Role of Nitric Oxide in Pulmonary Vascular Dysfunction

  • M. J. D. Griffiths
  • T. W. Evans
Part of the Update in Intensive Care and Emergency Medicine book series (UICM, volume 24)


Early descriptions of patients with septic shock in which invasive monitoring was used emphasized the failure of a sustained response of the central venous pressure and cardiac output to volume replacement indicating pathological dilation of peripheral blood vessels [1]. Apart from the hemodynamic changes associated with shock, metabolic derangement and failure of multiple organ systems, including acute lung injury (ALI), were recorded in the majority of patients. Since early reports that a calcium-independent nitric oxide synthase (NOS) could be induced by endotoxin (LPS) and proinflammatory cytokines in extra-endothelial vascular tissue [2], considerable evidence(vide supra) has accumulated implicating nitric oxide (NO), derived from inducible iNOS, as a final mediator of sepsis-associated vasodilation and hyporesponsiveness to vasopressors. More recently, with the increasing awareness of the importance of oxygen delivery in determining the outcome of patients with sepsis, attention has focused on the regional distribution of blood flow both at an organ system and microcirculatory level. In this chapter, the evidence implicating the L-arginine/NO pathway as an important effector of sepsis-induced pulmonary vascular dysfunction is discussed.


Nitric Oxide Acute Lung Injury Systemic Inflammatory Response Syndrome Adult Respiratory Distress Syndrome Hypoxic Pulmonary Vasoconstriction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    MacLean LD, Mulligan WG, McLean APH, Duff JH (1967) Patterns of septic shock in man - A detailed study of 56 patients. Annal Surg 166:543–562CrossRefGoogle Scholar
  2. 2.
    Rees DD, Cellek S, Palmer RM, Moncada S (1990) Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone: An insight into endotoxin shock. Biochem Biophys Res Commun 173:541–547PubMedCrossRefGoogle Scholar
  3. 3.
    Bone RC, Balk RA, Cerra FB, et al (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644–1655PubMedCrossRefGoogle Scholar
  4. 4.
    Marshall J, Sweeney D (1990) Microbial infection and the septic response in critical surgical illness. Arch Surg 125:17–23PubMedCrossRefGoogle Scholar
  5. 5.
    Rubin DB, Wiener-Kronish JP, Murray JF (1990) Elevated von Willebrand factor anti- genis: An early predictor of impending acute lung injury in nonpulmonary sepsis syndrome. J Clin Invest 86:474–480PubMedCrossRefGoogle Scholar
  6. 6.
    Bernard GR, Artigas A, Brigham KL, et al. (1994) The American-European consensus conference on ARDS: Definitions, mechanisms, relevant outcomes and clinical trial co-ordination. Am J Respir Crit Care Med 149:818–824PubMedGoogle Scholar
  7. 7.
    St John RC, Mizer LA, Kindt GC, et al (1993) Acid aspiration-induced acute lung injury causes leukocyte-dependent systemic organ injury. J Appl Physiol 74:1994–2003PubMedGoogle Scholar
  8. 8.
    Meduri GU, Belenchia JM, Estes RJ, et al (1991) Fibroproliferative phase of ARDS. Clinical findings and effects of corticosteroids. Chest 100:943–952PubMedCrossRefGoogle Scholar
  9. 9.
    Mizer LA, Weisbrode SE, Dorinsky PM (1989) Neutrophil accumulation and structural changes in nonpulmonary organs after acute lung injury induced by phorbol myristate acetate. Am Rev Respir Dis 139:1017–1026PubMedGoogle Scholar
  10. 10.
    Bone RC, Balk R, Slotman G, et al (1992) Adult respiratory distress syndrome. Sequence and importance of development of multiple organ failure. The Prostaglandin El Study Group. Chest 101:320–326PubMedCrossRefGoogle Scholar
  11. 11.
