Skip to main content
SpringerLink
Log in
Book cover

Septic Shock Methods and Protocols pp 115–131Cite as

Nitric Oxide Synthase Inhibitors

  • Protocol

  • 655 Accesses

Part of the book series: Methods in Molecular Medicine™ ((MIMM,volume 36))

Abstract

In 1990, several studies reported that an enhanced formation of endogenous nitric oxide (NO) contributes to the hypotension caused by endotoxin and tumor-necrosis factor-α (TNFα) (1–3). In addition, it became apparent that this overproduction of NO also plays an important role in the pathophysiology of the vascular hyporesponsiveness to vasoconstrictor agents (also termed vasoplegia) (4,5). Since then, many studies have reported on the effects and side effects of NO synthase (NOS) inhibitors in animal models of shock. Prior to discussing the pharmacology of various classes of NOS inhibitors, this chapter will briefly introduce the physiological role(s) of NO as well as the various (beneficial as well as detrimental) roles of NO in animal models of septic shock.

This is a preview of subscription content, log in via an institution.

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Thiemermann, C. and Vane, J. R. (1990) Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharide in the rat. Eur. J. Pharmacol. 182, 591–595.

    Article  CAS  PubMed  Google Scholar 

  2. Kilbourn, R. G., Juburan, A., Gross, S. S., Griffith, O. W., Levi, R., and Adams, J. (1990) Reversal of endotoxin-mediated shock by NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem. Biophys. Res. Commun. 172, 1132–1138.

    Article  CAS  PubMed  Google Scholar 

  3. Kilbourn, R. G., Gross, S. S., Jubran, A., Adams, J., Griffith, O. W., Levi, R., and Lodato, R. F. (1990) NG-methyl-L-arginine inhibits tumour necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc. Natl. Acad. Sci. USA 87, 3629–3632.

    Article  CAS  PubMed  Google Scholar 

  4. Julou-Schaeffer, G., Gray, G. A., Fleming, I., Schott, C., Parratt, J. R., and Stoclet, J. C. (1990) Loss of vascular responsiveness induced by endotoxin involves the L-arginine pathway. Am. J. Physiol. 259, H1038–H1043.

    CAS  PubMed  Google Scholar 

  5. Rees, D. D., Cellek, S., Palmer, R. M. J., and Moncada, S. (1990) Dexamethasone prevents the induction of nitric oxide synthase and the associated effects on the vascular tone: an insight into endotoxic shock. Biochem. Biophys. Res. Commun. 173, 541–547.

    Article  CAS  PubMed  Google Scholar 

  6. Nathan, C. (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J. 6, 3051–3064.

    CAS  PubMed  Google Scholar 

  7. Morris, S. M. and Billiar, T. R. (1994) New insights into the regulation of inducible nitric oxide synthase. Am. J. Physiol. 266, E829–E839.

    CAS  PubMed  Google Scholar 

  8. Moncada, S. and Higgs, A. (1993) The L-arginine-nitric oxide pathway. N. Eng. J. Med. 329, 2202–2212.

    Google Scholar 

  9. Southan, G. J. and Szabo, C. (1996) Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. Biochem. Pharmacol. 51, 383–394.

    Article  CAS  PubMed  Google Scholar 

  10. Thiemermann, C. (1994) The role of L-arginine:nitric oxide pathway in circulatory shock. Adv. Pharmacol. 28, 45–79.

    Article  CAS  PubMed  Google Scholar 

  11. Szabo, C. and Thiemermann, C. (1995) Regulation of the expression of the inducible isoform of nitric oxide synthase. Adv. Pharmacol. 34, 113–154.

    Article  CAS  PubMed  Google Scholar 

  12. Loscalzo, J. and Welsch, G. (1995) Nitric oxide and its role in the cardiovascular system. Proj. Cardiovasc. Dis. 38, 87–104.

