Skip to main content
SpringerLink
Log in

Salbutamol but not ipratropium abolishes leukotriene D4-induced gas exchange abnormalities in asthma

  • Pharmacodynamics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Leukotriene D4 (LTD4) is a central mediator in asthma inducing bronchoconstriction and profound disturbances in pulmonary gas exchange in asthmatic subjects. The aim of the study was to compare, for the first time, the influence of the bronchodilators salbutamol (400 μg) and ipratropium (80 μg) on lung function changes induced by inhaled LTD4.

Methods

Treatments were evaluated in a randomized, three-period, double-blind, placebo-controlled, cross-over study where spirometric and pulmonary gas exchange indices were followed in 12 subjects with mild asthma before and after LTD4 challenge.

Results

Compared with placebo, salbutamol provided significant protection against the fall in FEV1 (forced expiratory volume in 1 s) after LTD4 challenge. Salbutamol also abolished the LTD4-induced gas exchange disturbances [decreased arterial oxygen tension (PaO2) and increased alveolar–arterial oxygen tension difference (AaPO2)]. Ipratropium provided significant but less marked attenuation of the changes in FEV1 and arterial oxygenation induced by LTD4.

Conclusion

Despite the equal bronchodilatory effects of salbutamol and ipratropium before the challenge with LTD4, salbutamol was superior to ipratropium in preventing spirometric and gas exchange abnormalities. This result indicates a broader action of salbutamol on several of the disturbances that contribute to airway obstruction including, for example, exudation of plasma in the airway mucosa. The clinical implication of this new finding is that in this model of acute asthmatic airway obstruction, salbutamol was more effective than ipratropium.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bateman ED, Hurd SS, Barnes PJ et al (2008) Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 31:143–178

    Article  PubMed  CAS  Google Scholar 

  2. Global Initiative for Chronic Obstructive Lung Disease (GOLD) (2011) The Global strategy for the diagnosis, management and prevention of COPD, 2011 edn. Available at: http://www.goldcopd.org/. Accessed Dec 2011

  3. Peters SP, Kunselman SJ, Icitovic N et al (2010) National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 363:1715–1726

    Article  PubMed  CAS  Google Scholar 

  4. Peters-Golden M, Henderson WR Jr (2007) Leukotrienes. N Engl J Med 357:1841–1854

    Article  PubMed  CAS  Google Scholar 

  5. Dahlén S-E (2006) Treatment of asthma with antileukotrienes: First line or last resort therapy? Eur J Pharmacol 533:40–56

    Article  PubMed  Google Scholar 

  6. Price D, Musgrave SD, Shepstone L et al (2011) Leukotriene antagonists as first-line or add-on asthma-controller therapy. N Engl J Med 364:1695–1707

    Article  PubMed  CAS  Google Scholar 

  7. Roquet A, Dahlén B, Kumlin M et al (1997) Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am J Respir Crit Care Med 155:1856–1863

    PubMed  CAS  Google Scholar 

  8. Camargo CA Jr, Gurner DM, Smithline HA et al (2010) A randomized placebo-controlled study of intravenous montelukast for the treatment of acute asthma. J Allergy Clin Immunol 125:374–380

    Article  PubMed  CAS  Google Scholar 

  9. Bäck M, Dahlén SE, Drazen JM et al (2011) Leukotriene receptor nomenclature, distribution, and pathophysiological functions. Pharmacol Rev 63:539–584

    Article  PubMed  Google Scholar 

  10. Echazarreta AL, Dahlén B, García G et al (2001) Pulmonary gas exchange and sputum cellular responses to inhaled leukotriene D4 in asthma. Am J Respir Crit Care Med 164:202–206

    PubMed  CAS  Google Scholar 

  11. Casas A, Gómez FP, Dahlén B, Roca J, Barberà JA, Dahlén SE, Rodríguez-Roisin R (2005) Leukotriene D4-induced hypoxaemia in asthma is mediated by the cys-leukotriene1 receptor. Eur Respir J 26:442–448

