Digestive Diseases and Sciences

, Volume 52, Issue 2, pp 425–433 | Cite as

Effect of Different Cyclooxygenase Inhibitors on Gastric Adaptive Cytoprotection Induced by 20% Ethanol

  • Alessandra Gambero
  • Marta Maróstica
  • Tagliane Liza Becker
  • José Pedrazzoli Jr.
Original Paper


In this study, we evaluated the effect of two different dosages of therapeutically prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen, diclofenac, nimesulide, meloxicam, and celecoxib (ED80 for COX-1 and COX-2) on normal gastric mucosa and mucosa, previously exposed to 20% ethanol. At COX-2-inhibiting dosages, the NSAIDs tested were nonulcerogenic, and the same response profile was observed in “adapted” stomachs. Interestingly, low doses of nimesulide and celecoxib increase the levels of Prostaglandin E2 and COX-2, and protect against subsequent 100% ethanol exposition, suggesting that these drugs may act as “mild irritants” to gastric mucosa. The ulcerogenic response to NSAIDs was prevented by the previous 20% ethanol exposition, probably the result of nitric oxide synthesis, because PGE2 levels in gastric mucosa were reduced by these agents and a concomitant nitric oxide blockade reversed this protection.


Prostaglandin E2 Ibuprofen Meloxicam Nimesulide Diclofenac Celecoxib Nitric oxide Cyclooxygenase 


