THE EFFECT OF COMPOUND 48/80 ON CONTRACTIONS INDUCED BY TOLUENE DIISOCYANATE IN ISOLATED GUINEA-PIG BRONCHUS

We have investigated the ability of compound 48 80 and of histamine H1 and H2 receptor antagonists to inhibit toluene diisocyanate-induced contractions in isolated guinea-pig bronchi. Compound 48 80 (100 μg/ml) significantly inhibited toluene diisocyanate-induced contractions. By contrast, the two histamine H1 and H2 receptor antagonists, chlorpheniramine (10 μM) and cimetidine, (10 μM) did not affect toluene diisocyanate-induced contractions, but significantly inhibited contractions induced by exogenously applied histamine (100 μM) and by 48 80. We investigated which mechanisms 48 80 used to inhibit toluene diisocyanate-induced contractions, paying particular attention to the possible involvement of capsaicin-sensitive primary afferents. In vitro capsaicin desensitization (10 μM for 30 min followed by washing) significantly reduced compound 48 80-induced contractions. A capsaicin-resistant component of contraction was also evident. Ruthenium red (3 μM), an inorganic dye which acts as a selective functional antagonist of capsaicin, did not affect 48 80-induced contraction. MEN 10,207 (Tyr5, D-Trp6,8,9,Arg10)-neurokinin A A (4-10) (3 μM) a selective antagonist of NK2-tachykinin receptors significantly reduced 48 80-induced contractions. These results show that compound 48 80 inhibits toluene diisocyanate-induced contractions in isolated guinea-pig bronchi. It is likely that two mechanisms are involved in the inhibition: (1) the release of mediators other than histamine by mast cells, (2) an effect of 48 80 on sensory nerves. © 1993.