Agents and Actions

, Volume 36, Supplement 1, pp C3–C9 | Cite as

Actions of nitric oxide on the acute gastrointestinal damage induced by PAF in the rat

  • Nigel K. Boughton-Smith
  • Angela M. Deakin
  • Brendan J. R. Whittle
Experimental Aspects of Gastrointestinal Inflammation New Approaches to Therapy of Gastrointestinal Inflammation General Inflammation Research Topics 3rd Meeting on Side Effects of Anti-Inflammatory Drugs and 13th European Workshop on Inflammation Verona, Italy Experimental Aspects of Gastrointestinal Inflammation
  • 17 Downloads

Abstract

The actions of nitric oxide (NO) on the acute gastrointestinal damage induced by platelet-activating factor (PAF) have been investigated in the rat.S-nitroso-N-acetyl penicillamine, which spontaneously generates NO, dose-dependently inhibited PAF-induced gastrointestinal plasma leakage, a measure of the initiation of vascular damage. The inhibitor of NO synthase,NG-monomethyl-l-arginine substantially potentiated gastrointestinal damage and plasma leakage induced byE. coli endotoxin, but had no effect on that induced by intravenous infusion of PAF.

Endogenous NO may thus have a protective role in the gastrointestinal vascular that can be mimicked by generators of NO. The protection afforded by endogenous NO may, however, be dependent on the nature of the inflammatory stimulus used to induce gastrointestinal damage.

