Nitric Oxide Involvement in Septic Shock: Do Human Beings behave like Rodents?

  • J. C. Preiser
  • J. L. Vincent
Part of the Yearbook of Intensive Care and Emergency Medicine book series (YEARBOOK, volume 1996)


The tremendous interest in the physiological and pathological effects of nitric oxide (NO) is reflected in the enormous number of publications on this subject. Most of the studies investigating the effects of NO were performed in animal models. A Medline search from 1987 to November 1995, revealed that only 8 to 14% of the publications which include the keyword “nitric oxide” also include the keyword “human” (Fig. 1). However, there are several important differences between animal and human observations. The object of this chapter is to review the current knowledge about the role of NO in the hemodynamic alterations of septic shock, and to highlight the differences between animal and human studies.


Nitric Oxide Nitric Oxide Septic Shock Methylene Blue Retinal Pigment Epithelial Cell 
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  1. 1.
    Archer S (1993) Measurement of nitric oxide in biological models. FASEB J 7: 349–360PubMedGoogle Scholar
  2. 2.
    Zeballos GA, Bernstein RD, Thompson CI, et al (1995) Pharmacodynamics of plasma nitrate/nitrite as an indication of nitric oxide formation in conscious dogs. Circulation 91: 2982–2988PubMedGoogle Scholar
  3. 3.
    Rhodes PM, Leone AM, Francis PL, Struthers AD, Moncada S (1995) The L-arginine/nitric oxide pathway is the major source of plasma nitrite in fasted humans. Biochem Biophys Res Commun 209: 590–596PubMedCrossRefGoogle Scholar
  4. 4.
    Keaney JFJ, Puyana JC, Francis S, Loscalzo JF, Stamler JS, Loscalzo J (1994) Methylene blue reverses endotoxin-induced hypotension. Circ Res 74: 1121–1125PubMedGoogle Scholar
  5. 5.
    Westenberger U, Thanner S, Ruf HH, Sutter O, Lorentz S (1990) Formation of free radicals and nitric oxide derivative of hemoglobin in rats during shock syndrome. Free Rad Res Comm 11: 167–178CrossRefGoogle Scholar
  6. 6.
    Hecker M, Schott C, Bucher B, Busse R, Stoclet JC (1995) Increase in serum NG-hydroxy-L-arginine in rats treated with bacterial lipopolysaccharide. Eur J Pharmacol 275:R1-R3PubMedCrossRefGoogle Scholar
  7. 7.
    Tiao G, Rafferty J, Ogle C, Fischer JE, Hasselgren PO (1994) Detrimental effect of nitric oxide synthase inhibition during en do toxemia may be caused by high levels of tumor necrosis factor and interleukin-6. Surgery 116: 332–337PubMedGoogle Scholar
  8. 8.
    Gardiner SM, Kemp PA, March JE, Bennett T (1995) Cardiac and regional haemodynamics, inducible nitric oxide synthase (NOS) activity, and the effects of NOS inhibitors in conscious, en do toxaemic rats. Br J Pharmacol 116: 2005–2016PubMedGoogle Scholar
  9. 9.
    Billiar TR, Curran RD, Harbrecht BG, Stuehr DJ, Demetris AI, 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: 565–569PubMedGoogle Scholar
  10. 10.
    De Kimpe SJ, Hunter ML, Bryant CE, Thiemermann C, Vane JR (1995) Delayed circulatory failure due to the induction of nitric oxide synthase by lipoteichoic acid from Staphylococcus aureus in anaesthetized rats. Br J Pharmacol 114: 1317–1323PubMedGoogle Scholar
  11. 11.
    Mitaka C, Hirata Y, Ichikawa K, et al (1994) Effects of TNF-alpha on hemodynamic changes and circulating endothelium-derived vasoactive factors in dogs. Am J Physiol 267:H1530-H1536PubMedGoogle Scholar
  12. 12.
    Kilbourn RG, Owen-Schaub L, Cromeens D, et al (1994) NG-methyl-L-arginine, an inhibitor of nitric oxide formation, reverses IL-2-mediated hypotension in dogs. J Appl Physiol 76: 1130–1137PubMedGoogle Scholar
  13. 13.
    Bune AJ, Shergill JK, Cammack R, Cook HT (1995) L-arginine depletion by arginase reduces nitric oxide production in endotoxic shock: An electron paramagnetic resonance study. FEBS Lett 366: 127–130PubMedCrossRefGoogle Scholar
  14. 14.
    Wong HR, Carcillo JA, Burckart G, Shah N, Janosky JE (1995) Increased serum nitrite and nitrate concentrations in children with the sepsis syndrome. Crit Care Med 23: 835–842PubMedCrossRefGoogle Scholar
  15. 15.
