Effect of the long‐acting tachykinin NK₁ receptor antagonist MEN 11467 on tracheal mucus secretion in allergic ferrets

Abstract

We investigated the effect of MEN 11467 ((1R,2S)‐2‐N[1(H)indol‐3‐yl‐carbonyl]‐1‐N‐{Nα(p‐tolylacetyl)‐Nα(methyl)‐D‐3‐(2‐naphthyl)alanyl}diaminocyclohexane) on tachykinin‐induced mucus secretion in ferret trachea in vitro and determined its effect on secretion by tracheae from allergic ferrets in response to allergen challenge. Repeated administration of [Sar9,Met(O2)11]‐substance P ([Sar9]SP, 1 μM) maintained mucus output above control values for at least 1.75 h. MEN 11467 inhibited secretion in a concentration‐dependent manner with maximal inhibition at 10 μM and an approximate IC50 of 0.3 μM. Inhibition by MEN 11467 (0.1 – 10 μM) was maintained, to varying degree, for at least 1.75 h after washout in the continued presence of [Sar9]SP. In electrically stimulated tracheae, tachykininergic neural secretion was virtually abolished by 1 μM MEN 11467. In tracheae from ovalbumin‐sensitised animals, repeated administration of ovalbumin maintained mucus output above controls for 1.5 h. MEN 11467 inhibited ovalbumin‐induced secretion in a concentration‐dependent manner, with complete inhibition at 1 μM. Inhibition by MEN 11467 (1 and 10 μM) was maintained, to varying degree, after drug washout for the 1.5 h of ovalbumin stimulation. MEN 11467 1 μM did not affect secretion induced by either acetylcholine or histamine, whereas 10 μM MEN 11467 did inhibit agonist‐induced secretion. We conclude that, in ferret trachea in vitro, MEN 11467 at concentrations of 0.1 – 1 μM is a long acting and selective inhibitor of tachykininergic‐induced mucus secretion, and may have therapeutic potential for bronchial hypersecretion associated with allergic conditions, for example in asthma. British Journal of Pharmacology (2001) 132, 189–196; doi:

The role of the tachykinin NK1 receptor in airway changes in a mouse model of allergic asthma

“…Further evidence for this hypothesis is provided by their work demonstrating increased expression of substance P and its receptor in asthmatics, which was correlated with the mucus content in the airway epithelium. 43 In conclusion, the tachykinin NK 1 receptor is involved in the secretory response of goblet cells, [44][45][46][47][48] and we provide evidence for an involvement of this receptor in proliferation of these cells induced by antigen.…”

Tachykinin NK3 and NK1 receptor activation elicits secretion from porcine airway submucosal glands

“…We also showed by using the hillocks technique that SP is a potent airway submucosal gland secretagogue confirming reports using the same technique in pig (Haxhiu et al ., 1990) and other techniques in different species such as human (Rogers et al ., 1989), dog (Haxhiu et al ., 1988), ferret (Khan et al ., 2001), rat (Wagner et al ., 1999), and also in pig (Trout et al ., 2001) airways. The concentration of SP (1 μ M ) is commonly used in many studies of gland secretion (Rogers et al ., 1989; Haxhiu et al ., 1990; Wagner et al ., 1999; Trout et al ., 2001).…”

Current Animal Models of Bronchial Asthma

“…For example, it has been demonstrated that chronic inhalation of nicotine induces a shift from serous to mucous glands in the airways of ferrets [227]. More recently Khan et al, [228] has demonstrated that in the tracheae of ovalbumin sensitized animals repeated administration of ovalbumin continued to maintain mucus output above controls. In spite of these favorable features however the recent increase in the use of the ferret in asthma-related research resulted from another characteristic of this animal.…”