The Effect of an Inhaled Neutral Endopeptidase Inhibitor, Thiorphan, on Airway Responses to Neurokinin A in Normal HumansIn Vivo

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Abstract
Neuropeptides such as neurokinin A (NKA) have been proposed as important mediators of bronchoconstriction and airway hyperresponsiveness in asthma. Inhaled NKA causes bronchoconstriction in patients with asthma, but not in normal subjects. This is possibly due to the activity of an endogenous neuropeptide-degrading enzyme: neutral endopeptidase (NEP). We investigated whether a NEP-inhibitor, thiorphan, reveals bronchoconstriction to NKA or NKA-induced changes in airway responsiveness to methacholine in normal humans in vivo. Eight normal male subjects participated in a double-blind crossover study, using thiorphan as pretreatment to NKA challenge. Dose-response curves to inhaled NKA (8 to 1,000 µg/ml, 0.5 ml/dose) were recorded on 2 randomized days 1 wk apart, and methacholine tests were performed 48 h before and 24 h after the NKA challenge. Ten minutes prior to NKA challenge the subjects inhaled either thiorphan (2.5 mg/ml, 0.5 ml) or placebo. To detect a possible nonspecific effect of thiorphan, we investigated the effect of the same pretreatment with thiorphan or placebo on the dose-response curve to methacholine in a separate set of experiments. The response was measured by the flow from standardized partial expiratory flow-volume curves ( 40p), expressed in percent fall from baseline. NKA log dose-response curves were analyzed using the area under the curve (AUC) and the response to the highest dose of 1,000 µg/ml ( 40p, 1000). The methacholine dose-response curves were characterized by their position (PC40 40p) and the maximal-response plateau (M 40p). Baseline 40p was not affected by either pretreatment (p > 0.15). Both the AUC and 40p, 1000 to NKA were significantly greater after pretreatment with thiorphan than after placebo (p < 0.015). There was no change in PC40 40p or M 40p to methacholine 24 h after NKA as compared with 48 h before, using either pretreatment (p > 0.065). Nor was there a change in PC40 40p or M 40p to methacholine after pretreatment with thiorphan as compared with placebo (p > 0.30). We conclude that inhaled thiorphan enhances bronchoconstriction to NKA in nonasthmatic subjects, without affecting methacholine-induced bronchoconstriction or disclosing NKA-induced changes in airway responsiveness to methacholine. These results suggest that endogenous neutral endopeptidase degrades bronchoconstrictive neuropeptides in the airways of normal humans in vivo.