Skip to main content
SpringerLink
Log in

Antisecretory and Ulcer Healing Effects of S-0509, a Novel CCK-B/Gastrin Receptor Antagonist, in Rats

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

The effects of a novel CCK-B/gastrin receptorantagonist, S-0509, on gastric acid secretion and thehealing of acetic acid ulcers in rats were examined.S-0509, orally administered 1, 6, and 12 hr prior to a 3-hr pylorus ligation, significantlyinhibited basal gastric acid secretion in both normalrats and rats with gastric ulcers. The inhibition wasnearly dose-related, persisted for more than 15 hr, and proved to be more potent in rats withulcers than in normal rats. In addition, S-0509 markedlyinhibited pentagastrin- and carbachol-stimulated acidsecretion in both normal rats and rats with ulcers, but failed to inhibit histamine-stimulatedsecretions. In chronic gastric fistula rats, S-0509 alsosignificantly inhibited pentagastrin- andcarbacholstimulated gastric acid secretion in adose-related manner, but had no effect onhistaminestimulated secretion. These effects werelargely similar to those observed with famotidine,although famotidine also inhibited histamine-stimulatedsecretion. A two-week treatment with S-0509 markedly enhanced thespontaneous healing of acetic acid ulcers and preventedthe delay in ulcer healing caused by indomethacin.Gastric secretion was significantly inhibited and the plasma gastrin level was increased in theanimals studied. It is concluded that S-0509 is apromising new antisecretory drug for the treatment ofpeptic ulcers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Isenberg JI, McQuaid KR, Laine L, Walsh JH: Therapy for ulcer disease. In Textbook of Gastroenterology. T Yamada (eds). Philadelphia, Lippincott, 1995, pp 1378–1389

    Google Scholar 

  2. Hirschowitz BI, Kee ling D, Lewin M, Okabe S, Parsons M, Sewing K, Wallmark B, Sachs G: Pharmacological aspects of acid secretion. Dig Dis Sci 40:3S–23S, 1995

    Google Scholar 

  3. Graham DY, Colon-Pagan J, Morse RS, Johnson TL, Walsh JH, McCullough AJ, Marks JW, Sklar M, Stone RC, Cagliola AJ, Walton-Bowen KL, Humphries TJ: The Omeprazple Duodenal Ulcer Study Group: Ulcer recurrence following duodenal ulcer healing with omeprazole, ranitidine, or placebo: A double-blind, multicenter, 6-month study. Gastroenterology 102:1289–1294, 1992

    Google Scholar 

  4. Eckman L, Hansson E, Havu N, Carlsson E, Lundberg C: Toxicological studies on omeprazole. Scand J Gastroenterol 20( suppl 108):53–69, 1985

    Google Scholar 

  5. Poynter D, Pick CR, Harcourt RA, Selway SAM, Ainge G, Haranm IW, Spurling NW, Fluck PA, Cook JL: Association of long-lasting unsurmountable histamine H2 blockade and gastric carcinoid tumors in the rat. Gut 26:1284–1295, 1985

    Google Scholar 

  6. Axelson J, Hakanson R, Rosengren E, Sundler F: Hypergastrinemia induced by acid blockade evokes enterochromaffin like (ECL) cell hyperplasia in chicken, hamster and guinea pig stomach. Cell Tissue Res 105:15–21, 1988

    Google Scholar 

  7. Wallmark B, Skanberg I, Mattson H, Andersson K, Sundler F, Hakanson R, Carlsson E: Effects of 20 weeks ranitidine treatment on plasma gastrin levels and gastric enterochromaffin-like cell density in the rat. Digestion 45:181-188, 1990

    Google Scholar 

  8. Li H, Helander HF: Hypergastrinemia increases proliferation of gastroduodenal epithelium during gastric ulcer healing in rats. Dig Dis Sci 41:40–48, 1996

    Google Scholar 

  9. Haga Y, Nakatsura T, Shibata Y, Same shima H, Nakamura Y, Tanimura M, Ogawa M: Human gastric carcinoid detected during long-term antiulcer therapy of H2 receptor antagonist and proton pump inhibitor. Dig Dis Sci 43:253–257, 1998

