The mechanism of LTE4-induced histamine hyperresponsiveness in guinea-pig tracheal and human bronchial smooth muscle, in vitro.

1. Preincubation of guinea-pig tracheal smooth muscle with leukotriene E4 (LTE4) in vitro increased its subsequent responsiveness to histamine. 2. LTE4 pretreatment of guinea-pig tracheal strips did not affect the subsequent responsiveness to either the contractile agents, carbachol and KCl, or to the relaxant beta-adrenoceptor agonist, isoprenaline. 3. LTE4-induced airway histamine hyperresponsiveness was blocked by indomethacin (5 microM), GR32191 (3 microM), atropine (1 microM) and tetrodotoxin (1 microM). 4. U46619, a stable thromboxane A2-analogue, at a non-contractile concentration of 4 nM, increased tracheal smooth muscle sensitivity to histamine. 5. Both LTE4 and U46619 pretreatment increased the contractile response of tracheal smooth muscle to electrical field stimulation. 6. Preincubation of human bronchial spirals with LTE4 in vitro increased its subsequent responsiveness to histamine. 7. LTE4-induced histamine hyperresponsiveness of human bronchus was inhibited by GR32191 (3 microM) and atropine (1 microM). 8. It is proposed that LTE4 induces guinea-pig airway smooth muscle hyperresponsiveness to histamine via a facilitation of cholinergic neurotransmission, which is dependent upon the secondary generation of prostanoid mediator(s) acting on TP-receptors situated on cholinergic nerve terminals. In addition, it is suggested that LTE4 may induce histamine hyperresponsiveness of human bronchus in vitro by a similar mechanism as to that seen in guinea-pig central airway smooth muscle.