INHIBITORY EFFECT OF NPC-17731 ON BK-INDUCED AND ANTIGEN-INDUCED AIRWAY REACTIONS IN GUINEA-PIGS

Background Bradykinin (BK) has been suggested to act as a mediator in the airways in inflammatory conditions, such as asthma through the act ivation of B-2-receptors. NPC-17731 (D-Arg(0)[Hyp(3) D-HypE(trans-prop yl)(7), Oic(8)]BK) has potent antagonistic activity against Bz-recepto rs without agonistic activity. Objective We have evaluated the inhibit ory effect of NPC-17731 against BK in guineapig airways. In addition, we have investigated the effects of NPC-17731 on antigen-induced airwa y responses. Methods Bronchoconstriction was assessed as an increase i n lung resistance (R-L) and a decrease in dynamic compliance (C-dyn) A irway plasma leakage was assessed by extravasation of intravenously in jected Evans blue dye. To estimate the effect of drugs on antigen-indu ced reactions, guinea-pigs were actively sensitized by exposure to aer osol ovalbumin (OA) twice and challenged by OA inhalation. Acute bronc hoconstriction was measured for 15 min. Airway vascular leakage was me asured at 10 min after the challenge. Assessment of airway hyperrespon siveness against acetylcholine and bronchoalveolar lavage were conduct ed at 18-24 h after the antigen-challenge. Results NPC-17731 (0.3-30 m u g/kg, iv) inhibited intravenously applied BK-induced bronchoconstric tion in a dose-dependent manner. The 50% inhibitory doses (ID50) were 1.3 mu g/kg for R-L and 2.8 mu g/kg for C-dyn. NPC-17731 (1-10 mu g/kg , iv) inhibited BK-induced microvascular leakage in a dose-dependent m anner (ID50 = 4.2 mu g/kg). In addition, 10 mu g/kg of NPC-17731 aboli shed the inhaled BK-induced bronchoconstriction. In the sensitized ani mals, 100 mu g/kg NPC-17731 significantly reduced the airway microvasc ular leakage and the decrease in C-dyn induced by ovalbumin exposure ( P<0.05), but did not influence the increase in R-L. NPC-17731 (100 mu g/kg) inhibited the antigen-induced airway hyperresponsiveness and the increase in eosinophils in BAL fluids. Conclusion These results indic ate that NPC-17731 is a potent BK antagonist in vivo and that BK may p artially contribute to the antigen-induced airway responses in guinea- pigs.