Effect of non-peptide tachykinin NK1 receptor antagonists on non-adrenergic, non-cholinergic neurogenic mucus secretion in ferret trachea

We investigated, in ferret trachea in vitro, the binding characteristics and the inhibition of non-adrenergic, non-cholinergic (NANC) neural mucus secretion of four tachykinin receptor antagonists: the non-peptide tachykinin NK1 receptor antagonists CGP 49823 ((2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-(quinolin-mu-ylmethl amino) piperidine) and CGP 55000 ((2R,4S)-2-benzyl-1-(3,5-bistrifluoromethyl-benzoyl)-4-(quinolinyl-methylamino)piperidine) and CP 99,994 ((+)-(2S,3S)-3-methoxybenzyl amino)-2-phenylpiperidine), and the peptide tachykinin NK2 receptor antagonist MEN 10,627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta)). CGP 49823, CGP 55000 and CP 99,994 concentration-dependently displaced [I-125]Bolton-Hunter substance P binding in tracheal membranes with Hill coefficients not different from unity and IC50 values of 1.4, 1.7 and 1.3 nM, respectively. In contrast, MEN 10,627 displaced binding according to a two-site model, with IC(50)s of 0.2 nM and 1.3 mu M. Electrical stimulation of tracheal segments with adrenoceptor and cholinoceptor blockade increased output of the mucus marker (SO4)-S-35 by 59% above baseline (representing the NANC neural secretory response). CGP 49823, CGP 55000 or CP 99,994 concentration-dependently inhibited NANC neural secretion with IC50 values of 30, 8 and 120 nM, respectively. In contrast, MEN 10,627 (3 mu M) did not inhibit secretion. The NK1 antagonists, but not the NK2 antagonist, inhibited [Sar(9)]substance P-induced secretion, while none of the antagonists affected acetylcholine-induced secretion. We conclude that NANC neural secretion in ferret trachea in vitro is a useful test system for tachykinin NK1 receptor antagonists with therapeutic potential in conditions of the airways in which tachykininergic mechanisms and mucus hypersecretion are implicated in pathophysiology, for example asthma and chronic bronchitis. (C) 1999 Elsevier Science B.V. All rights reserved.