Keywords

Oxide Nitric Oxide Protective Role Intravenous Infusion Penicillamine 

References

  1. [1]
    P. Braquet, T.Y. Shen, L. Touqui and B.B. Vargaftig,Perspectives in platelet-activating factor research. Pharmacol. Rev.39, 97–145 (1987).PubMedGoogle Scholar
  2. [2]
    A.-C. Rosam, J.L. Wallace and B.J.R. Whittle,Potent ulcerogenic actions of platelet-activating factor on the stomach. Nature319, 54–56 (1986).CrossRefPubMedGoogle Scholar
  3. [3]
    B.J.R. Whittle, N.K. Boughton-Smith, I.R. Hutcheson, J.V. Esplugues and J.L. Wallace,Increased intestinal formation of PAF in endotoxin-induced damage in the rat. Br. J. Pharmacol.92, 3–4 (1987).PubMedGoogle Scholar
  4. [4]
    N. K. Boughton-Smith, I. Hutcheson and B.J.R. Whittle,Relationship between PAF-acether and thromboxane A 2 biosynthesis in endotoxin-induced intestinal damage in the rat. Prostaglandins38, 319–333 (1989).CrossRefPubMedGoogle Scholar
  5. [5]
    J. L. Wallace, G. Steel, B. J. R. Whittle, V. Lagenete and B. Vargaftig,Evidence for platelet-activating factor as a mediator of endotoxin-induced gastrointestinal damage in rat. Effects of three platelet-activating factor antagonists. Gastroenterology93, 765–773 (1987).PubMedGoogle Scholar
  6. [6]
    S. Moncada, R. M. J. Palmer and E. A. Higgs,Biosynthesis of nitric oxide from l-arginine. A pathway for regulation of cell function and communication. Biochem. Pharmacol.38, 1709–1715 (1989).CrossRefPubMedGoogle Scholar
  7. [7]
    R. M. J. Palmer, D. D. Rees, D. S. Ashton and S. Moncada,l-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem. Biophys. Res. Commun.153, 1251–1256 (1988).CrossRefPubMedGoogle Scholar
  8. [8]
    I. R. Hutcheson, B. J. R. Whittle and N. K. Boughton-Smith,Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat. Br. J. Pharmacol.101, 815–820 (1990).PubMedGoogle Scholar
  9. [9]
    L. J. Ignarro, H. Lippton, J. C. Edwards, W. H. Baricos, A. L. Hyman, J. Kadowitz and C. A. Greutter,Mechanisms of vascular smooth muscle relaxation by organic nitrates, nitrates, nitroprusside and nitric oxide. Evidence for the involvement of S-nitrosothiols as active ingredients. J. Pharmacol. Exp. Ther.218, 739–749 (1981).PubMedGoogle Scholar
  10. [10]
    N. K. Boughton-Smith, I. R. Hutcheson, A. M. Deakin, B. J. R. Whittle and S. Moncada,Protective effect of S-nitroso-N-acetyl-pencillamine in endotoxin-induced acute intestinal damage in the rat. Eur. J. Pharmacol.191, 485–488 (1990).CrossRefPubMedGoogle Scholar
  11. [11]
    J. L. Wallace and B. J. R. Whittle,Effects of inhibitors of arachidonic acid metabolism on PAF-induced gastric mucosal necrosis and haemoconcentration. Br. J. Pharmacol.89, 415–422 (1986).PubMedGoogle Scholar
  12. [12]
    B. J. R. Whittle, T. Morishita, Y. Ohya, F. W. Leung and P. H. Guth,Microvascular actions of platelet-activating factor on rat gastric mucosa and submucosa. Am. J. Physiol.251, G772-G778 (1986).PubMedGoogle Scholar
  13. [13]
    J. L. Wallace and B. J. R. Whittle,Picomole doses of platelet-activating factor predispose the gastric mucosa to damage by topical irritants. Prostaglandins31, 989–998 (1986).CrossRefPubMedGoogle Scholar
  14. [14]
    J. M. Pique, Y. Yonei, B. J. R. Whittle, F. W. Leung and P. J. Guth,Indomethacin potentiates endotoxin-induced blood flow reduction and histological injury in rat gastric mucosa. Br. J. Pharmacol.93, 925–931 (1988).PubMedGoogle Scholar
  15. [15]
    T. B. McCall, B. J. R. Whittle, N. K. Boughton-Smith and S. Moncada,Inhibition of FMLP-induced aggregation of rabbit neutrophils by nitric oxide. Br. J. Pharmacol.95, 571P (1988).Google Scholar
  16. [16]
    M. W. Radomski, R. M. J. Palmer and S. Moncada,Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancetii, 1057–1058 (1987).CrossRefGoogle Scholar
  17. [17]
    J. C. Fantone and P. A. Ward,Role of oxygen-derived free radicals and metabolites in leukocyte-dependent inflammatory reactions. Am. J. Pathol.107, 397–418 (1982).Google Scholar
  18. [18]
    J. P. Cueva and W. Hsueh,Role of oxygen-derived free radicals in platelet-activating factor induced bowel necrosis. Gut24, 1207–1212.Google Scholar
  19. [19]
    P. Kubes, M. Suzuki and N. Granger,Modulation of PAF-induced leukocyte adherence and increase in microvascular permeability. Am. J. Physiol.259, G859-G864 (1990).PubMedGoogle Scholar
  20. [20]
    T. B. McCall, N. K. Boughton-Smith, R. M. J. Palmer, B. J. R. Whittle and S. Moncada,Synthesis of nitric oxide from l-arginine by neutrophils. Release and interaction with superoxide anion. Biochem. J.261, 293–296 (1989).PubMedGoogle Scholar
  21. [21]
    J. S. Beckman, T. W. Beckman, J. Chen, P. A. Marshall and A. Freeman,Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. USA87, 1620–1624 (1990).PubMedGoogle Scholar
  22. [22]
    B. J. R. Whittle, J. Lopez-Belmonte and S. Moncada,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).PubMedGoogle Scholar
  23. [23]
    D. Salvemini, R. Korbut, E. Anggard and J. R. Vane,Immediate release of a nitric oxide-like factor from bovine aortic endothelial cells by Escherichia coli lipopolysacharide. Proc. Natl. Acad. Sci. USA87, 2593–2597 (1990).PubMedGoogle Scholar
  24. [24]
    R. G. Knowles, M. Salter, S. L. Brooks and S. Moncada,Anti-inflammatory glucocorticoids inhibit the induction by endotoxin of nitric oxide synthase in the lung, liver and aorta of the rat Biochem. Biophys. Res. Commun.172, 1042–1048 (1990).CrossRefPubMedGoogle Scholar
  25. [25]
    M. W. Radomski, R. M. J. Palmer and S. Moncada,Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc. Natl. Acad. Sci. USA87, 10043–10047 (1990).PubMedGoogle Scholar
  26. [26]
    D. D. Rees, S. Cellek, R. M. J. Palmer and S. Moncada,Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone: An insight into endotoxin shock. Biochem. Biophys. Res. Commun.173, 541–547 (1990).PubMedGoogle Scholar
  27. [27]
    P. Vallance and S. Moncada,Hypothesis: Induction of nitric oxide synthase in the vasculature underlies the hyperdynamic circulation of cirrhosis. Lancet337, 776–778 (1991).CrossRefPubMedGoogle Scholar
  28. [28]
    P. Pizcueta, J. M. Pique, J. Bosch, B. J. R. Whittle and S. Moncada,Effects of endogeneous nitric oxide inhibition on the hemodynamic changes of portal hypertensive rats. Gastroenterology100, (1991).Google Scholar
  29. [29]
    A. J. Wakefield, A. P. Dhillon, P. M. Rowles, A. M. Sawyer, R. M. Pittilo, A. A. M. Lewis and R. E. Pounder,Pathogenesis of Crohn's disease. Multifocal gastrointestinal infarction. Lancet 1057–1062 (1989).Google Scholar

Copyright information

© Birkhäuser Verlag 1992

Authors and Affiliations

  • Nigel K. Boughton-Smith
    • 1
  • Angela M. Deakin
    • 1
  • Brendan J. R. Whittle
    • 1
  1. 1.Department of PharmacologyWellcome Research LaboratoriesBeckenhamUK

Personalised recommendations