title: Characterisation of CGRP receptors in the human isolated middle meningeal artery.
abstract: Although the understanding of migraine pathophysiology is still incomplete, there seems to be little doubt that dilatation of cranial blood vessels, including meningeal arteries, is involved in the headache phase of migraine. Since calcitonin gene-related peptide (CGRP) has been implicated in this vasodilatation, the present study set out to compare the relaxant effects of the endogenous ligand h-alphaCGRP, and [ethylamide-Cys(2,7)]h-alphaCGRP ([Cys(Et)(2,7)]h-alphaCGRP), a CGRP(2) receptor agonist, on human isolated middle meningeal artery segments, precontracted with KCl. Classical Schild plot analysis was used to characterise the receptor population in this artery using BIBN4096BS and h-alphaCGRP(8-37) as antagonists. h-alphaCGRP relaxed arterial segments more potently than [Cys(Et)(2,7)]h-alphaCGRP (pEC(50): 8.51+/-0.16 and 7.48+/-0.24, respectively), while the maximal responses to these agonists were not significantly different. BIBN4096BS equipotently blocked the relaxations induced by both agonists with a pA(2) of approximately 10 and with a Schild plot slope not significantly different from unity. h-alphaCGRP(8-37) also antagonised the response to h-alphaCGRP with a pA(2) of 6.46+/-0.16 and a Schild plot slope not different from unity. Furthermore, the results obtained from RT-PCR studies confirmed the presence of all the essential components required for a functional CGRP(1) receptor in these arteries. Considering the high antagonist potency of BIBN4096BS, coupled to the lower agonist potency of [Cys (Et)(2,7)]h-alphaCGRP, it is reasonable to suggest a predominant role of CGRP(1) receptors in the human middle meningeal artery. This view is reinforced by Schild plot analysis, which revealed a slope of unity in all experiments, giving further evidence for a homogeneous CGRP receptor population in this vascular preparation.
authors.affiliation: Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Gupta
authors.forename: Suneet
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Cees J J
authors.initials: CJ
authors.lastname: Avezaat
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Villalón
authors.forename: Pramod R
authors.initials: PR
authors.lastname: Saxena
authors.forename: Antoinette
authors.initials: A
authors.lastname: Maassenvandenbrink
mesh_terms: D015740:Calcitonin Gene-Related Peptide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008576:Meningeal Arteries / Q000187:drug effects* / Q000502:physiology; D008881:Migraine Disorders / Q000235:genetics / Q000503:physiopathology; D010446:Peptide Fragments / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014664:Vasodilation / Q000235:genetics / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D008024:Ligands; D010446:Peptide Fragments; D010879:Piperazines; D011799:Quinazolines; D012333:RNA, Messenger; D018015:Receptors, Calcitonin Gene-Related Peptide; D014665:Vasodilator Agents; C512152:alpha-calcitonin gene-related peptide, ethylamide-Cys(2,7)-; C058636:calcitonin gene-related peptide (8-37); D015740:Calcitonin Gene-Related Peptide; C406305:olcegepant