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Effects of Cyclooxygenase-2 Selective and Nitric Oxide-Releasing Nonsteroidal Antiinflammatory Drugs on Mucosal Ulcerogenic and Healing Responses of the Stomach

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Abstract

Effects of selective cyclooxygenase-2 (COX-2)inhibitors (NS-398) and nitric oxide (NO)-releasingaspirin (NO-ASA) on gastric ulcerogenic and healingresponses were examined in comparison with nonselective COX inhibitors such as indomethacin and aspirin(ASA). Hypothermic stress (28-30°C, 4 hr) inducedgastric lesions in anesthetized rats with an increase ofacid secretion. The lesions induced by hypothermic stress were markedly worsened by subcutaneousadministration of both indomethacin and ASA but were notaffected by either NS-398 or NO-ASA, although theincreased acid secretion during hypothermia was not affected by any of the drugs. On the otherhand, the healing of gastric ulcers induced in mice bythermal cauterization (70°C, 15 sec) wassignificantly delayed by daily subcutaneousadministration of indomethacin and ASA as well as NS-398, but not by NO-ASA.COX-2 mRNA was not detected in the intact mucosa but waspositively expressed in the ulcerated mucosa, mostpotently on day 3 after ulceration. Prostaglandin contents in the intact mouse stomach werereduced by indomethacin, ASA, and NO-ASA, while theincreased prostaglandin generation in the ulceratedmucosa was inhibited by all drugs including NS-398.After subcutaneous administration of NO-ASA topylorus-ligated rats and mice, high amounts ofNOx were detected in both the gastriccontents and serum. In addition, both NS-398 and NO-ASAshowed an equipotent antiinflammatory effect againstcarrageenan-induced paw edema in rats as compared withindomethacin and ASA. These results suggest that bothindomethacin and ASA not only increased the mucosalulcerogenic response to stress but impaired the healingresponse of gastric ulcers as well. The former actionwas due to inhibition of COX-1, while the latter effectwas accounted for by inhibition of COX-2 and was mimicked by the COX-2-selective inhibitorNS-398. NO-ASA, although it inhibited both COX-1 andCOX-2 activity, had no deleterious effects on gastriculcerogenic and healing responses.

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REFERENCES

  1. Lanza FL: Endoscopic studies of gastric and duodenal injury after the use of ibuprofen, aspirin, and other nonsteroidal antiinflammatory agents. Am J Med 13:19 -24, 1984

    Google Scholar 

  2. Levi S, Goodlad RA, Lee CY, Stamp G, Walport MJ, Wright NA, Hodgson HJF: Inhibitory effect of non-steroidal antiin flammatory drugs on mucosal cell proliferation associated with gastric ulcer healing. Lancet 336:840 -843, 1990

    Article  PubMed  Google Scholar 

  3. Konturek PK, Brzozowski T, Konturek SJ, Dembinski A: Role of epidermal growth factor, prostaglandin, and sulfhydryls in stress-induced gastric lesions. Gastroenterology 99:1607-1615, 1990

    PubMed  Google Scholar 

  4. 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

    PubMed  Google Scholar 

  5. Arai I, Hamasaka Y, Futaki N, Takahashi S, Yoshikawa K, Higuchi S, Otomo S: Effect of NS-398, a new nonsteroidal anti-inflammatory agent, on gastric ulceration and acid secretion in rats. Res Commun Chem Pathol Pharmacol 81:259 - 270, 1993

    PubMed  Google Scholar 

  6. Futaki N, Takahashi S, Yokoyama M, Arai I, Higuchi S, Otomo S: NS-938, a new antiinflammatory agent, selectively inhibits prostaglandin G/H synthase /cyclo-oxyge nase (COX-2) activity in vitro.Prostaglandins 47:55-59, 1994

    PubMed  Google Scholar 

  7. Nakatsugi S, Terada N, Yoshimura T, Horie Y, Furukawa M: Effects of nimesulide, a prefential cyclooxygenase-2 inhibitor, on carragee nan-induced pleurisy and stre ss-induced gastric lesions in rats. Prostaglandins Leukot Essen Fatty Acids 55:395-402, 1996

