{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T12:10:17Z","timestamp":1697026217847},"reference-count":44,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2006,6,19]],"date-time":"2006-06-19T00:00:00Z","timestamp":1150675200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Auton Autocoid Pharmacol"],"published-print":{"date-parts":[[2006,7]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p> <jats:bold>1<\/jats:bold>\u2003Relaxation responses of the rat isolated duodenum to the putative M<jats:sub>1<\/jats:sub> muscarinic receptor agonist, McN\u2010A\u2010343, were examined to determine whether the response was due to the release of known non\u2010adrenergic, non\u2010cholinergic relaxant neurotransmitters and to establish the involvement of M<jats:sub>1<\/jats:sub> muscarinic receptors.<\/jats:p><jats:p> <jats:bold>2<\/jats:bold>\u2003The role of ATP was examined with the P<jats:sub>2<\/jats:sub> receptor antagonist, suramin, which at 30\u2003<jats:italic>\u03bc<\/jats:italic><jats:sc>m<\/jats:sc> antagonized the relaxant responses to <jats:italic>\u03b1<\/jats:italic>,<jats:italic>\u03b2<\/jats:italic>\u2010methylene ATP. The same dose, however, failed to inhibit the relaxation by McN\u2010A\u2010343.<\/jats:p><jats:p> <jats:bold>3<\/jats:bold>\u2003The role of nitric oxide (NO) was examined with the NO synthase inhibitor, <jats:italic>N<\/jats:italic><jats:sup>G<\/jats:sup>\u2010nitro\u2010<jats:sc>l<\/jats:sc>\u2010arginine methyl ester (<jats:sc>l<\/jats:sc>\u2010NAME; 100\u2003<jats:italic>\u03bc<\/jats:italic><jats:sc>m<\/jats:sc>), which failed to inhibit the responses to McN\u2010A\u2010343. As NO mediates relaxation of the duodenum via cGMP generation through guanylyl cyclase, whether the relaxation by McN\u2010A\u2010343 was also via cGMP was examined with the guanylyl cyclase inhibitor, 1H\u2010[1,2,4]oxadiazolo[4,3\u2010a]quinoxalin\u20101\u2010one (ODQ). The relaxation responses to the NO donor, <jats:italic>S<\/jats:italic>\u2010nitroso\u2010<jats:italic>N<\/jats:italic>\u2010acetyl penicillamine, were inhibited in the presence of ODQ (3\u2003<jats:italic>\u03bc<\/jats:italic><jats:sc>m<\/jats:sc>), but not those by McN\u2010A\u2010343.<\/jats:p><jats:p> <jats:bold>4<\/jats:bold>\u2003Release of <jats:italic>\u03b3<\/jats:italic>\u2010aminobutyric acid (GABA) was examined with the GABA<jats:sub>A<\/jats:sub> receptor antagonist, bicuculline (10\u2003<jats:italic>\u03bc<\/jats:italic><jats:sc>m<\/jats:sc>), which shifted the concentration\u2013response curves for the relaxation of the duodenum by GABA to the right. There was a similar degree of shift in the concentration\u2013response curve for McN\u2010A\u2010343 by bicuculline indicating that release of GABA from enteric neurones of the duodenum could explain the relaxation response to McN\u2010A\u2010343.<\/jats:p><jats:p> <jats:bold>5<\/jats:bold>\u2003To test whether the muscarinic receptors mediating the relaxation of the duodenum were of the M<jats:sub>1<\/jats:sub> subtype, the susceptibility to the selective competitive antagonist, pirenzepine and the selective muscarinic toxin from green mamba, MT7, was examined. Pirenzepine (1\u2003<jats:italic>\u03bc<\/jats:italic><jats:sc>m<\/jats:sc>) shifted the concentration\u2013response for McN\u2010A\u2010343 to the right in a parallel fashion with a dose ratio of 33.3\u2003\u00b1\u200320.2. This yielded a p<jats:italic>A<\/jats:italic><jats:sub>2<\/jats:sub> value of 7.5, which concords with those for other responses reputed to be mediated via M<jats:sub>1<\/jats:sub> muscarinic receptors. The toxin MT7 was used as an irreversible antagonist and following incubation with the duodenum was washed from the bath. An incubation time of 30\u2003min with 100\u2003n<jats:sc>m<\/jats:sc> of MT7 caused a significant parallel shift in the concentration\u2013response to McN\u2010A\u2010343 confirming the involvement of M<jats:sub>1<\/jats:sub> muscarinic receptors.<\/jats:p><jats:p> <jats:bold>6<\/jats:bold>\u2003This study has confirmed that McN\u2010A\u2010343 relaxes the rat duodenum via muscarinic receptors of the M<jats:sub>1<\/jats:sub> subtype and that these receptors are probably located on enteric neurones from which their stimulation releases GABA.<\/jats:p>","DOI":"10.1111\/j.1474-8673.2006.00353.x","type":"journal-article","created":{"date-parts":[[2006,6,19]],"date-time":"2006-06-19T10:08:50Z","timestamp":1150711730000},"page":"275-284","source":"Crossref","is-referenced-by-count":6,"title":["Investigation of the mechanism for the relaxation of rat duodenum mediated via M<sub>1<\/sub> muscarinic receptors"],"prefix":"10.1111","volume":"26","author":[{"given":"A. 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