Nitric Oxide as a Modulator of Sepsis: Therapeutic Possibilities

  • A. Neil Salyapongse
  • Timothy R. Billiar

Abstract

The systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and multiple organ failure (MOF) remain die most common causes of death in the intensive care unit. Despite the elucidation of many of the mediators contributing to the physiologic changes observed during these processes, a “magic bullet” capable of treating SIRS and preventing MODS/MOF continues to evade identification. This difficulty rests, at least in part, on the nature of these pathophysiologic states as final common pathways deriving from a variety of insults (e.g., infection, trauma, burns).1 Interest in nitric oxide (NO) as a potential mediator of SIRS, MODS, and MOF stems from its ability to modulate inflammation, vascular reactivity, and cardiac function, some of the key elements comprising these inflammatory syndromes. This chapter presents the evidence for NO as a key participant in these inflammatory syndromes and reviews the promises and limitations of NO modulation suggested by experimental and clinical trials.

Keywords

Glucocorticoid NADPH Cytosol Benzyl Nifedipine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Baue AE: Multiple organ failure, multiple organ dysfunction syndrome, and systemic inflammatory response syndrome: why no magic bullets? Arch Surg 1997; 132: 703–707.PubMedCrossRefGoogle Scholar
  2. 2.
    Nathan C: Nitric oxide as a secretory product of mammalian cells. FASEBJ 1992; 6: 3051–3064.Google Scholar
  3. 3.
    Lowenstein CJ, Dinerman JL, Snyder SH: Nitric oxide: a physiologic messenger. Ann Intern Med 1994; 120: 227–237.PubMedGoogle Scholar
  4. 4.
    Mitchell HH, Shonle HA, Grindley HS: The origin of nitrate in the urine. J Biol Chem 1916; 24: 461.Google Scholar
  5. 5.
    Green LC, Tannenbaum SR, Goldman P: Nitrate synthesis in the germ free and conventional rat. Science 1981; 212: 56–58.PubMedCrossRefGoogle Scholar
  6. 6.
    Tannenbaum SR, Fett D, Young VR, Land PD, Bruce WR: Nitrite and nitrate are formed by endogenous synthesis in the human intestine. Science 1978; 200: 1487–1489.PubMedCrossRefGoogle Scholar
  7. 7.
    Green LG, Ruiz de Luzuriaga K, Wagner DA: Nitrate biosynthesis in man. Proc Natl Acad Sci USA 1981; 78: 7764–7768.PubMedCrossRefGoogle Scholar
  8. 8.
    Wagner DA, Young VR, Tannenbaum SR: Mammalian nitrate biosynthesis: incorporation of 15NH3 into nitrate is enhanced by endotoxin treatment. Proc Natl Acad Sci USA 1983; 80: 4518–4521.PubMedCrossRefGoogle Scholar
  9. 9.
    Hibbs JBJ, Taintor RR, Vavrin Z: Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science 1987; 235: 473–476.PubMedCrossRefGoogle Scholar
  10. 10.
    Palmer RM, Ferrige AG, Moncada S: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327: 524–526.PubMedCrossRefGoogle Scholar
  11. 11.
    Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G: Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 1987; 84: 9265–9269.PubMedCrossRefGoogle Scholar
  12. 12.
    Furchgott RF, Zawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: 373–376.PubMedCrossRefGoogle Scholar
  13. 13.
    Stuehr DJ, Griffith OW: Mammalian nitric oxide synthases. Adv Enzymol Relat Areas Mol Biol 1992; 65: 287–346.PubMedGoogle Scholar
  14. 14.
    Bredt DS, Glatt CE, Hwang PM, Fotuhi M, Dawson TM, Snyder SH: Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron 1991; 7: 615–624.PubMedCrossRefGoogle Scholar
  15. 15.
    Marsden PA, Schappert KT, Chen HS, et al: Molecular cloning and characterization of human endothelial nitric oxide synthase. FEBS Lett 1992; 307: 287–293.PubMedCrossRefGoogle Scholar
  16. 16.
    Bredt DS, Snyder SH: Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 1990; 87: 682–685.PubMedCrossRefGoogle Scholar
  17. 17.
    Busse R, Mulsch A: Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin. FEBS Lett 1990; 265: 133–136.PubMedCrossRefGoogle Scholar
  18. 18.
    Nathan C, Xie QW: Regulation of biosynthesis of nitric oxide. J Biol Chem 1994; 269: 13725–13728.PubMedGoogle Scholar
  19. 19.
    Morris SMJ, Billiar TR: New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol 1994; 266: E829–E839.PubMedGoogle Scholar
  20. 20.
    Cho HJ, Xie QW, Calaycay J, et al: Calmodulin is a subunit of nitric oxide synthase from macrophages. J Exp Med 1992; 176: 599–604.PubMedCrossRefGoogle Scholar
  21. 21.
    Lancaster JRJ; Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc Natl Acad Sci USA 1994; 91: 8137–8141.PubMedCrossRefGoogle Scholar
  22. 22.
    Furchgott RF, Zawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: 373–376.PubMedCrossRefGoogle Scholar
  23. 23.
    Lowenstein CJ, Dinerman JL, Snyder SH: Nitric oxide: a physiologic messenger. Ann Intern Med 1994; 120: 227–237.PubMedGoogle Scholar
  24. 24.
    Nathan C: Nitric oxide as a secretory product of mammalian cells. FASEBJ 1992; 6: 3051–3064.Google Scholar
  25. 25.