    Montgomery AB, Stager MA, Carrico CJ, Hudson LD (1985) Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 132:485–489PubMedGoogle Scholar
  12. 12.
    Zapol WM, Snider MT (1977) Pulmonary hypertension in severe acute respiratory failure. N Engl J Med 296:476–480294PubMedCrossRefGoogle Scholar
  13. 13.
    M. J. D. Griffiths and T. W. Evans Jones R, Reid L (1992) Pulmonary vascular changes in adult respiratory distress syndrome. In: Artigas A, et al (eds) Adult respiratory distress syndrome. Churchill Livingstone, New York, pp 45–59Google Scholar
  14. 14.
    Leeman M (1991) The pulmonary circulation in acute lung injury: A review of some recent advances. Intensive Care Med 17:254–260PubMedCrossRefGoogle Scholar
  15. 15.
    Buchser E, Leuenberger P, Chiolero R, Perret C, Freeman J (1985) Reduced pulmonary capillary blood volume as a long-term sequel of ARDS. Chest 87:608–611PubMedCrossRefGoogle Scholar
  16. 16.
    Sibbald WJ, Driedger A A (1983) Right ventricular function in acute disease states: Pathophysiologic considerations. Crit Care Med 11:339–345PubMedCrossRefGoogle Scholar
  17. 17.
    Prewitt RM, McCarthy J, Wood LDH (1981) Treatment of acute low pressure pulmonary edema in dogs. J Clin Invest 67:409–418PubMedCrossRefGoogle Scholar
  18. 18.
    Cheney FW, Eisenstein BL, Bishop MJ (1989) Alveolar hypoxia, inhibition of hypoxic pulmonary vasoconstriction, and permeability edema. Respir Physiol 75:11–18PubMedCrossRefGoogle Scholar
  19. 19.
    Weir EK, Milczoch J, Reeves JT, Grover RF (1976) Endotoxin and prevention of hypoxic pulmonary vasoconstriction. J Lab Clin Med 68:975–983Google Scholar
  20. 20.
    Dantzker DR, Brook CJ, Dehart P, Lynch JP, Weg JG (1979) Ventilation-perfusion distributions in the adult respiratory distress syndrome. Am Rev Respir Dis 120: 1039–1052PubMedGoogle Scholar
  21. 21.
    Reyes A, Roca J, Rodriguez-Roisin R, et al. (1988) Effect of almitrine on ventilation- perfusion distribution in adult respiratory distress syndrome. Am Rev Respir Dis 137: 1062–1067PubMedGoogle Scholar
  22. 22.
    Wysocki M, Delclaux C, Roupie E, et al (1994) Additive effect on gas exchange of inhaled nitric oxide and intravenous almitrine bismesylate in the adult respiratory distress syndrome. Intensive Care Med 20:254–259PubMedCrossRefGoogle Scholar
  23. 23.
    Barnard JW, Wilson PS, Moore TM, Thompson WJ, Taylor AE (1993) Effect of nitric oxide and cyclooxygenase products on vascular resistance in dog and rat lungs. J Appl Physiol 74:2940–2948PubMedGoogle Scholar
  24. 24.
    Stamler JS, Loh E, Roddy M, Hoffman KE, Creager MA (1994) Nitric oxide regulates systemic and pulmonary vascular resistance in normal subjects. Circulation 89: 2035–2040PubMedGoogle Scholar
  25. 25.
    Chand N, Altura BM (1981) Acetylcholine and bradykinin relax intrapulmonary arteries by acting on endothelial cells: Role in lung vascular diseases. Science 213: 1376–1379PubMedCrossRefGoogle Scholar
  26. 26.
    Greenberg B, Rhoden K, Barnes PJ (1987) Endothelium-dependent relaxation of human pulmonary arteries. Am J Physiol 252: H434-H438PubMedGoogle Scholar
  27. 27.
