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Nitric Oxide Synthase Inhibition

Therapeutic Potential in Asthma

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  • Published:
Treatments in Respiratory Medicine

Abstract

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.

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References

  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: 852–7

    Article  PubMed  CAS  Google Scholar 

  2. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 2002–12

    Article  PubMed  CAS  Google Scholar 

  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: 175–80

    Article  PubMed  CAS  Google Scholar 

  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: 11419–23

    Article  PubMed  CAS  Google Scholar 

  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: 3491–5

    Article  PubMed  CAS  Google Scholar 

  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: 11600–5

    Article  PubMed  CAS  Google Scholar 

  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: 14519–22

    PubMed  CAS  Google Scholar 

  8. Marsden PA, Schappert KT, Chen HS, et al. Molecular cloning and characterization of human endothelial nitric oxide synthase. FEBS Lett 1992; 307: 287–93

    Article  PubMed  CAS  Google Scholar 

  9. Hamid Q, Springall DR, Riveros-Moreno V, et al. Induction of nitric oxide synthase in asthma. Lancet 1993; 342: 1510–3

    Article  PubMed  CAS  Google Scholar 

  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: 371–7

    PubMed  CAS  Google Scholar 

  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: 7809–13

    Article  PubMed  CAS  Google Scholar 

  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: 629–39

    PubMed  CAS  Google Scholar 

  13. Tracey WR, Xue C, Klinghofer V, et al. Immunochemical detection of inducible NO synthase in human lung. Am J Physiol 1994; 266: L722–L7

    PubMed  CAS  Google Scholar 

  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: 5970–80

    PubMed  CAS  Google Scholar 

  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: 209–18

    Article  PubMed  CAS  Google Scholar 

  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: 835–43

    Article  Google Scholar 

  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: 829–38

    Article  PubMed  CAS  Google Scholar 

  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: 10089–93

    Article  PubMed  CAS  Google Scholar 

  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: 144–51

    PubMed  CAS  Google Scholar 

  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: 1385–91

    Article  PubMed  CAS  Google Scholar 

  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: 175–84

    PubMed  CAS  Google Scholar 

  22. Ricciardolo FL, Timmers MC, Geppetti P, et al. Allergen-induced impairment of bronchoprotective nitric oxide synthesis in asthma. J Allergy Clin Immunol 2001; 108:198–204

    Article  PubMed  CAS  Google Scholar 

  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: 1810–6

    PubMed  CAS  Google Scholar 

  24. Hamad AM, Knox AJ. Mechanisms mediating the antiproliferative effects of nitric oxide in cultured human airway smooth muscle cells. FEBS Lett 2001; 506: 91–6

    Article  PubMed  CAS  Google Scholar 

  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: 214–21

    Article  PubMed  CAS  Google Scholar 

  26. Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993; 6: 1368–70

    PubMed  CAS  Google Scholar 

  27. Kharitonov SA, Yates D, Robbins RA, et al. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994; 343: 133–5

    Article  PubMed  CAS  Google Scholar 

  28. Persson MG, Zetterström O, Agrenius V, et al. Single-breath nitric oxide measurements in asthmatic patients and smokers. Lancet 1994; 343: 146–7

    Article  PubMed  CAS  Google Scholar 

  29. Lundberg JON, Nordvall SL, Weitzberg E, et al. Exhaled nitric oxide in paediatric asthma and cystic fibrosis. Arch Dis Child 1996; 75: 323–6

    Article  PubMed  CAS  Google Scholar 

  30. Nelson BV, Sears S, Woods J, et al. Expired nitric oxide as a marker for childhood asthma. J Pediatr 1997; 130: 423–7

    Article  PubMed  CAS  Google Scholar 

  31. Gerlach H, Rossaint R, Pappert D, et al. Autoinhalation of nitric oxide after endogenous synthesis in nasopharynx [letter]. Lancet 1994; 343: 518–9

