Treatments in Respiratory Medicine

, Volume 3, Issue 2, pp 79–88 | Cite as

Nitric Oxide Synthase Inhibition

Therapeutic Potential in Asthma
  • Siobhan A. Mulrennan
  • Anthony E. RedingtonEmail author
Leading Article


Nitric oxide (NO) is synthesized from L-arginine in the human respiratory tract by enzymes of the NO synthase (NOS) family. Levels of NO in exhaled air are increased in asthma, and measurement of exhaled NO has been advocated as a noninvasive tool to monitor the underlying inflammatory process. However, the relation of NO to disease pathophysiology is uncertain, and in particular the fundamental question of whether it should be viewed primarily as beneficial or harmful remains unanswered. Exogenously administered NO has both bronchodilator and bronchoprotective properties. Although it is unlikely that NO is an important regulator of basal airway tone, there is good evidence that endogenous NO release exerts a protective effect against various bronchoconstrictor stimuli. This response is thought to involve one or both of the constitutive NOS isoforms, endothelial NOS (eNOS) and neuronal NOS (nNOS). Therefore, inhibition of these enzymes is unlikely to be therapeutically useful in asthma and indeed may worsen disease control. On the other hand, the high concentrations of NO in asthma, which are believed to reflect upregulation of inducible NOS (iNOS) by proinflammatory cytokines, may produce various deleterious effects. These include increased vascular permeability, damage to the airway epithelium, and promotion of inflammatory cell infiltration. However, the possible effects of iNOS inhibition on allergic inflammation in asthma have not yet been described and studies in animal models have yielded inconsistent findings. Thus, the evidence to suggest that inhibition of iNOS would be a useful therapeutic strategy in asthma is limited at present. More definitive information will require studies combining agents that potently and specifically target individual NOS isoforms with direct measurement of inflammatory markers.


Nitric Oxide Asthma Asthmatic Patient Airway Smooth Muscle iNOS Expression 
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.



The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.


  1. 1.
    Gustafsson LE, Leone AM, Persson MG, et al. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 1991; 181: 852–7PubMedCrossRefGoogle Scholar
  2. 2.
    Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 2002–12PubMedCrossRefGoogle Scholar
  3. 3.
    Nakane M, Schmidt HHHW, Pollock JS, et al. Cloned human brain nitric oxide synthase is highly expressed in skeletal muscle. FEBS Lett 1993; 316: 175–80PubMedCrossRefGoogle Scholar
  4. 4.
    Charles IG, Palmer RMJ, Hickery MS, et al. Cloning, characterization, and expression of a cDNA encoding an inducible nitric oxide synthase from the human chondrocyte. Proc Natl Acad Sci U S A 1993; 90: 11419–23PubMedCrossRefGoogle Scholar
  5. 5.
    Geller DA, Lowenstein CJ, Shapiro RA, et al. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci U S A 1993; 90: 3491–5PubMedCrossRefGoogle Scholar
  6. 6.
    Sherman PA, Laubach VE, Reep BR, et al. Purification and cDNA sequence of an inducible nitric oxide synthase from a human tumor cell line. Biochemistry 1993; 32: 11600–5PubMedCrossRefGoogle Scholar
  7. 7.
    Janssens SP, Shimouchi A, Quertermous T, et al. Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. J Biol Chem 1992; 267: 14519–22PubMedGoogle Scholar
  8. 8.
    Marsden PA, Schappert KT, Chen HS, et al. Molecular cloning and characterization of human endothelial nitric oxide synthase. FEBS Lett 1992; 307: 287–93PubMedCrossRefGoogle Scholar
  9. 9.
    Hamid Q, Springall DR, Riveros-Moreno V, et al. Induction of nitric oxide synthase in asthma. Lancet 1993; 342: 1510–3PubMedCrossRefGoogle Scholar
  10. 10.
    Kobzik L, Bredt DS, Lowenstein CJ, et al. Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol 1993; 9: 371–7PubMedGoogle Scholar
  11. 11.
    Guo FH, Der Raeve H, Rice TW, et al. Continuous nitric oxide synthesis by inducible nitric oxide synthase in normal human airway epithelium in vivo. Proc Natl Acad Sci U S A 1995; 92: 7809–13PubMedCrossRefGoogle Scholar
  12. 12.
    Watkins DN, Peroni DJ, Basclain KA, et al. Expression and activity of nitric oxide synthases in human airway epithelium. Am J Respir Cell Mol Biol 1997; 16: 629–39PubMedGoogle Scholar
  13. 13.
    Tracey WR, Xue C, Klinghofer V, et al. Immunochemical detection of inducible NO synthase in human lung. Am J Physiol 1994; 266: L722–L7PubMedGoogle Scholar
  14. 14.
