Digestive Diseases and Sciences

, Volume 39, Issue 2, pp 366–373 | Cite as

Protection against gastric ischemia-reperfusion injury by nitric oxide generators

  • F. J. Andrews
  • C. Malcontenti-Wilson
  • P. E. O'Brien
Originals Articles


Nitric oxide appears to play an important role in maintaining gastric mucosal integrity. This study aimed to investigate whether a nitric oxide donor (sodium nitroprusside) or stimulation of endogenous nitric oxide synthesis (with acetylcholine) protects against gastric ischemia-reperfusion injury. Rats were subjected to 30 min of ischemia followed by 15 min of reperfusion. Injury was assessed by quantitative histology. Intravenous sodium nitroprusside (50–75 µg/kg) or acetylcholine (10–25 µg/kg), immediately before reperfusion, significantly reduced the percentage of mucosal injury compared with controls. Inhibition of nitric oxide synthesis by topical application of 12.5 mg/kgNG-methyl-l-arginine before acetylcholine treatment, abolished the effects of acetylcholine. The protective effects of acetylcholine and sodium nitroprusside did not appear to be related to local vasodilation since neither drug improved gastric blood flow and infusion of a nonnitric oxide vasodilator (papaverine, 1 mg/kg), had no protective effect on reperfusion injury. Sodium nitroprusside (50 µg/kg) and acetylcholine (25 µg/kg) significantly reduced polymorphonuclear leukocyte infiltration and extravasation into the mucosa compared with controls.NG-Methyl-l-arginine pretreatment before acetylcholine abolished these effects. We conclude that nitric oxide generators significantly reduce mucosal injury following ischemia-reperfusion and that this may occur via a reduction in polymorphonuclear leukocyte infiltration into the mucosa.

Key words

nitric oxide ischemia reperfusion gastric mucosa polymorphonuclear leukocyte reactive oxygen metabolite 


