Skip to main content
SpringerLink
Log in

Effects of Celecoxib on Acid-Challenged Gastric Mucosa of Rats: Comparison with Metamizol and Piroxicam

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

Abstract

Selective COX-2 inhibitors have been shown to produce fewer gastrointestinal adverse reactionsthan classical NSAIDs. Nevertheless, these new agents may worsen and delay the healing of ex-perimentallyinduced gastric ulcers in animals. In this study, we compared the effects of a selectiveCOX-2 inhibitor (celecoxib), a preferential COX-1 inhibitor (piroxicam), and a nonnarcotic anal-gesic(metamizol) on normal gastric mucosa of rats and, on the other hand, in a setting of preexistingacute gastric lesions induced by 0.6 N hydrochloric acid. Under normal conditions, only piroxicamproduced appreciable gastric lesions. However, after acid challenge the three assayed drugs inducedsignificant macroscopic and microscopic damage. Myeloperoxidase activity as an index of neutrophilinfiltration was elevated with celecoxib and piroxicam on normal gastric mucosa. On inflamed mu-cosa,celecoxib augmented enzymatic activity at the lower dose, which was parallelled by an increasein the interleukin 1β level. Acid instillaton produced a significant rise in PGE2 content at 7 hr. Drugtreatment after acid challenge decreased prostaglandin values in all cases, although to a lesser extentthan after single drug dose administration. COX-2 mRNA expression was visible 1 hr after acidapplication, whereas COX-2 protein could only be detected at 7 hr. Piroxicam increased both ex-pressionlevels. All NSAIDs enhanced transforming growth factor α and epidermal growth factorreceptor immunoreactivity around the acid-induced lesions. It is concluded that selective COX-2inhibitors, like conventional NSAIDs, impair the healing of gastric damage, and therefore specialattention should be paid in patients with gastric pathologies.

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. Botting RM: Mechanism of action of acetaminophen: Is there a cyclooxygenase 3? Clin Infect Dis 31(S5): S202–S210, 2000

    Google Scholar 

  2. Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR: TIS10, a phorbol ester tumor promoter-inducible mRNAfrom Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 266: 12866–12872, 1991

    Google Scholar 

  3. Sawaoka H, Tsuji S, Tsujii M, Gunawan ES, Nakama A, Takei Y, Nagano K, Matsui H, Kawano S, Hori M: Expression of cyclooxygenase-2 gene in gastric epithelium. J Clin Gastroenterol 25(Suppl 1): S105–S110, 1997

    Google Scholar 

  4. Sun WH, Tsuji S, Tsujii M, Gunawan ES, Sawaoka H, Kawai N, Iijima H, Kimura A, Kakiuchi Y, Yasumaru M, Sasaki Y, Kawano S, Hori M: Cyclooxygenase-2 inhibitors suppress epithelial cell kinetics and delay gastric wound healing in rats. J Gastroenterol Hepatol 15(7): 752–761, 2000

    Google Scholar 

  5. Botting JH: Nonsteroidal antiinflammatory agents. Drugs of Today 35(4–5): 225–235, 1999

    Google Scholar 

  6. Wallace JL, McKnight W, Reuter BK, Vergnolle N: NSAID-induced gastric damage in rats: Requirement for inhibition of both cyclooxy-genase 1 and 2. Gastroenterology 119(3): 706–714, 2000

    Google Scholar 

  7. Tanaka A, Araki H, Komoike Y, Hase S, Takeuchi K: Inhibition of both COX-1 and COX-2 is required for development of gastric damage in response to nonsteroidal antiinflammatory drugs. J Physiol Paris 95(1–6): 21–27, 2001

    Google Scholar 

  8. Bombardier C: An evidence-based evaluation of the gastrointestinal safety of coxibs. Am J Cardiol 89(6): 3–9, 2002

    Google Scholar 

  9. Mizuno H, Sakamoto C, Matsuda K, Wada K, Uchida T, Noguchi H, Akamatsu T, Kasuga M: Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 112: 387–397, 1997

    Google Scholar 

  10. Laudanno OM, Cesolari JA, Esnarriaga J, Rista L, Piombo G, Maglione C, Aramberry L, Sambrano J, Godoy A, Rocaspana A: Gastrointestinal damage induced by celecoxib and rofecoxib in rats. Dig Dis Sci 46(4): 779–784, 2001

    Google Scholar 

  11. Tibble J, Sigthorsson G, Caldwell C, Palmer RH, Bjarnason I: Effects of NSAIDs on cryoprobe-induced gastric ulcer healing in rats. Aliment Pharmacol Ther 15(12): 2001–2008, 2001

    Google Scholar 

  12. Colville-Nash PR, Gilroy DW: Potential adverse effects of cyclooxygenase-2 inhibition: Evidence from animal models of inflammation. BioDrugs 15(1): 1–9, 2001

    Google Scholar 

  13. Sun WH, Tsuji S, Tsuji M, Gunawan ES, Kawai N, Kimura A, Kakiuchi Y, Yasumaru M, Iijima H, Okuda Y, Sasaki Y, Hori M, Kawano S: Induction of cyclooxgenase-2 in rat gastric mucosa by rebamipide, a mucoprotective agent. J Pharmacol Exp Ther 295(2): 447–452, 2000

    Google Scholar 

  14. Berenguer B, Alarcón de la Lastra C, Moreno FJ, Martín MJ: Chronic gastric ulcer healing in rats subjected to selective and non-selective cyclooxygenase-2 inhibitors. Eur J Pharmacol 442: 125–135, 2002