    Liu SF, Crawley DE, Barnes PJ, Evans TW (1991) Endothelium-derived relaxing factor inhibits hypoxic pulmonary vasoconstriction in rats. Am Rev Respir Dis 143: 32–37PubMedGoogle Scholar
  28. 28.
    Liu SF, Crawley DE, Evans TW, Barnes PJ (1991) Endogenous nitric oxide modulates adrenergic neural vasoconstriction in guinea-pig pulmonary artery. Br J Pharmacol 104:565–569PubMedGoogle Scholar
  29. 29.
    Cremona G, Higenbottam T, Wood AM, Dinh Xuan AT (1992) importance of endogenous nitric oxide in the adaptation to increased blood flow in isolated human and sheep lungs. Am Rev Respir Dis 145: A206 (Abst)Google Scholar
  30. 30.
    Liu SF, Crawley DE, Rohde JA, Evans TW, Barnes PJ (1992) Role of nitric oxide and guanosine 3’,5’ -cyclic monophosphate in mediating nonadrenergic, noncholinergic relaxation in guinea-pig pulmonary arteries. Br J Pharmacol 107:861–866PubMedGoogle Scholar
  31. 31.
    Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM (1991) Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 83:2038–2047Google Scholar
  32. 32.
    Fratacci MD, Frostell CG, Chen TY, et al. (1991) Inhaled nitric oxide. A selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep. Anesthesiology 75:990–999PubMedCrossRefGoogle Scholar
  33. 33.
    Frostell CG, Blomqvist H, Hedenstierna G, Lundberg J, Zapol WM (1993) Inhaled nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilation. Anesthesiology 78:427–435PubMedCrossRefGoogle Scholar
  34. 34.
    Liu SF, Dewar A, Crawley DE, Barnes PJ, Evans TW (1992) Effect of tumor necrosis factor on hypoxic pulmonary vasoconstriction. J Appl Physiol 72:1044–1049PubMedGoogle Scholar
  35. 35.
    Tsuchida S, Hiraoka M, Sudo M, Kigoshi S, Muramatsu I (1995) Attenuation of sodium nitroprusside responses after prolonged incubation of rat aorta with endotoxin. Am J Physiol 267: H2305-H2310Google Scholar
  36. 36.
    Aoki N, Siegfried M, Lefer AM (1989) Anti-EDRF effect of tumor necrosis factor in isolated, perfused cat carotid arteries. Am J Physiol 256:H1509-H1512PubMedGoogle Scholar
  37. 37.
    Xie J, Wang Y, Lippton H, et al. (1993) Tumor necrosis factor inhibits stimulated but not basal release of nitric oxide. Am Rev Respir Dis 148:627–636PubMedCrossRefGoogle Scholar
  38. 38.
    Wang P, Ba ZF, Chaudry IH (1994) Administration of tumor necrosis factor alpha in vivo depresses endothelium-dependent relaxation. Am J Physiol 266: H2535-H2541PubMedGoogle Scholar
  39. 39.
    Späth JA, Sloane PJ, Gee MH, Albertine KH (1994) Loss of endothelium-dependent vasodilation in the pulmonary vessels of sheep after endotoxin. Am J Physiol 76: 361–369Google Scholar
  40. 40.
    Parker JL, Adams HR (1993) Selective inhibition of endothelium-dependent vasodila tor capacity by Escherichia coli endotoxemia. Circ Res 72:539–551PubMedGoogle Scholar
  41. 41.
    Parker JL, Keller RS, DeFily DV, Laughlin MH, Adams HR (1991) Coronary vascular smooth muscle function in E. coli endotoxemia in dogs. Am J Physiol 260: H832-H841PubMedGoogle Scholar
  42. 42.
    Umans JG, Wylam ME, Samsel RW, Edwards J, Schumacker PT (1993) Effects of endotoxin in vivo on endothelial and smooth muscle function in rabbit and rat aorta. Am Rev Respir Dis 148:1638–1645PubMedCrossRefGoogle Scholar
  43. 43.