    Evans T, Carpenter A, Kinderman H, Cohen J (1993) Evidence of increased nitric oxide production in patients with the sepsis syndrome. Circ Shock 41: 77–81PubMedGoogle Scholar
  16. 16.
    Gomez-Jimenez J, Salgado A, Mourelle M, et al (1995) L-arginine/nitric oxide pathway in endotoxemia and human septic shock. Crit Care Med 23: 253–258PubMedCrossRefGoogle Scholar
  17. 17.
    Preiser JC, Reper P, Vlasselaer D, et al (1996) Nitric oxide production is increased in patients after burn injury. J Trauma (In press)Google Scholar
  18. 18.
    Evans TG, Rasmussen K, Wiebke G, Hibbs JB Jr (1994) Nitric oxide synthesis in patients with advanced HIV infection. Clin Exp Immunol 97: 83–86PubMedCrossRefGoogle Scholar
  19. 19.
    Ochoa JB, Udekwu AO, Billiar TR, et al (1991) Nitrogen oxide levels in patients after trauma and during sepsis. Ann Surg 214: 621–626PubMedCrossRefGoogle Scholar
  20. 20.
    Jacob TD, Ochoa JB, Udekwu AO, et al (1993) Nitric oxide production is inhibited in trauma patients. J Trauma 35: 590–597PubMedCrossRefGoogle Scholar
  21. 21.
    Wennmalm A, Benthin G, Petersson AS (1992) Dependence of the metabolism of nitric oxide (NO) in healthy human whole blood on the oxygenation of its red cell haemoglobin. Br J Pharmacol 106: 507–508PubMedGoogle Scholar
  22. 22.
    Schneider F, Lutun P, Couchot A, Bilbault P, Tempé JD (1993) Plasma cyclic guanosine 3’ -5’ monophosphate concentrations and low vascular resistance in human septic shock. Intensive Care Med 19: 99–104PubMedCrossRefGoogle Scholar
  23. 23.
    Shotan A, Mehra A, Ostrzega E, et al (1993) Plasma cyclic guanosine monophosphate in chronic heart failure: Hemodynamic and neurohormonal correlations and response to nitrate therapy. Clin Pharmacol Ther 54: 638–644PubMedCrossRefGoogle Scholar
  24. 24.
    Matsumoto A, Ogura K, Hirata Y, et al (1995) Increased nitric oxide in the exhaled air of patients with decompensated liver cirrhosis. Ann Intern Med 123: 110–113PubMedGoogle Scholar
  25. 25.
    Kharitonov SA, Lubec G, Lubec B, Hjelm M, Barnes PJ (1995) L-arginine increases exhaled nitric oxide in normal human subjects. Clin Science 88: 135–139Google Scholar
  26. 26.
    Leone AM, Francis PL, Rhodes P, Moncada S (1994) A rapid and simple method for the measurement of nitrite and nitrate in plasma by high performance capillary electrophoresis. Biochem Biophys Res Comm 200: 951–957PubMedCrossRefGoogle Scholar
  27. 27.
    Castillo L, deRojas TC, Chapman TE, et al (1993) Splanchnic metabolism of dietary arginine in relation to nitric oxide synthesis in normal adult man. Proc Natl Acad Sci USA 90: 193–197PubMedCrossRefGoogle Scholar
  28. 28.
    Cortas NK, Wakid NW (1991) Pharmacokinetic aspects of inorganic nitrate ingestion in man. Pharmacol Toxicol 68: 192–195PubMedCrossRefGoogle Scholar
  29. 29.
    Liu S, Adcock IM, Old RW, Barnes PJ, Evans TW (1993) Lipopolysaccharide treatment in vivo induces widespread tissue expression of inducible nitric oxide synthase mRNA. Biochem Biophys Res Commun 196: 1208–1213PubMedCrossRefGoogle Scholar
  30. 30.
    Xie QW, Whisnant R, Nathan C (1993) Promoter of the mouse gene encoding calciumindependent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J Exp Med 177: 1779–1784PubMedCrossRefGoogle Scholar
  31. 31.
    Hom GJ, Grant SK, Wolfe G, Bach TJ, MacIntyre DE, Hutchinson NI (1995) Lipopolysaccharide-induced hypotension and vascular hypo reactivity in the rat: Tissue analysis of nitric oxide synthase mRNA and protein expression in the presence and absence of dexamethasone, NG-monomethyl-L-arginine, or indomethacin. J Pharmacol Exp Ther 272: 452–459PubMedGoogle Scholar
  32. 32.
    Morris SM Jr, Billiar TR (1994) New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol 266:E829-E839PubMedGoogle Scholar
  33. 33.
