The effects of a novel sulphidopeptide leukotriene antagonist, BAY x7195, against elicited bronchoconstriction in the anaesthetized guinea‐pig

The novel leukotriene antagonist Bay  x7195, has been evaluated against bronchoconstriction induced by leukotriene D4 (LTD4), the thromboxane A2 (TXA2) mimetic U46619, histamine and antigen, in the guinea-pig in vivo by use of a modified Konzett-Rossler preparation. LTD4, given intravenously (i.v.) at 1 or 3 μg kg−1 in the presence of indomethacin and sotalol, caused a 50–70% maximal bronchoconstriction in most animals. BAY x7195, given i.v., orally (p.o.), by aerosol or dry powder insufflation, in lactose, reduced LTD4-induced bronchoconstriction dose-dependently. The approximate ID50 values were 83 μg kg−1, 3 mg kg−1, 0.0003 % w/v for 20 breaths and 20 μg respectively. The action of BAY x7195 (10 mg kg−1, p.o.) was long lasting, causing significant inhibition of the LTD4-induced response (88% reduction) 8 h after dosing. When given intravenously, in the presence of selected antagonists, BAY x7195 caused a dose-related reduction in the antigen-induced response, with an approximate ID50 of 2 mg kg−1. At 3 mg kg−1, i.v., a dose which abolished the response to LTD4, BAY x7195 had no effect on U46619- or histamine-induced bronchoconstriction. BAY x7195 is a potent, selective and long acting antagonist of LTD4-induced bronchoconstriction, in an anaesthetized, ventilated guinea-pig model. It is therefore worthy of clinical evaluation in diseases believed to involve the sulphidopeptide leukotrienes, such as asthma. British Journal of Pharmacology (1998) 123, 39–44; doi:10.1038/sj.bjp.0701580