Leukotrienes and histamine mediate IgE-dependent contractions of human bronchi: pharmacological evidence obtained with tissues from asthmatic and non-asthmatic subjects.

Isolated human bronchi were challenged with anti-human IgE or specific allergen. The mediators of allergic constriction were characterized by pharmacological interventions. Experiments were performed on more than 180 preparations obtained from 48 non-asthmatic subjects and on 44 bronchial preparations from six asthmatic subjects. Addition of antihistamines (mepyramine and metiamide) to the organ bath abolished the response to exogenous histamine, but failed to alter the dose-response relationship of the reaction to cumulative challenge with rising titres of anti-IgE. On the other hand, pretreatment with drugs which blocked the action (receptor antagonists FPL55712, L-648,051 and ICI 198,615) or formation (biosynthesis inhibitors: U-60,257 and MK886) of leukotrienes consistently resulted in clear-cut inhibition of the allergic constriction in bronchi from both asthmatic and non-asthmatic subjects. In the presence of the most effective inhibitors (ICI 198,615 and MK886), the response to anti-IgE was depressed by more than 60%. In contrast, the cyclooxygenase inhibitor indomethacin and the antagonist of platelet activating factor (PAF) WEB 2086, failed to alter the response, indicating that prostanoids and PAF do not mediate IgE-dependent constriction of human bronchi. After the leukotriene antagonist ICI 198,615 had rendered the bronchi insensitive to exogenous leukotrienes, the residual component of the contractile response to anti-IgE was completely abolished by addition of antihistamines. Similar abolition of the Schultz-Dale reaction in bronchi of two allergic asthmatic patients was noted when antihistamines were administered together with ICI 198,615 or MK886. In conclusion, the leukotrienes appear to be the major and singularly most important mediators of the contraction, whereas histamine accounts for its minor residual component.