    Google Scholar 

  8. Simmons DL, Xie W, Chipman JG, Evett GE: Multiple cyclooxygenases: Cloning of a mitogen inducible from. InProstaglandins, Leukotrienes, Lipoxins, and PAF. JM Bailey (ed). New York, Plenum Press, 1991, pp 67-78

    Google Scholar 

  9. O'Banion MK, Sadowski HB, Winn V, Young DA: A serumand glucocorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein. J Biol Chem 266:23261-23267, 1991

    PubMed  Google Scholar 

  10. O'Neill GP, Ford-Hutchinson AW: Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissue. FEBS Lett 330:156 -160, 1993

    PubMed  Google Scholar 

  11. Futaki N, Yoshikawa K, Hamasaka Y, Arai I, Higuchi S, Iizuka H, Otomo S: NS-398, a novel non-steroidal antiinflammatory drug with potent analgesic and antipyretic effects, which causes minimal stomach lesions. Gen Pharmacol 24:105-110, 1993

    PubMed  Google Scholar 

  12. Vane JR, Botting RM: New insights into the mode of action of anti-inflammatory drugs. Inflamm Res 44:1-10, 1995

    PubMed  Google Scholar 

  13. Wallace JL, Reuter B, Cicala C, McKnight W, Grisham M, Cirino G: A diclofenac derivative without ulcerogenic properties. Eur J Pharmacol 257:249 -255, 1994

    Article  PubMed  Google Scholar 

  14. Wallace JL, Cirino G, McKnight G, Elliott SN: Reduction of gastrointestinal injury in acute endotoxic shock by flurbiprogen nitroxybutylester. Eur J Pharmacol 280:63-68, 1995

    Article  PubMed  Google Scholar 

  15. Davies NM, Roseth AG, Appleyard CB, McKnight W, Soldato PD, Calignano A, Cirino G, Wallace JL: NO-naproxen vs naproxen: Ulcerogenic, analgesic and anti-inflammatory effects. Aliment Pharmacol Ther 11:69 -79, 1997

    Article  PubMed  Google Scholar 

  16. Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: Physiology, pathophysiology and pharmacology. Pharmacol Rev 43:109- 142, 1991

    PubMed  Google Scholar 

  17. Elliott S, McKnight W, Cirino G, Wallace JL: A nitric oxiderele asing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats. Gastroenterology 109:524 -530, 1995

    PubMed  Google Scholar 

  18. Mizuno H, Sakamoto C, Mastsuda 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

    PubMed  Google Scholar 

  19. Niida H, Takeuchi K, Okabe S: Role of thyrotropin-rele asing hormone in acid secretory response induced by lowering of body temperature in the rat. Eur J Pharmacol 198:137-142, 1991

    Article  PubMed  Google Scholar 

  20. Hirata T, Ukawa H, Yamakuni H, Kato S, Takeuchi K: Cyclooxygenase isozymes in acute mucosal ulcerogenic and functional responses following barrier disruption in rat stomachs. Br J Pharmacol 122:447-454, 1997

    PubMed  Google Scholar 

  21. Takeuchi K, Ukawa H, Konaka A, Kitamura M, Sugawa Y: Effect of nitric oxide-releasing aspirin derivative on gastric functional and ulcerogenic responses in rats: Comparison with plain aspirin. J Pharmacol Exp Ther 1998 ( in press)

  22. Niida H, Takeuchi K, Ueshima K, Okabe S: Vagally mediated acid hypersecretion and lesion formation in anesthetized rat under hypothermic conditions. Dig Dis Sci 36:441-448, 1991

    PubMed  Google Scholar 

  23. Inatomi N, Ishihara Y, Okabe S: Effects of anti-ulcer agents on thermal-cortisone-induced ulcers in rats. Jpn J Pharmacol 29:486 -488, 1979

    PubMed  Google Scholar 

  24. Salvemini D, Wang ZQ, Wyatt PS, Bourdon DM, Marino MH, Manning PP, Currie MG: Nitric oxide: A key mediator in the early and late phase of carragee nan-induced rat paw inflammation. Br J Pharmacol 118:829 -838, 1996

