Effect of an inhaled neutral endopeptidase inhibitor, thiorphan, on airway responsiveness to leukotriene D4 in normal and asthmatic subjects

Abstract

Cysteinyl leukotrienes are potent inflammatory mediators that are considered to play a role in the pathophysiology of asthma. It can be postulated that leukotrienes exert their bronchoconstricting effects, in part, through secondary release of endogenous neuropeptides. We examined the effect of inhaled thiorphan, an inhibitor of a neuropeptide degrading enzyme, on the concentration-response curve to leukotriene D4 (LTD4) in a two-period, double-blind, cross-over and placebo-controlled study, in 16 nonasthmatic and 12 asthmatic subjects. Thiorphan or placebo were aerosolized and administered in two 0.5 ml doses of 1.25 mg.ml-1 each, 10 min prior to LTD4 inhalation. The airway response was measured by forced expiratory volume in one second (FEV1) and partial expiratory flow-volume curves (expiratory flow at 40% of forced vital capacity; V40p), and expressed as % fall from baseline. Complete concentration-response curves to inhaled LTD4 were recorded and characterized by their position (provocative concentration producing a 20% fall in FEV1 and a 40% fall in V40p; PC20FEV1 and PC40 V40p) and, in the nonasthmatics, also by the maximal-response plateau (MFEV1, MV40p). Post-pretreatment 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 between the two pretreatments mean difference +/- SD (in doubling concentrations): 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 maximal-response plateau could not be obtained in the majority of the asthmatic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Involvement of endogenous tachykinins in LTD4-induced airway responses

“…However, NK 2 -receptor antagonist, SR 48968, significantly inhibited the LTD 4 -induced RL elevation. These results are in keeping with observations in humans in vivo, showing a slight increase in maximal bronchoconstriction to LTD 4 following pretreatment with an inhibitor (thiorphan) or tachykinin-degrading enzyme, neutral endopeptidase [36]. Because tachykinins have been reported to cause airway smooth muscle contraction via NK 2 -receptors [6,27], the LTD 4 -induced RL elevation observed in the present study seems to be due to the airway smooth muscle contraction rather than airway plasma leakage and subsequent airway wall oedema.…”

The effect of inhaled thiorphan on allergen‐induced airway responses in asthmatic subjects

“…And finally, the present dose and dosing intervals of thiorphan administration were derived from previous observations, as was pointed out in the method section [6.8,18,19,24]. Throughout the allergen challenge, the cumulative dose of thiorphan was twice the dose which has been shown to enhance the bronchoconstrictor response to inhaled neurokinin A in non-asthmatic and mildly asthmatic humans [6,8] and to leukotriene D4 [18] and metabisulfite [19] in nonasthmatics. Since potentiation of the latter two challenges can be considered to be due to the reduced breakdown of endogenous neuropeptides, it seems likely that the present dose of thiorphan would have been sufficient to inhibit the cleavage of neuropeptides that are released secondary to allergen challenge.…”

“…maximal potentiation ofthe bronchoconstrictor response to exogenous NKA in asthmatic subjects [6]. Furthermore, without affecting the airway response to methacholine in asthmatics [6], 1.25 mg of inhaled thiorphan significantly enhanced the maximal response plateau to other pro-inflammatory stimuli, such as inhaled LTD4 [18] and metabisulfite [19] in non-asthmatic humans. Although in a pharmacokinetic study in guineapigs, inhaled thiorphan has been shown to possess a short duration of action (± 5 min) in potentiating the effect to inhaled SP [24], in previous studies in non-asthmatic subjects, we have shown that 1.25 mg of inhaled thiorphan has enhanced the maximum airway narrowing to inhaled NKA or LTD4 for at least ijh [8,18].…”

“…Thiorphan was stored at -20 C and warmed up on melting ice before nebulization. The aerosols were generated using a highly eflieient jet-nebulizer (Mallinckrodt Diagnostics, The Netherlands) [6,8,18]. This nebulizer was filled with 0.5 mL of each concentration, which was sprayed during 1 min by compressed nitrogen into a 30L collapsible drying chamber, in which the droplets (saline mass median aerodynamic diameter (MM AD) 2.5 {.im) quickly evaporate to dry particles (MMAD 0.6/im).…”

“…Subjects characteristics inhibitors might be a useful tool for examining the role of both exogenous and endogenous neuropeptides in asthma. Indeed, in previous human studies, inhaled NEP-inhibitors, such as thiorphan and phosphoramidon, have been shown lo potentiate the bronchoconstrictor response not only to exogenous NKA in nonasthmatic [8] and asthmatic subjects [6], but also to inhaled leukotriene D4 [18] and metabisulfite [19] in non-asthmatic, and to bradykinin in asthmatic individuals [20].…”