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Studies on the pharmacological properties of a novel animal model for gastric antral ulcer and on its application to drug evaluation for antiulcer drugs

Research Project

Project/Area Number 07457535
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionChiba University

Principal Investigator

WATANABE Kazuo  Chiba University, Faculty of Pharmaceutical Sciences Professor, 薬学部, 教授 (80019124)

Co-Investigator(Kenkyū-buntansha) TSUCHIYA Shizuko  Chiba University, Faculty of Pharmaceutical Sciences Research Associate, 薬学部, 助手 (60241973)
HORIE Syunji  Chiba University, Faculty of Pharmaceutical Sciences Associate Professor, 薬学部, 講師 (50209285)
YANO Shingo  Chiba University, Graduate School of Pharnaceutical Sciences Professor, 薬学部, 教授 (90009655)
Project Period (FY) 1995 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥7,600,000 (Direct Cost: ¥7,600,000)
Fiscal Year 1997: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1996: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1995: ¥4,100,000 (Direct Cost: ¥4,100,000)
Keywordsgastric ulcer / gastric antral ulcer / antiulcer drugs / Helicobacter pylori / gastric mucosal defense system / oxygen radical / glutamate receptor / enterocromaffin like cell / 実験潰瘍 / 幽門洞 / カプサイシン / GABA / 胃幽門洞 / 胃粘膜保護作用 / 胃酸分泌 / 胃粘膜血流 / ヘリコバクター ピロリ / 2-デオキシ-D-グルコース
Research Abstract

9-1 Aim of the project :
We previously reported an original method inducing gastric antral ulcer in rats, which was very unique from the pharmacological point of view. Thus we aimed to improve this method to make it more useful for the pharmacological researches and to clarifiy the etiology of the gastric ulceration, as well as the nervous control mechanism of gastric functions.
9-2 Establishment of the gastric antral ulcer model in rats :
Previously reported method by us was somewhat complicated in which three pharmacological agents were used in combination. We deviced again a novel method for inducing gastric antral ulcer in rats by loading the limited food intake schedule and oral administration of 0.6-1.0 N HCl. By this simple treatment, very extensive ulceration restricted in the antral region was induced in 4 days after the treatment. Through pharmacological reseaches on the etiology of the ulceration, it was found that free radicals production, blood flow reduction as well as endog … More enous gastric acid production were deeply implicated in the ulceration processes, and the direct necrotizing effect of hydrochloric acid was found to be a rather minor factor.
9-3 Role of Helicobacter pylori in gastric ulceration
Recent interest on the etiology of gastric ulceration has been focussed on the role of H.pylori in the stomach. We previously studied ammonia production in the stomach and noticed the urease enzyme contained in this bacteria which produce ammonia by hydrolysing the urea. We found the ingesting of dilute ammonia solusion significantly delayd the healing of gastric antral ulcer. Several kinds of antiulcer drugs were found to have the urease inhibitory effects, and to have bacteriocidal effects, especially under low pH condition mimicking the gastric mucosal environment. Among them, sucralfate was found very effective, and showed competitive urease inhibition with the substrate urea only under the low pH condition.
9-4 Involvement of capsaicin sensitive afferent nerve in the gastric mucosal defensive system
We found gastric antral ulcer was remarkably aggravated after the denervation of primary afferent nerve by repeated treatment with capsaicin. This means the involvement of sensory afferent nervous system in the defense mechanisms of gastric mucosa in the antral area.
9-5 Non-adrenergic, Non-cholinergic (NANC) nervous system in the gastric functions
We previously deviced a method to measure gastric motor function and acid secretion in the isolated mouse whole stomach preparation. By using this method, we found that relaxation of the stomach by vagal stimulation was mediated by NANC nerve, and also found that the mediator involved in this relaxation must be nitric oxide. Thus the importance of NO in the gastric functions was noticed. Nitric oxide synthetase inhibitors were found to have the aggravating effect on the antral ulceration.
9-6 Functional role of enterochlomaffin-like cells in gastric mucosa
Gastric acid secretion is well known to be mediated by gastric histamine containing cells. We found niric oxide synthetase inhibitors strongly inhibit the acid secretion induced by vagal stimulation in the isolated mouse whole stomach preparations. This means the stimulatory role of NO in the control of acid secretion. We reported the evidence that the endogenous NO stimulates the histamine release from the gastric enterochlomaffin-like cells.
9-7 Conclusion
In the present research project, we established a novel and useful method to induce the gastric ulcer in antral erea of the rat stomach which is closely related with the human gastric ulcer. Pharmacological factors involved in its etiology such as NO,primary afferent nerve, as well as H.pilori were studied. Less

