Skip to main content

Dual effects ofN-ethylmaleimide on ethanol-induced gastric lesions in rats

Digestive Diseases and Sciences volume 36, pages 870–879 (1991)Cite this article

Abstract

The effects ofN-ethylmaleimide (NEM), a sulfhydryl (SH) blocker, on ethanol-induced gastric lesions were investigated in rats by varying the route of administration. Oral administration of acidified ethanol (60% ethanol in 150 mM HCl, 1 ml) produced hemorrhagic bandlike lesions in the gastric mucosa. Pretreatment of the animals with orally administered NEM (0.1–10 mg/kg) dose-dependently inhibited these lesions (the inhibition was over 80% at 1mg/kg or greater) and the effects were partially reversed by indomethacin (5 mg/kg, subcutaneous). However, when NEM (10 mg/kg) was given subcutaneously, this agent significantly worsened the lesions. Intragastrically applied NEM produced a dose-dependent reduction of the transmucosal potential difference (PD) and the mucosal nonprotein SH levels, an, increase of the volume of gastric contents, and an inhibition of gastric motility, while these parameters remained unaltered after subcutaneous administration of the agent. The microvascular permeability in the mucosa was significantly increased by both oral and subcutaneous administration of NEM (10 mg/kg) but remained unchanged in response to lower doses of orally administered (<3 mg/kg). These results suggest that NEM given orally is cytoprotective, to the stomach against ethanol, probably by acting as a mild irritant and due to dilution of an irritant and inhibition of gastric motility (muscle relaxation), but when given subcutaneously it aggravates the lesions by unknown mechanisms.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Szabo S, Trier JS, Frankel PW: Sulfhydryl compounds may mediate gastric cytoprotection. Science 214:200–202, 1981

    Google Scholar 

  2. Szabo S, Szelenyi I: Cytoprotection, in gastrointestinal pharmacology. Trends Pharmacol Sci 8:149–154, 1987

    Google Scholar 

  3. Robert A, Aberle D, Kaplowitz N: Role of glutathione in gastric mucosal protection. Am J Physiol 247:G296-G304, 1984

    Google Scholar 

  4. Robert A, Lancaster C, Olfsson AS, Gilbertson SK:N-Ethylmaleimide (NEM) either protects or damages the gastric mucosa depending on route and duration of administration. Gastroenterology 94:A-377, 1988, (abstract)

    Google Scholar 

  5. Takeuchi K, Okabe S: Role of luminal alkalinization in repair process of ethanol-induced mucosal damage in rat stomach. Dig Dis Sci 28:993–1000, 1983

    Google Scholar 

  6. Mersereau WA, Hinchey EJ: Dissolution of mucosal foldings by prostaglandins; an explanation of cytoprotection. Gastroenterology 80:A-1230, 1981 (abstract)

    Google Scholar 

  7. Takeuchi K, Nishiwaki H, Ishihara Y, Okabe S: Roles of gastric motility changes in cytoprotection induced by acetazolamide and cysteamine in rats. Jpn J Pharmacol 44:269–281, 1987

    Google Scholar 

  8. Takeuchi K, Nishiwaki H, Okada M, Okabe S: Mucosal protective action of histamine against gastric motor activity mediated by H2-receptors. J Pharmacol Exp Ther 245:632–638, 1988

    Google Scholar 

  9. Takeuchi K, Nobuhara Y: Inhibition of gastric motor activity by 16,16-dimethyl prostaglandin, E2 in rats: A possible explanation for cytoprotection. Dig Dis Sci 31:1181–1188, 1985

    Google Scholar 

  10. Szabo S, Trier JS: Pathogenesis of acute gastric mucosal injury; Sulfhydryls as a protector, adrenal cortes as a modulator, and vascular endothelium as a target.In Mechanisms of Mucosal Protection in the Upper Gastrointestinal Tract. A Allen, A Garner G Flemstrom, W Silen LA Turnberg (eds). New York, Raven Press, 1984, pp 287–293

    Google Scholar 

  11. Nishiwaki H, Okada M, Hara N, Takeuchi K, Okabe S: Mechanisms involved in aggravation of ethanol-induced gastric mucosal lesions in adrenalectomized rats. Jpn J Pharmacol 49:27–36, 1989

    Google Scholar 

  12. Takeuchi K, Furukawa O, Nishiwaki H, Okabe S: 16,16-Dimethyl prostaglandin E2 aggravates gastric mucosal injury caused by histamine in rats; possible involvement of the increased vascular permeability. Gastroenterology 93:1276–1288

  13. Katayama S, Shionoya H, Ohtake S: A new method for extraction of extravasated dye in the skin and the influence of fasting stress on passive cutaneous anaphylaxis in guinea pigs and rats. Microbiol Immunol 22:89–101, 1978

