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.
Turner
D J
DJ
Department of Physiology, University of Western Australia, Australia.
Gupta
K
K
Yang
X X
XX
Martin
J G
JG
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology* / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D017998:Leukotriene D4 / Q000502:physiology*; D008297:Male; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000502:physiology; D015320:Tachykinins / Q000502:physiology*
D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; D017998:Leukotriene D4; D001920:Bradykinin