Bronchial hyperresponsiveness to contractile agonists and nonspecific irritants is a characteristic feature of bronchial asthma. The mechanisms causing this hyperirritability are unknown. The existence of separate receptors for leukotrienes C4 and D4 (LTC4 and LTD4) has been demonstrated previously by physiologic and radioligand binding studies. The rank order of potency of the sulfidopeptide leukotrienes for contracting tracheal spirals [leukotriene E4 (LTE4) greater than LTD4 = LTC4] is different from that for contracting parenchymal strips (LTD4 greater than LTE4 greater than LTC4), thereby suggesting the existence of a separate receptor for LTE4. We now report that LTE4, the most stable of the leukotrienes comprising slow reacting substance of anaphylaxis, enhances the contractile response of guinea pig tracheal spirals but not of parenchymal strips to histamine in a time- and dose-dependent fashion. The ability of LTE4 to increase histamine responsiveness occurred after removal of the free agonist and recovery of the tissues to baseline tensions and was not produced by leukotrienes C4 and D4, which elicited the same magnitude of contraction of tracheal smooth muscle as LTE4. These findings suggest that LTE4-induced airway hyperirritability is not mediated by the contractile response per se and may be mediated through a receptor distinct from those for leukotrienes C4 and D4.