Ma. Mcalexander et al., INHIBITION OF 5-LIPOXYGENASE DIMINISHES NEURALLY EVOKED TACHYKINERGICCONTRACTION OF GUINEA-PIG ISOLATED AIRWAY, The Journal of pharmacology and experimental therapeutics, 285(2), 1998, pp. 602-607
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.