The cysteinyl-leukotriene-1 receptor antagonist zafirlukast is a potent secretagogue in rat and human airways.
Cysteinyl-leukotriene-1 receptor antagonists are important tools in the therapy of asthma. Although many studies have been performed concerning their effects on airway smooth muscle tone, there are no basic data on their effects on airway secretions. Therefore, we assessed the effects of zafirlukast and montelukast on rat tracheal secretion by quantification of secreted 35S04 labelled mucus macromolecules, and determined the influence of the arachidonic acid pathway using the modified Ussing chamber technique. Zafirlukast (432+/-89.99%) and montelukast (167+/-16.74%) stimulated rat tracheal secretion. This was abolished by application of eicosatetraenoic acid, an inhibitor of the arachidonic acid metabolism. Whereas inhibition of cyclooxygenase did not show any significant effect on zafirlukast induced secretion, blockade of the 5-lipoxygenase pathway markedly reduced the secretagogue effects. Furthermore, inhibition of phosphatidylinositol-3-kinase completely inhibited the effects elicited by zafirlukast. Additional experiments revealed secretagogue effects of zafirlukast also in human bronchial tissue. In conclusion, zafirlukast is a potent inducer of tracheal secretion. Obviously, these effects are induced by involvement of a phosphatidylinositol-3-kinase dependent pathway mediated by products of the arachidonic acid metabolism.
Schmidt
Rene
R
Department of Anesthesiology, Albert-Ludwigs-University, Freiburg, Germany.
Staats
Petra
P
Groneberg
David A
DA
Wagner
Ulrich
U
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000085:Acetates / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D048448:Phenylcarbamates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018077:Receptors, Leukotriene / Q000378:metabolism; D013440:Sulfides; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism; D002722:Chlorobenzenes
D015117:5,8,11,14-Eicosatetraynoic Acid; D000085:Acetates; D016718:Arachidonic Acid; D002867:Chromones; D016861:Cyclooxygenase Inhibitors; D003521:Cyclopropanes; D007052:Ibuprofen; D007211:Indoles; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D009025:Morpholines; D048448:Phenylcarbamates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D013449:Sulfonamides; D014105:Tosyl Compounds; C060893:MK-886; D002722:Chlorobenzenes; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C083169:leukotriene D4 receptor; C093875:montelukast; C062735:zafirlukast