EP 4 prostanoid receptor‐mediated vasodilatation of human middle cerebral arteries

Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E 2 (PGE 2 ) 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 in vitro . In the presence of indomethacin (3 μ M ) and the TP receptor antagonist GR32191 (1 μ M ), PGE 2 was found to relax phenylephrine precontracted cerebral arterial rings in a concentration‐dependent manner (mean pEC 50 8.0±0.1, n =5). Establishment of a rank order of potency using the EP 4 >EP 2 agonist 11‐deoxy PGE 1 , and the EP 2 >EP 4 agonist PGE 1 ‐OH (mean pEC 50 of 7.6±0.1 ( n =6) and 6.4±0.1 ( n =4), respectively), suggested the presence of functional EP 4 receptors. Furthermore, the selective EP 2 receptor agonist butaprost at concentrations <1 μ M failed to relax the tissues. Blockade of EP 4 receptors with the EP 4 receptor antagonists AH23848 and EP 4 A caused significant rightward displacements in PGE 2 concentration–response curves, exhibiting pA 2 and pK B values of 5.7±0.1, n =3, and 8.4, n =3, respectively. The IP receptor agonists iloprost and cicaprost relaxed phenylephrine precontracted cerebral arterial rings (mean pEC 50 values 8.3±0.1 ( n =4) and 8.1±0.1 ( n =9), respectively). In contrast, the DP and FP receptor agonists PGD 2 and PGF 2 α failed to cause appreciable relaxation or contraction at concentrations of up to 30 μ M . In the absence of phenylephrine contraction and GR32191, the TP receptor agonist U46619 caused concentration‐dependent contraction of cerebral artery (mean pEC 50 7.4±0.3, n =3). These data demonstrate the presence of prostanoid EP 4 receptors mediating PGE 2 vasodilatation of human middle cerebral artery. IP receptors mediating relaxation and TP receptors mediating contraction were also functionally demonstrated.British Journal of Pharmacology (2004) 141 , 580–585. doi: 10.1038/sj.bjp.0705645