Hyperpnea-induced bronchoconstriction is dependent on tachykinin-induced cysteinyl leukotriene synthesis.

Abstract

The purpose of the study was to test the hypothesis that tachykinins mediate hyperpnea-induced 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 i.v.; n = 5), capsaicin (n = 4), neurokinin (NK) antagonists [NK1 (CP-99994) + NK2 (SR-48968) (1 mg/kg i.v.); n = 6], or the H1 antihistamine pyrilamine (2 mg/kg i.v.; 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 microCi [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.