  1. 1.
    Robert A, Nezamis JE, Lancaster C, Davis JP, Field SO, Hanchar AJ (1983) Mild irritants prevent gastric necrosis through “adaptive cytoprotection” mediated by prostaglandins. Am J Physiol 245:G113–G121PubMedGoogle Scholar
  2. 2.
    Konturek SJ, Brzozowski T, Piastucki I, Radecki T, Dembinski A, Dembinska-Kiec A (1982) Role of locally generated prostaglandins in adaptive gastric cytoprotection. Dig Dis Sci 27:967–971PubMedCrossRefGoogle Scholar
  3. 3.
    Brzozowski T, Konturek PC, Konturek SJ, Drozdowicz D, Pajdo R, Pawlik M, Brzozowska I, Hahn EG (2000) Expression of cyclo-oxygenase (COX)-1 and COX-2 in adaptive cytoprotection induced by mild stress. J Physiol Paris 94:83–91PubMedCrossRefGoogle Scholar
  4. 4.
    Robert A (1986) Cytoprotection and prostaglandins. Klin Wochenschr 7:40–43Google Scholar
  5. 5.
    Takeuchi K, Araki H, Umeda M, Komoike Y, Suzuki K (2001) Adaptive gastric cytoprotection is mediated by prostaglandin EP1 receptors: a study using rats and knockout mice. J Pharmacol Exp Ther 297:1160–1165PubMedGoogle Scholar
  6. 6.
    Tanaka K, Nishimoto K, Tomisato W, Tsutsumi S, Hoshino T, Tsuchiya T, Mizushima T (2004) Adaptive cytoprotection induced by pretreatment with ethanol protects against gastric cell damage by NSAIDs. Dig Dis Sci 49:210–217PubMedCrossRefGoogle Scholar
  7. 7.
    Tsutsumi S, Mima S, Tomisato W, Hoshino T, Tsuchiya T, Mizushima T (2003) Molecular mechanism of adaptive cytoprotection induced by ethanol in human gastric cells. Exp Biol Med 228:1089–1095Google Scholar
  8. 8.
    Konturek PC (1997) Physiological, immunohistochemical and molecular aspects of gastric adaptation to stress, aspirin and to H. pylori-derived gastrotoxins. J Physiol Pharmacol 48:3–42PubMedGoogle Scholar
  9. 9.
    Lewis JD, Kimmel SE, Localio AR, Metz DC, Farrar JT, Nessel L, Brensinger C, McGibney K, Strom BL (2005) Risk of serious upper gastrointestinal toxicity with over-the-counter nonaspirin nonsteroidal anti-inflammatory drugs. Gastroenterology 129:1865–1874PubMedCrossRefGoogle Scholar
  10. 10.
    Tomisato W, Tsutsumi S, Hoshino T, Hwang HJ, Mio M, Tsuchiya T, Mizushima T (2004) Role of direct cytotoxic effects of NSAIDs in the induction of gastric lesions. Biochem Pharmacol 67:575–585PubMedCrossRefGoogle Scholar
  11. 11.
    Ligumsky M, Sestieri M, Karmeli F, Rachmilewitz D (1986) Protection by mild irritants against indomethacin-induced gastric mucosal damage in the rat: role of prostaglandin synthesis. Isr J Med Sci 22:807–811PubMedGoogle Scholar
  12. 12.
    Tursi A, Cammarota G, Papa A, Cianci R, Cuoco L, Fedeli G, Gasbarrini G (1998) Effect of adequate alcohol intake, with or without cigarette smoking, on the risk of Helicobacter pylori infection. Hepatogastroenterology 45:1892–1895PubMedGoogle Scholar
  13. 13.
    Nobuhara Y, Takeuchi K, Okabe S (1986) Vinegar is a dietary mild irritant to the rat gastric mucosa. Jpn J Pharmacol 41:101–108PubMedGoogle Scholar
  14. 14.
    Gambero A, Becker TL, Zago AS, de Oliveira AF, Pedrazzoli Jr J (2005) Comparative study of anti-inflammatory and ulcerogenic activities of different cyclo-oxygenase inhibitors. Inflammopharmacology 13:441–454PubMedCrossRefGoogle Scholar
  15. 15.
    Gamberini MT, Skorupa LA, Souccar C, Lapa AJ (1991) Inhibition of gastric secretion by a water extract from Baccharis triptera, Mart. Mem Inst Oswaldo Cruz 2:137–139Google Scholar
  16. 16.
    Shay H, Komarov AS, Fels SS, Meranze D, Gruenstein M, Siplet H (1945) A simple method for the uniform production of gastric ulceration in rats. Gastroenterology 5:43–61Google Scholar
  17. 17.
    Oh TY, Ahn GJ, Choi SM, Ahn BO, Kim WB (2005) Increased susceptibility of ethanol-treated gastric mucosa to naproxen and its inhibition by DA-9601, an Artemisia asiatica extract. World J Gastroenterol 11:7450–7456PubMedGoogle Scholar
  18. 18.
    Davies NM, Sharkey KA, Asfaha S, Macnaughton WK, Wallace JL (1997) Aspirin causes rapid up-regulation of cyclo-oxygenase-2 expression in the stomach of rats. Aliment Pharmacol Ther 11:1101–1108PubMedCrossRefGoogle Scholar
  19. 19.
    Takeeda M, Hayashi Y, Yamato M, Murakami M, Takeuchi K (2004) Roles of endogenous prostaglandins and cyclooxygenase izoenzymes in mucosal defense of inflamed rat stomach. J Physiol Pharmacol 55:193–205PubMedGoogle Scholar
  20. 20.
    Tomisato W, Tanaka K, Tsutsumi S, Hoshino T, Yokomizo K, Suzuki K, Katsu T, Mizushima T, Mizushima T (2005) Low direct cytotoxicity and cytoprotective effects of nitric oxide releasing indomethacin. Dig Dis Sci 50:1927–1937PubMedCrossRefGoogle Scholar
  21. 21.
    Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, Lee L, Isakson P (1994) Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA 91:12013–12017PubMedCrossRefGoogle Scholar
  22. 22.
    Tomisato W, Tsutsumi S, Rokutan K, Tsuchiya T, Mizushima T (2001) NSAIDs induce both necrosis and apoptosis in guinea pig gastric mucosal cells in primary culture. Am J Physiol Gastrointest Liver Physiol 281:G1092–G1100PubMedGoogle Scholar
  23. 23.
    Suleyman H, Altinkaynak K, Gocer F, Maras A, Akcay F, Onuk MD, Gepdiremen A (2002) Effect of nimesulide on the indomethacin- and ibuprofen-induced ulcer in rat gastric tissue. Pol J Pharmacol 54:255–259PubMedGoogle Scholar
  24. 24.
    Suleyman H, Akcay F, Altinkaynak K (2002) The effect of nimesulide on the indomethacin- and ethanol-induced gastric ulcer in rats. Pharmacol Res 45:155–158PubMedCrossRefGoogle Scholar
  25. 25.
    Ogino K, Hatanaka K, Kawamura M, Ohno T, Harada Y (2000) Meloxicam inhibits prostaglandin E(2) generation via cyclooxygenase 2 in the inflammatory site but not that via cyclooxygenase 1 in the stomach. Pharmacology 61:244–250PubMedCrossRefGoogle Scholar
  26. 26.
    Patrignani P, Panara MR, Sciulli MG, Santini G, Renda G, Patrono C (1997) Differential inhibition of human prostaglandin endoperoxide synthase-1 and -2 by nonsteroidal anti-inflammatory drugs. J Physiol Pharmacol 48:623–631PubMedGoogle Scholar
  27. 27.
    Harada Y, Kawamura M, Hatanaka K, Saito M, Ogino M, Ohno T, Ogino K, Yang Q (1998) Differing profiles of prostaglandin formation inhibition between selective prostaglandin H synthase-2 inhibitors and conventional NSAIDs in inflammatory and non-inflammatory sites of the rat. Prostaglandins Other Lipid Mediat 55:345–358PubMedGoogle Scholar
  28. 28.
    Hirata T, Ukawa H, Yamakuni H, Kato S, Takeuchi K (1997) Cyclooxygenase isozymes in mucosal ulcergenic and functional responses following barrier disruption in rat stomachs. Br J Pharmacol 122:447–454PubMedCrossRefGoogle Scholar
  29. 29.
    Laudanno OM, Cesolari JA, Esnarriaga J, San Miguel P, Bedini OA (2000) In vivo selectivity of nonsteroidal antiinflammatory drugs and gastrointestinal ulcers in rats. Dig Dis Sci 45:1359–1365PubMedCrossRefGoogle Scholar
  30. 30.
    Reichstein BJ, Okamoto C, Forte JG (1986) Effect of ethanol on acid secretion by isolated gastric glands from rabbit. Gastroenterology 91:439–447PubMedGoogle Scholar
  31. 31.
    Singer MV, Leffmann C, Eysselein VE, Calden H, Goebell H (1987) Action of ethanol and some alcoholic beverages on gastric acid secretion and release of gastrin in humans. Gastroenterology 93:1247–1254PubMedGoogle Scholar
  32. 32.
    Ko JK, Cho CH, Lam SK (2004) Adaptive cytoprotection through modulation of nitric oxide in ethanol-evoked gastritis. World J Gastroenterol 10:2503–2508PubMedGoogle Scholar
  33. 33.
    West SD, Helmer KS, Chang LK, Cui Y, Greeley GH, Mercer DW (2003) Cholecystokinin secretagogue-induced gastroprotection: role of nitric oxide and blood flow. Am J Physiol Gastrointest Liver Physiol 284:G399–410PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Alessandra Gambero
    • 1
  • Marta Maróstica
    • 1
  • Tagliane Liza Becker
    • 1
  • José Pedrazzoli Jr.
    • 2
  1. 1.Clinical Pharmacology and Gastroenterology UnitSão Francisco University Medical SchoolBragança PaulistaBrazil
  2. 2.Core Clinical ResearchBragança PaulistaBrazil

Personalised recommendations