    Guc MO, Gray GA, Furman BL, Parratt JR (1991) Endotoxin-induced impairment of vasodepressor responses in the pithed rat. Eur J Pharmacol 204:63–70PubMedCrossRefGoogle Scholar
  44. 44.
    Martin CM, Yaghi A, Sibbald WJ, McCormack D, Paterson NA (1993) Differential impairment of vascular reactivity of small pulmonary and systemic arteries in hyperdynamic sepsis. Am Rev Respir Dis 148:164–172PubMedCrossRefGoogle Scholar
  45. 45.
    Wylam ME, Samsel RW, Umans JG, et al. (1990) Endotoxin in vivo impairs endo- thelium-dependent relaxation of canine arteries in vitro. Am Rev Respir Dis 142: 1263–1267PubMedGoogle Scholar
  46. 46.
    Waller J, Gardiner SM, Bennett T (1994) Regional haemodynamic reponses to acetylcholine, methoxamine, salbutamol and bradykinin during lipopolysaccharide infusion in conscious rats. Br J Pharmacol 112:1057–1064PubMedGoogle Scholar
  47. 47.
    Griffiths MJD, Liu S, Curzen NP, Messent M, Evans TW (1995) In vivo treatment with endotoxin-induced nitric oxide synthase in rat main pulmonary artery. Am J Physiol 268:L509-L518PubMedGoogle Scholar
  48. 48.
    Stewart TE, Valenza F, Ribiero SP, et al (1995) Increased nitric oxide in exhaled gas as an early marker of lung inflammation in a model of sepsis. Am J Respir Crit Care Med 151:713–718PubMedGoogle Scholar
  49. 49.
    Kiff RJ, Moss DW, Moncada S (1994) Effect of nitric oxide gas on the generation of nitric oxide by isolated blood vessels: Implications for inhalational therapy. Br J Pharmacol 113:496–498PubMedGoogle Scholar
  50. 50.
    Lorente JA, Landin L, de Pablo R, Renes E, Liste D (1993) L-arginine pathway in the sepsis syndrome. Crit Care Med 21:1287–1295PubMedCrossRefGoogle Scholar
  51. 51.
    Gossage JR, Christman BW (1994) Mediators of acute and chronic pulmonary hypertension. Sem Respir Crit Care Med 15:190–198CrossRefGoogle Scholar
  52. 52.
    Fink MP, O’Sullivan BP, Menconi MJ, et al (1993) A novel leukotriene B4-reeeptor antagonist in endotoxin shock: A prospective, controlled trial in a porcine model. Crit Care Med 21:1825–1837PubMedCrossRefGoogle Scholar
  53. 53.
    Christman BW, Lefferts PL, Blair IA, Snapper JR (1990) Effect of platelet-activating factor receptor antagonism on endotoxin-induced lung dysfunction in awake sheep. Am Rev Respir Dis 142:1272–1278PubMedGoogle Scholar
  54. 54.
    Huval NW, Lelcuk S, Shepro D, Hechtman HB (1984) Role of serotonin in patients with acute respiratory failure. Ann Surg 200:166–172PubMedCrossRefGoogle Scholar
  55. 55.
    Druml W, Steltzer H, Waldhausl W, et al (1993) Endothelin-1 in adult respiratory distress syndrome. Am Rev Respir Dis 148:1169–1173PubMedGoogle Scholar
  56. 56.
    Fink MP, Macvittie TJ, Casey LC (1984) Inhibition of prostaglandin synthesis restores normal haemodynamics in canine hyperdynamic sepsis. Ann Surg 200:619–626PubMedCrossRefGoogle Scholar
  57. 57.
    Crawley DE, Zhao L, Giembycz MA, et al (1992) Chronic hypoxia impairs soluble guanylyl cyclase-mediated pulmonary arterial relaxation in the rat. Am J Physiol 263: L325-L332PubMedGoogle Scholar
  58. 58.