    Article  PubMed  CAS  Google Scholar 

  12. Rodriguez-Roisin R (1997) Acute severe asthma: pathophysiology and pathobiology of gas exchange abnormalitities. Eur Respir J 10:1359–1371

    Article  PubMed  CAS  Google Scholar 

  13. Georgopoulos D, Giulekas D, Ilonidis G, Sichletidis L (1989) Effect of salbutamol, ipratropium bromide and cromolyn sodium on prostaglandin F2α -induced bronchospasm. Chest 96:809–814

    Article  PubMed  CAS  Google Scholar 

  14. Ihre E, Larsson K (1990) Airways responses to ipratropium bromide do not vary with time in asthmatic subjects. Studies of interindividual and intraindividual variation of bronchodilatation and protection against histamine-induced bronchoconstriction. Chest 97:46–51

    Article  PubMed  CAS  Google Scholar 

  15. Roca J, Felez MA, Chung KF, Barbera JA, Rotger M, Santos C, Rodriguez-Roisin R (1995) Salbutamol inhibits pulmonary effects of platelet activating factor in man. Am J Respir Crit Care Med 151:1740–1744

    PubMed  CAS  Google Scholar 

  16. Gyllfors P, Dahlén S-E, Kumlin M, Larsson K, Dahlén B (2006) Bronchial responsiveness to leukotriene D4 is resistant to inhaled fluticasone proprionate. J Allergy Clin Immunol 118:78–83

    Article  PubMed  CAS  Google Scholar 

  17. Gabrijelcic J, Acuña A, Profita M, Paterno A, Chung KF, Vignola AM, Rodriguez-Roisin R (2003) Neutrophil airway influx by platelet-activating factor in asthma: role of adhesion molecules and LTB4 expression. Eur Respir J 22:290–297

    Article  PubMed  CAS  Google Scholar 

  18. Greiff L, Wollmer P, Andersson M, Svensson C, Persson CG (1998) Effects of formoterol on histamine induced plasma exudation in induced sputum from normal subjects. Thorax 53:1010–1013

    Article  PubMed  CAS  Google Scholar 

  19. Díaz O, Barberà JA, Marrades R, Chung KF, Roca J, Rodriguez-Roisin R (1997) Inhibition of PAF-induced gas exchange defects by beta-adrenergic agonists in mild asthma is not due to bronchodilation. Am J Respir Crit Care Med 156:17–22

    PubMed  Google Scholar 

  20. Dahlén S-E, Hedqvist P, Hammarström S, Samuelsson B (1980) Leukotrienes are potent constrictors of human bronchi. Nature 288:484–486

    Article  PubMed  Google Scholar 

  21. Holroyde MC, Altounyan REC, Cole M, Dixon M, Elliott E (1981) Bronchoconstriction produced in man by leukotrienes C & D. Lancet 6:17–18

    Article  Google Scholar 

  22. Weiss JW, Drazen JM, Coles N et al (1982) Bronchoconstrictor effects of leukotriene C in humans. Science 216:196–198

    Article  PubMed  CAS  Google Scholar 

  23. Dahlén S-E, Björk J, Hedqvist P, Arfors K-E, Hammarström S, Lindgren JÅ, Samuelsson B (1981) Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response. Proc Natl Acad Sci USA 78:3887–3891

    Article  PubMed  Google Scholar 

  24. Muñoz NM, Douglas I, Mayer D, Herrnreiter A, Zhu X, Leff AR (1997) Eosinophil chemotaxis inhibited by 5-lipoxygenase blockade and leukotriene receptor antagonism. Am J Respir Crit Care Med 155:1398–1403

    PubMed  Google Scholar 

  25. Barnes PJ (2004) The role of anticholinergics in chronic obstructive pulmonary disease. Am J Med 117[Suppl 12A]:24S–32S

    PubMed  CAS  Google Scholar 

  26. Persson CG, Erjefält I, Andersson P (1986) Leakage of macromolecules from guinea-pig tracheobronchial microcirculation. Effects of allergen, leukotrienes, tachykinins, and anti-asthma drugs. Acta Physiol Scand 127:95–105