Report

(4 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • Research Products

    (36 results)

All Other

All Publications (36 results)

  • [Publications] K.Watanabe: "Ingibitory effect of mitragymine,an alkaloid with analgesic effect from Thai medicinal plant Mitragyna speciosa,on electrically stimulated contraction of isolated guinea-pig ileum through the opioid receptor." Life Sciences. 60. 933-942 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] M.Uchida: "Studies on establishment of a simple method for gastric antral ulcer in rats and on the related pharmacological facters." Ulcer Research. 24. 89-92 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Hasebe: "Inhibitory effect of L-NNA on gastric secretion induced by secretagogues and vagal stimulation in the isolated stomach." Eur.J.Pharmacol.(印刷中). (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takaaki, Tai: "Anti-emetic principles of Poria cocos." Planta Medica. 61. 527-530 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Toru, Noji: "Effect of NO donors and NOS inhibitorson gastric acid and mucus secretion." Ulcer Research. 22. 235-238 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Masayuki, Yamamoto: "Comparison of Effect of Famotidine on Vagally and Field-electrically Stimulated AcidScretion in the Isolated Mouse Whole Stomach." Japanese Journal of Pharmacology. 69. 259-268 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Shingo, Yano: "Pharmacological Features of Non-adrenergic Non-cholinergic(NANC)relaxation InducedbyElectrical Vagal Stimulation in Isolated Mouse Siomach." Japanese Journal of Pharmacology. 69. 9-15 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] W-C.Lin: "Effect of intracerebroventricular and intrahypothajamic administrations of picrotoxin on basal and stimulated gastric acid secretion." Res.Commun.Mol.Pathol.Pharmacol.89. 143-156 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Syunji Horie: "Intracellular alkalinazation by NH4Cl increases cytosolic Ca level and tension in the rat aorlic smooth muscle" Life Sciences. 56. 1835-1843 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Syunji, Horie: "Neurogenic Stimulation of Gastric AcidSecretion by the Na,K-ATPase Inhibitor Ourbain in Mouse Isolated Stomach" General Pharmacology. 27. 905-909 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Shizuko, Tsuchiya: "Mechanism of N-methyl-D-aspartate(NMDA)in stimulating gastric acid secretion:Involvement of nitric oxide(NO)-generating system" Ulcer Research. 23. 172-175 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.Watanabe(K.Watanabe 分担): "Recent Advances in Pharmacological Research on Traditional Herbal Medicine." Gordon and Breach,Science Publishers,Inc.(印刷中), (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Watanabe, S.Yano, S.Horie and L.T.Yamamoto: "Inhibitory effect of mitragynine, an alkaloid with analgesic effect from Thal medicinal plant Mitragyna speciosa, on electrically stimulated contraction of isolated guinea-pig ileum trough the opioid receptor." Life Sciences. 60(12). 933-942 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] M.Ushida, A.Gomori, S.Yano, K.Watanabe and Y.Kato: "Studies on establishment of a simple method for gastric antral ulcer in rats and on the related pharmacological factors." Ulcer Research. 24(2). 89-? (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Hasebe, S.Horie, S.Yano and K.Watanabe: "Inhibitory effect of L-NNA on gastric secretion induced by secretagogues and vagal stimulation in the isolated stomach." Eur.J.Pharmacol.(in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T.Tai, K.Kinoshita, K.Koyama, K.Takahashi and K.Watanabe: "Anti-emetic principles of Poria cocos." Planta Medica. 61. 527-530 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T.Noji, S.Yano and K.Watanabe: "Effect of NO donors and NOS inhibitors on gastric acid and mucus secretion" Ulcer Research. 22(2). 235-238 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] M.Yamamoto, S.Yano and K.Watanabe: "Comparison of effect of famotidine on vagally and field-electrically stimulated acid secretion in the isolated mouse whole stomach." Jpn.J.Pharmacol.69(3). 