1. We examined effects of
bradykinin (BK) receptor antagonists on
airway hyperresponsiveness and
eosinophilia in sensitized guinea-pigs that had been administered single, as well as repeated (chronic) challenges with inhaled
ovalbumin. In addition, the effects of BK antagonists on
antigen-induced respiratory distress during the chronic study were noted. 2. At 24 h following single
antigen challenge, guinea-pigs exhibited
airway hyperresponsiveness to the
bronchoconstrictor effect of i.v.
histamine, characterized by a left shift in the dose-response curve. In addition, responses to the maximum dose of
histamine that could be used were significantly increased in hyperresponsive guinea-pigs. The percentages of bronchoalveolar fluid, eosinophil and neutrophils also increased. 3. A BK B1 receptor antagonist, desArg9-[Leu8]-BK, significantly inhibited
airway hyperresponsiveness induced by single
antigen challenge. A B2 receptor antagonist, D-Arg-[Hyp3, Thi5,8,D-Phe7]-BK (
NPC 349) had a small, but statistically significant inhibitory effect on responsiveness to the highest
histamine dose in challenged animals. DesArg9-[Leu8]-BK significantly inhibited the neutrophilia, whereas
NPC 349 inhibited infiltration by both cell types. 4. Chronic
antigen challenge also caused
airway hyperresponsiveness to i.v.
acetylcholine (ACh), distinguished by an increase in the slope of the dose-response curve. Thus, the magnitude of the bronchoconstrictor responses to the maximum dose of ACh that could be used was significantly increased. No change in sensitivity to ACh was evident. Marked
eosinophilia was also noted in the trachea, bronchi and lung parenchyma. 5.
Airway hyperresponsiveness and
eosinophilia, induced by chronic
antigen challenge, were markedly inhibited by the B2 antagonists, D-Arg-[Hyp3,D-Phe7]-BK (
NPC 567) or D-Arg-[Hyp3,Thi5d-Tic7,Tic8]-BK (
NPC 16731).
NPC 16731 also abolished
antigen-induced
cyanosis, and delayed the onset of dyspnoea,doubling the time taken for animals to exhibit respiratory distress.6. The ability of BK receptor antagonists to inhibit
antigen-induced
airway hyperresponsiveness, in addition to
eosinophilia, indicates an important role for endogenous
kinins. Moreover, the abrogation of eosinophil infiltration suggests that BK has a significant function in maintaining allergic
inflammation of the airways.