    Guo FH, Comhair SAA, Zheng S, et al. Molecular mechanisms of increased nitric oxide (NO) in asthma: evidence for transcriptional and post-translational regulation of NO synthesis. J Immunol 2000; 164: 5970–80PubMedGoogle Scholar
  15. 15.
    Robbins RA, Barnes PJ, Springall DR, et al. Expression of inducible nitric oxide in human lung epithelial cells. Biochem Biophys Res Commun 1994; 203: 209–18PubMedCrossRefGoogle Scholar
  16. 16.
    Robbins RA, Springall DR, Warren JB, et al. Inducible nitric oxide synthase is increased in murine lung epithelial cells by cytokine stimulation. Biochem Biophys Res Commun 1994; 15: 835–43CrossRefGoogle Scholar
  17. 17.
    Guo FH, Uetani K, Haque SJ, et al. Interferon γ and interleukin 4 stimulate prolonged expression of inducible nitric oxide synthase in human airway epithelium though synthesis of soluble mediators. J Clin Invest 1997; 100: 829–38PubMedCrossRefGoogle Scholar
  18. 18.
    Asano K, Chee CBE, Gaston B, et al. Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. Proc Natl Acad Sci U S A 1994; 91: 10089–93PubMedCrossRefGoogle Scholar
  19. 19.
    Donnelly LE, Barnes PJ. Expression and regulation of nitric oxide synthase from human primary airway epithelial cells. Am J Respir Cell Mol Biol 2002; 26: 144–51PubMedGoogle Scholar
  20. 20.
    Coers W, Timens W, Kempinga C, et al. Specificity of antibodies to nitric oxide synthase isoforms in human, guinea pig, rat, and mouse trachea. J Histochem Cytochem 1998; 46: 1385–91PubMedCrossRefGoogle Scholar
  21. 21.
    Ward JK, Barnes PJ, Springall DR, et al. Distribution of i-NANC bronchodilator and nitric oxide-immunoreactive nerves. Am J Respir Cell Mol Biol 1995; 13: 175–84PubMedGoogle Scholar
  22. 22.
    Ricciardolo FL, Timmers MC, Geppetti P, et al. Allergen-induced impairment of bronchoprotective nitric oxide synthesis in asthma. J Allergy Clin Immunol 2001; 108:198–204PubMedCrossRefGoogle Scholar
  23. 23.
    Patel HJ, Belvisi MG, Donnelly LE, et al. Constitutive expression of type I NOS in human airway smooth muscle cells: evidence for an antiproliferative role. FASEB J 1999; 13: 1810–6PubMedGoogle Scholar
  24. 24.
    Hamad AM, Knox AJ. Mechanisms mediating the antiproliferative effects of nitric oxide in cultured human airway smooth muscle cells. FEBS Lett 2001; 506: 91–6PubMedCrossRefGoogle Scholar
  25. 25.
    Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333: 214–21PubMedCrossRefGoogle Scholar
  26. 26.
    Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993; 6: 1368–70PubMedGoogle Scholar
  27. 27.
    Kharitonov SA, Yates D, Robbins RA, et al. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994; 343: 133–5PubMedCrossRefGoogle Scholar
  28. 28.
    Persson MG, Zetterström O, Agrenius V, et al. Single-breath nitric oxide measurements in asthmatic patients and smokers. Lancet 1994; 343: 146–7PubMedCrossRefGoogle Scholar
  29. 29.
    Lundberg JON, Nordvall SL, Weitzberg E, et al. Exhaled nitric oxide in paediatric asthma and cystic fibrosis. Arch Dis Child 1996; 75: 323–6PubMedCrossRefGoogle Scholar
  30. 30.
    Nelson BV, Sears S, Woods J, et al. Expired nitric oxide as a marker for childhood asthma. J Pediatr 1997; 130: 423–7PubMedCrossRefGoogle Scholar
  31. 31.
    Gerlach H, Rossaint R, Pappert D, et al. Autoinhalation of nitric oxide after endogenous synthesis in nasopharynx [letter]. Lancet 1994; 343: 518–9PubMedCrossRefGoogle Scholar
  32. 32.
    Lundberg JON, Weitzberg E, Nordvall SL, et al. Primarily nasal origin of exhaled nitric oxide and absence in Kartagener’s syndrome. Eur Respir J 1994; 7: 1501–4PubMedCrossRefGoogle Scholar
  33. 33.
    Munch C, Monchi M, Fierobe L, et al. Absence of nitric oxide in airways of ventilated patients [letter]. Lancet 1994; 343: 1232–3PubMedCrossRefGoogle Scholar
  34. 34.
    Kharitonov SA, Chung KF, Evans D, et al. Increased exhaled nitric oxide in asthma is mainly derived from the lower respiratory tract. Am J Respir Crit Care Med 1996; 153: 1773–80PubMedGoogle Scholar
  35. 35.
