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 bronchoconstriction in asthmatic subjects. We have investigated the effect of a neurokinin receptor antagonist, FK-224, on bradykinin (BK)-induced bronchoconstriction, and have compared its effect with the spontaneous variability of BK responsiveness. Methods: Thirteen subjects with mild extrinsic bronchial asthma participated in the study. Four BK inhalation challenge tests (Study Days 2 to 5) were performed over a period of several 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 there 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 mean changes in BK responsiveness on the second BK challenge and placebo days compared to the first BK challenge were 0.6 and 1.3 doubling concentrations. We observed a significant fall in FEV(1) after inhalation 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 in mild asthmatic subjects and that its effect is similar to the variability in BK responsiveness assessed over several weeks.