Ikemura T, Sasaki Y, Ohmori K
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo, Shizuoka, Japan.
Clin Exp Allergy. 1998 May;28(5):635-43. doi: 10.1046/j.1365-2222.1998.00264.x.
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.
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.
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.
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.
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.
缓激肽（BK）被认为在炎症状态下，如哮喘时，通过激活B2受体在气道中充当介质。NPC-17731（D-Arg0[Hyp3, D-HypE（反式丙基）7, Oic8]BK）对B2受体具有强大的拮抗活性而无激动活性。
我们评估了NPC-17731对豚鼠气道中BK的抑制作用。此外，我们研究了NPC-17731对抗原诱导的气道反应的影响。
以肺阻力（RL）增加和动态顺应性（Cdyn）降低来评估支气管收缩。通过静脉注射伊文思蓝染料的外渗来评估气道血浆渗漏。为了评估药物对抗原诱导反应的影响，豚鼠通过暴露于雾化卵清蛋白（OA）两次进行主动致敏，并通过吸入OA进行激发。在15分钟内测量急性支气管收缩。在激发后10分钟测量气道血管渗漏。在抗原激发后18 - 24小时评估对乙酰胆碱的气道高反应性和支气管肺泡灌洗。
NPC-17731（0.3 - 30微克/千克，静脉注射）以剂量依赖性方式抑制静脉注射BK诱导的支气管收缩。RL的50%抑制剂量（ID50）为1.3微克/千克，Cdyn的为2.8微克/千克。NPC-17731（1 - 10微克/千克，静脉注射）以剂量依赖性方式抑制BK诱导的微血管渗漏（ID50 = 4.2微克/千克）。此外，10微克/千克的NPC-17731消除了吸入BK诱导的支气管收缩。在致敏动物中，100微克/千克NPC-17731显著降低了卵清蛋白暴露诱导的气道微血管渗漏和Cdyn降低（P < 0.05），但不影响RL增加。NPC-17731（100微克/千克）抑制了抗原诱导的气道高反应性和支气管肺泡灌洗中嗜酸性粒细胞的增加。
这些结果表明NPC-17731在体内是一种有效的BK拮抗剂，并且BK可能部分促成豚鼠抗原诱导的气道反应。