    Massaro AF, Mehta S, Lilly CM, et al. Elevated nitric oxide concentrations in isolated lower airway gas of asthmatic subjects. Am J Respir Crit Care Med 1996; 153: 1510–4PubMedGoogle Scholar
  36. 36.
    al-Ali MK, Eames C, Howarth PH. Exhaled nitric oxide; relationship to clinicophysiological markers of asthma severity. Respir Med 1998; 92: 908–13PubMedCrossRefGoogle Scholar
  37. 37.
    Dupont LJ, Rochette F, Demedts MG, et al. Exhaled nitric oxide correlates with airway hyperresponsiveness in steroid-naive patients with mild asthma. Am J Respir Crit Care Med 1998; 157: 894–8PubMedGoogle Scholar
  38. 38.
    Jatakanon A, Lim S, Kharitonov S, et al. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax 1998; 53: 91–5PubMedCrossRefGoogle Scholar
  39. 39.
    Kharitonov SA, O’Connor BJ, Evans DJ, et al. Allergen-induced late asthmatic reactions are associated with elevation of exhaled nitric oxide. Am J Respir Crit Care Med 1995; 151: 1894–9PubMedGoogle Scholar
  40. 40.
    Deykin A, Halpern O, Massaro AF, et al. Expired nitric oxide after broncho-provocation and repeated spirometry in patients with asthma. Am J Respir Crit Care Med 1998; 157: 769–75PubMedGoogle Scholar
  41. 41.
    de Gouw HWFM, Grünberg K, Schot R, et al. Relationship between exhaled nitric oxide and airway hyperresponsiveness following experimental rhinovirus infection in asthmatic subjects. Eur Respir J 1998; 11: 126–32PubMedCrossRefGoogle Scholar
  42. 42.
    Massaro AF, Gaston B, Kita D, et al. Expired nitric oxide levels during treatment of acute asthma. Am J Respir Crit Care Med 1995; 152: 800–3PubMedGoogle Scholar
  43. 43.
    Garnier P, Fajac I, Dessanges JF, et al. Exhaled nitric oxide during acute changes of airways calibre in asthma. Eur Respir J 1996; 9: 1134–8PubMedCrossRefGoogle Scholar
  44. 44.
    Yates DH, Kharitonov SA, Robbins RA, et al. Effect of a nitric oxide synthase inhibitor and a glucocorticosteroid on exhaled nitric oxide. Am J Respir Crit Care Med 1995; 152: 892–6PubMedGoogle Scholar
  45. 45.
    Kharitonov SA, Yates DH, Barnes PJ. Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1996; 153: 454–7PubMedGoogle Scholar
  46. 46.
    Kharitonov SA, Yates DH, Chung KF, et al. Changes in the dose of inhaled steroid affect exhaled nitric oxide levels in asthmatic patients. Eur Respir J 1996; 9: 196–201PubMedCrossRefGoogle Scholar
  47. 47.
    Bisgaard H, Loland L, Anhoj J. NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast. Am J Respir Crit Care Med 1999; 160: 1227–31PubMedGoogle Scholar
  48. 48.
    Redington AE, Meng Q-H, Springall DR, et al. Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in the airway epithelium of asthmatic subjects and regulation by corticosteroid treatment. Thorax 2001; 56: 351–7PubMedCrossRefGoogle Scholar
  49. 49.
    Saleh D, Ernst P, Lim S, et al. Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: effect of inhaled glucocorticoid. FASEB J 1998; 12: 929–37PubMedGoogle Scholar
  50. 50.
    Liu SF, Haddad E-B, Adcock I, et al. Inducible nitric oxide synthase after sensitization and allergen challenge of Brown Norway rat lung. Br J Pharmacol 1997; 121: 1241–6PubMedCrossRefGoogle Scholar
  51. 51.
    Renzi PM, Sebastiao N, Al Assaad AS, et al. Inducible nitric oxide synthase mRNA and immunoreactivity in the lungs of rats eight hours after antigen challenge. Am J Respir Cell Mol Biol 1997; 17: 36–40PubMedGoogle Scholar
  52. 52.
    De Sanctis GT, MacLean JA, Hamada K, et al. Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma. J Exp Med 1999; 189: 1621–30PubMedCrossRefGoogle Scholar
  53. 53.
    Koarai A, Ichinose M, Sugiura H, et al. Allergic airway hyperresponsiveness and eosinophil infiltration is redu0ced by a selective iNOS inhibitor, 1400W, in mice. Pulm Pharmacol Ther 2000; 13: 267–75PubMedCrossRefGoogle Scholar
  54. 54.
    Trifilieff A, Fujitani Y, Mentz F, et al. Inducible nitric oxide synthase inhibitors suppress airway inflammation in mice through down-regulation of chemokine expression. J Immunol 2000; 165: 1526–33PubMedGoogle Scholar
  55. 55.