    Dinh-Xuan AT, Higenbottam TW, Clelland CA, et al (1991) Impairment of endothelium-dependent pulmonary artery relaxation in chronic obstructive lung disease. N Engl J Med 324:1539–1547PubMedCrossRefGoogle Scholar
  59. 59.
    Fox GA, McCormack DG (1992) The pulmonary physician and critical care. 4. A new look at the pulmonary circulation in acute lung injury. Thorax 47:743–747PubMedCrossRefGoogle Scholar
  60. 60.
    Weitzberg E (1993) Circulatory responses to endothelin-1 and nitric oxide. Acta Physiol Scand 148:S611 (Abst)Google Scholar
  61. 61.
    Meyer J, Lentz CW, Stothert JC, et al (1994) Effects of nitric oxide synthesis inhibition in hyperdynamic endotoxemia. Crit Care Med 22:306–312PubMedCrossRefGoogle Scholar
  62. 62.
    Hanly P, Sienko A, Light RB (1987) Effect of cyclooxygenase blockade on gas exchange and hemodynamics in Pseudomonas pneumonia. J Appl Physiol 63: 1829–1836PubMedGoogle Scholar
  63. 63.
    Steinberg SM, Rodriguez JL, Bitzer LG, et al (1990) Indomethacin treatment of human adult respiratory distress syndrome. Circ Shock 30:375–384PubMedGoogle Scholar
  64. 64.
    Bernard GR, Reines HD, Metz CA, et al (1988) Effects of a short course of ibuprofen in patients with severe sepsis. Am Rev Respir Dis 137: A138 (Abst)Google Scholar
  65. 65.
    Leeman M, Boeynaems JM, Degaute JP, Vincent JL, Kahn RJ (1985) Administration of dazoxiben, a selective thromboxane synthetase inhibitor, in the adult respiratory distress syndrome. Chest 87:726–730PubMedCrossRefGoogle Scholar
  66. 66.
    Ignarro LJ, Burke TM, Wood KS, Wolin MS, Kadowitz PJ (1993) Association between cyclic GMP accumulation and acetylcholine-induced relaxation of bovine intrapulmonary artery. J Pharmacol Exp Ther 228:682–690Google Scholar
  67. 67.
    Compeau CG, Rotstein OD, Tohda H, et al (1994) Endotoxin-stimulated alveolar macrophages impair lung epithelial sodium ion transport by an L-arginine-dependent mechanism. Am J Physiol 266: C1330-C1341PubMedGoogle Scholar
  68. 68.
    Gutierrez HH, Pitt BR, Schwarz M, et al (1995) Pulmonary alveolar epithelial inducible NO synthase gene expression: Regulation by inflammatory mediators. Am J Physiol 268: L501-L508PubMedGoogle Scholar
  69. 69.
    Heiss LN, Lancaster JR, Corbett JA, Goldman WE (1994) Epithelial autotoxicity of nitric oxide: Role in the respiratory cytopathology of pertussis. Proc Natl Acad Sei USA 91:267–270CrossRefGoogle Scholar
  70. 70.
    Kwon NS, Stuehr DJ, Nathan CF (1991) Inhibition of tumor cell ribonucleotide reductase by macrophage-derived nitric oxide. J Exp Med 174:761–767PubMedCrossRefGoogle Scholar
  71. 71.
    Liew FY, Millott S, Parkinson C, Palmer RM, Moncada S (1990) Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine. J Immunol 144:4794–4797PubMedGoogle Scholar
  72. 72.
    Brune B, Dimmeier S, Vedia LM, Lapetina EG (1994) Nitric oxide: A signal for ADP- ribosylation of proteins. Life Sci 54:61–70PubMedCrossRefGoogle Scholar
  73. 73.
