Epithelial modulation of cholinergic responses in rabbit trachea is partly due to neutral endopeptidase activity

By the simultaneous measurement of acetylcholine release and smooth muscle contraction in rabbit tracheal segments with and without epithelium, pre- as well as postsynaptic effects of this cell layer were studied on cholinergic neurotransmission. The epithelial cell layer exerted a presynaptic inhibitory influence on acetylcholine release, induced by KCl and electrical stimulation, with a concomitant decrease in the smooth muscle contractions. The responses elicited by exogenous acetylcholine, acting postsynaptically, were also inhibited in the presence of the epithelium. The epithelial effect was not accounted for by the production of inhibitory prostaglandins or a nitric oxide-synthase product. Furthermore, the epithelium did not function as a metabolic site for the degradation of acetylcholine. Phosphoramidon, an inhibitor of neutral endopeptidase, mimicked the effects of epithelium removal on the cholinergic responses to high frequency stimulation and on the acetylcholine-induced effects. Neutral endopeptidase inhibition did not further enhance the responses in epithelium-denuded segments. We therefore suggest that the inhibitory function of the epithelium can be partly explained by the activity of neutral endopeptidase, limiting the excitatory effects of tachykinins on cholinergic responses. An alteration in the neutral endopeptidase activity as a result of inflammatory responses and epithelial damage can contribute to the mechanism of airway hyperreactivity in asthma.