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Leukotriene D₄-induced hypoxaemia in asthma is mediated by the cys-leukotriene₁ receptor

¹ Servei de Pneumologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain, ² Dept of Internal Medicine at Huddinge University Hospital and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

CORRESPONDENCE: R. Rodriguez-Roisin, Servei de Pneumologia, Hospital Clínic, Villarroel, 170. 08036-Barcelona, Spain. Fax: 34 932275404. E-mail: rororo@clinic.ub.es

Keywords: Leukotriene inhalation challenge, leukotriene receptor antagonists, ventilation-perfusion mismatching

Received: December 23, 2004
Accepted May 10, 2005

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 LTD₄ 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; normal3.0; 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.