The potential role of bradykinin antagonists in the treatment of asthma.

The potential role of bradykinin and the use of bradykinin antagonists in the treatment of allergic airway disease (asthma) was studied by determining the effects of the bradykinin B2 receptor antagonist, NPC-567 (D-Arg-[Hyp3,D-Phe7]-bradykinin) on antigen-induced early and late bronchial responses, airway inflammation, mediator release and airway hyperresponsiveness in the sheep model of allergic asthma. In the control trial, antigen challenge produced an early bronchoconstrictor response that was associated with an increase in immunoreactive-kinins in bronchoalveolar lavage fluid (BAL), and a late bronchial response that was associated with increased concentrations of leukotriene [LT]B4 and LTC4 and inflammatory cells (neutrophils and eosinophils) in the BAL. Aerosol NPC-567 given before, during and 4 h after antigen challenge had no protective effect on the early bronchoconstrictor response, but significantly inhibited the late bronchial response. This inhibition was correlated with a reduction in the inflammatory lipid mediators and inflammatory cells in BAL. These results suggest that antigen-induced kinin generation may be important for controlling the release of arachidonic acid metabolites from inflammatory cells that contribute to the development of late responses and airway hyperresponsiveness.