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 (CysLT1) receptor antagonists, pranlukast and zafirlukast, on 35SO4 labelled mucus output, in vitro, in guinea-pig trachea, induced by leukotriene D4 (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 35SO4 output in a concentration-related manner with a maximal increase of 23 fold above controls at 100 microM and an approximate EC50 of 2 microM. Combined mucosal and serosal addition of LTD4 did not significantly affect the secretory response compared with mucosal addition alone. Neither LTC4 nor LTE4 (10 microM each) affected 35SO4 output. Pranlukast or zafirlukast significantly inhibited 10 microM LTD4-evoked 35SO4 output in a concentration-dependent fashion, with maximal inhibitions of 83% at 10 microM pranlukast and 78% at 10 microM zafirlukast, and IC50 values of 0.3 microM for pranlukast and 0.6 microM for zafirlukast. Combined mucosal and serosal administration of the antagonists (5 microM each) gave degrees of inhibition of mucosal-serosal 10 microM LTD4-evoked 35SO4 output similar to those of the drugs given mucosally. Pranlukast (0.5 microM) caused a parallel rightward shift of the LTD4 concentration-response curve with a pKB of 7. Pranlukast did not inhibit ATP-induced 35SO4 output. 3. Ovalbumin (10-500 microg ml(-1) challenge of tracheae from guinea-pigs actively sensitized with ovalbumin caused a concentration-related increase in 35SO4 output with a maximal increase of 20 fold above vehicle controls at 200 microg ml(-1). The combination of the antihistamines pyrilamine and cimetidine (0.1 mM each) did not inhibit ovalbumin-induced 35SO4 output in sensitized guinea-pigs. Neither mucosal (10 microM or 100 microM) nor mucosal-serosal (100 microM) histamine had any significant effect on 35SO4 output. 4. Pranlukast or zafirlukast (5 microM 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 CysLT1 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.
Liu
Y C
YC
Thoracic Medicine, National Heart & Lung Institute (Imperial College School of Medicine), London.
Khawaja
A M
AM
Rogers
D F
DF
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D003545:Cysteine / Q000378:metabolism; D006168:Guinea Pigs; D006967:Hypersensitivity / Q000276:immunology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007211:Indoles; D020024:Leukotriene Antagonists; D017998:Leukotriene D4 / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D009093:Mucus / Q000187:drug effects / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D010323:Passive Cutaneous Anaphylaxis / Q000276:immunology; D048448:Phenylcarbamates; D018077:Receptors, Leukotriene; D013431:Sulfates / Q000378:metabolism; D013449:Sulfonamides; D013462:Sulfur Radioisotopes; D014105:Tosyl Compounds / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*
D018927:Anti-Asthmatic Agents; D002867:Chromones; D007211:Indoles; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D048448:Phenylcarbamates; D018077:Receptors, Leukotriene; D013431:Sulfates; D013449:Sulfonamides; D013462:Sulfur Radioisotopes; D014105:Tosyl Compounds; D017998:Leukotriene D4; D000255:Adenosine Triphosphate; D010047:Ovalbumin; C412375:cysteinyl leukotriene receptor 2; D003545:Cysteine; C083169:leukotriene D4 receptor; C047681:pranlukast; C062735:zafirlukast