The effect of epithelium removal on leukotriene E₄‐induced histamine hyperresponsiveness in guinea‐pig tracheal smooth muscle

Removal of the epithelium resulted in a threefold increase in guinea‐pig tracheal sensitivity to histamine without increasing the maximal response. Preincubation of epithelially‐denuded guinea‐pig tracheal smooth muscle with leukotriene E₄ (LTE₄) in vitro increased the subsequent maximal response of the tissues to histamine. The sensitivity of the tissues to histamine was unaffected by LTE₄ pretreatment. Pretreatment of the epithelially‐denuded tissues with the LTE₄‐analogue, 20‐COOH LTE₄, did not affect the maximal response to histamine. LTE₄ pretreatment increased the maximal response of the epithelially‐denuded tissues to substance P (SP) but did not affect the maximal response to carbachol, KCl nor to the β‐adrenoceptor agonist, isoprenaline. LTE₄‐induced airway histamine hyperresponsiveness was blocked by indomethacin (5 μm), GR32191 (3 μm) and atropine (1 μm). Both LTE₄ and U46619 pretreatment increased the contractile response of tracheal smooth muscle to electrical field stimulation. It is proposed that LTE₄ induces an increased maximal response of epithelially‐denuded guinea‐pig airway smooth muscle to both histamine and substance P via a facilitation of cholinergic neurotransmission, which is dependent upon the secondary generaton of prostanoid mediator(s) acting on TP‐receptors situated on cholinergic nerve terminals. Further, it is suggested that the increased maximal response of the epithelially‐intact tissues to both histamine and substance P, after LTE₄ pretreatment, may be suppressed by an epithelially‐derived factor. 1992 British Pharmacological Society