    Tannenbaum SR, Fett D, Young VR, Land PD, Bruce WR: Nitrite and nitrate are formed by endogenous synthesis in the human intestine. Science 1978; 200: 1487–1489.PubMedCrossRefGoogle Scholar
  26. 26.
    Green LC, Ruiz de Luzuriaga K, Wagner DA: Nitrate biosynthesis in man. Proc Natl Acad Sci USA 1981; 78: 7764–7768.PubMedCrossRefGoogle Scholar
  27. 27.
    Green LC, Tannenbaum SR, Goldman P: Nitrate synthesis in the germ free and conventional rat. Science 1981; 212: 56–58.PubMedCrossRefGoogle Scholar
  28. 28.
    Hibbs JBJ, Taintor RR, Vavrin Z: Macrophage cytotoxicity: role for l-arginine deiminase and amino nitrogen oxidation to nitrite. Science 1987; 235: 473–476.PubMedCrossRefGoogle Scholar
  29. 29.
    Xu L, Eu JP, Meissner G, Stamler JS: Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation. Science 1998; 279: 234–237.PubMedCrossRefGoogle Scholar
  30. 30.
    Mistry DK, Garland CJ: Nitric oxide (NO)-induced activation of large conductance Ca2+-dependent K+ channels [BK(Ca)] in smooth muscle cells isolated from the rat mesenteric artery. Br J Pharmacol 1998; 124: 1131–1140.PubMedCrossRefGoogle Scholar
  31. 31.
    McMahon TJ, Stamler JS: Concerted nitric oxide/oxygen delivery by hemoglobin. Methods Enzymol 1999; 301: 99–114.PubMedCrossRefGoogle Scholar
  32. 32.
    Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G: Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Nad Acad Sci USA 1987; 84: 9265–9269.CrossRefGoogle Scholar
  33. 33.
    Palmer RM, Ferrige AG, Moncada S: Nitric oxide release accounts for the biological activity of endothelium-derived relaxingfactor. Nature 1987; 327: 524–526.PubMedCrossRefGoogle Scholar
  34. 34.
    Marsden PA, Schappert KT, Chen HS, et al: Molecular cloning and characterization of human endothelial nitric oxide synthase. FEBS Lett 1992; 307: 287–293.PubMedCrossRefGoogle Scholar
  35. 35.
    Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH: Cloned and expressed nitric oxide synthase structurallyresembles cytochrome P-450 reductase. Nature 1991; 351: 714–718.PubMedCrossRefGoogle Scholar
  36. 36.
    Szabo C, Zingarelli B, O’Connor M, Salzman AL: DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proc Nad Acad Sci USA 1996; 93: 1753–1758.CrossRefGoogle Scholar
  37. 37.
    Viner RI, Huhmer AF, Bigelow DJ, Schoneich C: The oxidative inactivation of sarcoplasmic reticulum Ca2+-ATPase by peroxynitrite. Free Radic Res 1996; 24: 243–259.PubMedCrossRefGoogle Scholar
  38. 38.
    Szabo C: The pathophysiological role of peroxynitrite in shock, inflammation, and ischemia-reperfusion injury. Shock 1996; 6: 79–88.PubMedCrossRefGoogle Scholar
  39. 39.
    Paya D, Gray GA, Fleming I, Stoclet JC: Effect of dexamethasone on the onset and persistence of vascular hyporeactivity induced by E. coli lipopolysaccharide in rats. Circ Shock 1993; 41: 103–112.PubMedGoogle Scholar
  40. 40.
    Szabo C, Mitchell JA, Gross SS, Thiemermann C, Vane JR: Nifedipine inhibits the induction of nitric oxide synthase by bacterial lipopolysaccharide. J Pharmacol Exp Ther 1993; 265: 674–680.PubMedGoogle Scholar
  41. 41.
    Schini VB, Catovsky S, Schray-Utz B, Busse R, Vanhoutte PM: Insulin-like growth factor I inhibits induction of nitric oxide synthase in vascular smooth muscle cells. Circ Res 1994; 74: 24–32.PubMedCrossRefGoogle Scholar
  42. 42.
    Moro MA, Russel RJ, Cellek S, et al: cGMP mediates the vascular and platelet actions of nitric oxide: confirmation using an inhibitor of the soluble guanylyl cyclase. Proc Natl Acad Sci USA 1996; 93: 1480–1485.PubMedCrossRefGoogle Scholar
  43. 43.
    Southan GJ, Szabo C: Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. Biochem Pharmacol 1996; 51: 383–394.PubMedCrossRefGoogle Scholar
  44. 44.
    Garvey EP, Oplinger JA, Tanoury GJ, et al: Potent and selective inhibition of human nitric oxide synthases: inhibition by nonamino acid isothioureas. J Biol Chem 1994; 269: 26669–26676.PubMedGoogle Scholar
  45. 45.
    Garvey EP, Oplinger JA, Furfine ES, et al: 1400W is a slow, tight binding, and highly selective inhibitor of inducible nitric-oxide syndiase in vitro and in vivo. J Biol Chem 1997; 272: 4959–4963.PubMedCrossRefGoogle Scholar
  46. 46.
    Rees DD, Monkhouse JE, Cambridge D, Moncada S: Nitric oxide and the haemodynamic profile of endotoxin shock in the conscious mouse. Br J Pharmacol 1998; 124: 540–546.PubMedCrossRefGoogle Scholar
  47. 47.
