Effect of the long-acting tachykinin NK(1) receptor antagonist MEN 11467 on tracheal mucus secretion in allergic ferrets.
1. We investigated the effect of MEN 11467 ((1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N-[N(alpha)(p-tolylacetyl)-N(alpha)(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. 2. Repeated administration of [Sar(9),Met(O(2))(11)]-substance P ([Sar(9)]SP, 1 microM) 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 microM and an approximate IC(50) of 0.3 microM. Inhibition by MEN 11467 (0.1--10 microM) was maintained, to varying degree, for at least 1.75 h after washout in the continued presence of [Sar(9)]SP. 3. In electrically stimulated tracheae, tachykininergic neural secretion was virtually abolished by 1 microM MEN 11467. 4. 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 microM. Inhibition by MEN 11467 (1 and 10 microM) was maintained, to varying degree, after drug washout for the 1.5 h of ovalbumin stimulation. 5. MEN 11467 1 microM did not affect secretion induced by either acetylcholine or histamine, whereas 10 microM MEN 11467 did inhibit agonist-induced secretion. 6. We conclude that, in ferret trachea in vitro, MEN 11467 at concentrations of 0.1--1 microM 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.
Khan
S
S
Thoracic Medicine, National Heart & Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY.
Liu
Y C
YC
Khawaja
A M
AM
Manzini
S
S
Rogers
D F
DF
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects; D003514:Cyclohexylamines / Q000494:pharmacology*; D004558:Electric Stimulation; D005289:Ferrets; D006632:Histamine / Q000494:pharmacology; D006967:Hypersensitivity / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009093:Mucus / Q000378:metabolism*; D064729:Neurokinin-1 Receptor Antagonists; D010047:Ovalbumin / Q000276:immunology; D018040:Receptors, Neurokinin-1 / Q000819:agonists; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology; D013462:Sulfur Radioisotopes; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*
D003514:Cyclohexylamines; D007211:Indoles; C121095:MEN 11467; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D013462:Sulfur Radioisotopes; C062618:substance P, Sar(9)-Met(O2)(11)-; D013373:Substance P; D006632:Histamine; D010047:Ovalbumin; D000109:Acetylcholine