    Article  PubMed  CAS  Google Scholar 

  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: 1501–4

    Article  PubMed  CAS  Google Scholar 

  33. Munch C, Monchi M, Fierobe L, et al. Absence of nitric oxide in airways of ventilated patients [letter]. Lancet 1994; 343: 1232–3

    Article  PubMed  CAS  Google Scholar 

  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: 1773–80

    PubMed  CAS  Google Scholar 

  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: 1510–4

    PubMed  CAS  Google Scholar 

  36. al-Ali MK, Eames C, Howarth PH. Exhaled nitric oxide; relationship to clinicophysiological markers of asthma severity. Respir Med 1998; 92: 908–13

    Article  PubMed  CAS  Google Scholar 

  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: 894–8

    PubMed  CAS  Google Scholar 

  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: 91–5

    Article  PubMed  CAS  Google Scholar 

  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: 1894–9

    PubMed  CAS  Google Scholar 

  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: 769–75

    PubMed  CAS  Google Scholar 

  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: 126–32

    Article  PubMed  Google Scholar 

  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: 800–3

    PubMed  CAS  Google Scholar 

  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: 1134–8

    Article  PubMed  CAS  Google Scholar 

  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: 892–6

    PubMed  CAS  Google Scholar 

  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: 454–7

    PubMed  CAS  Google Scholar 

  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: 196–201

    Article  PubMed  CAS  Google Scholar 

  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: 1227–31

    PubMed  CAS  Google Scholar 

  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: 351–7

    Article  PubMed  CAS  Google Scholar 

  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: 929–37

    PubMed  CAS  Google Scholar 

  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: 1241–6

    Article  PubMed  CAS  Google Scholar 

  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: 36–40

    PubMed  CAS  Google Scholar 

  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: 1621–30

    Article  PubMed  Google Scholar 

  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: 267–75

    Article  PubMed  CAS  Google Scholar 

  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: 1526–33

    PubMed  CAS  Google Scholar 

  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: 436–42

    PubMed  CAS  Google Scholar 

  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–L8

    PubMed  Google Scholar 

  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: 247–50

    PubMed  CAS  Google Scholar 

  58. Hasan K, Heesen B-J, Corbett JA, et al. Inhibition of nitric oxide formation by guanidines. Eur J Pharmacol 1993; 249: 101–6

    Article  PubMed  CAS  Google Scholar 

  59. Misko TP, Moore WM, Kasten TP, et al. Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur J Pharmacol 1993; 233: 119–25

    Article  PubMed  CAS  Google Scholar 

  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: 1298–300

    PubMed  CAS  Google Scholar 

  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: 177–200

    Article  PubMed  CAS  Google Scholar 

  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: 10957–61

    Article  PubMed  CAS  Google Scholar 

  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: 978–84

    PubMed  CAS  Google Scholar 

  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: 154–60

    PubMed  CAS  Google Scholar 

  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: 1238–45

    PubMed  CAS  Google Scholar 

  66. Gaston B, Sears S, Woods J, et al. Bronchodilator S-nitrosothiol deficiency in asthmatic respiratory failure. Lancet 1998; 351: 1317–9

    Article  PubMed  CAS  Google Scholar 

  67. Lipton AJ, Johnson MA, Macdonald T, et al. S-Nitrosothiols signal the ventilatory response to hypoxia. Nature 2001; 413: 171–4

    Article  PubMed  CAS  Google Scholar 

  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: 5792–7

    Article  PubMed  CAS  Google Scholar 

  69. Hunt JF, Fang K, Malik R, et al. Endogenous airway acidification: implications for asthma pathophysiology. Am J Respir Crit Care Med 2000; 161: 694–9

    PubMed  CAS  Google Scholar 

  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: A15

    Google Scholar 

  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: 3203–7

    Article  PubMed  CAS  Google Scholar 

  72. Dupuy PM, Shore SA, Drazen JM, et al. Bronchodilator action of inhaled nitric oxide in guinea pigs. J Clin Invest 1992; 90: 421–8

