EFFECTS OF THE CYSTEINYL LEUKOTRIENE RECEPTOR ANTAGONISTS PRANLUKAST AND ZAFIRLUKAST ON TRACHEAL MUCUS SECRETION IN OVALBUMIN-SENSITIZED GUINEA-PIGS IN-VITRO

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 b y leukotriene D-4 (LTD4) or by antigen challenge of sensitized animals . Agonists and antagonists were administered mucosally, except in sele cted comparative experiments where drugs were administered both mucosa lly and serosally to assess the influence of the epithelium on evoked- secretion. 2 LTD4 increased (SO4)-S-35 output in a concentration-relat ed 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 addi tion of LTD4 did not significantly affect the secretory response compa red with mucosal addition alone. Neither LTC4 nor LTE4 (10 mu M each) affected (SO4)-S-35 output. Pranlukast or zafirlukast significantly in hibited 10 mu M LTD4-evoked (SO4)-S-35 output in a concentration-depen dent fashion, with maximal inhibitions of 83% at 10 mu M pranlukast an d 78% at 10 mu M zafirlukast, and IC50 values of 0.3 mu M for pranluka st and 0.6 mu M for zafirlukast. Combined mucosal and serosal administ ration 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 Ova lbumin (10-500 mu g ml(-1)) challenge of tracheae from guinea-pigs act ively sensitized with ovalbumin caused a concentration-related increas e in (SO4)-S-35 output with a maximal increase of 20 fold above vehicl e controls at 200 mu g ml(-1). The combination of the antihistamines p yrilamine and cimetidine (0.1 mM each) did not inhibit ovalbumin-induc ed (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 signi ficant effect on (SO4)-S-35 output. 4 Pranlukast or zafirlukast (5 mu M each) significantly suppressed ovalbumin-induced secretion in trache ae from sensitized guinea-pigs by 70% and 65%, respectively. 5 We conc lude that LTD4 or ovalbumin challenge of sensitized animals provokes m ucus secretion from guinea-pig trachea in vitro and this effect is inh ibited by the CysLT(1) receptor antagonists pranlukast and zafirlukast . These antagonists may be beneficial in the treatment of allergic air way diseases in which mucus hypersecretion is a clinical symptom, for example asthma and allergic rhinitis.