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. 1992 Dec;107(4):1159–1162. doi: 10.1111/j.1476-5381.1992.tb13423.x

Protective effects of inhibitors of nitric oxide synthase in immune complex-induced vasculitis.

M S Mulligan 1, S Moncada 1, P A Ward 1
PMCID: PMC1907958  PMID: 1281719

Abstract

1. The ability of analogues of L-arginine (N-iminoethyl-L-ornithine (L-NIO), NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine methyl ester (L-NAME) and NG-nitro-L-arginine (L-NNA)) to protect against inflammatory injury induced by activated neutrophils was investigated in rats following intradermal or intrapulmonary deposition of immune complexes. 2. The descending order of potency for protective effects of these analogues was: L-NIO > L-NMMA > L-NNA = L-NAME. The approximate IC50 value for L-NIO in the dermal vasculitis model was 65 microM. For all other compounds, the IC50 values were > 5 mM. 3. The protective effect of L-NIO in the skin was reversed in a dose-dependent manner by the presence of L-arginine, but not by D-arginine. L-Arginine also reversed the protective effects of L-NIO in immune complex-induced lung injury. 4. The protective effects of L-NIO were not associated with reductions in neutrophil accumulation, as measured by extraction from tissues of myeloperoxidase. 5. These data demonstrate that L-NIO has the most potent protective effects against immune complex-induced vascular injury induced by activated macrophages. Furthermore, they indicate that this injury is dependent upon the generation of nitric oxide.

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Selected References

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  1. Beckman J. S., Beckman T. W., Chen J., Marshall P. A., Freeman B. A. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1620–1624. doi: 10.1073/pnas.87.4.1620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Billiar T. R., Curran R. D., Ferrari F. K., Williams D. L., Simmons R. L. Kupffer cell:hepatocyte cocultures release nitric oxide in response to bacterial endotoxin. J Surg Res. 1990 Apr;48(4):349–353. doi: 10.1016/0022-4804(90)90073-b. [DOI] [PubMed] [Google Scholar]
  3. Curran R. D., Billiar T. R., Stuehr D. J., Ochoa J. B., Harbrecht B. G., Flint S. G., Simmons R. L. Multiple cytokines are required to induce hepatocyte nitric oxide production and inhibit total protein synthesis. Ann Surg. 1990 Oct;212(4):462–471. doi: 10.1097/00000658-199010000-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Drapier J. C., Hibbs J. B., Jr Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible. J Clin Invest. 1986 Sep;78(3):790–797. doi: 10.1172/JCI112642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Hibbs J. B., Jr, Taintor R. R., Vavrin Z., Rachlin E. M. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun. 1988 Nov 30;157(1):87–94. doi: 10.1016/s0006-291x(88)80015-9. [DOI] [PubMed] [Google Scholar]
  6. Hibbs J. B., Jr, Vavrin Z., Taintor R. R. L-arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells. J Immunol. 1987 Jan 15;138(2):550–565. [PubMed] [Google Scholar]
  7. Johnson K. J., Ward P. A. Acute immunologic pulmonary alveolitis. J Clin Invest. 1974 Aug;54(2):349–357. doi: 10.1172/JCI107770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Johnson K. J., Ward P. A. Role of oxygen metabolites in immune complex injury of lung. J Immunol. 1981 Jun;126(6):2365–2369. [PubMed] [Google Scholar]
  9. Marletta M. A., Yoon P. S., Iyengar R., Leaf C. D., Wishnok J. S. Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate. Biochemistry. 1988 Nov 29;27(24):8706–8711. doi: 10.1021/bi00424a003. [DOI] [PubMed] [Google Scholar]
  10. McCall T. B., Boughton-Smith N. K., Palmer R. M., Whittle B. J., Moncada S. Synthesis of nitric oxide from L-arginine by neutrophils. Release and interaction with superoxide anion. Biochem J. 1989 Jul 1;261(1):293–296. doi: 10.1042/bj2610293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. McCall T. B., Feelisch M., Palmer R. M., Moncada S. Identification of N-iminoethyl-L-ornithine as an irreversible inhibitor of nitric oxide synthase in phagocytic cells. Br J Pharmacol. 1991 Jan;102(1):234–238. doi: 10.1111/j.1476-5381.1991.tb12159.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Mulligan M. S., Hevel J. M., Marletta M. A., Ward P. A. Tissue injury caused by deposition of immune complexes is L-arginine dependent. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6338–6342. doi: 10.1073/pnas.88.14.6338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Schmidt H. H., Seifert R., Böhme E. Formation and release of nitric oxide from human neutrophils and HL-60 cells induced by a chemotactic peptide, platelet activating factor and leukotriene B4. FEBS Lett. 1989 Feb 27;244(2):357–360. doi: 10.1016/0014-5793(89)80562-9. [DOI] [PubMed] [Google Scholar]
  14. Stuehr D. J., Nathan C. F. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989 May 1;169(5):1543–1555. doi: 10.1084/jem.169.5.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Vogt W., Damerau B., von Zabern I., Nolte R., Brunahl D. Non-enzymic activation of the fifth component of human complement, by oxygen radicals. Some properties of the activation product, C5b-like C5. Mol Immunol. 1989 Dec;26(12):1133–1142. doi: 10.1016/0161-5890(89)90057-6. [DOI] [PubMed] [Google Scholar]
  16. Warren J. S., Yabroff K. R., Mandel D. M., Johnson K. J., Ward P. A. Role of O2- in neutrophil recruitment into sites of dermal and pulmonary vasculitis. Free Radic Biol Med. 1990;8(2):163–172. doi: 10.1016/0891-5849(90)90089-2. [DOI] [PubMed] [Google Scholar]
  17. Wright C. D., Mülsch A., Busse R., Osswald H. Generation of nitric oxide by human neutrophils. Biochem Biophys Res Commun. 1989 Apr 28;160(2):813–819. doi: 10.1016/0006-291x(89)92506-0. [DOI] [PubMed] [Google Scholar]
  18. von Zabern W. V., Hesse D., Nolte R., Haller Y. Generation of an activated form of human C5 (C5b-like C5) by oxygen radicals. Immunol Lett. 1987 Feb;14(3):209–215. doi: 10.1016/0165-2478(87)90103-9. [DOI] [PubMed] [Google Scholar]

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