Endothelin-1 inhibits pre-stimulated tracheal submucosal gland secretion and epithelial albumin transport.

1. Endothelin-1 potently contracts smooth muscle, including that in the airways. However, its effect on airway mucosal function has not so far been studied. 2. We have used the ferret whole trachea in vitro to examine the effect of endothelin-1 on tracheal smooth muscle tone, transepithelial potential difference (p.d.), submucosal gland secretion (including lysozyme secretion from serous cells) and active epithelial albumin transport. In addition we have examined the effects of endothelin on submucosal gland secretion and albumin transport pre-stimulated with the muscarinic agonist methacholine and the alpha-adrenoceptor agonist phenylephrine. The effects of the Ca2+ channel blocker nifedipine on the responses to endothelin have also been assessed. 3. Endothelin (0.1-100 nM) produced concentration-dependent increases in intraluminal tracheal pressure indicating smooth muscle contraction, and in the negativity of the transepithelial p.d. These effects were partially inhibited by nifedipine (10 microM). 4. Endothelin (0.01-100 nM) had no significant effect on baseline rates of mucus, lysozyme or albumin outputs, but produced concentration-dependent reductions in maintained methacholine- and phenylephrine-induced mucus, lysozyme and albumin outputs. In general endothelin was more potent against methacholine-induced effects. All of the concentration-response curves for endothelin were shallow and some appeared to be biphasic, suggesting the possibility of more than one mechanism of action of endothelin. 5. The effects of endothelin (at concentrations greater than 1 nM) on phenylephrine-induced mucus volume, lysozyme and albumin outputs were significantly inhibited by nifedipine. Similarly the effect of endothelin (greater than 1 nM) on methacholine-induced mucus volume and albumin outputs (but not lysozyme output) was attenuated by nifedipine. Similarly the effect of endothelin (>1 nM) on methacholine-induced mucus volume and albumin outputs (but not lysozyme output) was attenuated by nifedipine. The effects of endothelin (at concentrations <1 nM) on methacholine and phenylephrine-induced responses were generally not affected by nifedipine.6. Thus, endothelin contracts ferret tracheal smooth muscle and increases transepithelial p.d. at least in part by opening dihydropyridine-sensitive Ca2+ channels. Endothelin does not directly stimulate submucosal gland secretion or epithelial albumin transport, but inhibits methacholine- and phenylephrineinduced secretion and transport. The inhibitory effects produced by higher concentrations of endothelin may be mediated partially by activation of dihydropyridine-sensitive Ca2+ channels, although the explanation for this is not clear. The mechanism of action of endothelin in attenuating stimulated secretion and epithelial transport at lower concentrations is unknown.