    Feder LS, Stelts D, Chapman RW, et al. Role of nitric oxide on eosinophilic lung inflammation in allergic mice. Am J Respir Cell Mol Biol 1997; 17: 436–42PubMedGoogle Scholar
  56. 56.
    De Sanctis T, Mehta S, Kobzik L, et al. Contribution of type I NOS to expired gas NO and bronchial responsiveness in mice. Am J Physiol 1997; 273 (4 Pt 1): L883–L8PubMedGoogle Scholar
  57. 57.
    Yates DH, Kharitonov SA, Thomas PS, et al. Endogenous nitric oxide is decreased in asthmatic patients by an inhibitor of inducible nitric oxide synthase. Am J Respir Crit Care Med 1996; 154: 247–50PubMedGoogle Scholar
  58. 58.
    Hasan K, Heesen B-J, Corbett JA, et al. Inhibition of nitric oxide formation by guanidines. Eur J Pharmacol 1993; 249: 101–6PubMedCrossRefGoogle Scholar
  59. 59.
    Misko TP, Moore WM, Kasten TP, et al. Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur J Pharmacol 1993; 233: 119–25PubMedCrossRefGoogle Scholar
  60. 60.
    Hansel TT, Kharitonov SA, Donnelly LE, et al. A selective inhibitor of inducible nitric oxide synthase inhibits exhaled breath nitric oxide in healthy volunteers and asthmatics. FASEB J 2003; Jul; 17: 1298–300PubMedGoogle Scholar
  61. 61.
    Salerno L, Sorrenti V, Di Giacomo C, et al. Progress in the development of selective nitric oxide synthase (NOS) inhibitors. Curr Pharm Des 2002; 8: 177–200PubMedCrossRefGoogle Scholar
  62. 62.
    Gaston B, Reilly J, Drazen JM, et al. Endogenous nitric oxides and bronchodilator S-nitrosothiols in human airways. Proc Natl Acad Sci U S A 1993; 90: 10957–61PubMedCrossRefGoogle Scholar
  63. 63.
    Gaston B, Drazen JM, Jansen A, et al. Relaxation of human bronchial smooth muscle by S-nitrosothiols in vitro. J Pharmacol Exp Ther 1994; 268: 978–84PubMedGoogle Scholar
  64. 64.
    Jansen A, Drazen J, Osborne JA, et al. The relaxant properties in guinea pig airways of S-nitrosothiols. J Pharmacol Exp Ther 1992; 261: 154–60PubMedGoogle Scholar
  65. 65.
    Bannenberg G, Xue J, Engman L, et al. Characterization of bronchodilator effects and fate of S-nitrosothiols in the isolated perfused and ventilated guinea pig lung. J Pharmacol Exp Ther 1995; 272: 1238–45PubMedGoogle Scholar
  66. 66.
    Gaston B, Sears S, Woods J, et al. Bronchodilator S-nitrosothiol deficiency in asthmatic respiratory failure. Lancet 1998; 351: 1317–9PubMedCrossRefGoogle Scholar
  67. 67.
    Lipton AJ, Johnson MA, Macdonald T, et al. S-Nitrosothiols signal the ventilatory response to hypoxia. Nature 2001; 413: 171–4PubMedCrossRefGoogle Scholar
  68. 68.
    Moya MP, Gow AJ, McMahon TJ, et al. S-nitrosothiol repletion by an inhaled gas regulates pulmonary function. Proc Natl Acad Sci U S A 2001; 98: 5792–7PubMedCrossRefGoogle Scholar
  69. 69.
    Hunt JF, Fang K, Malik R, et al. Endogenous airway acidification: implications for asthma pathophysiology. Am J Respir Crit Care Med 2000; 161: 694–9PubMedGoogle Scholar
  70. 70.
    Ojoo JC, Kastelik JA, Morice AH, et al. Dissociation between airway acidification and elevated exhaled nitric oxide in subjects with mild asthma [abstract]. Am J Respir Crit Care Med 2002; 165: A15Google Scholar
  71. 71.
    Arnold WP, Mittal CK, Katsuki S, et al. Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci U S A 1977; 74: 3203–7PubMedCrossRefGoogle Scholar
  72. 72.
    Dupuy PM, Shore SA, Drazen JM, et al. Bronchodilator action of inhaled nitric oxide in guinea pigs. J Clin Invest 1992; 90: 421–8PubMedCrossRefGoogle Scholar
  73. 73.
    Högman M, Frosteil C, Arnberg H, et al. Inhalation of nitric oxide modulates methacholine-induced bronchoconstriction in the rabbit. Eur Respir J 1993; 6: 177–80PubMedGoogle Scholar
  74. 74.
    Högman M, Wei S-Z, Frostell C, et al. Effects of inhaled nitric oxide on methacholine-induced bronchoconstriction: a concentration response study in rabbits. Eur Respir J 1994; 7: 698–702PubMedCrossRefGoogle Scholar
  75. 75.