259-268 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] S.Yano, Y.Kiyota, M.Yamamoto and K.Watanabe: "Pharmacological features of non-adrenergic non-cholinergic (NANC) relaxation induced by electrical vagal stimulation in isolated mouse stomach." Jpn.J.Pharmacol.69(1). 9-15 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] W-C.Lirr, S.Yano and K.Watanabe: "Effect of intracerebroventricular and intrahypothalamic administrations of picrotoxin on basal and stimulated gastric acid secretion." Res.Commun.Mol.Pathol.Pharmacol.89(2). 143-156 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] S.Horie, S.Yano and K.Watanabe: "Intracellular Alkatlnazation by NH_4CI Increases Cytosolic Ca Level and Tension in the Rat Aortic Smooth Muscle." Life Sciences. 56. 1835-1843 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] S.Horie, T.Maruyama, S.Yano and K.Watanabe: "Neurogenic stimulation of gastric acid secretion by the Na, K-ATPase inhibitor ouabain in mouse isolated stomach." Gen.Pharmacol.27(5). 905-909 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] S.Tsuchiya, S.Yano and K.Watanabe: "Mechanism of N-methyl-D-aspartate (NMDA) in stimulating gastric acid secretion : Involvement of nitric oxide (NO)-generating system." Ulcer Research. 23(2). 172-175 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Watanabe: "Inhibitory effect of mitragynine,an alkaloid with analgesic effect from Thai medicinal plant Mitragyna speciosa, on electrically stimulated contraction of isolated guinea-pig ileum through the opioidreceptor" Life Sciences. 60(12). 933-942 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] M.Uchida: "Studies on establishment of a simple method for gastric antral ulcer in rats and on the related pharmacological facters." Ulcer Reserch. 24(2). 89-92 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.Hasebe: "Inhibitory effect of L-NNA on gastric secretion induced by secretagogues and vagal stimulation in the isolated stomach." Eur.J.Pharmacol.(印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Watanabe(K.Watanabe分担): "Recent Advances in Pharmacological Research on Traditional Herbal Medicine." Gordon and Breach,Science Publishers,Inc.(印刷中), (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Syunji Horie: "Neurogenic Stimulation of Gastric Acid Secretion by the Na,K-ATPase lnhibitor Ouabain in Mouse lsolated Stomach" General Pharmacology. 27・5. 905-909 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Shizuko Tsuchiya: "Mechanism of N-methyl-D-aspartate (NMDA) in stimulating gastric acid secretion : lnvolvement of nitric oxide (NO) -generating system" Ulcer Research. 23・2. 172-175 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Syunji Horie: "Neurogenic Stimulation of Gastric Acid Secretion by the Na,K-ATPase Inhibitor Ouabain in Mouse Isolated Stomach" General Pharmacology. (in press). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Syunji Horie: "Intracellular alkalinazation by NH4CI increases cytosolic Ca level and tension in the rat aortic smooth muscle" Life Sciences. 56. 1835-1843 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] W-C.Lin: "Effect of intracerebroventricular and intrahypothalamic administrations of picrotoxin on basal and stimulated gastric acid secretion." Res.Commun.Mol.Pathol.Pharmacol.89. 143-156 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Shingo Yano: "Pharmacological Features of Non-adrenergic Non-cholinergic(NANC)relaxation Induced by Electrical Vagal Stimulation in Isolated Mouse Stomach." Japanese Journal of Pharmacology. 69. 9-15 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Masayuki Yamamoto: "Comparison of Effect of Famotidine on Vagally and Field-electrically Stimulated Acid Secretion in the Isolated Mouse Whole Stomach." Japanese Journal of Pharmacology. 69. 259-268 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Totu Noji: "Effect of NO donors and NOS inhibitors on gastric acid and mucus secretion." Ulcer Research. 23(in press). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takaaki Tai: "Anti-emetic principles of Poria cocos." Planta Medica. 61. 527-530 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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