NEUTRAL ENDOPEPTIDASE ACTIVITY AND AIRWAY HYPERRESPONSIVENESS TO NEUROKININ-A IN ASTHMATIC SUBJECTS IN-VIVO

In a previous study we have shown that inhibition of the endogenous neuropeptide-degrading enzyme, neutral endopeptidase (NEP), potentiates airway narrowing to neurokinin A (NKA) in normal humans in vivo. In the present study, we tested the hypothesis that hyperresponsiveness to NKA in asthma is caused by a reduction in endogenous NEP activity. To that end, we used the NEP inhibitor, thiorphan, or placebo as inhaled pretreatment to NKA challenge in eight atopic asthmatic men, who were controlled by on-demand usage of beta(2)-agonists alone. The dose of thiorphan pretreatment was obtained from pilot experiments in which 0.5 ml of a 2.5-mg/ml concentration appeared to be the maximally effective nebulized dose. Dose-response curves to inhaled NKA (1 to 125 mu g/ml, 0.5 ml/dose) were recorded on 2 randomized days 1 wk apart, in a cross-over study. To detect any effects of thiorphan on bronchoconstriction per se, we also investigated the effect of thiorphan or placebo on the dose-response curve to inhaled methacholine in a separate set of experiments. The response was measured by FEV(1) and by partial expiratory flow-volume curves (V-40p). The position of the dose-response curves was expressed as the concentration causing a 20% fall in FEV(1) (PC(20)FEV(1)) or a 40% fall in V-40p (PC40V40p). Baseline FEV(1) and V-40p were not affected by either pretreatment (p > 0.06). PC(20)FEV(1) and PC40V40p to NKA were significantly lower after thiorphan pretreatment as compared with placebo (mean difference +/- SEM: 2.3 +/- 0.6 and 1.6 +/- 0.5 doubling dose, respectively; p < 0.015). There was no significant difference in PC(20)FEV(1) or PC40V40p to methacholine between thiorphan and placebo treatment (p > 0.70). We conclude that thiorphan enhances airway narrowing to neurokinin A in asthmatic subjects without affecting bronchoconstriction to methacholine. These results suggest that hyperresponsiveness to NKA in clinically stable asthmatics is not caused by a reduction in endogenous NEP activity.