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  1. 1.
    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, 1990Google Scholar
  2. 2.
    Lippe IT, Holzer P: Participation of endothelium-derived nitric oxide but not prostacyclin in the gastric mucosal hyperaemia due to acid back-diffusion. Br J Pharmacol 105:708–714, 1992Google Scholar
  3. 3.
    MacNaughton WK, Cirino G, Wallace JL: Endothelium-derived relaxing factor (nitric oxide) has protective actions in the stomach. Life Sci 45:1869–1876, 1989Google Scholar
  4. 4.
    Boughton-Smith NK, Deakin AM, Whittle BJR: Actions of nitric oxide on the acute gastrointestinal damage induced by PAF in the rat. Agents Actions Suppl:C3–C9, 1992Google Scholar
  5. 5.
    Pique JM, Whittle BJR, Esplugues JV: The vasodilator role of endogenous nitric oxide in the rat gastric microcirculation. Eur J Pharmacol 174:293–296, 1989Google Scholar
  6. 6.
    Lucas CE, Sugawa C, Riddle J, Rector F, Rosenberg B, Walt AJ: Natural history and surgical dilemma of stress gastric bleeding. Arch Surg 102:266–273, 1971Google Scholar
  7. 7.
    Guth PH, Paulsen G, Nagata H: Histologic and microcirculatory changes in alcohol-induced gastric lesions in the rat. Effect of prostaglandin cytoprotection. Gastroenterology 87:1083–1090, 1984Google Scholar
  8. 8.
    Kitahora T, Guth PH: Effect of aspirin plus hydrochloric acid on gastric mucosal microcirculation. Gastroenterology 93:810–817, 1987Google Scholar
  9. 9.
    Perry MA, Wadhwa S, Parks DA, Pickard W, Granger DN: Role of oxygen radicals in ischemia-induced lesions in the cat stomach. Gastroenterology 90:362–367, 1986Google Scholar
  10. 10.
    Perry MA, Wadhwa SS: Gradual reintroduction of oxygen reduces reperfusion injury in cat stomach. Am J Physiol 254:G366-G372, 1988Google Scholar
  11. 11.
    Andrews FJ, Malcontenti C, O'Brien PE: Sequence of gastric mucosal injury following ischemia and reperfusion: The role of reactive oxygen metabolites. Dig Dis Sci 37:1356–1362, 1992Google Scholar
  12. 12.
    Pohl U, Busse R: Hypoxia stimulates release of endothelium-derived relaxant factor. Am J Physiol 256:H1595-H1600, 1989Google Scholar
  13. 13.
    Gryglewski RJ, Palmer RMJ, Moncada S: Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 320:454–456, 1986Google Scholar
  14. 14.
    Johnson G, Tsao P, Lefer AM: Synergism between superoxide dismutase and sodium nitrite in cardioprotection following ischemia and reperfusion. Am Heart J 119:530–537, 1990Google Scholar
  15. 15.
    Masini E, Bianchi S, Mugnai L, Gambassi F, Lupini M, Pistelli A, Mannaioni PF: The effect of nitric oxide generators on ischemia reperfusion injury and histamine release in isolated perfused guinea-pig heart. Agents Actions 33:53–56, 1991Google Scholar
  16. 16.
    Lefer AM, Tsao PS, Lefer DJ, Ma XL: Role of endothelial dysfunction in the pathogenesis of reperfusion injury after myocardial ischemia. FASEB J 5:2029–2034, 1991Google Scholar
  17. 17.
    Tsao PS, Aoki N, Lefer DJ, Johnson G, Lefer AM: Time course of endothelial dysfunction and myocardial injury during myocardial ischemia and reperfusion in the cat. Circulation 82:1402–1412, 1990Google Scholar
  18. 18.
    Persson MG, Gustafsson LE, Wiklund NP, Hedqvist P, Moncada S: Endogenous nitric oxide as a modulator of rabbit skeletal muscle microcirculationin vivo. Br J Pharmacol 100:463–466, 1990Google Scholar
  19. 19.
    Kitagawa H, Takeda F, Kohei H: Effect of endothelium-derived relaxing factor on the gastric lesion induced by HCl in rats. J Pharmacol Exp Ther 253:1133–1137, 1990Google Scholar
  20. 20.
    O'Brien PE, Schultz C, Gannon B: An evaluation of the phenomenon of cytoprotection using quantitative histological criteria. J Gastroenterol Hepatol 2:113–121, 1987Google Scholar
  21. 21.
    Andrews FJ, Malcontenti C, O'Brien PE: Polymorphonuclear leukocyte infiltration into the gastric mucosa following ischemia/reperfusion. Am J Physiol 1993 (in press)Google Scholar
  22. 22.
    Holm-Rutili L, Obrink KJ: Rat gastric microcirculationin vivo. Am J Physiol 248:G741-G746, 1985Google Scholar
  23. 23.
    Winer BJ: Statistical Principles in Experimental Design. New York, McGraw-Hill, 1971Google Scholar
  24. 24.
    Ratych RE, Chuknyiska RS, Bulkley GB: The primary localization of free radical generation after anoxia/reoxygenation in isolated endothelial cells. Surgery 102:122–131, 1987Google Scholar
  25. 25.
    Hernandez LA, Grisham MB, Twohig B, Arfors KE, Harlan JM, Granger DN: Role of neutrophils in ischemia-reperfusion-induced microvascular injury. Am J Physiol 253:H699-H703, 1987Google Scholar
  26. 26.
    Aoki N, Johnson G, Lefer AM: Beneficial effects of two forms of NO administration in feline splanchnic artery occlusion shock. Am J Physiol 258:G275-G281, 1990Google Scholar
  27. 27.
    Radomski MW, Palmer RMJ, Moncada S: Endogenous nitric oxide inhibits platelet adhesion to vascular endothelium. Lancet 2:1057–1058, 1987Google Scholar
  28. 28.
    Kubes P, Suzuki M, Granger DN: Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 88:4651–4655, 1991Google Scholar
  29. 29.
    Grisham MB, Hernandez LA, Granger DN: Xanthine oxidase and neutrophil infiltration in intestinal ischemia. Am J Physiol 251:G567-G574, 1986Google Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • F. J. Andrews
    • 1
  • C. Malcontenti-Wilson
    • 1
  • P. E. O'Brien
    • 1
  1. 1.From the Department of SurgeryMonash Medical School, Alfred HospitalPrahranAustralia

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