Characterisation of CGRP receptors in the human isolated middle meningeal artery

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-αCGRP, and [ethylamide-Cys2,7]h-αCGRP ([Cys(Et)2,7]h-αCGRP), a CGRP2 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-αCGRP8–37 as antagonists. h-αCGRP relaxed arterial segments more potently than [Cys(Et)2,7]h-αCGRP (pEC50: 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 pA2 of ∼ 10 and with a Schild plot slope not significantly different from unity. h-αCGRP8–37 also antagonised the response to h-αCGRP with a pA2 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 CGRP1 receptor in these arteries. Considering the high antagonist potency of BIBN4096BS, coupled to the lower agonist potency of [Cys (Et)2,7]h-αCGRP, it is reasonable to suggest a predominant role of CGRP1 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.