    Google Scholar 

  10. Lotti VJ, Chang RSL: A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin receptor (CCK-B) ligand: L-365,260. Eur J Pharmacol 162:273–280, 1989

    Google Scholar 

  11. Hirst BH, Elliott K, Ryder H, Sze lke M: Inhibition of gastrinand histamine-stimulated gastric acid secretion by gastrin and cholecystokinin antagonists in the rat. Aliment Pharmacol Ther 5:31–39, 1991

    Google Scholar 

  12. Charles EP, Leo RF, Richard WE, Bruce FM, Gregory EM: The gastrin/cholecystokinin-B receptor antagonist L-365,260 reduce s basal acid secretion and prevents gastrointestinal damage induced by aspirin, ethanol and cysteamine in the rat. J Pharmacol Exp Ther 265:1348–1354, 1993

    Google Scholar 

  13. Horwell DC, Hughes J, Hunter JC, Pritchard MC, Richardson RS, Roberts E, Woodruff GN: Rationally designed dioeptoid analogues of CCK. α-methyltryptophan derivatives as highly selective and orally active gastrin and CCK-B antagonists with potent anxiolytic properties. J Med Chem 34:404–414, 1991

    Google Scholar 

  14. Nishida A, Miyata K, Tsutsumi R, Yuki H, Akuzawa S, Kobayashi A, Kamato T, Ito H, Yamano M, Katuyama Y, Satoh M, Ohta M, Honda K: Pharmacological profile of (R)-1-[2,3-dihydro-1-(29-methyl-phenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-me thylphenyl)urea (YM022), a new potent and sele ctive gastrin/cholecystokinin-B re ceptor antagonist, in vitro and in vivo. J Pharmacol Exp Ther 269:725–731, 1994

    Google Scholar 

  15. Nishida A, Takinami Y, Yuki H, Kobayashi A, Akuzawa S, Kamato T, Ito H, Yamano M, Nagakura Y, Miyata K: YM022 (R)-1-[2,3-dihydro-1-(2'-methyl-phe nacyl)-2-oxo-5-phenyl-1H-1,4-be nzodiazepin-3-yl]-3-(3-methylphenyl)urea, a potent and selective gastrin/chole cystokinin-B receptor antagonist, preve nts gastric and duodenal lesions in rats. J Pharmacol Exp Ther 270:1256–1261, 1994

    Google Scholar 

  16. Nishida A, Kobayashi-Uchida A, Akuzawa S, Takinami Y, Shishido T, Kamato T, Ito H, Yamano M, Yuki H, Nagakura Y, Honda K, Miyata K: Gastrin receptor antagonist YM022 prevents hyperse cretion after long-term acid suppression. Am J Physiol 269:G699–G705, 1995

    Google Scholar 

  17. Hagishita S, Murakami Y, Seno K, Kamata S, Haga N, Konoike T, Kanda Y, Kiyama R, Shiota T, Ishihara Y, Ishikawa M, Shimamura M, Abe K, Yoshimura K: Synthesis and pharmacological properties of ureidome thylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509. Bio Med Chem 5:1695–1714, 1997

    Google Scholar 

  18. Konturek SJ, Brzozowski T, Piastucki I, Radecki T, Dembinski A, Dembinska-Kiec A: Role of locally generated prostaglandins in adaptive gastric cytoprotection. Dig Dis Sci 27:967–971, 1982

    Google Scholar 

  19. Tsukimi Y, Okabe S: Validity of kissing gastric ulcers induced in rats for screening of antiulcer drugs. J Gastroenterol Hepatol 9:S60–S65, 1994

    Google Scholar 

  20. Tsukimi Y, Okabe S: Effect of anterior unilateral vagotomy on healing of kissing gastric ulcers induced in rats. Jpn J Pharmacol 66:105–114, 1994

    Google Scholar 

  21. Tsukimi Y, Nozue C, Okabe S: Effects of leminoprazole, omeprazole and sucralfate on indomethacin-induced delayed healing of kissing gastric ulcers in rats. J Gastroente rol Hepatol 11:335–340, 1996

