Tachykinin control of ferret airways: Mucus secretion, bronchoconstriction and receptor mapping

Abstract

The effects of synthetic tachykinin receptor agonists on mucus secretion by ferret trachea was determined in vitro in Ussing chambers using 35SO4 as a mucus marker and the synthetic peptides [Sar9,Met(O2)11]substance P (SarSP), [βAla8]neurokinin A-(4-10) and [MePhe7] neurokinin B which are selective for NK1, NK2 and NK3 tachykinin-receptors respectively. The bronchomotor effects of the same agonists were also studied in vitro and tachykinin receptors were localized by autoradiographic mapping. SarSP was the only synthetic agonist able to elicit a concentration-dependent increase in mucus secretion and was much more potent than SP. The EC50 for SarSP was 1.7 x 10-6 M. Moreover, the maximal increase in release of 35SO4 produced by SarSP 10-5 M was 95% of the increase produced by methacholine 10-4 M indicating that this concentration of SarSP induced a near maximal secretory response. There was no significant difference in the secretory action of SP administered from the luminal or the submucosal side of the tissue. Only the NK2 agonist was able to produce a concentration-dependent contractility of bronchial ring preparations and its effect was relatively weak (EC50 6.4 x 10-6 M). Capsaicin (10-5 M) produced only a slight increase in tracheal mucus secretion (28 ± 5%; n = 6) and was completely ineffective in inducing bronchoconstriction. Binding sites for [125I]-Bolton Hunter SP were more evident than sites for [125I]-NKA on submucosal glands and epithelium. In contrast, only binding sites to NKA could be observed over the smooth muscle. We conclude that in ferret trachea activation of NK1 receptors is able to elicit output of 35SO4-labelled mucins whilst activation of NK2 or NK3 receptors does not. The bronchomotor response seems to be dependent on the activation of NK2 receptors.