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Inhibition of Nitric Oxide Synthase During Sepsis and Endotoxemia May Be Detrimental

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Book cover Shock, Sepsis, and Organ Failure — Nitric Oxide

Abstract

Both in patients and in experimental animals sepsis and endotoxemia are associated with increased production of nitric oxide (NO), documented by urinary excretion of N03 and elevated plasma levels of nitrite and nitrate (N02/ N03), the stable end-products of NO [1–3]. Results in previous reports suggest that NO may be responsible for hemodynamic and metabolic consequences of sepsis and endotoxemia, and that inhibition of NO synthesis may be beneficial during these conditions [4–6]. Results observed in two patients with septic shock following treatment with the NO synthase inhibitor NG-monomethyl-l-arginine (NMA) were interpreted as indicating that NO contributes to the pathogenesis of septic shock, and that inhibition of NO synthesis may be a therapeutic option in septic patients [7]. In contrast, several recent studies, including reports from our laboratory, suggest that inhibition of NO synthase activity during sepsis and endotoxemia may be detrimental. Thus, evidence of increased mortality, liver and lung injury, and decreased intestinal integrity has been reported following treatment with NO synthase inhibitors during sepsis and endotoxemia.

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References

  1. Wagner DA, Young VR, Tannenbaum SR (1983) Mammalian nitrate biosynthesis: incorporation of 15NH3 into nitrate is enhanced by endotoxin treatment. Proc Natl Acad Sci USA 80: 4518–4521

    Article  PubMed  CAS  Google Scholar 

  2. Stuehr DJ, Marietta MA (1985) Mammalian nitrate biosynthesis: mouse macrophages induce nitrite and nitrate in response to Escherichia coli lipopolysaccharide. Proc Natl Acad Sci USA 82: 7738–7742

    Article  PubMed  CAS  Google Scholar 

  3. OchoaJB, Udekwu AO, BilliarTR, Curran RD, Cerra FB, Simmons RL, PeitzmanAB (1991) Nitrogen oxide levels in patients after trauma and sepsis. Ann Surg 214: 621–626

    Google Scholar 

  4. Kilbourn RG, Gross SS, Jubran A, Adams J, Griffith OW, Levi R, Lodato RF (1990) NG- 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 

  5. Kilbourn RG, Jubran A, Gross SS, Griffith OW, Levi R, Adams J, Lodato RF (1991) Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 172: 1132–1138

    Article  Google Scholar 

  6. 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

    Google Scholar 

  7. 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 

  8. Tiao G, Rafferty J, Ogle C, Fischer JE, Hasseigren PO (1994) Detrimental effect of nitric oxide synthase inhibition during endotoxemia may be caused by high levels of TNF and 1L–6. Surgery 116: 332–338

    PubMed  CAS  Google Scholar 

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

    Google Scholar 

  10. Minnard EA, Shou J, Naama H, Cech A, Gallagher H, Daly J (1994) Inhibition of nitric oxide synthesis is detrimental during endotoxemia. Arch Surg 129: 142–148

    Article  PubMed  CAS  Google Scholar 

  11. Waage A, Brandtzaeg P, Halstensen A, Kierluf P, Espevik T (1989) The complex pattern of cytokines in serum from patients with meningococcal septic shock. J Exp Med 169: 333–338

    Article  PubMed  CAS  Google Scholar 

  12. Sullivan JS, Kilpatrick L, Costarino AT, Lee SC, Harris MC (1992) Correlation of plasma cytokine elevations with mortality rate in children with sepsis. J Pediatr 120: 510–515

    Article  PubMed  CAS  Google Scholar 

  13. Tracey KJ (1991) Tumor necrosis factor (cachectin) in the biology of septic shock syndrome. Circ Shock 35: 123–128.

    PubMed  CAS  Google Scholar 

  14. Damas P, Ledoux D, Nys M, Vrindts Y, de Grou D, Franchimont P, Lamy M (1992) Cytokine serum levels during severe sepsis in human: IL-6 as a marker of severity. Ann Surg 215: 356–362

    Article  PubMed  CAS  Google Scholar 

  15. Stadler, Harbrecht BG, DiSilvio M, Curran RD, Jordan ML, Simmons RL, Billiar TR (1993) Endogenous nitric oxide inhibits the synthesis of cyclooxygenase products and interleukin-6 by rat Kupffer cells. J Leukoc Biol 53: 165–172

    PubMed  CAS  Google Scholar 

  16. Eigler A, Sinha B, Endres S (1993) Nitric oxide-releasing agents enhance cytokine- induced tumor necrosis factor synthesis in human mononuclear cells. Biochem Biophys Res Commun 196: 494–501

