{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T08:10:02Z","timestamp":1746259802505,"version":"3.40.4"},"reference-count":30,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2014,6,6]],"date-time":"2014-06-06T00:00:00Z","timestamp":1402012800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Norgine Pharmaceuticals Ltd"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurogastroenterology Motil"],"published-print":{"date-parts":[[2014,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The role of<jats:italic>\u03b1<\/jats:italic>\u2010adrenoceptors in promoting continence through modulation of sphincter tone has focused primarily on the effects of<jats:italic>\u03b1<\/jats:italic><jats:sub>1<\/jats:sub>\u2010adrenoceptors. We have used three clinically available agents, which are selective for<jats:italic>\u03b1<\/jats:italic><jats:sub>2<\/jats:sub>\u2010adrenoceptors, to investigate their role in contractile and neurogenic responses on the internal anal sphincter (<jats:styled-content style=\"fixed-case\">IAS<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">IAS<\/jats:styled-content>strips, which had spontaneously generated tone, were used to investigate the contractile effect of lofexidine, brimonidine, and dexmedetomidine on muscle tone in the presence or absence of subtype selective antagonists. The effect of brimonidine on the magnitude and time course of neurogenic responses generated by electrical field stimulation (<jats:styled-content style=\"fixed-case\">EFS<\/jats:styled-content>) was also examined. The affinity of test compounds at<jats:italic>\u03b1<\/jats:italic><jats:sub>1<\/jats:sub>\u2010 and<jats:italic>\u03b1<\/jats:italic><jats:sub>2<\/jats:sub>\u2010adrenoceptors was established by competition binding with [3H]\u2010prazosin and [3H]\u2010<jats:styled-content style=\"fixed-case\">RX<\/jats:styled-content>821002.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>All agonists caused concentration\u2010dependent contraction of the<jats:styled-content style=\"fixed-case\">IAS<\/jats:styled-content>and lofexidine demonstrated an enantiomeric difference in potency with a 10\u2010fold difference between the (\u2212) and (+) isomers. Responses to lofexidine and dexmedetomidine were inhibited in the presence of the<jats:italic>\u03b1<\/jats:italic><jats:sub>1<\/jats:sub>\u2010adrenoceptor selective antagonist prazosin, but not in the presence of<jats:styled-content style=\"fixed-case\">RX<\/jats:styled-content>811059 (<jats:italic>\u03b1<\/jats:italic><jats:sub>2<\/jats:sub>\u2010adrenoceptor selective antagonist); brimonidine responses were inhibited by<jats:styled-content style=\"fixed-case\">RX<\/jats:styled-content>811059 and, to a lesser extent, by prazosin. Brimonidine affected both magnitude and duration of neurogenic responses, which was reversed in the presence of<jats:styled-content style=\"fixed-case\">RX<\/jats:styled-content>811059.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions &amp; Inferences<\/jats:title><jats:p>We conclude that<jats:italic>\u03b1<\/jats:italic><jats:sub>2<\/jats:sub>\u2010adrenoceptors can mediate contraction of<jats:styled-content style=\"fixed-case\">IAS<\/jats:styled-content>, although this effect is most evident with efficacious imidazoline agonists rather than the most selective ligand. In addition, this receptor subtype can directly inhibit noradrenergic contractile responses to<jats:styled-content style=\"fixed-case\">EFS<\/jats:styled-content>and, indirectly, enhance nitrergic relaxatory responses.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nmo.12363","type":"journal-article","created":{"date-parts":[[2014,6,6]],"date-time":"2014-06-06T10:06:41Z","timestamp":1402049201000},"page":"1095-1103","source":"Crossref","is-referenced-by-count":1,"title":["Dual effects of<i>\u03b1<\/i><sub>2<\/sub>\u2010adrenoceptors in modulating myogenic tone in sheep isolated internal anal sphincter"],"prefix":"10.1111","volume":"26","author":[{"given":"S. J.","family":"Rayment","sequence":"first","affiliation":[{"name":"Division of GI Surgery School of Medicine University of Nottingham Queen's Medical Centre Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. A. D.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Division of GI Surgery School of Medicine University of Nottingham Queen's Medical Centre Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.","family":"Eames","sequence":"additional","affiliation":[{"name":"Division of GI Surgery School of Medicine University of Nottingham Queen's Medical Centre Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. G.","family":"Acheson","sequence":"additional","affiliation":[{"name":"Division of GI Surgery School of Medicine University of Nottingham Queen's Medical Centre Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. R.","family":"Dashwood","sequence":"additional","affiliation":[{"name":"Clinical Biochemistry Royal Free and University College Medical School London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y.","family":"Henry","sequence":"additional","affiliation":[{"name":"Clinical Development Norgine Ltd R&amp;D Division Harefield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Gruss","sequence":"additional","affiliation":[{"name":"Clinical Development Norgine Ltd R&amp;D Division Harefield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. H.","family":"Scholefield","sequence":"additional","affiliation":[{"name":"Division of GI Surgery School of Medicine University of Nottingham Queen's Medical Centre Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V. 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