Leukotriene D4-induced hypoxaemia in asthma is mediated by the cys-leukotriene1 receptor.
Bronchoprovocation with cysteinyl-leukotrienes (LTs) induces airflow obstruction and gas exchange abnormalities, namely ventilation-perfusion ratio (V'(A)/Q') imbalance. However, it is unknown which of the two different receptors for cysteinyl-LTs mediate these V'(A)/Q' disturbances. In a double-blinded, crossover design, 10 patients with mild asthma were randomised to receive an oral single dose of the selective cysteinyl-LT1 receptor antagonist montelukast (40 mg) or placebo before leukotriene (LT)D4 inhalation challenge. Gas exchange, including V'(A)/Q' descriptors were measured at baseline, 3 h after montelukast/placebo pretreatment and 5, 15 and 45 min after the LTD4 challenge. Compared with montelukast, inhalation of LTD(4) induced a marked fall in forced expiratory volume in one second (mean+/-se 33+/-2%) and profound V'(A)/Q' mismatching, reflected by a decreased arterial oxygen tension (from 100+/-4 to 75+/-3 mmHg) and an increased overall index of V'(A)/Q' heterogeneity dispersion of retention minus excretion inert gases corrected for dead space (from 4.9+/-1.2 to 8.4+/-1.1; normal< or =3.0; dimensionless), 5 min after placebo. Following montelukast, LTD4 produced no significant changes in any of the variables. In conclusion, these findings point to the view that leukotriene D4)-induced gas exchange disturbances and bronchoconstriction are both mediated by the cysteinyl-leukotriene1 receptor.
Casas
A
A
Servei de Pneumologia, Hospital Clínic, Villarroel, 170. 08036-Barcelona, Spain.
Gómez
F P
FP
Dahlén
B
B
Roca
J
J
Barberà
J A
JA
Dahlén
S-E
SE
Rodríguez-Roisin
R
R
D000085:Acetates / Q000494:pharmacology; D000328:Adult; D001249:Asthma / Q000150:complications / Q000503:physiopathology*; D001985:Bronchial Provocation Tests; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced* / Q000503:physiopathology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000187:drug effects*; D012720:Severity of Illness Index; D013440:Sulfides; D014692:Ventilation-Perfusion Ratio / Q000187:drug effects*
D000085:Acetates; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D017998:Leukotriene D4; C083169:leukotriene D4 receptor; C093875:montelukast