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Furthermore, elevated levels of prostaglandin E<jats:sub>2<\/jats:sub> (PGE<jats:sub>2<\/jats:sub>) occur in the blood, plasma and saliva of migraineurs during an attack, suggestive of a contributory role. In the present study, we have characterised the prostanoid receptors involved in the relaxation and contraction of human middle cerebral arteries <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In the presence of indomethacin (3 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>) and the TP receptor antagonist GR32191 (1 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>), PGE<jats:sub>2<\/jats:sub> was found to relax phenylephrine precontracted cerebral arterial rings in a concentration\u2010dependent manner (mean pEC<jats:sub>50<\/jats:sub> 8.0\u00b10.1, <jats:italic>n<\/jats:italic>=5).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Establishment of a rank order of potency using the EP<jats:sub>4<\/jats:sub>&gt;EP<jats:sub>2<\/jats:sub> agonist 11\u2010deoxy PGE<jats:sub>1<\/jats:sub>, and the EP<jats:sub>2<\/jats:sub>&gt;EP<jats:sub>4<\/jats:sub> agonist PGE<jats:sub>1<\/jats:sub>\u2010OH (mean pEC<jats:sub>50<\/jats:sub> of 7.6\u00b10.1 (<jats:italic>n<\/jats:italic>=6) and 6.4\u00b10.1 (<jats:italic>n<\/jats:italic>=4), respectively), suggested the presence of functional EP<jats:sub>4<\/jats:sub> receptors. Furthermore, the selective EP<jats:sub>2<\/jats:sub> receptor agonist butaprost at concentrations &lt;1 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc> failed to relax the tissues.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Blockade of EP<jats:sub>4<\/jats:sub> receptors with the EP<jats:sub>4<\/jats:sub> receptor antagonists AH23848 and EP<jats:sub>4<\/jats:sub>A caused significant rightward displacements in PGE<jats:sub>2<\/jats:sub> concentration\u2013response curves, exhibiting pA<jats:sub>2<\/jats:sub> and pK<jats:sub>B<\/jats:sub> values of 5.7\u00b10.1, <jats:italic>n<\/jats:italic>=3, and 8.4, <jats:italic>n<\/jats:italic>=3, respectively.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The IP receptor agonists iloprost and cicaprost relaxed phenylephrine precontracted cerebral arterial rings (mean pEC<jats:sub>50<\/jats:sub> values 8.3\u00b10.1 (<jats:italic>n<\/jats:italic>=4) and 8.1\u00b10.1 (<jats:italic>n<\/jats:italic>=9), respectively). In contrast, the DP and FP receptor agonists PGD<jats:sub>2<\/jats:sub> and PGF<jats:sub>2<jats:italic>\u03b1<\/jats:italic><\/jats:sub> failed to cause appreciable relaxation or contraction at concentrations of up to 30 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>. In the absence of phenylephrine contraction and GR32191, the TP receptor agonist U46619 caused concentration\u2010dependent contraction of cerebral artery (mean pEC<jats:sub>50<\/jats:sub> 7.4\u00b10.3, <jats:italic>n<\/jats:italic>=3).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These data demonstrate the presence of prostanoid EP<jats:sub>4<\/jats:sub> receptors mediating PGE<jats:sub>2<\/jats:sub> vasodilatation of human middle cerebral artery. IP receptors mediating relaxation and TP receptors mediating contraction were also functionally demonstrated.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2004) <jats:bold>141<\/jats:bold>, 580\u2013585. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0705645\">10.1038\/sj.bjp.0705645<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0705645","type":"journal-article","created":{"date-parts":[[2004,2,19]],"date-time":"2004-02-19T18:17:58Z","timestamp":1077214678000},"page":"580-585","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":110,"title":["EP<sub>4<\/sub> prostanoid receptor\u2010mediated vasodilatation of human middle cerebral arteries"],"prefix":"10.1111","volume":"141","author":[{"given":"Richard J","family":"Davis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin E","family":"Murdoch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mozam","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Purbrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rivka","family":"Ravid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon S","family":"Baxter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Tilford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L G","family":"Sheldrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth L","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A","family":"Coleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,1,30]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.1988.8"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1959.tb00928.x"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(96)00928-3"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(97)01383-6"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2001.20916"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0202-136"},{"key":"e_1_2_6_8_1","first-page":"F485","article-title":"Cloning and expression of the rabbit prostaglandin EP4 receptor","volume":"270","author":"BREYER R.M.","year":"1996","journal-title":"Am. 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