    Pieper GM: Review of alterations in endothelial nitric oxide production in diabetes: protective role of orginine on endothelial dysfunction. Hypertension 1998; 31: 1047–1060.PubMedCrossRefGoogle Scholar
  48. 48.
    Moore WM, Webber RK, Jerome GM, Tjoeng FS, Misko TP, Currie MG: l-N 6-(1-iminoethytyl)lysine: a selective inhibitor of inducible nitric oxide synthase. J Med Chem 1994; 37: 3886–3888.PubMedCrossRefGoogle Scholar
  49. 49.
    Corbett JA, Tilton RG, Chang K, et al: Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes 1992; 41: 552–556.PubMedCrossRefGoogle Scholar
  50. 50.
    Ikeda K, Gutierrez OGJ, Yamori Y: Dietary N G-nitro-l-arginine induces sustained hypertension in normotensive Wistar-Kyoto rats. Clin Exp Pharmacol Physiol 1992; 19: 583–586.PubMedCrossRefGoogle Scholar
  51. 51.
    Kobayashi Y, Ikeda K, Shinozuka K, Nara Y, Yamori Y, Hattori K: l-Nitroarginine increases blood pressure in the rat. Clin Exp Pharmacol Physiol 1991; 18: 397–399.PubMedCrossRefGoogle Scholar
  52. 52.
    Baylis C, Mitruka B, Deng A: Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest 1992; 90: 278–281.PubMedCrossRefGoogle Scholar
  53. 53.
    Perrella MA, Hildebrand FLJ, Margulies KB, Burnett JCJ: Endothelium-derived relaxing factor in regulation of basal cardiopulmonary and renal function. Am J Physiol 1991; 261: R323–R328.PubMedGoogle Scholar
  54. 54.
    Persson PB, Baumann JE, Ehmke H, Nafz B, Wittmann U, Kirchheim HR: Phasic and 24-h blood pressure control by endothelium-derived relaxing factor in conscious dogs. Am J Physiol 1992; 262; H1395: H1400.Google Scholar
  55. 55.
    Haynes WG, Noon JP, Walker BR, Webb DJ: Inhibition of nitric oxide synthesis increases blood pressure in healthy humans. J Hypertens 1993; 11: 1375–1380.PubMedCrossRefGoogle Scholar
  56. 56.
    Vallance P, Collier J, Moncada S: Effects of endothelium-derived nitrix oxide on peripheral arteriolar tone in man. Lancet 1989; 2: 997–1000.PubMedCrossRefGoogle Scholar
  57. 57.
    Faraci FM, Breese KR: Nitric oxide mediates vasodilatation in response to activation of N-methyl-D-aspartate receptors in brain. Circ Res 1993; 72: 476–480.PubMedCrossRefGoogle Scholar
  58. 58.
    Toda N, Okamura T: Mechanism underlying the response to vasodilator nerve stimulation in isolated dog and monkey cerebral arteries. Am J Physiol 1990; 259: H1511–H1517.PubMedGoogle Scholar
  59. 59.
    Broten TP, Miyashiro JK, Moncada S, Feigl EO: Role of endothelium-derived relaxing factor in parasympathetic coronary vasodilation. Am J Physiol 1992; 262: H1579–H1584.PubMedGoogle Scholar
  60. 60.
    Iwata F, Joh T, Kawai T, Itoh M: Role of EDRF in splanchnic blood flow of normal and chronic portal hypertensive rats. Am J Physiol 1992; 263: G149–G154.PubMedGoogle Scholar
  61. 61.
    Huang PL, Huang Z, Mashimo H, et al: Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995; 377: 239–242.PubMedCrossRefGoogle Scholar
  62. 62.
    Kilbourn RG, Belloni P: Endothelial cell production of nitrogen oxides in response to interferon gamma in combination with tumor necrosis factor, interleukin-1, or endotoxin. J Natl Cancer Inst 1990; 82: 772–776.PubMedCrossRefGoogle Scholar
  63. 63.
    Ochoa JB, Curti B, Peitzman AB, et al: Increased circulating nitrogen oxides after human tumor immunotherapy: correlation with toxic hemodynamic changes. J Natl Cancer Inst 1992; 84: 864–867. Erratum. J Natl Cancer Inst 1992;84: 1291.PubMedCrossRefGoogle Scholar
  64. 64.
    Kilbourn RG, Gross SS, Jubran A, et al: N G-Methyl-l-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci USA 1990; 87: 3629–3632.PubMedCrossRefGoogle Scholar
  65. 65.
    Kilbourn RG, Gross SS, Lodato RF, et al: Inhibition of interleukin-1-alpha-induced nitric oxide synthase in vascular smooth muscle and full reversal of interleukin-1-alpha-induced hypotension by N-omega-amino-l-arginie. J Natl Cancer Inst 1992; 84: 1008–1016.PubMedCrossRefGoogle Scholar
  66. 66.
    Kilbourn RG, Owen-Schaub LB, Cromeens DM: N G-Methyl-l-arginine, an inhibitor of nitric oxide formation, reverses IL-2-mediated hypotension in dogs. J Appl Physiol 1994; 76: 1130–1137.PubMedGoogle Scholar
  67. 67.
    Kilbourn RG, Fonseca GA, Griffith OW, et al: N G-Methyl-l-arginine, an inhibitor of nitric oxide synthase, reverses interleukin-2-induced hypotension. Crit Care Med 1995; 23: 1018–1024.PubMedCrossRefGoogle Scholar
  68. 68.