    Article  CAS  Google Scholar 

  13. Szabo, C. (1995) Alterations in nitric oxide production in various forms of circulatory shock. Horizon 1, 2–32.

    Google Scholar 

  14. MacMicking, J. D., Nathan, C., Hom, G. et al. (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81, 641–650.

    Article  CAS  PubMed  Google Scholar 

  15. Wei, X., Charles, I. G., Smith, A. et al. (1995) Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375, 408–411.

    Article  CAS  PubMed  Google Scholar 

  16. Kilbourn, R. G., Traber, D. L., and Szabo, C. (1997) Beneficial versus detrimental effects of nitric oxide synthase inhibitors in circulatory shock: lessons learned from experimental and clinical studies. Shock 7, 235–246.

    Article  CAS  PubMed  Google Scholar 

  17. Wu, C. C., Ruetten, H., and Thiemermann, C. (1996) Comparison of the effects of aminoguanidine and NG-nitro-L-arginine methyl ester on the multiple organ dysfunction caused by endotoxemia in the rat. Eur. J. Pharmacol. 300, 99–104.

    Article  CAS  PubMed  Google Scholar 

  18. Gross, S. S., Stuehr, D. J., Aisaka, K., Jaffe, E. A., Levi, R., and Griffith, O. W. (1990) Macrophage and endothelial nitric oxide synthesis: cell-type selective inhibition by NG-aminoarginine, NG-nitroarginine and NG-methyl-arginine. Biochem. Biophys. Res. Commun. 170, 96–103.

    Article  CAS  PubMed  Google Scholar 

  19. Feldmann, P. L., Griffith, O. W., Honh, H., and Stuehr, D. (1993) Irreversible inactivation of macrophage and brain nitric oxide synthase by L-NG-methyl arginine requires NADPH-dependent hydroxylation. J. Med. Chem. 36, 491–496.

    Article  Google Scholar 

  20. Shultz, P. J. and Raij, L. (1992) Endogenously synthetized nitric oxide prevents endotoxin-induced glomerular thrombosis. J. Clin. Invest. 90, 1718–1725.

    Article  CAS  PubMed  Google Scholar 

  21. Meyer, J., Traber, L. D., Nelson, S., Lentz, C. W., Nakazawa, H., Herndon, D. N., Noda, H., and Traber, D. L. (1992) Reversal of hyperdynamic response to continuous endotoxin administration by inhibition of NO synthesis. J. Appl. Physiol. 73, 324–328.

    CAS  PubMed  Google Scholar 

  22. Meyer, J., Lentz, C. W., Stothert, J. C., Traber, L. D., Herndon, D. N., and Traber, D. L. (1994) Effects of nitric oxide synthesis inhibition in hyperdynamic endotoxemia. Crit. Care. Med. 22, 306–312.

    Article  CAS  PubMed  Google Scholar 

  23. Strohmeier, W., Werner, E. R., Redl, H., Wachter, H., and Schlag, G. (1995) Plasma nitrate and pteridine levels in experimental bacteremia in baboons. Pteridines 6, 8–11.

    Google Scholar 

  24. Corbett, J. A., Tilton, R. G., Chang, K., Hasan, K. S., Ido, Y., Wang, J. L., Sweetland, M. A., Lancaster, J. R., Williamson, J. R., and McDaniel, M. L. (1992) Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes 41, 552–558.

    Article  CAS  PubMed  Google Scholar 

  25. Misko, T. P., Moore, W. M., Kasten, T. P., Nickols, D. A., Corbett, J. A., Tilton, R. G., McDaniel, M. L., Williamson, J. R., and Currie, M. G. (1993) Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur. J. Pharmacol. 233, 119–125.

    Article  CAS  PubMed  Google Scholar 

  26. Griffith, M. J., Messent, M., MacAllister, R. J., and Evans, T. W. (1993) Aminoguanidine selectively inhibits inducible nitric oxide synthase. Br. J. Pharmacol. 110, 963–968.

    Google Scholar 

  27. Joly, G. A., Ayres, M., Chelly, F., and Kilbourn, R. G. (1990) Effects of NG-methyl-L-arginine, NG-nitro-L-arginine and aminoguanidine on constitutive and inducible nitric oxide synthase in rat aorta. Biochem. Biophys. Res. Commun. 199, 147–154.