    Google Scholar 

  14. Kaplowitz N, Kuhlenkamp J, Goldstein JL, Reeve J: Effect of salicylates and phenobarbital on hepatic glutathione in the rat. J Pharmacol Exp Ther 212:240–245, 1980

    Google Scholar 

  15. Dunnett CW: A multiple comparison procedure for comparing several treatments with a control. Am J Stat Assoc 50:1096–1121, 1955

    Google Scholar 

  16. Hiroshige Y: The effects of copper and copperO-phenanthroline complex on the intact human erythrocytes. Tohoku J Med 130:385–402, 1980

    Google Scholar 

  17. Takeuchi K, Okada M, Niida H, Okabe S: Role of sulfhydryls in mucosal, injury caused by ethanol; Relation to microvascular permeability, gastric mobility and cytoprotection. J Pharmacol Exp Ther 248:836–841, 1989

    Google Scholar 

  18. Dupuy D, Szabo S: Protection by metals against ethanol-induced gastric mucosal injury in the rat; Comparative biochemical and pharmacologic studies implicate protein sulfhydryls. Gastroenterology 91:966–974, 1986

    Google Scholar 

  19. Takeuchi K, Yamakuni H, Nobuhara Y, Okabe S: Functional and morphologic alterations in the rat stomach following exposure to hypertonic NaCl solutions. Jpn J Pharmacol 42:549–560, 1986

    Google Scholar 

  20. Takeuchi K, Ohno T, Okabe S: Irritative and protective activity of mild irritants in the rat stomach. Dig Dis Sci 32:889–896, 1987

    Google Scholar 

  21. Robert A, Nezamis JE, Lancaster C, Davis JP, Field SO, Hachar AJ: Mild irritants prevent gastric necrosis through “adaptive cytoprotection” mediated by prostaglandins. Am J Physiol 245:G113-G121, 1983

    Google Scholar 

  22. Szabo S, Pihan G, Rozo A, Mullon EA, Hausohka FV: Multiple mechanisms of cell injury in the gastric mucosa. Fed Proc 46:1152, 1987 (abstract)

    Google Scholar 

  23. Szabo S, Trier JS, Brown A, Schnoor J: Sulfhydryl blockers induce severe inflammatory gastritis in the rat. Gastroenterology 86:1271, 1984 (abstract)

    Google Scholar 

  24. Dupuy D, Kronauge JF, Jones AG, Szabo S: Gastric mucosal protection may be mediated through increases in vascular permeability which creates a histo-dilutional barrier. Gastroenterology 94:A-615, 1988 (abstract)

    Google Scholar 

  25. Palitzsch KD, Morales RE, Kronauge JF, Szabo S: Biphasic effect of histamine on hemorrhagic mucosal lesions is related to vascular permeability; Studies with histamine, H1-, H2-, and H3-agonists and bradykinin. Gastroenterology 96:A-381, 1989 (abstract)

    Google Scholar 

  26. Takeuchi K, Nishiwaki H, Okabe S: Effects of dopamine on gastric mucosal lesions induced by ethanol in rats: Possible involvement of antigastric motor activity mediated with 879-1. Dig Dis Sci 33:1560–1568, 1988

    Google Scholar 

  27. Szabo S, Trier JS, Brown A, Schnoor J: Early vascular injury and increased vascular permeability in gastric mucosal injury caused by ethanol in the rat. Gastroenterology 88:228–236, 1985

    Google Scholar 

  28. Bou-Abboud CF, Wayland H, Paulsen G, Guth PH: Microcirculatory stasis precedes tissue necrosis in ethanol-induced gastric mucosal injury in the rat. Dig Dis Sci 33:872–877, 1988

    Google Scholar 

  29. Neering DR, Glover WE: The role of sulfhydryl groups in contraction of vascular smooth muscle. J Pharmacol Exp Ther 208:335–340, 1979

    Google Scholar 

Download references

Author information

Affiliations

  1. Department of Applied Pharmacology, Kyoto Pharmaceutical University, Misasagi, Yamashina, 607, Kyoto, Japan

    Koji Takeuchi PhD, Megumu Okada MA, Hiromichi Niida MA & Susumu Okabe PhD

Authors
  1. Koji Takeuchi PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Megumu Okada MA
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiromichi Niida MA
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susumu Okabe PhD
    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

Takeuchi, K., Okada, M., Niida, H. et al. Dual effects ofN-ethylmaleimide on ethanol-induced gastric lesions in rats. Digest Dis Sci 36, 870–879 (1991). https://doi.org/10.1007/BF01297134

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01297134

Key Words

  • ethanol
  • gastric lesion
  • N-ethylmaleimide
  • sulfhydryl
  • route of administration