    Article  PubMed  CAS  Google Scholar 

  17. Billiar TR, Curran RD, Stuehr DJ, Stadler J, Simmons RL, Murray SA (1990) Inducible cytosolic enzyme activity for the production of nitrogen oxides from L-arginine in hepatocytes. Biochem Biophys Res Commun 168: 1034–1040

    Article  PubMed  CAS  Google Scholar 

  18. Harbrecht BG, Billiar TR, Stadler J, Demetris AJ, Ochoa J, Curran RD, Simmons RL (1992) Inhibition of nitric oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury. J Leukoc Biol 52: 390–394

    PubMed  CAS  Google Scholar 

  19. Curran RD, Ferrari RJ, Kispert PH, Stadler J, Stuehr DJ, Simmons RL, Billiar TR (1991) Nitric oxide and nitric oxide-generating compounds inhibit hepatocyte protein synthesis. FASEB J 5: 2085–2092

    PubMed  CAS  Google Scholar 

  20. Frederick JA, Hasselgren PO, Davis S, Higashiguchi T, Jacobs TD, Fischer JE (1993) Nitric oxide may upregulate in vivo hepatic protein synthesis during endotoxemia. Arch Surg 128: 152–157

    Article  PubMed  CAS  Google Scholar 

  21. McNurlan MA, Tomkins AM, Garlick PJ (1979) The effect of starvation on the rate of protein synthesis in rat liver and small intestine. Biochem J178: 373–379

    CAS  Google Scholar 

  22. Jepson MM, Pell JM, Bates PC, Millward DJ (1986) The effects of endotoxemia on protein metabolism in skeletal muscle and liver of fed and fasted rats. Biochem J 235: 329–336

    PubMed  CAS  Google Scholar 

  23. Sax HC, Talamini MA, Hasselgren PO, Rosenblum L, Ogle CK, Fischer JE (1988) Increased synthesis of secreted hepatic proteins during abdominal sepsis. J Surg Res 44: 109–116

    Article  PubMed  CAS  Google Scholar 

  24. Clowes GHA, Hirsch E, George BC, Bigatello LM, Mazuski JE, Villee CA (1985) Survival from sepsis. The significance of altered protein metabolism regulated by proteolysis inducing factor, the circulating cleavage product of interleukin-i. Ann Surg 202: 446–458

    Google Scholar 

  25. Moncada S, Palmer RMJ, Higgs EA (1988) The discovery of nitric oxide as the endogenous nitrovasodilator. Hypertension 12: 365–372

    PubMed  CAS  Google Scholar 

  26. Mellion BT, Ignarro LJ, Ohlstein EH, Pontecorvo EG, Hyman AL, Kadowitz PJ (1981) Evidence for the inhibitory role of guanosine 3,5-monophosphate in ADP-induced human platelet aggregation in the presence of nitric oxide and related vasodilators. Blood 57: 946–955

    PubMed  CAS  Google Scholar 

  27. Radowski MW, Palmer RMJ, Moncada S (1987) Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 2: 1057–1058.

    Article  Google Scholar 

  28. Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM (1993) Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328: 399–405

    Article  PubMed  CAS  Google Scholar 

  29. ShahNS, Nakayama DK, Jacob TD, Nishio I, ImaiT, Billiar TR, Exler R, Yousem SA, Motoyama EK, Peitzman AB (1994) Efficacy of inhaled nitric oxide in a porcine model of adult respiratory distress syndrome. Arch Surg 129: 158–164

    Google Scholar 

  30. Robertson FM, Offner PJ, Ciceri DP, Becker WK, Pruitt BA (1994) Detrimental hemodynamic effects of nitric oxide synthase inhibition in septic shock. Arch Surg 129: 149–156

    Article  PubMed  CAS  Google Scholar 

  31. Brashers VL, Peach MJ, Rose EC (1988) Augmentation of hypoxic pulmonary vasoconstriction in the isolated perfused rat lung by in vitro antagonists of endothelium- dependent relaxation. J Clin Invest 82: 1495–1502

    Article  PubMed  CAS  Google Scholar 

  32. Archer SL, Tolins JP, Raij L, Weir EK (1989) Hypoxic pulmonary vasoconstriction is enhanced by inhibition of the synthesis of an endothelium-derived relaxing factor. Biochem Biophys Res Commun 164: 1198–1205

    Article  PubMed  CAS  Google Scholar 

  33. Hutcheson IR, Whittle BJR, Boughton-Smith NK (1990) Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat. Br J Pharmacol 101: 815–820

    PubMed  CAS  Google Scholar 

  34. Quaroni A, Wands J, Trelstad RL, Isselbacher KJ (1979) Epithelioid cell cultures from rat small intestine. J Cell Biol 80: 248–265

