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 activation of B2-receptors. NPC-17731 (D-Arg0[Hyp3, D-HypE(trans-propyl)7, Oic8]BK) has potent antagonistic activity against B2-receptors without agonistic activity.


OBJECTIVE
We have evaluated the inhibitory effect of NPC-17731 against BK in guinea-pig airways. In addition, we have investigated the effects of NPC-17731 on antigen-induced airway responses.


METHODS
Bronchoconstriction was assessed as an increase in lung resistance (RL) and a decrease in dynamic compliance (Cdyn). Airway plasma leakage was assessed by extravasation of intravenously injected Evans blue dye. To estimate the effect of drugs on antigen-induced reactions, guinea-pigs were actively sensitized by exposure to aerosol ovalbumin (OA) twice and challenged by OA inhalation. Acute bronchoconstriction was measured for 15 min. Airway vascular leakage was measured at 10 min after the challenge. Assessment of airway hyperresponsiveness against acetylcholine and bronchoalveolar lavage were conducted at 18-24 h after the antigen-challenge.


RESULTS
NPC-17731 (0.3-30 microg/kg, i.v.) inhibited intravenously applied BK-induced bronchoconstriction in a dose-dependent manner. The 50% inhibitory doses (ID50) were 1.3 microg/kg for RL and 2.8 microg/kg for Cdyn. NPC-17731 (1-10 microg/kg, i.v.) inhibited BK-induced microvascular leakage in a dose-dependent manner (ID50 = 4.2 microg/kg). In addition, 10 microg/kg of NPC-17731 abolished the inhaled BK-induced bronchoconstriction. In the sensitized animals, 100 microg/kg NPC-17731 significantly reduced the airway microvascular leakage and the decrease in Cdyn induced by ovalbumin exposure (P < 0.05), but did not influence the increase in RL. NPC-17731 (100 microg/kg) inhibited the antigen-induced airway hyperresponsiveness and the increase in eosinophils in BAL fluids.


CONCLUSIONS
These results indicate that NPC-17731 is a potent BK antagonist in vivo and that BK may partially contribute to the antigen-induced airway responses in guinea-pigs.
Ikemura
T
T
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo, Shizuoka, Japan.
Sasaki
Y
Y
Ohmori
K
K
D000403:Airway Resistance / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D001920:Bradykinin / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D001980:Bronchi / Q000098:blood supply; D016535:Bronchial Hyperreactivity / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology; D013997:Time Factors
D009842:Oligopeptides; C071327:NPC 17731; D010047:Ovalbumin; D001920:Bradykinin