EFFECT OF AN INHALED NEUTRAL ENDOPEPTIDASE INHIBITOR, THIORPHAN, ON AIRWAY RESPONSIVENESS TO LEUKOTRIENE-D(4) IN NORMAL AND ASTHMATIC SUBJECTS

Cysteinyl leukotrienes are potent inflammatory mediators that are cons idered to play a role in the pathophysiology of asthma. It can be post ulated that leukotrienes exert their bronchoconstricting effects, in p art, through secondary release of endogenous neuropeptides. We examine d the effect of inhaled thiorphan, an inhibitor of a neuropeptide degr ading enzyme, on the concentration-response curve to leukotriene D4 (L TD4) in a two-period, double-blind, cross-over and placebo-controlled study, in 16 nonasthmatic and 12 asthmatic subjects. Thiorphan or plac ebo were aerosolized and administered in two 0.5 ml doses of 1.25 mg.m l-1 each, 10 min prior to LTD4 inhalation. The airway response was mea sured by forced expiratory volume in one second (FEV1) and partial exp iratory flow-volume curves (expiratory flow at 40 % of forced vital ca pacity; V40p), and expressed as % fall from baseline. Complete concent ration-response curves to inhaled LTD4 were recorded and characterized by their position (provocative concentration producing a 20% fall in FEV, and a 40% fall in V40p; PC20FEV1 and PC40V40p) and, in the nonast hmatics, also by the maximal-response plateau (MFEV1, MV40p). Post-pre treatment baseline values of FEV1 and V40p were not different between thiorphan and placebo pretreatment. In both groups of subjects, there was no significant difference in lnPC40V40p or lnPC20FEV1 to LTD4 betw een the two pretreatments mean difference+/-SD (in doubling concentrat ions): 0.12+/-0.73 and -0.19+/-1.23, respectively, in asthmatics; and 0.17+/-0.95 and -0.99+/-1.95, respectively, in nonasthmatics. The maxi mal-response plateau could not be obtained in the majority of the asth matic subjects. In the normals, however, MV40p was significantly incre ased by thiorphan as compared to placebo pretreatment (mean difference +/-SD: 5.7+/-8.1% fall; p=0.013) whereas the difference in MFEV1 faile d to reach significance (mean difference+/- SD: 2.7+/-5.3% fall). We c onclude that thiorphan slightly potentiates maximal airway narrowing t o inhaled LTD4 in normal humans in vivo, without affecting the sensiti vity to LTD4. These findings suggest that cysteinyl leukotrienes exert their inflammatory effects, at least in part, by the release of endog enous neuropeptides in human airways in vivo.