    Article  PubMed  CAS  Google Scholar 

  27. Dent G, Giembycz MA, Evans PM, Rabe KF, Barnes PJ (1994) Suppression of human eosinophil respiratory burst and cyclic AMP hydrolysis by inhibitors of type IV phosphodiesterase: interaction with the beta adrenoceptor agonist albuterol. J Pharmacol Exp Ther 271:1167–1174

    PubMed  CAS  Google Scholar 

  28. Diamant Z, Hiltermann JT, van Rensen EL et al (1997) The effect of inhaled leukotriene D4 and methacholine on sputum cell differentials in asthma. Am J Respir Crit Care Med 155:1247–1253

    PubMed  CAS  Google Scholar 

  29. Mulder A, Gauvreau GM, Watson RM, O'Byrne PM (1999) Effect of inhaled leukotriene D4 on airway eosinophilia and airway hyperresponsiveness in asthmatic subjects. Am J Respir Crit Care Med 159:1562–1567

    PubMed  CAS  Google Scholar 

  30. Kumlin M, Dahlén B, Björck T, Zetterström O, Granström E, Dahlén S-E (1992) Urinary excretion of leukotriene E4 and 11-dehydro-thromboxane B2 in response to bronchial provocations with allergen, aspirin, leukotriene D4 and histamine in asthmatics. Am Rev Respir Dis 146:96–103

    PubMed  CAS  Google Scholar 

  31. Hui KP, Barnes NC (1991) Lung function improvement in asthma with a cysteinyl-leukotriene receptor antagonist. Lancet 337(8749):1062–1063

    Article  PubMed  CAS  Google Scholar 

  32. Gaddy JN, Margolskee DJ, Bush RK, Williams VC, Busse WW (1992) Bronchodilation with a potent and selective leukotriene D4 (LTD4) receptor antagonist (MK-571) in patients with asthma. Am Rev Respir Dis 146:358–363

    PubMed  CAS  Google Scholar 

  33. Dahlén B, Margolskee DJ, Zetterström O, Dahlén SE (1993) Effect of the leukotriene receptor antagonist MK-0679 on baseline pulmonary function in aspirin sensitive asthmatic subjects. Thorax 48:1205–1210

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Josep L. Valera RN and Laurie Lau for technical assistance. The study was supported by The Swedish Heart Lung Foundation, the Swedish MRC, the Stockholm County Council Research Funds (ALF) and Vinnova (CiDAT), the Fondo de Investigación Sanitaria (FIS 00/617). the Generalitat de Catalunya (2009SGR 00911) and the Sociedad Española de Neumología y Cirugıa Torácica (SEPAR).

Conflict of interest statement

This is an investigator-initiated and -conducted study. There is no conflict of interest to declare.

Author information

Authors and Affiliations

  1. Lung and Allergy Clinic, Department of Medicine at Karolinska University Hospital Huddinge and The Centre for Allergy Research, Karolinska Institutet, 141 86, Stockholm, Sweden

    Barbro Dahlén

  2. Servei de Pneumologia (Thorax Institute), Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain

    Federico P Gómez, Alejandro Casas & Robert Rodriguez-Roisin

  3. Ciber Enfermedades Respiratorias (CIBERES), Barcelona, Spain

    Federico P Gómez, Alejandro Casas & Robert Rodriguez-Roisin

  4. Southampton General Hospital, University of Southampton, Southampton, UK

    Peter H Howarth

  5. Unit for Experimental Asthma & Allergy Research, The National Institute of Environmental Medicine and The Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden

    Sven-Erik Dahlén

Authors
  1. Barbro Dahlén
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Federico P Gómez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alejandro Casas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter H Howarth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sven-Erik Dahlén
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert Rodriguez-Roisin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Barbro Dahlén.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dahlén, B., Gómez, F.P., Casas, A. et al. Salbutamol but not ipratropium abolishes leukotriene D4-induced gas exchange abnormalities in asthma. Eur J Clin Pharmacol 68, 1375–1383 (2012). https://doi.org/10.1007/s00228-012-1256-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-012-1256-z

Keywords

Search

Navigation