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

Preincubation of guinea‐pig tracheal smooth muscle with leukotriene E₄ (LTE₄) in vitro increased its subsequent responsiveness to histamine. 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 β‐adrenoceptor agonist, isoprenaline. LTE₄‐induced airway histamine hyperresponsiveness was blocked by indomethacin (5 μm), GR32191 (3 μm), atropine (1 μm) and tetrodotoxin (1 μm). U46619, a stable thromboxane A₂‐analogue, at a non‐contractile concentration of 4 nm, increased tracheal smooth muscle sensitivity to histamine. Both LTE₄ and U46619 pretreatment increased the contractile response of tracheal smooth muscle to electrical field stimulation. Preincubation of human bronchial spirals with LTE₄ in vitro increased its subsequent responsiveness to histamine. LTE₄‐induced histamine hyperresponsiveness of human bronchus was inhibited by GR32191 (3 μm) and atropine (1 μm). 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. 1991 British Pharmacological Society