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EP4 prostanoid receptor-mediated vasodilatation of human middle cerebral arteries.

Abstract

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 microm) and the TP receptor antagonist GR32191 (1 microM), 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 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 microM failed to relax the tissues. 4. 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. 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 microm. 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 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.

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    Pharmagene Laboratories, 2 Orchard Road, Royston, Herts SG8 5HD. richard.davis@pharmagene.com

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    Source

    British journal of pharmacology 141:4 2004 Feb pg 580-5

    MeSH

    15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
    Aged
    Aged, 80 and over
    Biphenyl Compounds
    Dinoprostone
    Dose-Response Relationship, Drug
    Female
    Heptanoic Acids
    Humans
    Iloprost
    In Vitro Techniques
    Indomethacin
    Male
    Middle Aged
    Middle Cerebral Artery
    Muscle Contraction
    Muscle, Smooth, Vascular
    Phenylephrine
    Receptors, Prostaglandin E
    Receptors, Prostaglandin E, EP2 Subtype
    Receptors, Prostaglandin E, EP4 Subtype
    Vasoconstrictor Agents
    Vasodilation
    Vasodilator Agents

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    14744815

    Citation

    Davis, Richard J., et al. "EP4 Prostanoid Receptor-mediated Vasodilatation of Human Middle Cerebral Arteries." British Journal of Pharmacology, vol. 141, no. 4, 2004, pp. 580-5.
    Davis RJ, Murdoch CE, Ali M, et al. EP4 prostanoid receptor-mediated vasodilatation of human middle cerebral arteries. Br J Pharmacol. 2004;141(4):580-5.
    Davis, R. J., Murdoch, C. E., Ali, M., Purbrick, S., Ravid, R., Baxter, G. S., ... Coleman, R. A. (2004). EP4 prostanoid receptor-mediated vasodilatation of human middle cerebral arteries. British Journal of Pharmacology, 141(4), pp. 580-5.
    Davis RJ, et al. EP4 Prostanoid Receptor-mediated Vasodilatation of Human Middle Cerebral Arteries. Br J Pharmacol. 2004;141(4):580-5. PubMed PMID: 14744815.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - EP4 prostanoid receptor-mediated vasodilatation of human middle cerebral arteries. AU - Davis,Richard J, AU - Murdoch,Colin E, AU - Ali,Mozam, AU - Purbrick,Stuart, AU - Ravid,Rivka, AU - Baxter,Gordon S, AU - Tilford,Nick, AU - Sheldrick,Robert L G, AU - Clark,Kenneth L, AU - Coleman,Robert A, Y1 - 2004/01/26/ PY - 2004/1/28/pubmed PY - 2004/10/16/medline PY - 2004/1/28/entrez SP - 580 EP - 5 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 141 IS - 4 N2 - 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 microm) and the TP receptor antagonist GR32191 (1 microM), 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 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 microM failed to relax the tissues. 4. 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. 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 microm. 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 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. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/14744815/full_citation L2 - https://doi.org/10.1038/sj.bjp.0705645 DB - PRIME DP - Unbound Medicine ER -