CROSS-TACHYPHYLACTIC AIRWAY RESPONSE TO INHALED BRADYKININ, KALLIDIN AND [DESARG9]-BRADYKININ IN ASTHMATIC SUBJECTS

Kinins are oligopeptides that may act as mediators in the pathogenesis of bronchial asthma by interacting with specific cell surface recepto rs designated B1 and B2. When administered by inhalation to asthmatic subjects, bradykinin and kallidin, but not [desArg9]-bradykinin, provo ke potent bronchoconstriction, thus suggesting a specific effect compa tible with the stimulation of B2 receptors. To characterize further th e receptor(s) mediating this bronchospastic response we have carried o ut cross-tachyphylactic studies with inhaled bradykinin, kallidin, and [desArg9]-bradykinin, administered in a randomized double-blind fashi on in a group of 10 asthmatic subjects. Inhalation of bradykinin and k allidin, but not [desArg9]-bradykinin, elicited concentration-related falls in forced expiratory volume in one second (FEV1) in all the subj ects studied. The geometric mean provocation concentrations of inhaled agonists reducing FEV1 by 20% of baseline (PC20) were 0.12 and 0.28 m g.ml-1 for bradykinin and kallidin, respectively. When inhaled at conc entrations up to 10.62 mg.ml-1, [desArg9]-bradykinin failed to provoke any significant fall in FEV1 from baseline in any of the subjects stu died. Following recovery from the second bradykinin challenge, provoca tion with kallidin revealed a reduced response to this agonist, the PC 20 value increasing from 0.28 to 1.23 mg.ml-1. Similarly, once the air ways had recovered from the second kallidin challenge, provocation wit h bradykinin also showed a reduced response, the PC20Bk increasing fro m 0.12 to 0.94 mg-ml-1. Surprisingly, despite failing to cause broncho constriction, repeated exposures with inhaled [desArg9]-bradykinin red uced the airway response to bradykinin, the PC20Bk increasing from 0.1 2 to 0.41 mg.ml-1. The airway response to inhaled histamine was not si gnificantly changed after bronchial provocation with any of the kinins tested. These findings suggest a complex action of kinins on asthmati c airways, probably involving more than one receptor subtype.