    Högman M, Frostell CG, Hedenström H, et al. Inhalation of nitric oxide modulates adult human bronchial tone. Am Rev Respir Dis 1993; 148: 1474–8PubMedCrossRefGoogle Scholar
  76. 76.
    Kacmarek RM, Ripple R, Cockrill BA, et al. Inhaled nitric oxide: a bronchodilator in mild asthmatics with methacholine-induced bronchospasm. Am J Respir Crit Care Med 1996; 153: 128–35PubMedGoogle Scholar
  77. 77.
    Pfeffer KD, Ellison G, Robertson D, et al. The effect of inhaled nitric oxide in pediatric asthma. Am J Respir Crit Care Med 1996; 153: 747–51PubMedGoogle Scholar
  78. 78.
    Sanna A, Kurtansky A, Veriter C, et al. Bronchodilator effect of inhaled nitric oxide in healthy men. Am J Respir Crit Care Med 1994; 150: 1702–4PubMedGoogle Scholar
  79. 79.
    Roger N, Barberà JA, Farré R, et al. Effect of nitric oxide inhalation on respiratory system resistance in chronic obstructive pulmonary disease. Eur Respir J 1996; 9: 190–5PubMedCrossRefGoogle Scholar
  80. 80.
    Kharitonov SA, Lubec G, Lubec B, et al. L-Arginine increases exhaled nitric oxide in normal human subjects. Clin Sci 1995; 88: 135–9PubMedGoogle Scholar
  81. 81.
    Kharitonov SA, Yates DH, Barnes PJ. L-arginine increases exhaled nitric oxide in patients with asthma without changing airway function [abstract]. Am J Respir Crit Care Med 1995; 151: A698Google Scholar
  82. 82.
    Sapienza MA, Kharitonov SA, Horvath I, et al. Effect of inhaled L-arginine on exhaled nitric oxide in normal and asthmatic subjects. Thorax 1998; 53: 172–5PubMedCrossRefGoogle Scholar
  83. 83.
    Nijkamp FP, van der Linde HJ, Folkerts G. Nitric oxide synthesis inhibitors induce airway hyperresponsiveness in the guinea pig in vivo and in vitro: role of the epithelium. Am J Respir Crit Care Med 1993; 148: 727–34CrossRefGoogle Scholar
  84. 84.
    Ricciardolo FLM, Nadel JA, Yoishihara S, et al. Evidence for reduction of bradykinin-induced bronchoconstriction in guinea-pigs by release of nitric oxide. Br J Pharmacol 1994; 113: 1147–52PubMedCrossRefGoogle Scholar
  85. 85.
    Schlemper V, Calixto JB. Nitric oxide pathway-mediated relaxant effect of bradykinin in the guinea-pig isolated trachea. Br J Pharmacol 1994; 111: 83–8PubMedCrossRefGoogle Scholar
  86. 86.
    Figini M, Ricciardolo FLM, Javdan P, et al. Evidence that epithelium-derived relaxing factor released by bradykinin in the guinea pig trachea is nitric oxide. Am J Respir Crit Care Med 1996; 153: 918–23PubMedGoogle Scholar
  87. 87.
    Folkerts G, van der Linde HJ, Nijkamp FP. Virus-induced airway hyperresponsiveness in guinea pigs is related to a deficiency in nitric oxide. J Clin Invest 1995; 95: 26–30PubMedCrossRefGoogle Scholar
  88. 88.
    Ricciardolo FLM, Vergnani L, Wiegand S, et al. Detection of nitric oxide release induced by bradykinin in guinea pig trachea and main bronchi using a porphyrinic microsensor. Am J Respir Cell Mol Biol 2000; 22: 97–104PubMedGoogle Scholar
  89. 89.
    de Gouw HWFM, Verbruggen MB, Twiss IM, et al. Effect of oral L-arginine on airway hyperresponsiveness to histamine in asthma. Thorax 1999; 54: 1033–5PubMedCrossRefGoogle Scholar
  90. 90.
    Ricciardolo FLM, Geppetti P, Mistretta A, et al. Randomised double-blind placebo-controlled study of the effect of inhibition of nitric oxide synthesis in bradykinin-induced asthma. Lancet 1996; 348: 374–7PubMedCrossRefGoogle Scholar
  91. 91.
    Taylor DA, McGrath JL, Orr LM, et al. Effect of endogenous nitric oxide inhibition on airway responsiveness to histamine and adenosine-5′-monophosphate in asthma. Thorax 1998; 53: 483–9PubMedCrossRefGoogle Scholar
  92. 92.
    Ricciardolo FLM, Di Maria GU, Mistretta A, et al. Impairment of bronchoprotection by nitric oxide in severe asthma. Lancet 1997; 350: 1297–8PubMedCrossRefGoogle Scholar
  93. 93.