    Article  Google Scholar 

  28. Wu, C. C., Chen, S. J., Szabo, C., Thiemermann, C., and Vane, J. R. (1995) Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock. Br. J. Pharmacol. 114, 1666–1672.

    CAS  PubMed  Google Scholar 

  29. Wolff, D. J. and Lubeskie, A. (1995) Aminoguanidine is an isoform-selective, mechanism-based inactivator of nitric oxide synthase. Arch. Biochem. Biophys. 316, 290–301.

    Article  CAS  PubMed  Google Scholar 

  30. Ruetten, H., Southan, G. J., Abate, A., and Thiemermann, C. (1996) Attenuation of the multiple organ dysfunction caused by endotoxin by 1-amino-2-hydroxy-guanidine, a potent inhibitor of inducible nitric oxide synthase. Br. J. Pharmacol. 118, 261–270.

    CAS  PubMed  Google Scholar 

  31. Seo, H. G., Fujiwara, N., Kaneto, H., Asashi, M., Fujii, J., and Taniguchi, N. (1996) Effect of the nitric oxide synthase inhibitor, S-ethyl-isothiourea, on cultured cells and cardiovascular functions of normal and lipopolysaccharide-treated rabbits. J. Biochem. 119, 553–558.

    CAS  PubMed  Google Scholar 

  32. Muller, C. M., Scierka, A., Stiller, R. L., Kim, Y. M., Cook, D. R., Lancaster, J. R., Buffington, C. W., and Watkins, W. D. (1996) Nitric oxide mediates hepatic cytochrome P450 dysfunction induced by endotoxin. Anesthesiology 84, 1435–1442.

    Article  CAS  PubMed  Google Scholar 

  33. Ou, J., Molina, L., Kim, Y. M., and Billiar, T. R. (1996) Excessive NO production does not account for the inhibition of hepatic gluconeogenesis in endotoxemia. Am. J. Physiol. 271, 621–628.

    Google Scholar 

  34. Klabunde, R. E. and Coston, A. F. (1995) Nitric oxide synthase inhibition does not prevent cardiac depression in endotoxic shock. Shock 3, 73–78.

    CAS  PubMed  Google Scholar 

  35. Sorrells, D. L., Friend, C., Koltuksuk, U., Courcoulas, A., Boyle, P., Garrett, M., Watkins, S., Rowe, M. I., and Ford, H. R. (1996) Inhibition of nitric oxide with aminoguanidine reduces bacterial translocation after endotoxin challenge in vivo. Arch. Surg. 131, 1155–1163.

    CAS  PubMed  Google Scholar 

  36. Boje, K. M. (1996) Inhibition of nitric oxide synthase attenuates blood-brain barrier disruption during experimental meningitis. Brain Res. 720, 75–83.

    Article  CAS  PubMed  Google Scholar 

  37. Arkovitz, M. S., Wispe, J. R., Garcia, V. F., and Szabo, C. (1996) Selective inhibition of the inducible isoform of nitric oxide synthase prevents pulmonary transvascular flux during acute endotoxemia. J. Pediatr. Surg. 31, 1009–1015.

    Article  CAS  PubMed  Google Scholar 

  38. Bieganski, T., Kusche, J., Lorenz, W., Hesterberg, R., Stahlknecht, C. D., and Feussner, K. D. (1983) Distribution and properties of human diamine oxidase and its relevance for the histamine catabolism. Biochem. Biophys. Acta 756, 196–203.

    CAS  PubMed  Google Scholar 

  39. Seiler, N., Bolkenius, F. N., and Knodgen, B. (1985) The influence of catabolic reactions on polyamine excretion. Biochem. J. 225, 219–226.

    CAS  PubMed  Google Scholar 

  40. Ou, P. and Wolff, S. P. (1993) Aminoguanidine: a drug proposed for prophylaxis in diabetes inhibits catalase and generates hydrogen peroxide in vitro. Biochem. Pharmacol. 46, 1139–1144.