    Julou-Schaeffer G, Gray GA, Fleming I, Schott C, Parratt JR, Stoclet JC: Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway. Am J Physiol 1990; 259: H1038–H1043.PubMedGoogle Scholar
  69. 69.
    Knowles RG, Salter M, Brooks SL, Moncada S: Anti-inflammatory glucocorticoids inhibit the induction by endotoxin of nitric oxide synthase in die lung, liver and aorta of the rat. Biochem Biophys Res Commun 1990; 172: 1042–1048.PubMedCrossRefGoogle Scholar
  70. 70.
    De Groote MA, Fang FC: NO inhibitions: antimicrobial properties of nitric oxide. Clin Infect Dis 1995; 21(suppl 2): S162–S165.PubMedCrossRefGoogle Scholar
  71. 71.
    Remick D, Villarete L: Regulation of cytokine expression by reactive oxygen and reactive nitrogen intermediates. J Leukoc Biol 1996; 59: 471–475.PubMedGoogle Scholar
  72. 72.
    Van Dervort A, Yan L, Madara P, et al: Nitric oxide regulates endotoxin-induced TNF-alpha production by human neutrophils. J Immunol 1994; 152: 4102–4109.PubMedGoogle Scholar
  73. 73.
    Hierholzer C, Harbrecht B, Menezes JM, et al: Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock. J Exp Med 1998; 187: 917–928.PubMedCrossRefGoogle Scholar
  74. 74.
    Diefenbach A, Schindler H, Donhauser N, et al: Type 1 interferon (IFNalpha/beta) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite. Immunity 1998; 8: 77–87.PubMedCrossRefGoogle Scholar
  75. 75.
    Ochoa JB, Udekwu AO, Billiar TR, et al: Nitrogen oxide levels in patients after trauma and during sepsis. Ann Surg 1991; 214: 621–626.PubMedCrossRefGoogle Scholar
  76. 76.
    Wong HR, Carcillo JA, Burckart G, Shah N, Janosky JE: Increased serum nitrite and nitrate concentrations in children with the sepsis syndrome. Crit Care Med 1995; 23: 835–842.PubMedCrossRefGoogle Scholar
  77. 77.
    Evans T, Carpenter A, Kinderman H, Cohen J: Evidence of increased nitric oxide production in patients with the sepsis syndrome. Circ Shock 1993; 41: 77–81.PubMedGoogle Scholar
  78. 78.
    Gomez-Jimenez J, Salgado A, Mourelle M, et al: L-Arginine: nitric oxide pathway in endotoxemia and human septic shock. Crit Care Med 1995; 23: 253–258.PubMedCrossRefGoogle Scholar
  79. 79.
    MacMicking JD, Nathan C, Hom G, et al: Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 1995; 81: 641–650. Erratum. Cell 1995; 81 following 1170.PubMedCrossRefGoogle Scholar
  80. 80.
    Thiemermann C, Ruetten H, Wu CC, Vane JR: The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. Br J Pharmacol 1995; 116: 2845–2851.PubMedCrossRefGoogle Scholar
  81. 81.
    Nava E, Palmer RM, Moncada S: The role of nitric oxide in endotoxic shock: effects of N G-monomethyl-l-arginine. J CardiovascPharmacol 1992; 20(suppl 12): S132–S134.Google Scholar
  82. 82.
    Meyer J, Lenti CW, Stothert JCJ, Traber LD, Herndon DN, Traber DL: Effects of nitric oxide synthesis inhibition in hyperdynamic endotoxemia. Crit Care Med 1994; 22: 306–312.PubMedCrossRefGoogle Scholar
  83. 83.
    Meyer J, Traber LD, Nelson S, et al: Reversal of hyperdynamic response to continuous endotoxin administration by inhibition of NO synthesis. J Appl Physiol 1992; 73: 324–328.PubMedGoogle Scholar
  84. 84.
    Wu CC, Chen SJ, Szabo C, Thiemermann C, Vane JR: Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock. Br J Pharmacol 1995; 114: 1666–1672.PubMedCrossRefGoogle Scholar
  85. 85.
    Seo HG, Fujiwara N, Kaneto H, Asahi M, Fujii J, Taniguchi N: Effect of a nitric oxide synthase inhibitor, S-ethylisothiourea, on cultrured cells and cardiovascular functions of normal and lipopolysaecharide-treated rabbits. J Biochem (Tokyo) 1996; 119: 553–558.PubMedCrossRefGoogle Scholar
  86. 86.
    Szabo C, Southan GJ, Thiemermann C: Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. Proc Natl Acad Sci USA 1994; 91: 12472–12476.PubMedCrossRefGoogle Scholar
  87. 87.
    Vromen A, Szabo C, Southan GJ, Salzman AL: Effects of S-isopropyl isothiourea, a potent inhibitor of nitric oxide synthase, in severe hemorrhagic shock. J Appl Physiol 1996; 81: 707–715.PubMedGoogle Scholar
  88. 88.
    Lin PJ, Chang CH, Chang JP: Reversal of refractory hypotension in septic shock by inhibitor of nitric oxide synthase. Chest 1994; 106: 626–629.PubMedCrossRefGoogle Scholar
  89. 89.
    Petros A, Bennett D, Vallance P: Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 1991; 338: 1557–1558.PubMedCrossRefGoogle Scholar
  90. 90.
    Petros A, Lamb G, Leone A, Moncada S, Bennett D, Vallanee P: Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc Res 1994; 28: 34–39.PubMedCrossRefGoogle Scholar
  91. 91.
