REPRODUCIBILITY OF AIRWAY RESPONSE TO INHALED BRADYKININ AND EFFECT OF THE NEUROKININ RECEPTOR ANTAGONIST FK-224 IN ASTHMATIC SUBJECTS

Objective: Inhaled neurokinins have been shown to induce bronchoconstr iction in asthmatic subjects. We have investigated the effect of a neu rokinin receptor antagonist, FK-224, on bradykinin (BK)-induced bronch oconstriction, and have compared its effect with the spontaneous varia bility of BK responsiveness. Methods: Thirteen subjects with mild extr insic bronchial asthma participated in the study. Four BK inhalation c hallenge tests (Study Days 2 to 5) were performed over a period of sev eral weeks. On Study Days 4 and 5 subjects inhaled either 2 mg FK-224 or placebo 30 min before the BK challenge. Results: The geometric mean PC(20)FEV(1) of BK was 0.04, 0.06, and 0.10 mg . ml(-1) on the first and second BK challenge and after placebo. Mean PC(20)FEV(1) after FK- 224 was 0.20 mg . ml(-1) and was not different from placebo, whereas t here was a significant effect in PC(15)FEV(1). The mean shift in PC(20 )FEV(1) after FK-224 vs placebo was 1.0 doubling concentrations. The m ean changes in BK responsiveness on the second BK challenge and placeb o days compared to the first BK challenge were 0.6 and 1.3 doubling co ncentrations. We observed a significant fall in FEV(1) after inhalatio n of saline plus ethanol, which was the diluent for BK (mean decrease 4.2%). Conclusion: The data demonstrate that inhalation of 2 mg FK-224 is only marginally effective against BK-induced bronchoconstriction i n mild asthmatic subjects and that its effect is similar to the variab ility in BK responsiveness assessed over several weeks.