    PubMed  Google Scholar 

  25. Futaki N, Arai I, Hamasaka Y, Takahashi S, Higuchi S, Otomo S: Selective inhibition of NS-398 on prostanoid production in inflamed tissue in rat carragee nan-air pouch inflammation. J Pharm Pharmacol 45:753-755, 1993

    PubMed  Google Scholar 

  26. Wallace JL, Mccready DR, Chin BC, Track NS, Cohen MM: Prostaglandin biosynthesis by gastric mucosa. 1. Studies in rat. Clin Biochem 17:179 -182, 1984

    PubMed  Google Scholar 

  27. Makino R, Sekiya T, Hayashi K: Evaluation of quantitative dete ction of mRNA by the reverse transcription polymerase chain reaction. Technique 2:295-301, 1990

    Google Scholar 

  28. Green LCD, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR: Analysis of nitrate, nitrite and 15N-nitrate in biological fluids. Anal Biochem 126:131-138, 1982

    PubMed  Google Scholar 

  29. Konturek PK, Brzozowski T, Konturek SJ, Dembinski A: Role of epidermal growth factor, prostaglandin, and sulfhydryls in stress-induced gastric lesions. Gastroenterology 99:1607-1615, 1990

    PubMed  Google Scholar 

  30. Ligmusky M, Golanska EM, Hansen DG, Kauffman GL: Aspirin can inhibit gastric mucosal cyclooxygenase without causing lesions in rats. Gastroenterology 84:756 -761, 1983

    PubMed  Google Scholar 

  31. Wallace JL, McKnight W, Soldato PD, Baydoun AR, Cirino G: Anti-thrombotic e ffects of a nitric oxide-releasing, gastricsparing aspirin derivative. J Clin Invest 96:2711-2718, 1995

    PubMed  Google Scholar 

  32. Konturek SJ, Brzozowski T, Stachura J, Konturek P, Ernst H, Hahn EG: Gastric adaptation to aspirin (ASA) acce lerates healing of chronic gastric ulcers. Gastroenterology 108:A–3107, 1995 (abstract)

    Google Scholar 

  33. Wallace JL, McKnight GW, Bell CJ: Adaptation of rat gastric mucosa to aspirin requires mucosal contact. Am J Physiol 268:G134 -G138, 1995

    PubMed  Google Scholar 

  34. Konturek SJ, Brzozowski T, Majka J, Pytko0Polmczyk J, Stachula J: Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers. Eur J Pharmacol 239:215-217, 1993

    Article  PubMed  Google Scholar 

  35. Takeuchi K, Kato S, Takehara K, Asada Y, Yasuhiro T: Role of nitric oxide in mucosal blood flow response and the healing of HCl-induced lesions in the rat stomach. Digestion 58:19 -27, 1997

    PubMed  Google Scholar 

  36. Whittle BJR, Lopez-Belmonte J, Moncada S: Regulation of gastric mucosal integrity by endogenous nitric oxide: interactions with prostanoids and sensory neuropeptides in the rat. Br J Pharmacol 99:607-611, 1990

    PubMed  Google Scholar 

  37. Masferrer JL, Zweifel BS, Manning PA, Hauser SD, Leahy KM, Smith WG, Isakson PC, Seibert K: Selective inhibition of inducible COX-2 in vivois anti-inflammatory and nonulcerogenic. Proc Natl Acad Sci USA 91:3228 -3232, 1994

    PubMed  Google Scholar 

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Authors
  1. Hideki Ukawa
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  2. Hisashi Yamakuni
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  3. Shinichi Kato
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  4. Koji Takeuchi
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Ukawa, H., Yamakuni, H., Kato, S. et al. Effects of Cyclooxygenase-2 Selective and Nitric Oxide-Releasing Nonsteroidal Antiinflammatory Drugs on Mucosal Ulcerogenic and Healing Responses of the Stomach. Dig Dis Sci 43, 2003–2011 (1998). https://doi.org/10.1023/A:1018846912032

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