    Lorente JA, Landin L, DePablo R, Renes E, Liste D: l-Arginine pathway in the sepsis syndrome. Crit Care Med 1993; 21: 1287–1295.PubMedCrossRefGoogle Scholar
  92. 92.
    Avontuur JA, Tutein NR, vanBodegom JW, Bruining HA: Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical study. Crit Care Med 1998; 26: 660–667.PubMedCrossRefGoogle Scholar
  93. 93.
    Anonymous editor: Nitric oxide synthase inhibition: clinical aspects. Acta Hostichemica 1997; 99: 127–128.Google Scholar
  94. 94.
    Mourelatos MG, Enzer N, Ferguson JL, Rypins EB, Burhop KE, Law WR: The effects of diaspirin cross-linked hemoglobin in sepsis. Shock 1996; 5: 141–148.PubMedCrossRefGoogle Scholar
  95. 95.
    Reah G, Bodenham AR, Mallick A, Daily EK, Przybelski RJ: Initial evaluation of diaspirin cross-linked hemoglobin (DCLHb) as a vasopressor in critically ill patients. Crit Care Med 1997; 25: 1480–1488.PubMedCrossRefGoogle Scholar
  96. 96.
    Moisan S, Drapeau G, Burhop KE, Rioux F: Mechanism of the acute pressor effect and bradycardia elicited by diaspirin crosslinked hemoglobin in anesthetized rats. Can J Physiol Pharmacol 1998; 76: 434–442.PubMedCrossRefGoogle Scholar
  97. 97.
    Fink MP, Fiallo V, Stein KL, Gardiner WM: Systemic and regional hemodynamic changes after intraperitoneal endotoxin in rabbits: development of a new model of the clinical syndrome of hyperdynamic sepsis. Circ Shock 1987; 22: 73–81.PubMedGoogle Scholar
  98. 98.
    Millar CG, Thiemermann C: Intrarenal haemodynamics and renal dysfunction in endotoxemia: effects of nitric oxide synthase inhibition. Br J Pharmacol 1997; 121: 1824–1830.PubMedCrossRefGoogle Scholar
  99. 99.
    Spain DA, Wilson MA, Bloom ITM, Garrison RN: Renal microvascular responses to sepsis are dependent on nitric oxide. J Surg Res 1994; 56: 524–529.PubMedCrossRefGoogle Scholar
  100. 100.
    Shultz PJ, Raij L: Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis. J Clin Invest 1992; 90: 1718–1725.PubMedCrossRefGoogle Scholar
  101. 101.
    Schwartz D, Mendonca M, Schwartz I, et al: Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. J Clin Invest 1997; 100: 439–448.PubMedCrossRefGoogle Scholar
  102. 102.
    Groeneveld PH, Kwappenberg KM, Langermans JA, Nibbering PH, Curtis L: Nitric oxide (NO) production correlates with renal insufficiency and multiple organ dysfunction syndrome in severe sepsis. Intensive Care Med 1996; 22: 1197–1202.PubMedCrossRefGoogle Scholar
  103. 103.
    Fox GA, McCormack DG: The pulmonary physician and critical care 4. A new look at the pulmonary circulation in acute lung injury. Thorax 1992; 47: 743–747.PubMedCrossRefGoogle Scholar
  104. 104.
    Tavaf-Motamen H, Miner TJ, Starnes BW, Shea-Donohue T: Nitric oxide mediates acute lung injury by modulation of inflammation. J Surg Res 1998; 78: 137–142.PubMedCrossRefGoogle Scholar
  105. 105.
    Turnage RH, Wright JK, Iglesias J, et al: Intestinal reperfusioninduced pulmonary edema is related to increased pulmonary inducible nitric oxide synthase activity. Surgery 1998; 124: 457–462.PubMedCrossRefGoogle Scholar
  106. 106.
    Mehta S, Boudreau J, Lilly CM, Drazen JM: Endogenous pulmonary nitric oxide in the regulation of airway microvascular leak. Am J Physiol 1998; 275: L961–L968.PubMedGoogle Scholar
  107. 107.
    Arkovitz MS, Wispe JR, Garcia VF, Szabo C: Selective inhibition of the inducible isoform of nitric oxide synthase prevents pulmonary transvascular flux during acute endotoxemia. J Pediatr Surg 1996; 31: 1009–1015.PubMedCrossRefGoogle Scholar
  108. 108.
    Kristof AS, Goldberg P, Laubach V, Hussain SN: Role of inducible nitric oxide synthase in endotoxin-induced acute lung injury. Am J Respir Crit Care Med 1998; 158: 1883–1889.PubMedCrossRefGoogle Scholar
  109. 109.
    Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM: Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993; 328: 399–405.PubMedCrossRefGoogle Scholar
  110. 110.
    Demling RH, Smith M, Gunther R, Flynn JT, Gee MH: Pulmonary injury and prostaglandin production during endotoxemia in conscious sheep. Am J Physiol 1981; 240: H348–H353.PubMedGoogle Scholar
  111. 111.
    Benedict CR, Grahame-Smith DG: Plasma noradrenaline and adrenaline concentrations and dopamine-beta-hydroxylase activity in patients with shock due to septicaemia, trauma and haemorrhage. QJ Med 1978; 47: 1–20.Google Scholar
  112. 112.
    Rayhrer CS, Edmisten TD, Cephas GA, Tribble CG, Kron IL, Young JS: Nitric oxide potentiates acute lung injury in an isolated rabbit lung model. Ann Thorac Surg 1998; 65: 935–938.PubMedCrossRefGoogle Scholar
  113. 113.
    Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM: Inhaled nitric oxide: a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991; 83: 2038–2047. Erratum. Circulation 1991;84: 2212.PubMedCrossRefGoogle Scholar
  114. 114.
    Fratacci MD, Frostell CG, Chen TY, Wain JCJ, Robinson DR, Zapol WM: Inhaled nitric oxide: a selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep. Anesthesiology 1991; 75: 990–999.PubMedCrossRefGoogle Scholar
  115. 115.
    Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J: Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991; 338: 1173–1174.PubMedCrossRefGoogle Scholar
  116. 116.
    Weitzberg E, Rudehill A, Lundberg JM: Nitric oxide inhalation attenuates pulmonary hypertension and improves gas exhange in endotoxin shock. Eur J Pharmacol 1993; 233: 85–94.PubMedCrossRefGoogle Scholar
  117. 117.
    Dahm PL, Jonson B, DeRobertis E, et al: The effects of nitric oxide inhalation on respiratory mechanics and gas exchange during endotoxaemia in the pig. Acta Anaesthesiol Scand 1998; 42: 536–544.PubMedCrossRefGoogle Scholar
  118. 118.
    Ogura H, Offner PJ, Saitoh D, et al: The pulmonary efffect of nitric oxide synthase inhibition following endotoxemia in a swine model. Arch Surg 1994; 129: 1233–1239.PubMedCrossRefGoogle Scholar
  119. 119.
    Offner PJ, Ogura H, Jordan BS, Pruitt BAJ, Cioffi WG: Effects of inhaled nitric oxide on right ventricular function in endotoxin shock. J Trauma 1995; 39: 179–185.PubMedCrossRefGoogle Scholar
  120. 120.
    Shah NS, Nakayama DK, Jacob TD, et al: Efficacy of inhaled nitric oxide in a porcine model of adult respiratory distress syndrome. Arch Surg 1994; 129: 158–164.PubMedCrossRefGoogle Scholar
  121. 121.
    Okamoto K, Hamaguchi M, Kukita I, Kikuta K, Sato T: Efficacy of inhaled nitric oxide in children with ARDS. Cheit 1998; 114: 827–833.Google Scholar
  122. 122.
    Troncy E, Collet JP, Shapiro S, et al: Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study. Am J Respir Grit Care Med 1998; 157: 1483–1488.CrossRefGoogle Scholar
  123. 123.
    Doering EB, Hanson CW, Reily DJ, Marshall C, Marshall BE: Improvement in oxygenation by phenylephrine and nitric oxide in patients with adult respiratory distress syndrome. Anesthesiology 1997; 87: 18–25.PubMedCrossRefGoogle Scholar
  124. 124.
    Gillart T, Bazin JE, Cosserant B, et al: Combined nitric oxide inhalation, prone positioning and almitrine infusion improveoxygenation in severe ARDS. Can J Anaesth 1998; 45: 402–409.PubMedCrossRefGoogle Scholar
  125. 125.
    Robertson FM, Oftner PJ, Ciceri DP, Becker WK, Praitt BAJ;Detrimental hemodynamic effects of nitric oxide synthase inhibitionin septic shock. Arch Surg 1994; 129: 149–155.PubMedCrossRefGoogle Scholar
  126. 126.
    Weitzberg E, Rudehill A, Modin A, Lundberg JM: Effect of combined nitric oxide inhalation and N G-nitro-l-arginine infusion in porcine endotoxin shock. Crit Care Med 1995; 23: 909–918.PubMedCrossRefGoogle Scholar
  127. 127.
    Klemm P, Thiemermann C, Winklmaier G, Martorana PA, Henning R: Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxin shock. Br J Pharmacol 1995; 114: 363–368.PubMedCrossRefGoogle Scholar
  128. 128.
    Suffredini AF, Fromm RE, Parker MM, et al: The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989; 321: 280–287.PubMedCrossRefGoogle Scholar
  129. 129.
    Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL: Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257: 387–389.PubMedCrossRefGoogle Scholar
  130. 130.
    Weyrich AS, Ma XL, Buerke M, et al: Physiological concentrations of nitric oxide do not elicit an acute negative inotropic effect in unstimulated cardiac muscle. Circ Res 1994; 75: 692–700.PubMedCrossRefGoogle Scholar
  131. 131.
    Brady AJ, Poole-Wilson PA, Harding SE, Warren JB: Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol 1992; 263: H1963–H1966.PubMedGoogle Scholar
  132. 132.
    Brady AJ, Warren JB, Poole-Wilson PA, Williams TJ, Harding SE: Nitric oxide attenuates cardiac myocyte contraction. Am J Physiol 1993; 265: H176–H182.PubMedGoogle Scholar
  133. 133.
    Klabunde RE, Ritger RC: N G-Monomethyl-l-arginine (NMA) restores arterial blood pressure but reduces cardiac output in a canine model of endotoxic shock. Biochem Biophys Res Gommun 1991; 178: 1135–1140.CrossRefGoogle Scholar
  134. 134.
    Statman R, Cheng W, Cunningham JN, et al: Nitric oxide inhibition in the treatment of the sepsis syndrome is detrimental to tissue oxygenation. J Surg Res 1994; 57: 93–98.PubMedCrossRefGoogle Scholar
  135. 135.
    Freeman BD, Zeni F, Banks SM, et al: Response of the septic vasculature to prolonged vasopressor therapy with N ω-monomethyl-l-arginine and epinephrine in canines. Crit Care Med 1998; 26: 877–886.PubMedCrossRefGoogle Scholar
  136. 136.
