Airway neural responses to kinins: tachyphylaxis and role of receptor subtypes

To further define the role of neural responses in the hyperreactivity of inflamed human upper airways to bradykinin (BK), we determined if repeated challenges with BK led to tachyphylaxis of neurally mediated responses in subjects with perennial allergic rhinitis. We also tested the hypothesis that enhanced reactivity to kinins in inflamed airways was caused by induction of B1-kinin receptors by comparing the effects of the selective B1-receptor agonist, des-Arg10-lysylbradykinin, and the B2 receptor agonist, BK, in the lower airways of asthmatics and in the upper airways of subjects with perennial allergic rhinitis. Repeated BK challenges led to tachyphylaxis of sneezing and of neurally mediated serous glandular secretion in subjects with perennial allergic rhinitis. Surprisingly, tachyphylaxis of increased local vascular permeability was also observed. By contrast, repeated challenges with BK in normal subjects led to reproducible increases in vascular permeability. Provocation with des-Arg10-lysylbradykinin did not cause bronchoconstriction in asthmatic subjects or increase glandular secretion or vascular permeability in the upper airways of subjects with rhinitis. We conclude that increased reactivity to kinins in inflamed human airways is mediated, at least in part, by neural reflexes, and is not caused by induction of B1-receptors.