Skip to main content
SpringerLink
Log in

Is Inhibition of Nitric Oxide Synthase an Appropriate Therapeutic Target in Sepsis?

  • Conference paper
Yearbook of Intensive Care and Emergency Medicine 1994

Part of the book series: Yearbook of Intensive Care and Emergency Medicine 1994 ((YEARBOOK,volume 1994))

  • 102 Accesses

Abstract

Profound unresponsive hypotension characterized by low vascular resistance and which is refractory to vasopressors is one of the cardinal features of established septic shock. In 1987, Moncada et al, and independently, Ignarro et al reported the endothelium derived relaxing factor was indistinguishable from the free radical NO, a finding which has prompted an extraordinary outpouring of investigation into fields as diverse as vascular biology, endocrinology and neuroscience (for review see [1]). Vasodilation is one of the key properties of NO, and from an early stage it has been apparent that NO may play a role in the hypotension of sepsis. If that were true, then it may offer a novel therapeutic target for clinicians faced with a septic patient with refractory hypotension. The principal purpose of this chapter is to consider the evidence implicating NO in the clinical setting of sepsis; however it is necessary first to review briefly the experimental data which underpin the hypothesis.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight 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

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Moncada S, Palmer RM, Higgs EA (1991) Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109–142

    PubMed  CAS  Google Scholar 

  2. Geller DA, Lowenstein CJ, Shapiro RA, et al (1993) Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci USA 90: 3491–3495

    Article  PubMed  CAS  Google Scholar 

  3. Palmer RM, Hickery MS, Charles IG, Moncada S, Bayliss MT (1993) Induction of nitric oxide synthase in human chondrocytes. Biochem Biophys Res Commun 193: 398–405

    Article  PubMed  CAS  Google Scholar 

  4. Kilbourn RG, Griffith OW (1992) Overproduction of nitric oxide in cytokine-mediated and septic shock. J Natl Cancer Inst 84: 827–831

    Article  PubMed  CAS  Google Scholar 

  5. Julou-Schaeffer G, Gray GA, Fleming I, Schott C, Parratt JR, Stoclet JC (1990) Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway. Am J Physiol 259: H1038 - H1043

    PubMed  CAS  Google Scholar 

  6. Kilbourn RG, Gross SS, Jubran A, et al (1990) N-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: Implications for the involvement of nitric oxide. Proc Natl Acad Sci USA 87: 3629–3632

    Article  PubMed  CAS  Google Scholar 

  7. Klabunde RE, Ritger RC (1991) NG-monomethyl-L-arginine ( NMA) restores arterial blood pressure but reduces cardiac output in a canine model of endotoxic shock. Biochem Biophys Res Commun 178: 1135–1140

    Article  PubMed  CAS  Google Scholar 

  8. Thiemermann C, Vane JR (1990) Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo. Eur J Pharmacol 182: 591–595

    Article  PubMed  CAS  Google Scholar 

  9. Cobb JP, Natanson C, Hoffman WD, et al (1992) N“-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin. J Exp Med 176: 1175–1182

    Article  PubMed  CAS  Google Scholar 

  10. Lorente JA, Landín L, Renes E, et al (1993) Role of nitric oxide in the hemodynamic changes of sepsis. Crit Care Med 21: 759–767

    Article  PubMed  CAS  Google Scholar 

  11. Billiar TR, Curran RD, Harbrecht BG, Stuehr DJ, Demetris AJ, Simmons RL (1990) Modulation of nitrogen oxide synthesis in vivo: N°-monomethyl-L-arginine inhibits endotoxin-induced nitrite/nitrate biosynthesis while promoting hepatic damage. J Leuk Biol 48: 565–569

    CAS  Google Scholar 

  12. Shultz PJ, Raij L (1992) Endogenously synthesized nitric oxide prevents endotoxininduced glomerular thrombosis. J Clin Invest 90: 1718–1725

    Article  PubMed  CAS  Google Scholar 

  13. Cohen J, Silva AT (1992) NO inhibitors and septic shock. Lancet 339: 751

    Article  PubMed  CAS  Google Scholar 

  14. Nava E, Palmer RM, Moncada S (1991) Inhibition of nitric oxide synthesis in septic shock: How much is beneficial? Lancet 338: 1555–1557

