Crimi N, Polosa R, Pulvirenti G, Magrì S, Santonocito G, Prosperini G, Mastruzzo C, Mistretta A
Istituto Malattie Apparato Respiratorio, Università di Catania, Italy.
Thorax. 1995 May;50(5):505-10. doi: 10.1136/thx.50.5.505.
Bradykinin is a potent vasoactive peptide which has been proposed as an important inflammatory mediator in asthma since it provokes potent bronchoconstriction in asthmatic subjects. Little is known at present about the potential role of lung peptidases in modulating bradykinin-induced airway dysfunction in vivo in man. The change in bronchial reactivity to bradykinin was therefore investigated after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double blind, placebo controlled, randomised study of 10 asthmatic subjects.
Subjects attended on six separate occasions at the same time of day during which concentration-response studies with inhaled bradykinin and histamine were carried out, without treatment and after each test drug. Subjects received nebulised phosphoramidon sodium salt (10(-5) M, 3 ml) or matched placebo for 5-7 minutes using an Inspiron Mini-neb nebuliser 5 minutes before the bronchoprovocation test with bradykinin or histamine. Agonists were administered in increasing concentrations as an aerosol generated from a starting volume of 3 ml in a nebuliser driven by compressed air at 8 1/min. Changes in airway calibre were measured as forced expiratory volume in one second (FEV1) and responsiveness as the provocative concentration causing a 20% fall in FEV1 (PC20).
Phosphoramidon administration caused a transient fall in FEV1 from baseline, FEV1 values decreasing 6.3% and 5.3% on the bradykinin and histamine study days, respectively. When compared with placebo, phosphoramidon elicited a small enhancement of the airways response to bradykinin, the geometric mean PC20 value (range) decreasing from 0.281 (0.015-5.575) to 0.136 (0.006-2.061) mg/ml. In contrast, NEP blockade failed to alter the airways response to a subsequent inhalation with histamine, the geometric mean (range) PC20 histamine value of 1.65 (0.17-10.52) mg/ml after placebo being no different from that of 1.58 (0.09-15.21) mg/ml obtained after phosphoramidon.
The small increase in bronchial reactivity to bradykinin after phosphoramidon exposure suggests that endogenous airway NEP may play a modulatory role in the airways response to inflammatory peptides in human asthma.
缓激肽是一种强效血管活性肽，由于它能在哮喘患者中引发强烈的支气管收缩，因此被认为是哮喘中一种重要的炎症介质。目前对于肺肽酶在体内调节缓激肽诱导的气道功能障碍中的潜在作用知之甚少。因此，在一项对10名哮喘患者进行的双盲、安慰剂对照、随机研究中，研究了吸入磷酰胺（一种强效中性内肽酶（NEP）抑制剂）治疗后支气管对缓激肽反应性的变化。
受试者在一天中的同一时间分六次就诊，期间进行了吸入缓激肽和组胺的浓度 - 反应研究，分别在未治疗时以及每次使用测试药物后进行。在使用缓激肽或组胺进行支气管激发试验前5分钟，受试者使用Inspiron Mini - neb雾化器雾化吸入磷酰胺钠盐（10⁻⁵ M，3 ml）或匹配的安慰剂5 - 7分钟。激动剂以递增浓度作为由压缩空气以8 l/min驱动的雾化器中从3 ml起始体积产生的气雾剂给药。气道口径变化以一秒用力呼气量（FEV1）测量，反应性以导致FEV1下降20%的激发浓度（PC20）测量。
给予磷酰胺后，FEV1从基线短暂下降，在缓激肽和组胺研究日，FEV1值分别下降6.3%和5.3%。与安慰剂相比，磷酰胺引起气道对缓激肽反应的小幅增强，几何平均PC20值（范围）从0.281（0.015 - 5.575）降至0.136（0.006 - 2.061）mg/ml。相比之下，NEP阻断未能改变气道对随后吸入组胺的反应，安慰剂后组胺的几何平均（范围）PC20值为1.65（0.17 - 10.52）mg/ml，与磷酰胺后获得的1.58（0.09 - 15.21）mg/ml无差异。
暴露于磷酰胺后支气管对缓激肽反应性的小幅增加表明内源性气道NEP可能在人类哮喘气道对炎症肽的反应中起调节作用。
