l-Arginine reverses cigarette-induced reduction of fractional exhaled nitric oxide in asthmatic smokers

Inflammopharmacology volume 18, pages9–16(2010)Cite this article

Abstract

Introduction

Complex mechanisms regulate nitric oxide (NO) synthesis. Cigarette smoking decreases fractional exhaled NO (FENO), while asthmatic inflammation increases FENO. To assess whether the smoking-induced decrease in FENO levels was reversible, asthmatic and non-asthmatic smokers inhaled the NO synthase (NOS) substrate, l-arginine. Aminoguanidine, a relatively selective Type II NOS inhibitor, was used also to assess the role of NOS subtypes in these changes of FENO.

Methods

The study was a single-blinded, placebo-controlled, cross-over design in two parts. Part I: smoking asthmatic and non-asthmatic smoking subjects smoked one cigarette and then inhaled nebulised l-arginine or l-alanine (control). Spirometry, FENO, nasal NO (FNNO), FECO, were measured for 4 h. Part II: subjects inhaled nebulised aminoguanidine prior to an identical protocol as in Part I. Change in FENO was assessed as area under the curve (AUC).

Results

Part I: In asthmatic smokers, cigarette smoking followed by l-arginine caused a significant median increase in AUC of 29.2(17)% FENO change/hour (p = 0.04), which did not occur in non-asthmatic smokers (baseline FENO 12.7(7.1–18) vs. 6.7(4–9.2) ppb, respectively).

Part II: Aminoguanidine prior to smoking caused a significant fall in FENO in both asthmatic and non-asthmatic smokers. l-arginine showed significant reversal of this effect in both asthmatic and non-asthmatic subjects.

Conclusions

In asthmatic smokers, l-arginine increases FENO after cigarette smoking but not in non-asthmatic smokers. The decrease in FENO after aminoguanidine and subsequent partial reversal by l-arginine in both groups, suggests that Type II NOS contributes to the FENO in both.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant access to the full article PDF.

US$ 39.95

Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. American Thoracic Society ATS/ERS (2005) Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 171:912–930

    Article  Google Scholar 

  2. Balint B, Donnelly LE, Hanazawa T, Kharitonov SA, Barnes PJ (2001) Increased nitric oxide metabolites in exhaled breath condensate after exposure to tobacco smoke. Thorax 56:456–461

    Article  CAS  PubMed  Google Scholar 

  3. Bergeron C, Boulet LP, Page N, Laviolette M, Rothenberg ME, Hamid Q (2005) Influence of cigarette smoke on arginase 1 and ornithine decarboxylase expression in asthmatic airways. Proc Am Thor Soc 2: A33 (abstract)

  4. Böger RH, Bode-Böger SM (2001) The clinical pharmacology of l-arginine. Annu Rev Pharmacol Toxicol 41:79–99

    Article  PubMed  Google Scholar 

  5. Bruce C, Yates DH, Thomas PS (2002) Caffeine decreases exhaled nitric oxide. Thorax 57:361–363

    Article  CAS  PubMed  Google Scholar 

  6. Gerlach H, Rossaint R, Pappert D, Knorr M, Falke KJ (1994) Auto-inhalation of nitric oxide after endogenous synthesis in nasopharynx. Lancet 343:518–519

    Article  CAS  PubMed  Google Scholar 

  7. Gustaffson LE, Leone AM, Persson MG, Wikuld NP, Moncada S (1991) Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 181:852–857

    Article  Google Scholar 

  8. Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne E, Barnes PJ (1994) Increased nitric oxide in exhaled air of asthmatic patients. Lancet 343:133–135

    Article  CAS  PubMed  Google Scholar 

  9. Kharitonov SA, Lubec G, Lubec B, Hjelm M, Barnes PJ (1995a) l-Arginine increases exhaled nitric oxide in normal human subjects. Clin Sci 88:135–139

    CAS  PubMed  Google Scholar 

  10. Kharitonov SA, Robbins RA, Yates D, Keatings V, Thomas PS, Barnes PJ (1995b) Acute and chronic effects of cigarette smoking on exhaled nitric oxide. Am J Respir Crit Care Med 152:609–612

    CAS  PubMed  Google Scholar 

  11. Lane C, Knight D, Burgess S, Franklin P, Horak F et al (2004) Epithelial inducible nitric oxide synthase activity is the major determinant of nitric oxide concentration in exhaled breath. Thorax 59:757–760

    Article  CAS  PubMed  Google Scholar 

  12. Lehtimaki L, Kankaanranta H, Saarelainen S, Hahtola P, Jarvenpaa R et al (2001) Extended exhaled NO measurement differentiates between alveolar and bronchial inflammation. Am J Respir Crit Care Med 163:1557–1561

