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Effects of the cysteinyl leukotriene receptor antagonists pranlukast and zafirlukast on tracheal mucus secretion in ovalbumin‐sensitized guinea‐pigs in vitro
Author(s) -
Liu YuChih,
Khawaja Aamir M,
Rogers Duncan F
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701886
Subject(s) - ovalbumin , zafirlukast , mucus , guinea pig , leukotriene d4 , secretion , leukotriene , in vitro , immunology , medicine , chemistry , biology , antigen , asthma , biochemistry , ecology
We investigated the inhibitory effects of the cysteinyl leukotriene (CysLT 1 ) receptor antagonists, pranlukast and zafirlukast, on 35 SO 4 labelled mucus output, in vitro , in guinea‐pig trachea, induced by leukotriene D 4 (LTD 4 ) or by antigen challenge of sensitized animals. Agonists and antagonists were administered mucosally, except in selected comparative experiments where drugs were administered both mucosally and serosally to assess the influence of the epithelium on evoked‐secretion. LTD 4 increased 35 SO 4 output in a concentration‐related manner with a maximal increase of 23 fold above controls at 100 μ M and an approximate EC 50 of 2 μ M . Combined mucosal and serosal addition of LTD 4 did not significantly affect the secretory response compared with mucosal addition alone. Neither LTC 4 nor LTE 4 (10 μ M each) affected 35 SO 4 output. Pranlukast or zafirlukast significantly inhibited 10 μ M LTD 4 ‐evoked 35 SO 4 output in a concentration‐dependent fashion, with maximal inhibitions of 83% at 10 μ M pranlukast and 78% at 10 μ M zafirlukast, and IC 50 values of 0.3 μ M for pranlukast and 0.6 μ M for zafirlukast. Combined mucosal and serosal administration of the antagonists (5 μ M each) gave degrees of inhibition of mucosal‐serosal 10 μ M LTD 4 ‐evoked 35 SO 4 output similar to those of the drugs given mucosally. Pranlukast (0.5 μ M ) caused a parallel rightward shift of the LTD 4 concentration‐response curve with a p K B of 7. Pranlukast did not inhibit ATP‐induced 35 SO 4 output. Ovalbumin (10–500 μg ml −1 ) challenge of tracheae from guinea‐pigs actively sensitized with ovalbumin caused a concentration‐related increase in 35 SO 4 output with a maximal increase of 20 fold above vehicle controls at 200 μg ml −1 . The combination of the antihistamines pyrilamine and cimetidine (0.1 m M each) did not inhibit ovalbumin‐induced 35 SO 4 output in sensitized guinea‐pigs. Neither mucosal (10 μ M or 100 μ M ) nor mucosal‐serosal (100 μ M ) histamine had any significant effect on 35 SO 4 output. Pranlukast or zafirlukast (5 μ M each) significantly suppressed ovalbumin‐induced secretion in tracheae from sensitized guinea‐pigs by 70% and 65%, respectively. We conclude that LTD 4 or ovalbumin challenge of sensitized animals provokes mucus secretion from guinea‐pig trachea in vitro and this effect is inhibited by the CysLT 1 receptor antagonists pranlukast and zafirlukast. These antagonists may be beneficial in the treatment of allergic airway diseases in which mucus hypersecretion is a clinical symptom, for example asthma and allergic rhinitis.