EFFECT OF AN INHALED NEUTRAL ENDOPEPTIDASE INHIBITOR, PHOSPHORAMIDON,ON BASE-LINE AIRWAY CALIBER AND BRONCHIAL RESPONSIVENESS TO BRADYKININ IN ASTHMA

Background - Bradykinin is a potent vasoactive peptide which has been proposed as an important inflammatory mediator in asthma since it prov okes potent bronchoconstriction in asthmatic subjects. Little is known at present about the potential role of lung peptidases in modulating bradykinin-induced airway dysfunction in vive in man. The change in br onchial reactivity to bradykinin was therefore investigated after trea tment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP ) inhibitor, in a double blind, placebo controlled, randomised study o f 10 asthmatic subjects. Methods - Subjects attended on six separate o ccasions at the same time of day during which concentration-response s tudies with inhaled bradykinin and histamine were carried out, without treatment and after each test drug. Subjects received nebulised phosp horamidon sodium salt (10(-5) M, 3 ml) or matched placebo for 5-7 minu tes using an Inspiron Mini-neb nebuliser 5 minutes before the bronchop rovocation test with bradykinin or histamine. Agonists were administer ed in increasing concentrations as an aerosol generated from a startin g volume of 3 ml in a nebuliser driven by compressed air at 8 l/min. C hanges in airway calibre were measured as forced expiratory volume in one second (FEV(1)) and responsiveness as the provocative concentratio n causing a 20% fall in FEV(1) (PC20). Results - Phosphoramidon admini stration caused a transient fall in FEV(1) from baseline, FEV(1) value s decreasing 6.3% and 5.3% on the bradykinin and histamine study days, respectively. When compared with placebo, phosphoramidon elicited a s mall 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 airw ays response to a subsequent inhalation with histamine, the geometric mean (range) PC20 histamine value of 1.65 (0.17-10.52) mg/ml after pla cebo being no different from that of 1.58 (0.09-15.21) mg/ml mi obtain ed after phosphoramidon. Conclusions - The small increase in bronchial reactivity to bradykinin after phosphoramidon exposure suggests that endogenous airway NEP may play a modulatory role in the airways respon se to inflammatory peptides in human asthma.