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The nonselective NO synthase (NOS) inhibitor<jats:italic>N<\/jats:italic><jats:sup>G<\/jats:sup>-nitro-<jats:sc>l<\/jats:sc>-arginine methyl ester hydrochloride increased responses to tactile mechanical stimuli of mucosal afferent endings in two species, in some cases severalfold. This was mimicked by a neuronal NOS inhibitor but not an endothelial NOS inhibitor. NOS inhibitors did not affect the responsiveness of smooth muscle afferent endings, suggesting that the endogenous source of NO is exclusively accessible to mucosal receptors. The role of the NO-soluble guanylyl cyclase (sGC)\u2013cGMP pathway was confirmed using the sGC inhibitor 1<jats:italic>H<\/jats:italic>-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one and the cGMP phosphodiesterase 5\u2032 inhibitor sildenafil. The first enhanced and the second inhibited mechanosensory function. Exogenous NO, from the donor<jats:italic>S<\/jats:italic>-nitroso-<jats:italic>N<\/jats:italic>-acetylpenicillamine, significantly reduced mechanosensitivity of both types of ending. Up to one-third of stomach-projecting afferent neurons in the nodose ganglia expressed neuronal NOS (nNOS). However, anterograde-traced vagal endings were nNOS negative, indicating NOS is not transported peripherally and there are alternative sources of NO for afferent modulation. A subpopulation of enteroendocrine cells in the gut mucosa were nNOS positive, which were found anatomically in close apposition with mucosal vagal afferent endings. These results indicate an inhibitory neuromodulatory role of epithelial NO, which targets a select population of vagal afferents. This interaction is likely to play a role in generation of symptoms and behaviors from the upper gastrointestinal system.<\/jats:p>","DOI":"10.1523\/jneurosci.6099-08.2009","type":"journal-article","created":{"date-parts":[[2009,6,3]],"date-time":"2009-06-03T17:37:34Z","timestamp":1244050654000},"page":"7246-7255","source":"Crossref","is-referenced-by-count":37,"title":["Nitric Oxide as an Endogenous Peripheral Modulator of Visceral Sensory Neuronal Function"],"prefix":"10.1523","volume":"29","author":[{"given":"Amanda J.","family":"Page","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tracey A.","family":"O'Donnell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole J.","family":"Cooper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard L.","family":"Young","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L. 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