    CAS  PubMed  Google Scholar 

  13. Leiper J, Vallance P (1999) Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovascular Res 43:542–548

    Article  CAS  Google Scholar 

  14. Lundberg JO, Weitzberg E (1999) Nasal nitric oxide in man. Thorax 54:947–955

    Article  CAS  PubMed  Google Scholar 

  15. Misko TP, Moore WM, Kasten TP, Nickols GA, Corbett JA et al (1993) Selective inhibition of inducible nitric oxide synthase by aminoguanidine. Eur J Pharmacol 233:119–125

    Article  CAS  PubMed  Google Scholar 

  16. Nathan C, Xie QW (1994) Regulation of biosynthesis of nitric oxide. J Biol Chem 269:13725–13728

    CAS  PubMed  Google Scholar 

  17. Persson MG, Zetterstrom O, Argrenius V, Ihre E, Gustafsson LE (1994) Single-breath nitric oxide measurements in asthmatic patients and smokers. Lancet 343:146–147

    Article  CAS  PubMed  Google Scholar 

  18. Redington AE, Meng QH, Springall DR et al (2001) Increased expression of inducible nitric oxide synthase and cyclo-oxygenase-2 in the airway epithelium of asthmatic subjects and regulation by corticosteroid treatment. Thorax 56:351–357

    Article  CAS  PubMed  Google Scholar 

  19. Robbins RA, Barnes PJ, Springall DR, Warren JB, Kwon OJ et al (1994) Expression of inducible nitric oxide synthase in human bronchial epithelial cells. Biochem Biophys Res Commun 203:209–218

    Article  CAS  PubMed  Google Scholar 

  20. Sapienza MA, Kharitonov SA, Horvath I, Chung KF, Barnes PJ (1998) Effect of inhaled l-arginine on exhaled nitric oxide in normal and asthmatic subjects. Thorax 53:172–175

    Article  CAS  PubMed  Google Scholar 

  21. Sharma JN, Al-Omran A, Parvathy SS (2007) Role of nitric oxide in inflammatory diseases. Inflammopharmacology 15:252–259

    Article  CAS  PubMed  Google Scholar 

  22. Tan K, Bruce C, Birkhead A, Thomas PS (2001) Nasal and exhaled nitric oxide in response to occupational latex exposure. Allergy 56:627–632

    Article  CAS  PubMed  Google Scholar 

  23. Thomas PS, Heywood G (2002) Effects of inhaled tumor necrosis factor alpha in subjects with mild asthma. Thorax 57:774–778

    Article  CAS  PubMed  Google Scholar 

  24. Wei XM, Kim HS, Kumar RK, Heywood GJ, Hunt JE, McNeil HP, Thomas PS (2005) Effects of cigarette smoke on degranulation and NO production by mast cells and epithelial cells. Respir Res 6:108. doi:10.1186/1465-9921-6-108

    Article  PubMed  CAS  Google Scholar 

  25. Yates DH (2001) Role of exhaled nitric oxide in asthma. Immunol Cell Biol 79:178–190

    Article  CAS  PubMed  Google Scholar 

  26. Yates DH, Kharitonov SA, Thomas PS, Barnes PJ (1996a) Endogenous nitric oxide is decreased in asthmatic patients by an inhibitor of inducible nitric oxide synthase. Am J Respir Crit Care Med 154:247–250

    CAS  PubMed  Google Scholar 

  27. Yates DH, Kharitonov SA, Barnes PJ (1996b) An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled β2 agonist. Am J Respir Crit Care Med 154:1603–1607

    CAS  PubMed  Google Scholar 

  28. Yates DH, Kharitonov SA, Robbins RA, Thomas PS, Barnes PJ (1996c) Effect of alcohol ingestion on exhaled nitric oxide. Eur Respir J 9:1130–1133

    Article  CAS  PubMed  Google Scholar 

  29. Yates DH, Breen H, Thomas PS (2001) Passive smoke inhalation decreases exhaled nitric oxide in normal subjects. Am J Respir Crit Care Med 164:1043–1046

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank the subjects for their participation. Supported by NH&MRC, Australia.

Author information

Affiliations

  1. Centre for Infection and Inflammation Research and POWH Clinical School, Faculty of Medicine , University of New South Wales, Randwick, NSW, Australia

    C. T. Bruce, D. Zhao & Paul S. Thomas

  2. Department of Respiratory Medicine, Prince of Wales Hospital, Randwick, NSW, 2031, Australia

    C. T. Bruce & Paul S. Thomas

  3. Department of Thoracic Medicine, St Vincent’s Hospital, Darlinghurst, Sydney, NSW, Australia

    D. H. Yates

Authors
  1. C. T. Bruce
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. H. Yates
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paul S. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul S. Thomas.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bruce, C.T., Zhao, D., Yates, D.H. et al. l-Arginine reverses cigarette-induced reduction of fractional exhaled nitric oxide in asthmatic smokers. Inflammopharmacol 18, 9–16 (2010). https://doi.org/10.1007/s10787-009-0017-9

Download citation

Keywords

  • Aminoguanidine
  • Asthma
  • Cigarette smoking
  • Nitric oxide