title: Pharmacological and expression profile of the prostaglandin I(2) receptor in the rat craniovascular system.
abstract: Activation of the trigeminal nerve terminals around cerebral and meningeal arteries is thought to be an important patho-mechanism in migraine. Vasodilatation of the cranial arteries may also play a role in increasing nociception. Prostaglandin I(2) (PGI(2)) is capable of inducing a headache in healthy volunteers, a response that is likely to be mediated by the prostaglandin I(2) receptor (IP). This study investigates the functional and molecular characteristics of the IP receptor in the rat craniovascular system. In the closed cranial window model, iloprost, an IP receptor agonist, dilated the rat middle meningeal artery (MMA) (E(max)=170%±16%; pED(50)=6.5±0.2) but not the rat cerebral artery (CA) in vivo. The specific antagonist of the IP receptor, CAY10441, significantly blocked the iloprost-induced response dose-dependently, with the highest dose attenuating iloprost (1μgkg(-1)) induced dilatations by 70% (p<0.05). CAY10441 did not have any effect on the prostaglandin E(2)-induced vasodilatory response, thus suggesting no interaction with EP(2) and EP(4) receptors. IP receptor mRNA transcripts and protein were present in meningeal as well as in cerebral rat vasculature, and localized the IP receptor protein to the smooth vasculature of the cranial arteries (MMA, MCA and basilar artery). Together, these results demonstrate that the IP receptor mediates the dilatory effect of PGI(2) in the cranial vasculature in rats. Antagonism of this receptor might be of therapeutic relevance in acute migraine treatment.
authors.affiliation: Danish Headache Center, Department of Neurology, Glostrup Research Institute, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, DK-2600 Glostrup, Denmark.
authors.forename: Maja
authors.initials: M
authors.lastname: Myren
authors.forename: Jes
authors.initials: J
authors.lastname: Olesen
authors.forename: Saurabh
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects* / Q000378:metabolism*; D011464:Epoprostenol / Q000819:agonists* / Q000096:biosynthesis*; D016285:Iloprost / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008576:Meningeal Arteries / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D059225:Nociception / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044006:Receptors, Epoprostenol / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C514222:(2-(4-(4-isopropoxybenzyl)-phenylamino) imidazoline); D001593:Benzyl Compounds; D007093:Imidazoles; D044006:Receptors, Epoprostenol; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014665:Vasodilator Agents; D011464:Epoprostenol; D016285:Iloprost