    Belvisi MG, Stretton CD, Yacoub M, et al. Nitric oxide is the endogenous neurotransmitter of bronchodilator nerves in humans. Eur J Pharmacol 1992; 210: 221–2PubMedCrossRefGoogle Scholar
  94. 94.
    Belvisi MG, Stretton CD, Miura M, et al. Inhibitory NANC nerves in human trachel smooth muscle: a quest for the neurotransmitter. J Appl Physiol 1992; 73: 2505–10PubMedGoogle Scholar
  95. 95.
    Fuller RW, Dixon CMS, Cuss FMC, et al. Bradykinin-induced bronchoconstriction in humans: mode of action. Am Rev Respir Dis 1987; 135: 176–80PubMedGoogle Scholar
  96. 96.
    Holtzman MJ, Sheller JR, DiMeo M, et al. Effect of ganglionic blockade on bronchial reactivity in atopic subjects. Am Rev Respir Dis 1980; 122: 17–25PubMedGoogle Scholar
  97. 97.
    Mann JS, Cushley MJ, Holgate ST. Adenosine-induced bronchoconstriction in asthma: role of parasympathetic stimulation and adrenergic inhibition. Am Rev Respir Dis 1985; 132: 1–6PubMedGoogle Scholar
  98. 98.
    Ward JK, Belvisi MG, Fox AJ, et al. Modulation of cholinergic neural bronchoconstriction by endogenous nitric oxide and vasoactive intestinal peptide in human airways in vitro. J Clin Invest 1993; 92: 736–42PubMedCrossRefGoogle Scholar
  99. 99.
    Miura M, Yamauchi H, Ichinose M, et al. Impairment of neural nitric oxide-mediated relaxation after antigen exposure in guinea pig airways in vitro. Am J Respir Crit Care Med 1997; 156: 217–22PubMedGoogle Scholar
  100. 100.
    Feletou M, Lonchampt M, Coge F, et al. Regulation of murine airway responsiveness by endothelial nitric oxide synthase. Am J Physiol Lung Cell Mol Physiol 2001; 281(1): L258–L67PubMedGoogle Scholar
  101. 101.
    Ten Broeke R, Folkerts G, De Crom R, et al. Overexpression of eNOS suppresses asthmatic features in a mouse model of allergic asthma [abstract]. Eur Respir J 2002; 20Suppl. 38: 28sGoogle Scholar
  102. 102.
    de Boer J, Meurs H, Coers W, et al. Deficiency of nitric oxide in allergen-induced airway hyperreactivity to contractile agonists after the early asthmatic reaction: an ex vivo study. Br J Pharmacol 1996; 119: 1109–16PubMedCrossRefGoogle Scholar
  103. 103.
    de Boer J, Duyvendak M, Schuurman FE, et al. Role of L-arginine in the deficiency of nitric oxide and airway hyperreactivity after the allergen-induced early asthmatic reaction in guinea-pigs. Br J Pharmacol 1999; 128: 1114–20PubMedCrossRefGoogle Scholar
  104. 104.
    Meurs H, McKay S, Maarsingh H, et al. Increased arginase activity underlies allergen-induced deficiency of cNOS-derived nitric oxide and airway hyperresponsiveness. Br J Pharmacol 2002; 136: 391–8PubMedCrossRefGoogle Scholar
  105. 105.
    Erjefält JS, Erjefält I, Sundler F, et al. Mucosal nitric oxide may tonically suppress airways plasma exudation. Am J Respir Crit Care Med 1994; 150: 227–32PubMedGoogle Scholar
  106. 106.
    Bernareggi M, Mitchell JA, Barnes PJ, et al. Dual action of nitric oxide on airway plasma leakage. Am J Respir Crit Care Med 1997; 155: 869–74PubMedGoogle Scholar
  107. 107.
    Frosteil CG, Blomqvist H, Hedenstierna G, et al. Inhaled nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilation. Anesthesiology 1993; 78: 427–35CrossRefGoogle Scholar
  108. 108.
    Alving K, Fornhem C, Weitzberg E, et al. Nitric oxide mediates cigarette smoke-induced vasodilatory responses in the lung. Acta Physiol Scand 1992; 146: 407–8PubMedCrossRefGoogle Scholar
  109. 109.
    Kuo H-P, Liu S, Barnes PJ. The effect of endogenous nitric oxide on neurogenic plasma exudation in guinea-pig airways. Eur J Pharmacol 1992; 221: 385–8PubMedCrossRefGoogle Scholar
  110. 110.
    Kageyama N, Miura M, Ichinose M, et al. Role of endogenous nitric oxide in airway microvascular leakage induced by inflammatory mediators. Eur Respir J 1997; 10: 13–9PubMedCrossRefGoogle Scholar
  111. 111.