    Article  PubMed  CAS  Google Scholar 

  35. Johnson G, Tsao PS, Lefer AM (1991) Cardioprotective effects of authentic nitric oxide in myocardial ischemia with reperfusion. Crit Care Med 19: 244–249

    Article  PubMed  Google Scholar 

  36. Rubanyi GM, Ho EH, Cantor EH, Lumma WC, Parker Bothelo LH (1991) Cytoprotective function of nitric oxide: inactivation of superoxide radicals produced by human leukocytes. Biochem Biophys Res Commun 181: 1392–1397

    Article  PubMed  CAS  Google Scholar 

  37. Lyons CR, Orloff GJ, Cunningham JM (1992) Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line. J Biol Chem 267: 6370–6374

    PubMed  CAS  Google Scholar 

  38. Lamas S, Marsden PA, Li GI, Tempst P, Michel T (1992) Endothelial nitric oxide synthase: molecular cloning and characterization of a distinct constitutive enzyme isoform. Proc Natl Acad Sci USA 89: 6348–6352

    Article  PubMed  CAS  Google Scholar 

  39. Geller DA, Lowenstein CJ, Shapiro RA, Nussler AK, DiSilvio M, Wang SC, Nakayama DK, Simmons RL, Snyder SH, Billiar TR (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 

  40. Geller DA, Billiar TR (1993) Should surgeons clone genes? The strategy behind the cloning of the human inducible nitric oxide synthase gene. Arch Surg 128: 1212–1220

    Article  PubMed  CAS  Google Scholar 

  41. Moncada S, Palmer RMJ, Higgs EA (1991) Nitric oxide; physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109–142

    PubMed  CAS  Google Scholar 

  42. Gross SS, Stuehr DJ, Kazuo A, Jaffe EA, Levi R, Griffith OW (1990) Macrophage and endothelial cell nitric oxide synthesis: cell-type selective inhibition by NG-aminoarginine, NG-nitroarginine, and NG-methylarginine. Biochem Biophys Res Commun 170: 96–103

    Google Scholar 

  43. Lambert LE, Whitten JP, Baron BM, Cheng HC, Doherty NS, McDonald H (1991) Nitric oxide synthesis in the CNS, endothelium and macrophages differs in its sensitivity to inhibition by arginine analogues. Life Sci 48: 69–75

    Article  PubMed  CAS  Google Scholar 

  44. Nussler AK, Billiar TR (1993) Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol 54: 171–178

    PubMed  CAS  Google Scholar 

  45. Gross SS, Levi R (1992) Tetrahydrobiopterin synthesis: an absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle. J Biol Chem 267: 25722–25729

    PubMed  CAS  Google Scholar 

  46. Cho HJ, Xie Q, Calaycay J, Mumford RA, Swiderek KM, Lee TD, Nathan C (1992) Calmodulin is a subunit of nitric oxide synthase from macrophages. J Exp Med 176: 599–604

    Article  PubMed  CAS  Google Scholar 

  47. Stadler J, Bergonia HA, DiSilvio M, Sweetland MA, Billiar TR, Simmons RL, Lancaster JR (1993) Nonheme iron-nitrosyl complex formation in rat hepatocytes: detection by electron paramagnetic resonance spectroscopy. Arch Biochem Biophys 302: 4–11

    Article  PubMed  CAS  Google Scholar 

  48. Rogers NE, Ignarro LJ (1992) Constitutive nitric oxide synthase from cerebellum is reversibly inhibited by nitric oxide formed from L-arginine. Biochem Biophys Res Commun 189: 242–249

    Article  PubMed  CAS  Google Scholar 

  49. Assreuy J, Cunha FQ, Liew FY, Moncada S (1993) Feedback inhibition of nitric oxide synthase activity by nitric oxide. Br J Pharmacol 108: 833–837

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. P. O. Hasselgren
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  2. J. E. Fischer
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  3. T. A. Meyer
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  4. G. Tiao
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Editors and Affiliations

  1. Ludwig-Boltzmann-Institut für experimentelle und klinische Traumatologie, Donaueschingenstraße 13, 1200, Wien, Austria

    Günther Schlag  & Heinz Redl  & 

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© 1995 Springer-Verlag Berlin Heidelberg

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Hasselgren, P.O., Fischer, J.E., Meyer, T.A., Tiao, G. (1995). Inhibition of Nitric Oxide Synthase During Sepsis and Endotoxemia May Be Detrimental. In: Schlag, G., Redl, H. (eds) Shock, Sepsis, and Organ Failure — Nitric Oxide. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-79343-1_10

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  • DOI: https://doi.org/10.1007/978-3-642-79343-1_10

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-79345-5

  • Online ISBN: 978-3-642-79343-1

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