1 We investigated the inhibitory effects of the cysteinyl leukotriene (CysLT(1)) receptor antagonists, pranlukast and zafirlukast, on (SO4)-S-35 labelled mucus output, in vitro, in guinea-pig trachea, induced by leukotriene D-4 (LTD4) 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. 2 LTD4 increased (SO4)-S-35 output in a concentration-related manner with a maximal increase of 23 fold above controls at 100 mu M and an approximate EC50 of 2 mu M. Combined mucosal and serosal addition of LTD4 did not significantly affect the secretory response compared with mucosal addition alone. Neither LTC4 nor LTE4 (10 mu M each) affected (SO4)-S-35 output. Pranlukast or zafirlukast significantly inhibited 10 mu M LTD4-evoked (SO4)-S-35 output in a concentration-dependent fashion, with maximal inhibitions of 83% at 10 mu M pranlukast and 78% at 10 mu M zafirlukast, and IC50 values of 0.3 mu M for pranlukast and 0.6 mu M for zafirlukast. Combined mucosal and serosal administration of the antagonists (5 mu M each) gave degrees of inhibition of mucosal-serosal 10 mu M LTD4-evoked (SO4)-S-35 output Similar to those of the drugs given mucosally. Pranlukast (0.5 mu M) caused a parallel rightward shift of the LTD4 concentration-response curve with a pK(B) of 7. Pranlukast did not inhibit ATP-induced (SO4)-S-35 output. 3 Ovalbumin (10-500 mu g ml(-1)) challenge of tracheae from guinea-pigs actively sensitized with ovalbumin caused a concentration-related increase in (SO4)-S-35 output with a maximal increase of 20 fold above vehicle controls at 200 mu g ml(-1). The combination of the antihistamines pyrilamine and cimetidine (0.1 mM each) did not inhibit ovalbumin-induced (SO4)-S-35 output in sensitized guinea-pigs. Neither mucosal (10 mu M or 100 mu M) nor mucosal-serosal (100 mu M) histamine had any significant effect on (SO4)-S-35 output. 4 Pranlukast or zafirlukast (5 mu M each) significantly suppressed ovalbumin-induced secretion in tracheae from sensitized guinea-pigs by 70% and 65%, respectively. 5 We conclude that LTD4 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.