    Miura M, Ichinose M, Kageyama N, et al. Endogenous nitric oxide modifies antigen-induced microvascular leakage in sensitized guinea pig airways. J Allergy Clin Immunol 1996; 98: 144–51PubMedCrossRefGoogle Scholar
  112. 112.
    Brown RH, Zerhouni EA, Mitzner W. Airway edema potentiates airway reactivity. J Appl Physiol 1995; 79: 1242–8PubMedGoogle Scholar
  113. 113.
    Heiss LN, Lancaster Jr JR, Corbett JA, et al. Epithelial autotoxicity of nitric oxide: role in the respiratory cytopathology of pertussis. Proc Natl Acad Sci U S A 1994; 91: 267–70PubMedCrossRefGoogle Scholar
  114. 114.
    Karupiah G, Chen J-H, Nathan CF, et al. Identification of nitric oxide synthase 2 as an innate resistance locus against ectromelia virus infection. J Virol 1998; 72: 7703–6PubMedGoogle Scholar
  115. 115.
    MacLean A, Wei X-Q, Huang F-P, et al. Mice lacking inducible nitric-oxide synthase are more susceptible to herpes simplex virus infection despite enhanced Th1 cell responses. J Gen Virol 1998; 79: 825–30PubMedGoogle Scholar
  116. 116.
    MacMicking JD, Nathan C, Horn G, et al. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 1995; 81: 641–560PubMedCrossRefGoogle Scholar
  117. 117.
    MacMicking JD, North RJ, LaCourse R, et al. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci U S A 1997; 94: 5243–8PubMedCrossRefGoogle Scholar
  118. 118.
    Wei X-Q, Charles IG, Smith A, et al. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 1995; 375: 408–11PubMedCrossRefGoogle Scholar
  119. 119.
    Diefenbach A, Schindler H, Donhauser N, et al. Type 1 Interferon (IFNα/β) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite. Immunity 1998; 8: 77–87PubMedCrossRefGoogle Scholar
  120. 120.
    Radi R, Beckman JS, Bush KM. Peroxynitrite oxidation of sulphydryls: the cytotoxic potential of Superoxide and nitric oxide. J Biol Chem 1991; 266: 4244–50PubMedGoogle Scholar
  121. 121.
    Radi R, Beckman JS, Bush KM, et al. Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of Superoxide and nitric oxide. Arch Biochem Biophys 1991; 288: 481–7PubMedCrossRefGoogle Scholar
  122. 122.
    Sadeghi-Hashjin G, Folkerts G, Henricks PAJ, et al. Peroxynitrite induces airway hyperresponsiveness in guinea pigs in vitro and in vivo. Am J Respir Crit Care Med 1996; 153: 1697–701PubMedGoogle Scholar
  123. 123.
    Wu W, Chen Y, Hazen SL. Eosinophil peroxidase nitrates protein tyrosyl residues: implications for oxidative damage by nitrating intermediates in eosinophilc inflammatory disorders. J Biol Chem 1999; 274: 25933–44PubMedCrossRefGoogle Scholar
  124. 124.
    van der Vliet A, Eiserich JP, Halliwell B, et al. Formation of reactive nitrogen species during peroxidase-catalyzed oxidation of nitrite. J Biol Chem 1997; 272: 7617–25PubMedCrossRefGoogle Scholar
  125. 125.
    Eiserich JP, Hristova M, Cross CE, et al. Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 1998; 391: 393–7PubMedCrossRefGoogle Scholar
  126. 126.
    Brennan M-L, Wu W, Fu X, et al. A tale of two controversies: defining both the role of peroxidases in nitrotyrosine formation in vivo using eosinophil peroxidase and myeloperoxidase-deficient mice, and the nature of peroxidase-generated reactive nitrogen species. J Biol Chem 2002; 277: 17415–27PubMedCrossRefGoogle Scholar
  127. 127.
    Thomazzi SM, Ferreira HHA, Conran N, et al. Role of nitric oxide on in vitro human eosinophil migration. Biochem Pharmacol 2001; 62: 1417–21PubMedCrossRefGoogle Scholar
  128. 128.
    Belenky SN, Robbins RA, Rubinstein I. Nitric oxide synthase inhibitors attenuate human monocyte chemotaxis in vitro. J Leukoc Biol 1993; 53: 498–503PubMedGoogle Scholar
  129. 129.
    Kaplan SS, Billiar T, Curran RD, et al. Inhibition of chemotaxis with NG-monomethyl-L-arginine: a role for cyclic GMP. Blood 1989; 74: 1885–7PubMedGoogle Scholar
  130. 130.
    Belenky SN, Robbins RA, Rennard SI, et al. Inhibitors of nitric oxide synthase attenuate human neutrophil chemotaxis in vitro. J Lab Clin Med 1993; 122: 388–94PubMedGoogle Scholar
  131. 131.
