EP4 prostanoid receptor‐mediated vasodilatation of human middle cerebral arteries

British Journal of Pharmacology - Tập 141 Số 4 - Trang 580-585 - 2004
Richard J. Davis1, Colin E. Murdoch1, Mozam Ali1, Stuart Purbrick1, Rivka Ravid2, G S Baxter3, Nick Tilford3, R.L.G. Sheldrick1, Kenneth L. Clark1, Robert A. Coleman1
1Pharmagene Laboratories, 2 Orchard Road, Royston, Herts SG8 5HD
2Netherlands Brain Bank, Meibergdreef 33, 1105 AZ, Amsterdam 20, Netherlands
3BioWisdom Ltd, Babraham Hall, Babraham, Cambridge CB2 4AT

Tóm tắt

Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E2 (PGE2) 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 μM) and the TP receptor antagonist GR32191 (1 μM), PGE2 was found to relax phenylephrine precontracted cerebral arterial rings in a concentration‐dependent manner (mean pEC50 8.0±0.1, n=5).

Establishment of a rank order of potency using the EP4>EP2 agonist 11‐deoxy PGE1, and the EP2>EP4 agonist PGE1‐OH (mean pEC50 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 μM failed to relax the tissues.

Blockade of EP4 receptors with the EP4 receptor antagonists AH23848 and EP4A caused significant rightward displacements in PGE2 concentration–response curves, exhibiting pA2 and pKB 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 pEC50 values 8.3±0.1 (n=4) and 8.1±0.1 (n=9), respectively). In contrast, the DP and FP receptor agonists PGD2 and PGF2α failed to cause appreciable relaxation or contraction at concentrations of up to 30 μM. In the absence of phenylephrine contraction and GR32191, the TP receptor agonist U46619 caused concentration‐dependent contraction of cerebral artery (mean pEC50 7.4±0.3, n=3).

These data demonstrate the presence of prostanoid EP4 receptors mediating PGE2 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

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Tài liệu tham khảo

10.1038/jcbfm.1988.8

10.1111/j.1476-5381.1959.tb00928.x

10.1016/0014-5793(96)00928-3

10.1016/S0014-2999(97)01383-6

10.1053/gast.2001.20916

10.1038/nm0202-136

BREYER R.M., 1996, Cloning and expression of the rabbit prostaglandin EP4 receptor, Am. J. Physiol., 270, F485

10.1016/0028-3908(91)90165-8

CARLSON L.A., 1968, Clinical and metabolic effects of different doses of prostaglandin E1 in man. Prostaglandin and related factors, Acta Med. Scand., 83, 423, 10.1111/j.0954-6820.1968.tb10502.x

10.1046/j.1526-4610.2001.041007665.x

10.1016/0090-6980(94)90084-1

COLEMAN R.A., 1994, VIII. Internation Union of Pharmacology Classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes, Pharmacol. Rev., 46, 205

10.1038/sj.bjp.0703525

10.1212/WNL.58.11.1660

10.1046/j.1468-2982.1999.019006581.x

10.1016/S0306-4522(98)00366-2

10.1002/1531-8249(200101)49:1<7::AID-ANA4>3.0.CO;2-K

10.1016/S0167-0115(97)02141-1

10.1007/s00296-002-0187-x

10.1111/j.1476-5381.1986.tb10155.x

10.1002/ana.410330109

10.1007/s002280050336

10.1016/S0028-3908(05)80004-8

10.1016/0165-6147(91)90630-B

10.1038/sj.bjp.0704357

10.1046/j.1468-2982.2000.00055.x

10.1038/sj.bjp.0701367

10.1111/j.1476-5381.1993.tb13983.x

10.1111/j.1476-5381.1989.tb12017.x

10.1124/mol.60.1.36

10.1124/mol.64.1.192

10.1097/00004647-200110000-00005

10.1016/0165-6147(92)90097-P

10.3171/jns.1988.68.5.0757

10.1111/j.1526-4610.1989.hed22904233.x

10.1016/0005-2760(95)00146-4

10.1111/j.1526-4610.1989.hed2908498.x

10.1016/0376-8716(83)90016-9

10.1046/j.1468-2982.1989.0903165.x

10.1111/j.1526-4610.1981.hed2105190.x

10.1046/j.1468-2982.2002.00419.x

10.1152/ajpcell.1996.270.5.C1379

10.1046/j.1468-2982.2000.00146.x

THE DICLOFENAC‐K/SUMATRIPTAN MIGRAINE STUDY GROUP. (1999).Acute treatment of migraine attacks: efficacy and safety of a nonsteroidal anti‐inflammatory drug diclofenac‐potassium in comparison to oral sumatriptan and placebo.Cephalalgia 19 232–240.

10.1038/jcbfm.1983.32

10.1016/0090-6980(89)90045-2

10.1046/j.1468-2982.1997.1704525.x

10.1016/S0304-3959(02)00027-1

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British Journal of Pharmacology

Tập 141 Số 4

580-585

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