    Google Scholar 

  22. Wang JY, Yamasaki S, Takeuchi K, Okabe S: Delayed healing of acetic acid-induced gastric ulcers in rats by indomethacin. Gastroenterology 96:393–402, 1989

    Google Scholar 

  23. Larsson H, Carlsson E, Junggren U, Olbe L, Sjostrand E, Skanberg I, Sundell G: Inhibition of gastric acid secretion by omeprazole in the dog and rat. Gastroenterology 85:900–907, 1983

    Google Scholar 

  24. Okabe S, Takagi K, Inoue K: Effect of NC-1300-03 on healing of acetic acid-induced gastric ulcers in rats. Jpn J Pharmacol 62:25–33, 1993

    Google Scholar 

  25. Harty RF, Maico DG, McGuigan JE: Comparison of adrenergic and cholinergic receptor-mediated stimulation of gastrin release from rat antral fragments. Peptides 9:463–468, 1988

    Google Scholar 

  26. Koop I, Squires PE, Meloche RM, Buchan AM: Effect of cholinergic agonists on gastrin release from primary cultures of human antral G cells. Gastroente rology 112:357–363, 1997

    Google Scholar 

  27. Nishida A, Yuki H, Tsutsumi R, Miyata K, Kamato T, Ito H, Yamano M, Honda K: L-365,260, a potent CCK-B/gastrin receptor antagonist, suppresses gastric acid secretion induced by histamine and bethanechol as well as pentagastrin in rats. Jpn J Pharmacol 58:137–145, 1992

    Google Scholar 

  28. Nishida A, Kobayashi-Uchida A, Takemoto Y, Akuzawa S, Miyata K: Comparative evaluation of the role of endogenous gastrin in basal acid secretion in conscious fistula rats and pylorus-ligated rats. Jpn J Pharmacol 71:223–230, 1996

    Google Scholar 

  29. Okabe S, Nozue C, Amagase K: Mechanism by which omeprazole and leminoprazole enhance healing of acetic acid gastric ulcers in rats: Role of circulating gastrin. In Gastroduodenal Mucosal Damage: Problems of Protection and Healing. R Cheli, G Iaquinto, S Szabo (eds). Naples, Mediserve, 1997, pp 169–182

    Google Scholar 

  30. Takagi K, Okabe S, Saziki R: A new method for the production of chronic gastric ulcers in rats and the effects of several drugs on their healing. Jpn J Pharmacol 69:418–426, 1969

    Google Scholar 

  31. Lee H, Hansson HA, Norstrom E, Helander HF: Immunore-activities for epidermal growth factor (EGF) and for EGF receptors in rats with gastric ulcers. Cell Tissue Res 265:211–218, 1991

    Google Scholar 

  32. Keto S, Takahashi S, Okabe S. Healing of Heliocobacter pyloriinduced gastric ulcers in mongolian gerbils: Combined treatment with omeprazole and clarithromycin. Dig Dis Sci ( in press)

  33. Cardiot G, Lehy T, Bonfils S: Action of somatostatin analogue (SMS201-995) on the growth promoting effect resulting from sustained achlorhydria in rat gastric mucosa, with special reference to endocrine cell behavior. Eur J Clin Invest 18:360–368, 1988

    Google Scholar 

  34. Meijer JL, Jansen JBMJ, Crobach LFSJ, Biemond K, Lamers CBHW: Inhibition of omeprazole-induced hypergastrinemia by SMS 201-995, a long-acting somatostatin analogue in man. Gut 34:1186–1190, 1993

    Google Scholar 

Download references

Authors
  1. Kikuko Amagase
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyoko Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susumu Okabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Amagase, K., Ikeda, K. & Okabe, S. Antisecretory and Ulcer Healing Effects of S-0509, a Novel CCK-B/Gastrin Receptor Antagonist, in Rats. Dig Dis Sci 44, 879–888 (1999). https://doi.org/10.1023/A:1026631808011

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026631808011

Search

Navigation