INHIBITION OF 5-LIPOXYGENASE DIMINISHES NEURALLY EVOKED TACHYKINERGICCONTRACTION OF GUINEA-PIG ISOLATED AIRWAY

The role of endogenous 5-lipoxygenase products in modulating tachykine rgic neurotransmission in guinea pig isolated trachea was investigated . Tachykinin-containing afferent nerve fibers were stimulated with eit her electrical field stimulation or antidromic stimulation of the righ t vagus nerve. This resulted in contractions of the isolated caudal tr achea and bronchus that could be blocked with either tetrodotoxin or a combination of neurokinin-l and neurokinin-e receptor antagonists. Th e 5-lipoxygenase inhibitor ZD 2138 (1 mu M) significantly inhibited th ese neurally mediated tachykinergic contractions, by approximately 50% , yet had no effect on the contractions evoked by stimulating tachykin ergic fibers in an action potential-independent fashion with capsaicin or by exogenously applied neurokinin A. The effect of ZD 2138 on acti on potential-driven tachykinergic contractions was mimicked by pobiluk ast, pranlukast, montelukast and zafirlukast, four structurally unrela ted antagonists of the cysteinyl leukotriene 1 receptor subtype. Pobil ukast had no effect on the tachykinergic contraction in tissues pretre ated with ZD 2138. Likewise, ZD 2138 had no effect on the tachykinergi c contractions in tissues pretreated with pobilukast. Intracellular el ectrophysiological recording of the membrane properties of jugular gan glion neurons, the source of tachykinins in the guinea pig trachea/bro nchus, demonstrated that leukotriene D-4 caused a membrane depolarizat ion of vagal afferent C-fiber neurons and an increase in input impedan ce, both of which were abolished by zafirlukast. Taken together, these data indicate that in the resting guinea pig isolated trachea/bronchu s, endogenous 5-lipoxygenase activity leads to the production of cyste inyl leukotrienes that amplify action potential-dependent release of t achykinins from airway afferent nerve fibers.