    McDonough KH, Smith T, Patel K, Quinn M: Myocardial dysfunction in the septic rat heart: tirole of nitric oxide. Shock 1998; 10: 371–376.PubMedCrossRefGoogle Scholar
  137. 137.
    Avontuur JA, Bruining HA, Ince C: Inhibition of nitric oxide synthesis causes myocardial ischemia in endotoxemic rats. Circ Res 1995; 76: 418–425.PubMedCrossRefGoogle Scholar
  138. 138.
    Gurran RD, Billiar TR, Stuehr DJ, Hofmann K, Simmons RL: Hepatocytes produce nitrogen oxides from L-arginine in response to inflammatory products of Kupffer cells. J Exp Med 1989; 170: 1769–1774.CrossRefGoogle Scholar
  139. 139.
    Nussler AK, Di Silvio M, Billiar TR, et al: Stimulation of the nitric oxide synthase pathway in human hepatocytes by cytokines and endotoxin. J Exp Med 1992; 176: 261–264.PubMedCrossRefGoogle Scholar
  140. 140.
    Geller DA, Nussler AK, Di Silvio M, et al: Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. Proc Natl Acad Sci USA 1993; 90: 522–526.PubMedCrossRefGoogle Scholar
  141. 141.
    Geller DA, Di Silvio M, Nussler AK, et al: Nitric oxide synthase expression is induced in hepatocytes in vivo during hepatic inflammation. J Surg Res 1993; 55: 427–432.PubMedCrossRefGoogle Scholar
  142. 142.
    Klotz FW, Scheller LF, Seguin MC, et al: Co-localization of inducible-nitric oxide synthase and plasmodium berghei in hepatocytes from rats immunized with irradiated sporozoites. J Immunol 1995; 154: 3391–3395.PubMedGoogle Scholar
  143. 143.
    Billiar TR, Curran RD, Stuehr DJ, West MA, Bentz BG, Simmons RL: An l-arginie-dependent mechanism mediates Kupffer cell inhibition of hepatocyte protein synthesis in vitro. J Exp Med 1989; 169: 1467–1472.PubMedCrossRefGoogle Scholar
  144. 144.
    Stadler J, Billiar TR, Gurran RD, Stuehr DJ, Ochoa JB, Simmons RL: Effect of exogenous and endogenous nitric oxide on mitochondrial respiration of rat hepatocytes. Am J Physiol 1991; 260: C910–C916.PubMedGoogle Scholar
  145. 145.
    Muller CM, Scierka A, Stiller RL, et al: Nitric oxide mediates hepatic cytochrome P450 dysfunction induced by endotoxin. Anesthesiology 1996; 84: 1435–1442.PubMedCrossRefGoogle Scholar
  146. 146.
    Harbrecht BG, Billiar TR, Stadler J, et al: Nitric oxide synthesis serves to reduce hepatic damage during acute murine endotoxemia. Crit Care Med 1992; 20: 1568–1574.PubMedCrossRefGoogle Scholar
  147. 147.
    Harbrecht BG, Billiar TR, Stadler J, et al: Inhibition of nitric oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury. J Leukoc Biol 1992; 52: 390–394.PubMedGoogle Scholar
  148. 148.
    Pastor CM, Losser MR, Payen D: Nitric oxide donor prevents hepatic and systemic perfusion decrease induced by endotoxin in anesthetized rabbits. Hepatology 1995; 22: 1547–1553.PubMedGoogle Scholar
  149. 149.
    Liaudet L, Feihl F, Rosselet A, Markert M, Hurni JM, Perret C: Beneficial effects of L-canavanine, a selective inhibitor of inducible nitric oxide synthase, during rodent endotoxaemia. Clin Sci (Colch) 1996; 90: 369–377.Google Scholar
  150. 150.
    Ruetten H, Southan GJ, Abate A, Thiemermann C: Attenuation of endotoxin-induced multiple organ dysfunction by 1-amino-2-hydroxy-guanidine, a potent inhibitor of inducible nitric oxide synthase. Br J Pharmacol 1996; 118: 261–270.PubMedCrossRefGoogle Scholar
  151. 151.
    Ou J, Carlos TM, Watkins SC, et al: Differential effects of nonselective nitric oxide synthase (NOS) and selective inducible NOS inhibition on hepatic necrosis, apoptosis, ICAM-1 expression, and neutrophil accumulation during endotoxemia. Nitric Oxide 1997; 1: 404–416.PubMedCrossRefGoogle Scholar
  152. 152.
    Kim YM, de Vera ME, Watkins SC, Billiar TR: Nitric Oxide protects cultured rat hepatocytes from tumor necrosis factor-alpha-induced apoptosis by inducing heat shock protein 70 expression. J Biol Chem 1997; 272: 1402–1411PubMedCrossRefGoogle Scholar
  153. 153.
    Tzeng E, Kim YM, Pitt BR, Lizonova A, Kovesdi I, Billiar TR: Adenoviral transfer of the inducible nitric oxide synthase gene blocks endothelial cell apoptosis. Surgery 1997; 122: 255–263.PubMedCrossRefGoogle Scholar
  154. 154.
    Peralta C, Hotter G, Closa D, Gelpi E, Bulbena O, Rosello Catafau J: Protective effect of preconditioning on the injury associated to hepatic ischemia-reperfusion in the rat: tirole of nitric oxide and adenosine. Hepatology 1997; 25: 934–937.PubMedCrossRefGoogle Scholar
  155. 155.