    Ferreira HHA, Medeiros MV, Lima CSP, et al. Inhibition of eosinophil chemotaxis by chronic blockade of nitric oxide biosynthesis. Eur J Pharmacol 1996; 310: 201–7PubMedCrossRefGoogle Scholar
  132. 132.
    Taylor-Robinson AW, Liew FY, Severn A, et al. Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells. Eur J Immunol 1994; 24: 980–4PubMedCrossRefGoogle Scholar
  133. 133.
    Niedbala W, Wei X-Q, Piedrafita D, et al. Effects of nitric oxide on the induction and differentiation of Th1 cells. Eur J Immunol 1999; 29: 2498–505PubMedCrossRefGoogle Scholar
  134. 134.
    Galigniana MD, Piwien-Pilipuk G, Assreuy J. Inhibition of glucocorticoid receptor binding by nitric oxide. Mol Pharmacol 1999; 55: 317–23PubMedGoogle Scholar
  135. 135.
    Garvey EP, Oplinger JA, Furfine ES, et al. 1400W is a slow, tight-binding, and highly selective inhibitor of inducible nitric oxide synthase in vitro and in vivo. J Biol Chem 1999; 272: 4959–63Google Scholar
  136. 136.
    Ferreira HHA, Bevilacqua E, Gagioti SM, et al. Nitric oxide modulates eosinophil infiltration in antigen-induced airway inflammation in rats. Eur J Pharmacol 1998; 358: 253–9PubMedCrossRefGoogle Scholar
  137. 137.
    Muijsers RBR, van Ark I, Folkerts G, et al. Apocynin and 1400 W prevents airway hyperresponsiveness during allergic reactions in mice. Br J Pharmacol 2001; 134: 434–40PubMedCrossRefGoogle Scholar
  138. 138.
    Blease K, Kunkel SL, Hogaboam CM. Acute inhibition of nitric oxide exacerbates airway hyper-responsiveness, eosinophilia and C-C chemokine generation in a murine model of fungal asthma. Inflamm Res 2000; 49: 297–304PubMedCrossRefGoogle Scholar
  139. 139.
    Xiong Y, Karupiah G, Hogan SP, et al. Inhibition of allergic airway inflammation in mice lacking nitric oxide synthase 2. J Immunol 1999; 162: 445–52PubMedGoogle Scholar
  140. 140.
    Taylor DA, McGrath JL, O’Connor BJ, et al. Allergen-induced early and late asthmatic responses are not affected by inhibition of endogenous nitric oxide. Am J Respir Crit Care Med 1998; 158: 99–106PubMedGoogle Scholar
  141. 141.
    Albina JE. On the expression of nitric oxide synthase in human macrophages: why no NO? J Leukoc Biol 1995; 58: 643–9PubMedGoogle Scholar
  142. 142.
    Chu SC, Marks-Konczalik J, Wu H-P, et al. Analysis of the cytokine-stimulated human inducible nitric oxide synthase (iNOS) gene: characterization of differences between human and mouse iNOS promoters. Biochem Biophys Res Commun 1998; 248: 871–8PubMedCrossRefGoogle Scholar
  143. 143.
    Redington AE, Howarth PH. Airway wall remodelling in asthma. Thorax 1997; 52: 310–2PubMedCrossRefGoogle Scholar
  144. 144.
    Naka M, Nanbu T, Kobayashi K, et al. A potent inhibitor of inducible nitric oxide synthase, ONO-1714, a cyclic amidine derivative. Biochem Biophys Res Commun 2000; 270: 663–7PubMedCrossRefGoogle Scholar
  145. 145.
    Kita Y, Muramoto M, Fujikawa A, et al. Discovery of novel inhibitors of inducible nitric oxide synthase. J Pharm Pharmacol 2002; 54: 1141–5PubMedCrossRefGoogle Scholar
  146. 146.
    Young RJ, Beams RM, Carter K, et al. Inhibition of inducible nitric oxide synthase by acetamidine derivatives of hetero-substituted lysine and homolysine. Bioorg Med Chem Lett 2000; 10: 597–600PubMedCrossRefGoogle Scholar
  147. 147.
    Evans SM, Whittle BJR. Interactive roles of Superoxide and inducible nitric oxide synthase in rat intestinal injury provoked by non-steroidal anti-inflammatory drugs. Eur J Pharmacol 2001; 429: 287–96PubMedCrossRefGoogle Scholar
  148. 148.
    Naito Y, Takagi T, Ishikawa T, et al. The inducible nitric oxide synthase inhibitor ONO-1714 blunts dextran sulfate sodium colitis in mice. Eur J Pharmacol 2001; 412: 91–9PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Division of Academic Medicine, Postgraduate Medical InstituteUniversity of HullHullEngland

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