    Article  CAS  PubMed  Google Scholar 

  41. Picard, S., Parthasarathy, S., Fruebis, J., and Witzum, J. L. (1992) Aminoguanidine inhibits oxidative modification of low density lipoprotein and the subsequent increase in uptake by macrophage scavenger receptors. Proc. Natl. Acad. Sci. USA 89, 6876–6880.

    Article  CAS  PubMed  Google Scholar 

  42. Ruetten, H. and Thiemermann, C. (1986) Prevention of the expression of inducible nitric oxide synthase by aminoguanidine or aminoethylisothiourea in macrophages and in the rat. Biochem. Biophys. Res. Commun. 225, 525–530.

    Article  Google Scholar 

  43. Garvey, P. E., Oplinger, J. A., Tanoury, G. J., Sherman, P. A., Fowler, M., Marshall, S., Marmon, M. F., Paith, J. E., and Furfine, E. S. (1994) Potent and selective inhibition of human nitric oxide synthases. Inhibition by non-amino acid isothioureas. J. Biol. Chem. 269, 26,669–26,676.

    CAS  PubMed  Google Scholar 

  44. Szabo, C., Southan, G., and Thiemermann, C. (1994) Beneficial effects and improved survival in rodent models of septic shock with S-methyl-isothiourea sulfate, a novel, potent and selective inhibitor of inducible nitric oxide synthase. Proc. Natl. Acad. Sci. USA 91, 12,472–12,476.

    Article  CAS  PubMed  Google Scholar 

  45. Southan, G., Szabo, C., and Thiemermann, C. (1995) Isothioureas: potent inhibitors of nitric oxide synthases with variable isoform selectivity. Br. J. Pharmacol. 114, 510–516.

    CAS  PubMed  Google Scholar 

  46. Southan, G. J., Zingarelli, B., O’Conner, M., Salzman, A. L., and Szabo, C. (1996) Spontaneous rearrangement of aminoalkylisothioureas into mercaptoalkyl-guanidines, a novel class of nitric oxide synthase inhibitors with selectivity towards the inducible isoform. Br. J. Pharmacol. 117, 619–632.

    CAS  PubMed  Google Scholar 

  47. Martinez, M. C., Muller, B., Stoclet, J. C., and Andriantsitohaina, R. (1996) Alteration by lipopolysaccharide of the relationship between intracellular calcium levels and contraction in rat mesenteric artery. Br. J. Pharmacol. 118, 1218–1222.

    CAS  PubMed  Google Scholar 

  48. Thiemermann, C., Ruetten, H., Wu, C. C., and Vane, J. R. (1995) The multiple organ dysfunction syndrome caused by endotoxin in the rat: Attenuation of liver dysfunction by inhibitors of nitric oxide synthase. Br. J. Pharmacol. 116, 2845–2851.

    CAS  PubMed  Google Scholar 

  49. Saetre, T., Gundersen, Y., Thiemermann, C., Lilleansen, P., and Aasen, A. O. (1998) Aminoethyl-isothiourea, a selective inhibitor of inducible nitric oxide synthase activity, improves liver circulation and oxygen metabolism in a porcine model of endotoxaemia. Shock 9, 109–115.

    Article  CAS  PubMed  Google Scholar 

  50. Muraki, T., Fujii, E., Okada, M., Horikawa, H., Irie, K., and Ohba, K. (1996) Effect of S-ethyl-isothiourea, a putative inhibitor of inducible nitric oxide synthase, on mouse skin vascular permeability. Jpn. J. Pharmacol. 70, 269–271.

    Article  CAS  PubMed  Google Scholar 

  51. Vromen, A., Szabo, C., Southan, G. J., and Salzman, A. L. (1996) Effects of S-isopropyl isothiourea, a potent inhibitor of nitric oxide synthase, in severe hemorrhagic shock. J. Appl. Physiol. 81, 707–715.

    CAS  PubMed  Google Scholar 

  52. Southan, G. J., Szabo, C., O’Conner, M. P., Salzman, A. C., and Thiemermann, C. (1995) Amidines are potent inhibitors of nitric oxide synthases: preferential inhibition of the inducible isoform. Eur. J. Pharmacol. 291, 311–318.