    Stamler JS, Jaraki O, Osborne J, et al (1992) Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin. Proc Natl Acad Sei USA 89:7674–7677CrossRefGoogle Scholar
  74. 74.
    Clancy RM, Levartovsky D, Leszcznska-Piziak J, Yegudin J, Abramson SB (1994) Nitric oxide reacts with intracellular glutathione and activates the heose monophosphate shunt in human neutrophils: Evidence for S-nitrosoglutathione as a bioactive intermediary. Proc Natl Acad Sei USA 91:3680–3684CrossRefGoogle Scholar
  75. 75.
    Stadler J, Billiar TR, Curran RD, et al (1991) Effect of exogenous and endogenous nitric oxide on mitochondrial respiration of rat hepatocytes. Am J Physiol 260: C910-C916PubMedGoogle Scholar
  76. 76.
    Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci 87:1620–1624PubMedCrossRefGoogle Scholar
  77. 77.
    Nguyen T, Brunson D, Crespi CL, et al (1992) DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc Natl Acad Sei 89:3030–3034CrossRefGoogle Scholar
  78. 78.
    Haddad IY, Ischiropoulos H, Holm BA, et al (1993) Mechanisms of peroxynitrite- induced injury to pulmonary surfactants. Am J Physiol 265: L555-L564PubMedGoogle Scholar
  79. 79.
    Rubanyi GM, Ho E, Cantor EH, Lumma WC, Parker Botelho LH (1991) Cytoprotec- tive function of nitric oxide: Inactivation of superoxide radicals produced by human leukocytes. Biochem Biophys Res Commun 181:1392–1397PubMedCrossRefGoogle Scholar
  80. 80.
    Griffiths MJD, Curzen NP, Sair M, Evans TW (1994) Nitric oxide synthase inhibitors in septic shock: Theoretical considerations. Clin Intensive Care 5:29–36Google Scholar
  81. 81.
    Rossaint R, Falke KJ, Lopez F, et al (1993) Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328:399–405PubMedCrossRefGoogle Scholar
  82. 82.
    Oda H, Nogami H, Kusomoto S, et al. (1976) Long-term exposure to nitric oxide in mice. J Jpn Soc Air Pollut 11:150–160Google Scholar
  83. 83.
    Gerlach H, Pappert D, Lewandowski K, Rossaint R, Falke KJ (1993) Long-term inhalation with evaluated low doses of nitric oxide for selective improvement in oxygenation in patients with adult respiratory distress syndrome. Intensive Care Med 19: 443–449PubMedCrossRefGoogle Scholar
  84. 84.
    Zapol WM (1993) Minidose inhaled nitric oxide: Less is better. Intensive Care Med 19:433–434PubMedCrossRefGoogle Scholar
  85. 85.
    Wessel DL, Adatia I, Thompson JE, Hickey PR (1994) Delivery and monitoring of inhaled nitric oxide in patients with pulmonary hypertension. Crit Care Med 22: 930–938PubMedCrossRefGoogle Scholar
  86. 86.
    Walder CE, Thiemermann C, Vane JR (1991) The involvement of endothelium-de- rived relaxing factor in the regulation of renal cortical blood flow in the rat. Br J Pharmacol 102:967–973PubMedGoogle Scholar
  87. 87.
    Hutcheson IR, Whittle BJ, Boughton-Smith NK (1990) Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat. Br J Pharmacol 101:815–820PubMedGoogle Scholar
  88. 88.
    Umans JG, Samsel RW (1992) L-canavanine selectively augments contraction in aortas from endotoxemic rats. Eur J Pharmacol 210:343–346PubMedCrossRefGoogle Scholar
  89. 89.
    Griffiths MJD, Messent M, MacAllister RJ, Evans TW (1993) Aminoguanidine selectively inhibits inducible nitric oxide synthase. Br J Pharmacol 110:963–968PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • M. J. D. Griffiths
  • T. W. Evans

There are no affiliations available

Personalised recommendations