    Article  PubMed  CAS  Google Scholar 

  15. Teale DM, Atkinson AM (1992) Inhibition of nitric oxide synthesis improves survival in a murine peritonitis model of sepsis that is not cured by antibiotics alone. J Antimic Che-mother 30: 839–842

    Article  CAS  Google Scholar 

  16. Evans TE, Carpenter A, Silva AT, Cohen J (1994) Inhibition of nitric oxide synthase in experimental Gram negative sepsis. J Infect Dis (In press)

    Google Scholar 

  17. Ochoa JB, Udekwu AO, Billiar TR, et al (1991) Nitrogen oxide levels in patients after trauma and during sepsis. Ann Surg 214: 621–626

    Article  PubMed  CAS  Google Scholar 

  18. Evans TE, Carpenter A, Kinderman H, Cohen J (1993) Evidence of increased nitric oxide production in patients with the sepsis syndrome. Circ Shock 41: 77–81

    PubMed  CAS  Google Scholar 

  19. Ochoa JB, Curti B, Peitzman AB, et al (1992) Increased circulating nitrogen oxides after human tumor immunotherapy: Correlation with toxic hemodynamic changes. J Natl Cancer Inst 84: 864–867

    Article  PubMed  CAS  Google Scholar 

  20. Hibbs JR Jr, Westernfelder C, Taintor R, et al (1992) Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy. J Clin Invest 89: 867–877

    Article  PubMed  Google Scholar 

  21. Freund H, Ryan JA, Fischer JE (1978) Amino acids derangements in patients with sepsis: Treatment with branched chain amino acid rich infusions. Ann Surg 188: 423–429

    Article  PubMed  CAS  Google Scholar 

  22. Freund H, Atamian S, Holroyde J, Fischer JE (1979) Plasma amino acids as predictors of the severity and outcome of sepsis. Ann Surg 190: 571–576

    Article  PubMed  CAS  Google Scholar 

  23. Madden HP, Breslin RJ, Wasserkrug HL, Efron G, Barbul A (1988) Stimulation of T cell immunity by arginine enhances survival in peritonitis. J Surg Res 44: 658–663

    Article  PubMed  CAS  Google Scholar 

  24. Petros A, Bennett D, Vallance P (1991) Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 338: 1557–1558

    Article  PubMed  CAS  Google Scholar 

  25. Geroulanos S, Schilling J, Cakmakci M, Jung HH, Largiader F (1992) Inhibition of NO synthesis in septic shock. Lancet 339: 434–435

    Google Scholar 

  26. Schneider F, Lutun P, Hasselman M, Stoclet JC, Tempé JD (1992) Methylene blue increases systemic vascular resistance in human septic shock. Preliminary observations. Intensive Care Med 18: 309–311

    Article  PubMed  CAS  Google Scholar 

  27. Schneider F, Lutun P, Runge I, Couchot A, Tempe JD (1992) Effects of soluble guanylyl cyclase inhibition by methylene blue on the loss of vascular responsiveness to norepinephrine in human beings with either gram-negative or gram-positive septic shock. Clin Intensive Care 3 (Suppl): 11 (Abst)

    Google Scholar 

  28. Vallance P, Petros A, Lamb G, Leone A, Bennett D (1993) Hemodynamic, biochemical and hematological effects of a nitric oxide synthase inhibitor in patients with septic shock: A randomized study. Endothelium 1 (Suppl): s15 (Abst)

    Google Scholar 

  29. Lorente JA, Landín L, De Pablo R, Renes E, Liste D (1993) L-arginine pathway in the sepsis syndrome. Crit Care Med 21: 1287–1295

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. J. Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Intensive Care Erasme Hospital, Free University of Brussels, Route de Lennik 808, B-1070, Brussels, Belgium

    Jean-Louis Vincent (Clinical Director) (Clinical Director)

Rights and permissions

Reprints and permissions

Copyright information

© 1994 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Cohen, J. (1994). Is Inhibition of Nitric Oxide Synthase an Appropriate Therapeutic Target in Sepsis?. In: Vincent, JL. (eds) Yearbook of Intensive Care and Emergency Medicine 1994. Yearbook of Intensive Care and Emergency Medicine 1994, vol 1994. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-85068-4_7

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-85068-4_7

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-57613-6

  • Online ISBN: 978-3-642-85068-4

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation