Bradykinin-induced airway constriction in guinea-pigs: role of leukotriene D(4).

Tachykinins (TK) have been implicated in both bradykinin-(BK) and hyperpnea-induced broncho-constriction (HIB) in the guinea-pig. However, TKs appear to have an indirect effect in HIB by releasing leukotriene (LT)D(4). We postulated that BK may cause bronchoconstriction through a cascade involving TK and LTD(4). We examined the role of TK and LTD(4)in BK-induced bronchoconstriction in ventilated Hartley guinea-pigs. Respiratory resistance (R(rs)) was monitored for 2 h following insufflation of BK (150 nM). Animals were pretreated with propranolol, then with either neurokinin (NK)1 (CP-99,994)+NK2 (SR-48,968) receptor antagonists or pranlukast (90 microg or 900 microg), an LTD(4)antagonist. Control animals received no pretreatment. BK-induced bronchoconstriction was significantly lower in NK1/NK2 (128%+/-6% baseline R(rs)SEM) and pranlukast (90 microg; 205+/-22, 900 microg; 169+/-20) animals compared to controls (284+/-22), P<0.0001 ANOVA. Bile from control and saline challenged animals was analysed for LTD(4)by HPLC and radio-immunoassay. However, LTD(4)excretion rate showed no significant difference over a 2-h collection period following insufflation of either BK or saline, respectively; baseline =2.5 pmol/h+/-0.6 SEM vs. 2.3+/-0.2, 0-1 h=2.8+/-0.7 vs. 2.0+/-0.6, 1-2 h=2.3+/-0.6 vs. 1.7+/-0.7. We conclude that BK-induced bronchoconstriction is mediated in part through the release of both TK and LTD(4), but the latter is released in insufficient quantities to be detectable by biliary analysis. Copyright 2000 Academic Press.