    Shiraishi M, Kusano T, Aihara T, Ikeda Y, Koyama Y, Muto Y: Protection against hepatic ischemia/reperfusion injury by exogenous L-arpnine. Transplant Proc 1996; 28: 1887–1888.PubMedGoogle Scholar
  156. 156.
    Peralta C, Closa D, Hotter G, Gelpi E, Prats N, Rosello-Catafau J: Liver ischemic preconditioning is mediated by the inhibitory action of nitric oxide on endothelin. Biochem Biophys Res Commun 1996; 229: 264–270.PubMedCrossRefGoogle Scholar
  157. 157.
    Swank GM, Deitch EA: Role of the gut in multiple organ failure: bacterial translocation and permeability changes. World J Surg 1996; 20: 411–417.PubMedCrossRefGoogle Scholar
  158. 158.
    Nelson DP, Samsel RW, Wood LD, Schumacker PT: Pathological supply dependence of systemic and intestinal O2 uptake during endotoxemia. J Appl Physiol 1988; 64: 2410–2419.PubMedGoogle Scholar
  159. 159.
    Theuer CJ, Wilson MA, Steeb GD, Garrison RN: Microvascular vasoconstriction and mucosal hypoperfusion of the rat small intestine during bacteremia. Circ Shock 1993; 40: 61–68.PubMedGoogle Scholar
  160. 160.
    Mitchell JA, Kohlhaas KL, Sorrentino R, Warner TD, Murad F, Vane JR: Induction by endotoxin of nitric oxide synthase in the rat mesentery: lack of effect on action of vasoconstrictors. Br J Pharmacol 1993; 109: 265–270.PubMedCrossRefGoogle Scholar
  161. 161.
    Laszlo F, Whittle BJ, Moncada S: Time-dependent enhancement or inhibition of endotoxin-induced vascular injury in rat intestine by nitric oxide synthase inhibitors. Br J Pharmacol 1994; 111: 1309–1315.PubMedCrossRefGoogle Scholar
  162. 162.
    Hutcheson IR, Whittle BJ, Boughton-Smith NK: Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat. Br J Pharmacol 1990; 101: 815–820.PubMedCrossRefGoogle Scholar
  163. 163.
    Boughton-Smith NK, Hutcheson IR, Deakin AM, Whittle BJ, Moncada S: Protective effect of S-nitroso-N-acetyl-penicttlamine in endotoxin-induced acute intestinal damage in the rat. Eur J Pharmacol 1990; 191: 485–488.PubMedCrossRefGoogle Scholar
  164. 164.
    Herach M, Madorin WS, Sibbald WJ, Martin CM: Selective gut microcirculatory control (SGMC) in septic rats: a novel approach with a locally applied vasoactive drag. Shock 1998; 10: 292–297.CrossRefGoogle Scholar
  165. 165.
    Sorrells DL, Friend C, Koltuksuz U, et al: Inhibition of nitric oxide with aminoguanidine reduces bacterial translocation after endotoxin challenge in vivo. Arch Surg 1996; 131: 1155–1163.PubMedCrossRefGoogle Scholar
  166. 166.
    Stark ME, Bauer AJ, Szurszewski JH: Effect of nitric oxide on circular muscle of the canine small intestine. J Physiol (Lond) 1991; 444: 743–761.Google Scholar
  167. 167.
    Russo A, Fraser R, Adachi K, Horowitz M, Boeckxstaens G: Evidence that nitric oxide mechanisms regulate small intestinal motility in humans. Gut 1999; 44: 72–76.PubMedCrossRefGoogle Scholar
  168. 168.
    Eskandari MK, Kalff JC, Lee KK, Bauer AJ: Lipopolysaccharide activates jejunal muscularis macrophages and suppresses circular muscularis activity. Transplant Proc 1998; 30: 2670.PubMedCrossRefGoogle Scholar
  169. 169.
    Minnard EA, Shou J, Naama H, Cech A, Gallagher H, Daly JM: Inhibition of nitric oxide synthesis is detrimental during endotoxemia. Arch Surg 1994; 129: 142–147.PubMedCrossRefGoogle Scholar
  170. 170.
    Fukatsu K, Saito H, Fukushima R, et al: Detrimental effects of a nitric oxide synthase inhibitor N ω-nitro-l-argimne-methyl-ester) in a murine sepsis model. Arch Surg 1995; 130: 410–414.PubMedCrossRefGoogle Scholar
  171. 171.
    Evans T, Carpenter A, Silva A, Cohen J: Inhibition of nitric oxide synthase in experimental gram-negative sepsis. J Infect Dis 1994; 169: 343–349.PubMedCrossRefGoogle Scholar
  172. 172.
    Cobb JP, Natanson C, Hoffman WD, et al: N ω-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 1992; 176: 1175–1182.PubMedCrossRefGoogle Scholar
  173. 173.
    Laubach VE, Shesely EG, Smithies O, Sherman PA: Mice lacking inducible nitric oxide synthase are not resistant to lipopoly-saccharide-induced death. Proc Natl Acad Sci USA 1995; 92: 10688–10692.PubMedCrossRefGoogle Scholar
  174. 174.
    Grover R, Lopez A, Lorente J, Steingrub J, Bakker J, Wilatts S: Multi-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546V88: effect on survival in patients with septic shock. Crit Care Med 1999; 27: A33.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • A. Neil Salyapongse
  • Timothy R. Billiar

There are no affiliations available

Personalised recommendations