    Article  PubMed  CAS  Google Scholar 

  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: 177–80

    PubMed  Google Scholar 

  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: 698–702

    Article  PubMed  Google Scholar 

  75. Högman M, Frostell CG, Hedenström H, et al. Inhalation of nitric oxide modulates adult human bronchial tone. Am Rev Respir Dis 1993; 148: 1474–8

    Article  PubMed  Google Scholar 

  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: 128–35

    PubMed  CAS  Google Scholar 

  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: 747–51

    PubMed  CAS  Google Scholar 

  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: 1702–4

    PubMed  CAS  Google Scholar 

  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: 190–5

    Article  PubMed  CAS  Google Scholar 

  80. Kharitonov SA, Lubec G, Lubec B, et al. L-Arginine increases exhaled nitric oxide in normal human subjects. Clin Sci 1995; 88: 135–9

    PubMed  CAS  Google Scholar 

  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: A698

    Google Scholar 

  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: 172–5

    Article  PubMed  CAS  Google Scholar 

  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: 727–34

    Article  CAS  Google Scholar 

  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: 1147–52

    Article  PubMed  CAS  Google Scholar 

  85. Schlemper V, Calixto JB. Nitric oxide pathway-mediated relaxant effect of bradykinin in the guinea-pig isolated trachea. Br J Pharmacol 1994; 111: 83–8

    Article  PubMed  CAS  Google Scholar 

  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: 918–23

    PubMed  CAS  Google Scholar 

  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: 26–30

    Article  PubMed  CAS  Google Scholar 

  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: 97–104

    PubMed  CAS  Google Scholar 

  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: 1033–5

    Article  PubMed  Google Scholar 

  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: 374–7

    Article  PubMed  CAS  Google Scholar 

  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: 483–9

    Article  PubMed  CAS  Google Scholar 

  92. Ricciardolo FLM, Di Maria GU, Mistretta A, et al. Impairment of bronchoprotection by nitric oxide in severe asthma. Lancet 1997; 350: 1297–8

    Article  PubMed  CAS  Google Scholar 

  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: 221–2

    Article  PubMed  CAS  Google Scholar 

  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: 2505–10

    PubMed  CAS  Google Scholar 

  95. Fuller RW, Dixon CMS, Cuss FMC, et al. Bradykinin-induced bronchoconstriction in humans: mode of action. Am Rev Respir Dis 1987; 135: 176–80

    PubMed  CAS  Google Scholar 

  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: 17–25

    PubMed  CAS  Google Scholar 

  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: 1–6

    PubMed  CAS  Google Scholar 

  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: 736–42

    Article  PubMed  CAS  Google Scholar 

  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: 217–22

    PubMed  CAS  Google Scholar 

  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–L67

    PubMed  CAS  Google Scholar 

  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: 28s

    Google Scholar 

  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: 1109–16

    Article  PubMed  Google Scholar 

  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: 1114–20

    Article  PubMed  CAS  Google Scholar 

  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: 391–8

    Article  PubMed  CAS  Google Scholar 

  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: 227–32

    PubMed  Google Scholar 

  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: 869–74

    PubMed  CAS  Google Scholar 

  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: 427–35

    Article  Google Scholar 

  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: 407–8

    Article  PubMed  CAS  Google Scholar 

  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: 385–8

    Article  PubMed  CAS  Google Scholar 

  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: 13–9

    Article  PubMed  CAS  Google Scholar 

  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: 144–51

    Article  PubMed  CAS  Google Scholar 

  112. Brown RH, Zerhouni EA, Mitzner W. Airway edema potentiates airway reactivity. J Appl Physiol 1995; 79: 1242–8

    PubMed  CAS  Google Scholar 

  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: 267–70

    Article  PubMed  CAS  Google Scholar 

  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: 7703–6

    PubMed  CAS  Google Scholar 

  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: 825–30

    PubMed  CAS  Google Scholar 

  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: 641–560

    Article  PubMed  CAS  Google Scholar 

  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: 5243–8

    Article  PubMed  CAS  Google Scholar 

  118. Wei X-Q, Charles IG, Smith A, et al. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 1995; 375: 408–11

    Article  PubMed  CAS  Google Scholar 

  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: 77–87

    Article  PubMed  CAS  Google Scholar 

  120. Radi R, Beckman JS, Bush KM. Peroxynitrite oxidation of sulphydryls: the cytotoxic potential of Superoxide and nitric oxide. J Biol Chem 1991; 266: 4244–50

