Effect of the lipoxygenase inhibitor N-hydroxy-N-(6-methoxy-3,4-dihydro-2-naphthylmethyl)urea on bronchoconstriction and lung vascular permeability in anaphylactic guinea pigs.
Narrowing of the airway lumen as a result of plasma exudation could augment airflow obstruction after allergen-induced bronchoconstriction. Because leukotrienes are putative mediators of bronchial asthma, the effects of a lipoxygenase inhibitor, VZ564 (N-hydroxy-N-(6-methoxy-3,4-dihydro-2- naphthylmethyl) urea. CAS 147495-99-6), on increased pulmonary permeability and bronchoconstriction during anaphylactic reaction were studied in guinea pigs and compared to the effects of the phosphodiesterase inhibitor theophylline. An anaphylactic reaction was induced by ovalbumin challenge (0.2 mg/kg i.v.) in passively sensitized and antihistamine (mepyramine)-pretreated guinea pigs; bronchoconstriction was measured as increased intratracheal pressure; lung vascular permeability was evaluated as extravasation of Evans blue dye up to 10 min after antigenic challenge. Ovalbumin challenge induced an increase in intratracheal pressure by 31 +/- 3 mmHg; the pulmonary permeability index was higher in ovalbumin-challenged versus saline (sham)-challenged guinea pigs (1.49 +/- 0.17 vs 0.56 +/- 0.04, p < 0.05). VZ564 and theophylline dose-dependently reduced increased pulmonary permeability and bronchoconstriction. VZ564 (10 and 46.4 mg/kg p.o., given 1 h before ovalbumin challenge) inhibited increased lung permeability by 42% and 95% and reduced bronchoconstriction by 61% at the higher dose. Theophylline (1 and 10 mg/kg i.v., given 10 min before ovalbumin challenge) diminished increased pulmonary permeability by 88% and reduced bronchoconstriction by 63% at the higher dose. In conclusion, the novel lipoxygenase inhibitor VZ564 inhibits after oral application important symptoms of asthma, namely bronchoconstriction and alveolar exudation of plasma in anaphylactic guinea pigs. The acute effects of VZ564 in this experimental model are comparable with the effects of the well known antiasthmatic substance theophylline.
Geist
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Grünenthal GmbH, Center of Research, Aachen, Germany.
Schneider
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J
Zimmer
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O
D000707:Anaphylaxis / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology; D011652:Pulmonary Circulation / Q000187:drug effects; D013806:Theophylline / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; C092916:VZ 564; D014508:Urea; D010047:Ovalbumin; D013806:Theophylline