SENSORY-EFFERENT NEURAL CONTROL OF MUCUS SECRETION - CHARACTERIZATIONUSING TACHYKININ RECEPTOR ANTAGONISTS IN FERRET TRACHEA IN-VITRO

1 We characterized the tachykinin receptor(s) mediating 'sensory-effer ent' neural control of release of (SO4)-S-35-labelled macromolecules ( mucus) from ferret trachea in vitro in Ussing chambers using selective tachykinin antagonists. Secretion was induced by substance P (SP), ne urokinin A (NKA), capsaicin, the NK1 tachykinin receptor agonist [Sar( 9), Met(O-2)(11)]substance P ([Sar(9)]SP), or acetylcholine (ACh), or by electrical stimulation of nerves. Antagonists used were FK888 and L -668,169, selective for the NK1 receptor, SR 48968, selective for the NK2 receptor, and FK224, a dual antagonist at NK1 and NK2 receptors. T he selectivity of FK888 and SR 48968 was examined on NKA-induced contr action of ferret tracheal smooth muscle in vitro. 2 SP (1 mu M) increa sed mucus secretion by 695% above vehicle controls. FK888(0.1 mu M-30 mu M) inhibited SP-induced secretion in a dose-dependent manner, with complete inhibition at 10 mu M and an IC50 of 1 mu M L-668,169 (1 mu M ) also completely inhibited SP-induced secretion. 3 NKA (1 mu M) signi ficantly increased mucus secretion by 271% above baseline, a response which was completely inhibited by FK888 (10 mu M) or L-668,169 (mu M). Secretion induced by ACh (10 mu M: 317% above baseline) was not inhib ited by FK888 but was inhibited by atropine. Capsaicin (10 mu M)-induc ed secretion (456% above vehicle controls) was significantly inhibited by FK888 and by L-668,169 (111% and 103% inhibition respectively). 4 Electrical stimulation (50 V, 10 Hz, 0.5 ms, 5 min) increased mucus ou tput above baseline (increased by 12 to 26 fold), a response blocked b y tetrodotoxin (0.1 mu M). FK888 (10 mu M) inhibited the increase in s ecretion due to electrical stimulation by 47%. Atropine, propranolol a nd phentolamine in combination (APP) inhibited the response to electri cal stimulation by 48%. The remaining NANC response, i.e. in the prese nce of APP, was further reduced by 66% with FK888. FK224 (10 mu M) inh ibited neurally-evoked secretion by 73%. SR 48968 (0.1 mu M) had no ef fect on electrically-stimulated or [Sar(9)]SP-induced secretion. 5 NKA (10 nM-10 mu M: in the presence of DMSO control vehicle) induced trac heal smooth muscle contraction in a concentration-dependent manner wit h a maximal contraction of 30% of the maximal response to ACh (10 mM) and an EC(50) Of 0.3 mu M, SR 48968 (O.1 mu M in DMSO) inhibited the N KA-induced contraction whereas FK888 did not. Neither antagonist had a ny inhibitory effect on ACh-induced contraction. 6 We conclude that 's ensory-efferent' neurogenic mucus secretion in ferret trachea in vitro is mediated via tachykinin NK1 receptors with no involvement of NK2 r eceptors. Potent and selective tachykinin antagonists may have therape utic potential in bronchial diseases such as asthma and chronic bronch itis in which neurogenic mucus hypersecretion may be aetiologically im portant.