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Meakins-Christie Laboratories, McGill University Montreal, Quebec, Canada H2X 2P2
Received 7 November 1995; accepted in final form 16 October 1996.
Yang, X. X., W. S. Powell, M. Hojo, and J. G. Martin.
Hyperpnea-induced bronchoconstriction is dependent on
tachykinin-induced cysteinyl leukotriene synthesis. J. Appl. Physiol. 82(2): 538-544, 1997.
The purpose
of the study was to test the hypothesis that tachykinins mediate
hyperpnea-induced bronchoconstriction indirectly by triggering
cysteinyl leukotriene (LT) synthesis in the airways. Guinea pigs
(350-600 g) were anesthetized with xylazine and pentobarbital sodium and received hyperpnea challenge (tidal volume 3.5-4.0 ml,
frequency 150 breaths/min) with either humidified isocapnic gas
(n = 6) or dry gas
(n = 7). Dry gas challenge was
performed on animals that received MK-571
(LTD4 antagonist; 2 mg/kg iv; n = 5), capsaicin
(n = 4), neurokinin (NK) antagonists
[NK1 (CP-99994) + NK2 (SR-48968) (1 mg/kg iv);
n = 6], or the
H1 antihistamine pyrilamine (2 mg/kg iv; n = 5). We measured the
tracheal pressure and collected bile for 1 h before and 2 h after
hyperpnea challenge. We examined the biliary excretion of cysteinyl
LTs; the recovery of radioactivity in bile after instillation of 1 µCi
[3H]LTC4
intratracheally averaged 24% within 4 h
(n = 2). The major cysteinyl LT
identified was LTD4 (32% recovery
of radioactivity). Cysteinyl LTs were purified from bile of animals
undergoing hyperpnea challenge by using reverse-phase high-pressure
liquid chromatography and quantified by radioimmunoassay. There was a
significant increase in the peak value of tracheal pressure after
challenge, indicating bronchoconstriction in dry gas-challenged animals
but not after humidified gas challenge. MK-571, capsaicin, and NK
antagonists prevented the bronchoconstriction; pyrilamine did
not. Cysteinyl LT levels in the bile after challenge were
significantly increased from baseline in dry gas-challenged animals
(P < 0.05) and were higher than in
the animals challenged with humidified gas or dry gas-challenged
animals treated with capsaicin or NK antagonists (P < 0.01). The results indicate
that isocapnic dry gas hyperpnea-induced bronchoconstriction is LT
mediated and the role of tachykinins in the response is indirect
through release of LTs. Endogenous histamine does not contribute to the
response.
leukotriene D4; exercise-induced asthma; neurokinin antagonists
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