EP4 prostanoid receptor-mediated vasodilatation of human middle cerebral arteries

被引:96
作者
Davis, RJ
Murdoch, CE
Ali, M
Purbrick, S
Ravid, R
Baxter, GS
Tilford, N
Sheldrick, RLG
Clark, KL
Coleman, RA
机构
[1] Pharmagene Labs, Royston SG8 5HD, Herts, England
[2] Netherlands Brain Bank, NL-1105 AZ Amsterdam, Netherlands
[3] BioWisdom Ltd, Cambridge CB2 4AT, England
关键词
prostaglandin E-2; EP4; receptor; human middle cerebral artery; migraine;
D O I
10.1038/sj.bjp.0705645
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 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. 2 In the presence of indomethacin (3 mum) and the TP receptor antagonist GR32191 (1 mum), 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). 3 Establishment of a rank order of potency using the EP4 > EP2 agonist 11-deoxy PGE(1), and the EP2 > EP4 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 EP4 receptors. Furthermore, the selective EP2 receptor agonist butaprost at concentrations < 1 mu M failed to relax the tissues. 4 Blockade of EP4 receptors with the EP4 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. 5 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 alpha) failed to cause appreciable relaxation or contraction at concentrations of up to 30 mu 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). 6 These data demonstrate the presence of prostanoid EP4 receptors mediating PGE(2) vasodilatation of human middle cerebral artery. IP receptors mediating relaxation and TP receptors mediating contraction were also functionally demonstrated.
引用
收藏
页码:580 / 585
页数:6
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