    Salvemini D, Settle SL, Masferrer JL, Seibert K, Currie MG, Needleman P (1995) Regulation of prostaglandin production by nitric oxide: An in vivo analysis. Br J Pharmacol 114: 1171–1178PubMedGoogle Scholar
  34. 34.
    Myers PR, Wright TF, Tanner MA, Adams HR (1992) Endothelial-derived relaxing factor and nitric oxide production in cultured endothelial cells: Direct inhibition by E. coli endotoxin. Am J Physiol 262: H710-H718PubMedGoogle Scholar
  35. 35.
    Sherman PA, Laubach VE, Reep BR, Wood ER (1993) Purification and eDNA sequence of an inducible nitric oxide synthase from a human tumor cell line. Biochemistry 32: 11600–11605PubMedCrossRefGoogle Scholar
  36. 36.
    Reiling N, Ulmer AJ, Duchrow M, Ernst M, Flad HD, Hauschildt S (1994) Nitric oxide synthase: mRNA expression of different isoforms in human monocytes/macrophages. Eur J Immunol 24: 1941–1944PubMedCrossRefGoogle Scholar
  37. 37.
    Schneemann M, Schoedon G, Hofer S, Blau N, Guerrero L, Schaffner A (1993) Nitric oxide synthase is not a constituent of the antimicrobial armature of human mononuclear phagocytes. J Infect Dis 167: 1358–1363PubMedCrossRefGoogle Scholar
  38. 38.
    Geller DA, Lowenstein CJ, Shapiro RA, Nussler AK, Di Silvio M, Wang SC (1993) Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci USA 90: 3491–3495PubMedCrossRefGoogle Scholar
  39. 39.
    Nicolson AG, Haites NE, McKay NG, Wilson HM, MacLeod AM, Benjamin N (1993) Induction of nitric oxide synthase in human mesangial cells. Biochem Biophys Res Commun 193: 1269–1274PubMedCrossRefGoogle Scholar
  40. 40.
    Goureau O, Hicks D, Courtois Y (1994) Human retinal pigmented epithelial cells produce nitric oxide in response to cytokines. Biochem Biophys Res Commun 198: 120–126PubMedCrossRefGoogle Scholar
  41. 41.
    Robbins RA, Barnes PJ, Springall DR, et al (1994) Expression of inducible nitric oxide in human lung epithelial cells. Biochem Biophys Res Commun 203: 209–218PubMedCrossRefGoogle Scholar
  42. 42.
    Beasley D, McGuiggin M (1994) Interleukin-1 activates soluble guanylate cyclase in human vascular smooth muscles through a novel nitric oxide-independent pathway. J Exp Med 179: 71–80PubMedCrossRefGoogle Scholar
  43. 43.
    MacNaul KL, Hutchinson NI (1993) Differential expression of iNOS and eNOS mRNA in human vascular smooth muscle cells and endothelial cells under normal and inflammatory conditions. Biochem Biophys Res Commun 196: 1330–1334PubMedCrossRefGoogle Scholar
  44. 44.
    Schaffner A, Blau N, Schneemann M, Steurer J, Edgell CJ, Schoedon G (1994) Tetrahydrobiopterin as another EDRF in man. Biochem Biophys Res Commun 205: 516–523PubMedCrossRefGoogle Scholar
  45. 45.
    Goode H, Howdle P, Walker B, Webster N (1995) Nitric oxide synthase activity is increased in patients with sepsis syndrome. Clin Science 88: 131–133Google Scholar
  46. 46.
    Palmer RM, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327: 524–526PubMedCrossRefGoogle Scholar
  47. 47.
    Hollenberg SM, Cunnion RE, Zimmerberg J (1993) Nitric oxide synthase inhibition reverses arteriolar hyporesponsiveness to catecholamines in septic rats. Am J Physiol 264: H660-H663PubMedGoogle Scholar
  48. 48.
    Fleming I, Gray GA, Stoclet JC (1993) Influence of endothelium on induction of the L-arginine-nitric oxide pathway in rat aortas. Am J Physiol 264:H1200-H1207PubMedGoogle Scholar
  49. 49.
    Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL (1992) Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257: 378–389CrossRefGoogle Scholar
  50. 50.
    Brady AJ, Poole-Wilson PA, Harding SZ, Warren JB (1992) Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol 32: H1963-H1966Google Scholar
  51. 51.
    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-H1043PubMedGoogle Scholar
  52. 52.
    Balligand JL, Ungureanu D, Kelly RA, et al (1993) Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J Clin Invest 91: 2314–2319PubMedCrossRefGoogle Scholar
  53. 53.