    PubMed  CAS  Google Scholar 

  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: 481–7

    Article  PubMed  CAS  Google Scholar 

  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: 1697–701

    PubMed  CAS  Google Scholar 

  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: 25933–44

    Article  PubMed  CAS  Google Scholar 

  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: 7617–25

    Article  PubMed  Google Scholar 

  125. Eiserich JP, Hristova M, Cross CE, et al. Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 1998; 391: 393–7

    Article  PubMed  CAS  Google Scholar 

  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: 17415–27

    Article  PubMed  CAS  Google Scholar 

  127. Thomazzi SM, Ferreira HHA, Conran N, et al. Role of nitric oxide on in vitro human eosinophil migration. Biochem Pharmacol 2001; 62: 1417–21

    Article  PubMed  CAS  Google Scholar 

  128. Belenky SN, Robbins RA, Rubinstein I. Nitric oxide synthase inhibitors attenuate human monocyte chemotaxis in vitro. J Leukoc Biol 1993; 53: 498–503

    PubMed  CAS  Google Scholar 

  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: 1885–7

    PubMed  CAS  Google Scholar 

  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: 388–94

    PubMed  CAS  Google Scholar 

  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: 201–7

    Article  PubMed  CAS  Google Scholar 

  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: 980–4

    Article  PubMed  CAS  Google Scholar 

  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: 2498–505

    Article  PubMed  CAS  Google Scholar 

  134. Galigniana MD, Piwien-Pilipuk G, Assreuy J. Inhibition of glucocorticoid receptor binding by nitric oxide. Mol Pharmacol 1999; 55: 317–23

    PubMed  CAS  Google Scholar 

  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: 4959–63

    Google Scholar 

  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: 253–9

    Article  PubMed  CAS  Google Scholar 

  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: 434–40

    Article  PubMed  CAS  Google Scholar 

  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: 297–304

    Article  PubMed  CAS  Google Scholar 

  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: 445–52

    PubMed  CAS  Google Scholar 

  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: 99–106

    PubMed  CAS  Google Scholar 

  141. Albina JE. On the expression of nitric oxide synthase in human macrophages: why no NO? J Leukoc Biol 1995; 58: 643–9

    PubMed  CAS  Google Scholar 

  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: 871–8

    Article  PubMed  CAS  Google Scholar 

  143. Redington AE, Howarth PH. Airway wall remodelling in asthma. Thorax 1997; 52: 310–2

    Article  PubMed  CAS  Google Scholar 

  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: 663–7

    Article  PubMed  CAS  Google Scholar 

  145. Kita Y, Muramoto M, Fujikawa A, et al. Discovery of novel inhibitors of inducible nitric oxide synthase. J Pharm Pharmacol 2002; 54: 1141–5

    Article  PubMed  CAS  Google Scholar 

  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: 597–600

    Article  PubMed  CAS  Google Scholar 

  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: 287–96

    Article  PubMed  CAS  Google Scholar 

  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: 91–9

    Article  PubMed  CAS  Google Scholar 

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  1. Division of Academic Medicine, Postgraduate Medical Institute, University of Hull, Hull, England

    Siobhan A. Mulrennan &  Anthony E. Redington

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Mulrennan, S.A., Redington, A.E. Nitric Oxide Synthase Inhibition. Treat Respir Med 3, 79–88 (2004). https://doi.org/10.2165/00151829-200403020-00002

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