ORIGINAL ARTICLE

Role of cysteinyl leukotrienes in adenosine 5`-monophosphate induced bronchoconstriction in asthma

S Rorke, S Jennison, J A Jeffs, A P Sampson, H Arshad, S T Holgate

Division of Respiratory Cell and Molecular Biology, University of Southampton School of Medicine, Southampton General Hospital, Southampton SO16 6YD, UK

Correspondence to:
Correspondence to:
Dr S Rorke, Level D (810), Centre Block, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK;
s.rorke{at}soton.ac.uk

Background: Adenosine induced bronchoconstriction in patients with asthma is thought to be mediated by the synthesis and release of autacoids from airway mast cells. In vitro, adenosine induced constriction of asthmatic bronchi is blocked by a combination of specific histamine and cysteinyl leukotriene receptor antagonists, but the relative contribution of these mediators in vivo is unclear. We hypothesised that adenosine induced bronchoconstriction in asthmatic patients may be blocked by pretreatment with the orally active selective cysteinyl leukotriene-1 (CysLT₁) receptor antagonist, montelukast.

Methods: In a randomised, double blind, crossover study, oral montelukast (10 mg) or placebo was administered once daily on two consecutive days to 18 patients with mild to moderate persistent atopic asthma. Incremental doses of adenosine 5`-monophosphate (AMP) from 0.39 to 400 mg/ml were inhaled by dosimeter and the dose producing a 20% fall in FEV₁ (PC₂₀AMP) after AMP inhalation was recorded. Leukotriene E₄ (LTE₄) urinary concentrations were measured by enzyme immunoassay 4 hours after AMP challenge.

Results: Montelukast pretreatment provided highly significant protection against adenosine induced bronchoconstriction, with geometric mean PC₂₀AMP values of 52.6 mg/ml (95% CI 35.2 to 78.7) after placebo and 123.9 mg/ml (95% CI 83.0 to 185.0) after montelukast (p=0.006). The geometric mean of the montelukast/placebo PC₂₀AMP ratio was 2.4 (95% CI 1.3 to 4.2). Montelukast had no significant effect on 4 hour urinary excretion of LTE₄ compared with placebo.

Conclusions: Selective CysLT₁ receptor antagonism with montelukast provides highly significant protection against AMP induced bronchoconstriction in patients with atopic asthma, implying that cysteinyl leukotrienes are generated from airway mast cells through preferential activation of their A_2B receptors.

Keywords: adenosine induced bronchoconstriction; montelukast; cysteinyl leukotrienes; asthma

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