    Baydoun AR, Bogle RG, Pearson JD, Mann GE (1993) Selective inhibition by dexamethasone of induction of NO synthase, but not of induction of L-arginine transport, in activated murine macrophage J774 cells. Br J Pharmacol 110: 1401–1406PubMedGoogle Scholar
  54. 54.
    Kilbourn RG, Jubran A, Gross SS, et al (1990) Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 172: 1132–1138PubMedCrossRefGoogle Scholar
  55. 55.
    Thiemermann C, Vane J (1990) Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo. Eur J Pharmacol 182: 591–595PubMedCrossRefGoogle Scholar
  56. 56.
    Klabunde RE, Helgren MC (1991) Inhibition of nitric oxide production by NG-monomethyl-L-arginine (NMA) does not normalize cardiovascular function in dogs subjected to endotoxic shock. FASEB J 5: A398 (Abst)Google Scholar
  57. 57.
    Meyer J, Traber LD, Nelson S, et al (1992) Reversal of hyperdynamic response to continuous endotoxin administration by inhibition of NO synthesis. J Appl Physiol 73: 324–328PubMedGoogle Scholar
  58. 58.
    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: 1175–1182PubMedCrossRefGoogle Scholar
  59. 59.
    Wright CH, Rees DD, Moncada S (1992) Protective and pathological roles of nitric oxide in endotoxin shock. Cardiovasc Res 26: 48–57PubMedCrossRefGoogle Scholar
  60. 60.
    Preiser JC, Zhang H, Wachel D, Boeynaems JM, Buurman W, Vincent JL (1994) Is the endotoxin-induced hypotension related to nitric oxide formation? Eur Surg Res 26: 10–18PubMedCrossRefGoogle Scholar
  61. 61.
    Szabo C, Mitchell JA, Thiemermann C, Vane JR (1993) Nitric oxide-mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock. Br J Pharmacol 108: 786–792PubMedGoogle Scholar
  62. 62.
    Winn MJ, Vallet B, Asante NK, Curtis SE, Cain SM (1993) Effects of NG-substituted arginines on coronary vascular function after endotoxin. J Appl Physiol 75: 424–431PubMedGoogle Scholar
  63. 63.
    Bogle RG, MacAllister RJ, Whitley G, Vallance P (1995) Induction of NG-monomethyl-L-arginine uptake: A mechanism for differential inhibition of NO synthase? Am J Physiol 269: C750-C756PubMedGoogle Scholar
  64. 64.
    Arnal JF, Schott C, Stoclet JC, Michel JB (1993) Vascular relaxation and cyclic guanosine monophosphate in a rat model of high output heart failure. Cardiovasc Res 27: 1651–1656PubMedCrossRefGoogle Scholar
  65. 65.
    Kumar A, Kosuri R, Thota V, et al (1993) Effect of nitric oxide synthetase inhibition of human septic serum-induced myocardial cell depression in vitro. Circ Shock 39: 22 (Abst)Google Scholar
  66. 66.
    Thorin-Trescases N, Hamilton CA, Reid JL, et al (1995) Inducible L-arginine/nitric oxide pathway in human internal mammary artery and saphenous vein. Am J Physiol 268: H1122-H1132PubMedGoogle Scholar
  67. 67.
    Yokokawa K, Mankus R, Saklayen MG, et al (1995) Increased nitric oxide production in patients with hypotension during hemodialysis. Ann Intern Med 123: 35–37PubMedGoogle Scholar
  68. 68.
    Petros A, Bennett D, Vallance P (1991) Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 338: 1557–1558PubMedCrossRefGoogle Scholar
  69. 69.
    Petros A, Lamb G, Leone A, Moncada S, Bennett D, Vallance P (1994) Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc Res 28: 34–39PubMedCrossRefGoogle Scholar
  70. 70.
    Vallance P, Collier J, Moncada S (1989) Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 2: 997–1000PubMedCrossRefGoogle Scholar
  71. 71.
    Preiser JC, Lejeune P, Roman A, et al (1995) Methylene blue administration in septic shock: A clinical trial. Crit Care Med 23: 259–264PubMedCrossRefGoogle Scholar
  72. 72.
    Daemen-Gubbels CR, Groeneveld PH, Groeneveld AB, van Kamp GJ, Bronsveld W, Thijs LG (1995) Methylene blue increases myocardial function in septic shock. Crit Care Med 23: 1363–1370PubMedCrossRefGoogle Scholar
  73. 73.
    Birch AA, Boyce WH (1976) Hypertension and decreased renal blood flow following methylene blue injection. Anesth Analg 55: 674–676PubMedCrossRefGoogle Scholar
  74. 74.
    Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite and (15N) nitrate in biological fluids. Analytical Biochemistry 126: 131–138PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1996

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  • J. C. Preiser
  • J. L. Vincent

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