    Google Scholar 

  15. Villegas I, Martín MJ, La Casa C, Motilva V, Alarcón de la Lastra C: Effects of oxicam inhibitors of cyclooxygenase on oxidative stress generation in rat gastric mucosa. A comparative study. Free Rad Res 36(7): 769–777, 2002

    Google Scholar 

  16. Sánchez S, Martín MJ, Ortiz P, Motilva V, Alarcón de la Lastra C: Effects of dipyrone on inflammatory infiltration and oxidative metabolism in gastric mucosa: Comparison with acetaminophen and diclofenac. Dig Dis Sci 47(6): 1389–1398, 2002

    Google Scholar 

  17. Grisham MB, Beniot JN, Granger DN: Assessement of leucocyte involvement during ischemia and reperfusion on the intestine. In Methods in Enzymology. Oxygen Radicals in Biological Systems.L Packer, AE Glazer (eds). San Diego, Academic Press, 1990, pp 729–741

    Google Scholar 

  18. Chomcynsky P, Sacchi N: Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159, 1987

    Google Scholar 

  19. Gretzer B, Ehrlich K, Maricic N, Lambrecht N, Respondek M, Peskar BM: Selective cyclooxygenase-2 inhibitors and their influence on the protective effect of a mild irritant in the rat stomach. Br J Pharmacol 123: 927–935, 1998

    Google Scholar 

  20. Schmassmann A, Peskar BM, Stettler C: Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. Br J Pharmacol 123: 795–804, 1998

    Google Scholar 

  21. Gretzer B, Maricic N, Respondek M, Schuligoi R, Peskar BM: Effects of specific inhibition of cyclooxygenase-2 in the rat stomach with normal mucosa and after acid challenge. Br J Pharmacol 132(7): 1565–1573, 2001

    Google Scholar 

  22. Gretzer B, Maricic N, Schuligoi R, Peskar BM: Effect of SC-560, a selective cyclooxygenase (COX)-1 inhibitor, and its modification by COX-2 inhibition in the rat stomach. Gastroenerology 118(4): A240, 2000

    Google Scholar 

  23. Peskar BM, Maricic N, Gretzer B, Schuligoi R, Schmassmann A: Role of cyclooxygenase-2 in gastric mucosal defense. Life Sci 69(25–26): 2993–3003, 2001

    Google Scholar 

  24. Kishimoto Y, Wada K, Nakamoto K, Kawasaki H, Hasegawa J: Quantitative analysis of cyclooxygenase-2 gene expression on acute gastric injury induced by ischemia/reperfusion in rats. Life Sci 60: 127–133, 1998

    Google Scholar 

  25. Tarnawski A: Cellular and molecular mechanisms of ulcer healing. Drugs Today 33(10): 697–706, 1997

    Google Scholar 

  26. Tarnawski A, Stachura J, Durbin T, Sarfeh IJ, Gergely H: Increased expression of epidermal growth factor receptor during gastric ulcer healing in rats. Gastroenterology 102: 695–698, 1992

    Google Scholar 

  27. Konturek SJ, Brzozowski T, Dembinski A: Gastric protective and ulcer-healing action of epidermal growth factor. In Advances in Drug Therapy of Gastrointestinal Ulceration. A Garner, BJR Whittle (eds). New York, Wiley-Interscience, 1989, pp 261–273

    Google Scholar 

  28. Terano A, Sakata-Horie K, Shimada T, Hiraishi H, Yoshiura K, Yoneda M, Takahashi M, Fujimori T: The role of cellular migration in the repair process of gastric epithelial cells. Life Sci 69(25–26): 3083–3089, 2001

    Google Scholar 

  29. Schmassmann A: Mechanisms of ulcer healing and effects of non-steroidal antiinflammatory drugs. Am J Med 104(3A): 43S–51S, 1998

    Google Scholar 

  30. Takahashi S, Kobahashi N, Okabe S: Regulation by endogenous interleukin-1 of mRNA expression of healing-related factors in gastric ulcers in rats. J Pharmacol Exp Ther 291(2): 634–641, 1999

    Google Scholar 

  31. Brzozowski T, Konturek PC, Konturek SJ, Drozdowicz D, Kwiecien S, Pajdo R, Bielanski W, Hahn EG: Role of gastric acid secretion in progression of acute gastric erosions induced by ischemia-reperfusion into gastric ulcers. Eur J Pharmacol 398: 147–158, 2000

    Google Scholar 

  32. Jüni P, Rutjes AWS, Dieppe PA: Are selective COX-2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? Adequate analysis of the CLASS trial indicates that this may not be the case. Br Med J 324: 287–288, 2002

    Google Scholar 

  33. Boers M: Seminal pharmaceutical trials: Maintaining masking in analysis. Lancet 360: 100–101, 2002

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Pharmacy, USA

    Bettina Berenguer, Catalino Alarcón De la Lastra, Virginia Motilva, Carmen La Casa & María José Martin Calero

  2. Virgen Macarena Hospital, University of Sevilla, Sevilla, Spain

    Juan Manuel Herrerías & David Pozo

Authors
  1. Bettina Berenguer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catalino Alarcón De la Lastra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Virginia Motilva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carmen La Casa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juan Manuel Herrerías
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Pozo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. María José Martin Calero
    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

Berenguer, B., De la Lastra, C.A., Motilva, V. et al. Effects of Celecoxib on Acid-Challenged Gastric Mucosa of Rats: Comparison with Metamizol and Piroxicam. Dig Dis Sci 49, 937–947 (2004). https://doi.org/10.1023/B:DDAS.0000034552.20917.5e

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:DDAS.0000034552.20917.5e

Search

Navigation