of 50 mg/kg of prednisolone once daily for 4 days to non-fasted rats. Daily oral administration of antipeptic, antisecretory agents and 16-dmPGE2 significantly inhibited the lesions. Antacids and PGI2 had little or not effect. These results suggest that the concomitant use of the above agents with steroid therapy to provide protection of the gastric mucosa warrants further attention.

Animals↗
PubMed1985

Role of gastric acid and bile acids in the pathogenesis of compound 48/80-induced gastric lesions in rats.

We studied the effects of various agents, which influence gastric acidity and bile acids, on compound 48/80 (48/80)-induced gastric lesions in rats. 48/80-Induced gastric lesions were produced by repeated intraperitoneal administration of 48/80 at 0.75 mg/kg once daily for 4 days. Test agents were given orally twice daily (30 min before and 9 hr after 48/80 administration) for 4 days. AI(OH)3 and sucralfate at 2000 mg/kg/day, a weak antacid dose, significantly inhibited (about 50-60%) the development of 48/80-induced lesions. Propantheline at 60 mg/kg/day and omeprazole at 60 or 200 mg/kg/day, which reduced gastric secretion for more than 12 hr, also significantly inhibited (about 30-40%) these lesions. Cimetidine at 200 mg/kg/day, which reduced gastric secretion for only 5 hr, had little effect on the lesion formation. Cholestyramine, which is a potent bile acids binding agent, had no effect on 48/80-induced lesions in doses of 600 or 2000 mg/kg/day. These results suggest that gastric acid, but not bile acids, is partly involved in the pathogenesis of 48/80-induced gastric lesions.

Animals↗
PubMed1984

Effects of a proton pump inhibitor, omeprazole, on gastric secretion and gastric and duodenal ulcers or erosions in rats.

The effects of omeprazole, a proton pump inhibitor, on gastric secretion and gastric or duodenal ulcers or erosions in rats were studied. Omeprazole, given intraduodenally, dose-dependently inhibited the gastric secretion (volume, acid and pepsin output) of pylorus-ligated rats. The antisecretory activity of omeprazole at 100 mg/kg persisted for 14 hr after treatment. Acutely induced gastric ulcers or erosions such as Shay ulcers, water-immersion stress-, indomethacin-, aspirin-, or prednisolone-induced erosions were all markedly inhibited by oral or intraduodenal administration of 10-100 mg/kg of omeprazole. The development of duodenal ulcers and gastric erosions caused by mepirizole was also potently inhibited by omeprazole at 3-10 mg/kg given orally. Repeated administration of omeprazole, 200 mg/kg/day in two divided doses for 14 days, significantly accelerated the spontaneous healing of acetic acid-induced gastric ulcers. The mechanism by which omeprazole inhibits the development of acute ulcers and accelerates healing of preexisting ulcers appears to be mainly due to its potent and long-lasting antisecretory activity. The antisecretory and antiulcer activities of omeprazole are equal to or exceed those of cimetidine, both in the maximum inhibitory response and ED50 values.

Animals↗
PubMed1984

Factors related to gastric hypersecretion during pregnancy and lactation in rats.

We attempted to elucidate the factors involved in gastric hypersecretion of rats during pregnancy and lactation. Acid secretion in pylorus-ligated and vagally denervated fistula rats stimulated with histamine, tetragastrin, and methacholine increased from midterm pregnancy and persisted during lactation. Pepsin secretion remained unaltered during pregnancy but increased during lactation. Vagal denervation itself abolished this hypersecretion. In late pregnancy, a delayed appearance of maximal acid response to histamine was apparent, as compared to nonpregnant rats, and was abolished by aminoguanidine treatment. There was a delay in the maximal response to tetragastrin but not to methacholine. Serum histamine concentrations were 3-4 times higher in late pregnancy, as compared to nonpregnant, lactating and nonlactating rats. Gastric DNA and protein concentrations were significantly increased in lactating rats with concomitant elevation of food intake and serum gastrin levels. Those changes disappeared in nonlactating rats, and gastric secretion was much the same in the nonpregnant rats. These results indicate that acid hypersecretion during pregnancy was exclusively associated with vagal innervation plus high serum histamine levels, while acid and pepsin hypersecretion in lactating rats were associated with vagal innervation plus hyperplastic gastric mucosa and high serum gastrin levels.

Animals↗
PubMed1984

Gastric secretory conditions and plasma gastrin levels in rats after prolonged treatment with cimetidine.

Effects of 4 weeks of treatment with oral cimetidine, 100 mg/kg twice daily, on gastric secretion and plasma gastrin levels were studied in rats. Pylorus ligation-induced and pentagastrin-stimulated gastric secretions were little changed at days 1, 3, and 10 after cessation of cimetidine treatment as compared to the controls. Histamine-stimulated acid secretion was significantly higher in the cimetidine-treated group than in the controls at day 3 after cimetidine treatment but was unchanged at days 1 and 10. A single oral administration of cimetidine at 100 mg/kg significantly increased plasma gastrin levels 4 hr after the treatment in refed rats but not at 2 and 8 hr later. Plasma gastrin levels significantly decreased at days 3 and 10 after cessation of cimetidine treatment as compared to the controls. Thus, while prolonged treatment with cimetidine induces a transient increase in response of parietal cells to histamine and a reduction of food-stimulated gastrin release, it does not seem to induce other appreciable changes in gastric secretion.

Animals↗