    Article  CAS  PubMed  Google Scholar 

  53. Garvey, E. P., Oplinger, J. A., Furfine, E. S., Kiff, R. J., Laszlo, F., Whittle, B. J. R., and Knowles, R. G. (1997) 1400W is a slow, tight binding, and highly selective inhibitor of inducible nitric oxide synthase in vitro and in vivo. J. Biol. Chem. 272, 4959–4963.

    Article  CAS  PubMed  Google Scholar 

  54. Moore, W. M., Webber, R. K., Jerome, G. M., Tjoeng, F. S., Misko, T. P., and Currie, M. G. (1994) L-N6-(l-iminoethyl)lysine: a selective inhibitor of inducible nitric oxide synthase. J. Med. Chem. 3886-3888.

    Google Scholar 

  55. Salvemini, D., Wang, Z. Q., Wyatts, P. S., Bourdon, D. M., Marino, M. H., Manning, P. T., and Currie, M. G. (1996) Nitric oxide: a key mediator in the early and late phase of carageenan-induced rat paw inflammation. Br. J. Pharmacol. 118, 829–838.

    CAS  PubMed  Google Scholar 

  56. Ridger, V. C., Pettipher, E. R., Bryant, C. E., and Brain, S. D. (1997) Effect of inducible nitric oxide synthase inhibitors aminoguanidine and L-N6-(l-iminoethyl)lysine on zymosan-induced plasma extravasation in rat skin. J. Immunol. 159, 383–390.

    CAS  PubMed  Google Scholar 

  57. Moralez-Ruiz, M., Jiminez, W., Ros, J., Sole, M., Leivas, A., Bosch-Marce, M., Rivera, F., Arroyo, V., and Rodes, J. (1997) Nitric oxide production in peritoneal macrophages of cirrhotic rats: a host response against bacterial peritonitis. Gas-troenterology 112, 2056–2064.

    Article  Google Scholar 

  58. Faraci, W. S., Nagel, A. A., Verdies, K. A., Vincent, L. A., Xu, H., Nichols, L. E., Labasi, J. M., Salter, E. D., and Pettipher, E. R. (1996) 2-amino-4-pyrimidine is a potent inhibitor of inducible NO synthase activity in vitro and in vivo. Br. J. Pharmacol. 119, 1101–1108.

    CAS  PubMed  Google Scholar 

  59. Wray, G. M., Millar, C. G., Hinds, C. J., and Thiemermann, C. (1998) Selective inhibition of the activity of inducible nitric oxide synthase prevents the circulatory failure, but not the organ injury/dysfunction caused by endotoxin. Shock 9, 329–335.

    Article  CAS  PubMed  Google Scholar 

  60. Laubach, V. E., Sheseley, E. G., Smithies, O., and Sherman, P. A. (1995) Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc. Natl. Acad. Sci. USA 92, 10,668–10,692.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Moorfields Eye Hospital, London, UK

    Dilani K. Siriwardena

  2. Department of Neonatology, Nagoya City University Medical School, Nagoya, Japan

    Hajime Tagori

  3. The William Harvey Research Institute, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, London, UK

    Christoph Thiemermann

Authors
  1. Dilani K. Siriwardena
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hajime Tagori
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christoph Thiemermann
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Imperial College School of Medicine, London, UK

    Thomas J. Evans

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Humana Press Inc.

About this protocol

Cite this protocol

Siriwardena, D.K., Tagori, H., Thiemermann, C. (2000). Nitric Oxide Synthase Inhibitors. In: Evans, T.J. (eds) Septic Shock Methods and Protocols. Methods in Molecular Medicine™, vol 36. Humana Press. https://doi.org/10.1385/1-59259-216-3:115

Download citation

  • DOI: https://doi.org/10.1385/1-59259-216-3:115

  • Publisher Name: Humana Press

  • Print ISBN: 978-0-89603-730-4

  • Online ISBN: 978-1-59259-216-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation