Role of cysteinyl leukotrienes in adenosine 5'-monophosphate induced bronchoconstriction in asthma.
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 (CysLT(1)) 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 FEV(1) (PC(20)AMP) after AMP inhalation was recorded. Leukotriene E(4) (LTE(4)) 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 PC(20)AMP 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 PC(20)AMP ratio was 2.4 (95% CI 1.3 to 4.2). Montelukast had no significant effect on 4 hour urinary excretion of LTE(4) compared with placebo.


CONCLUSIONS
Selective CysLT(1) 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.
Rorke
S
S
Division of Respiratory Cell and Molecular Biology, University of Southampton School of Medicine, Southampton General Hospital, Southampton SO16 6YD, UK. s.rorke@soton.ac.uk
Jennison
S
S
Jeffs
J A
JA
Sampson
A P
AP
Arshad
H
H
Holgate
S T
ST
D000085:Acetates / Q000627:therapeutic use*; D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000009:adverse effects*; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology / Q000652:urine; D016084:Bronchoconstriction / Q000187:drug effects*; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000502:physiology; D006801:Humans; D020024:Leukotriene Antagonists / Q000627:therapeutic use*; D017999:Leukotriene E4 / Q000652:urine; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D011804:Quinolines / Q000627:therapeutic use*; D018077:Receptors, Leukotriene; D013440:Sulfides
D000085:Acetates; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D000249:Adenosine Monophosphate; D017999:Leukotriene E4; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor; C093875:montelukast