Gupta Saurabh, Mehrotra Suneet, Avezaat Cees J J, Villalón Carlos M, Saxena Pramod R, Maassenvandenbrink Antoinette
Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
Life Sci. 2006 Jun 13;79(3):265-71. doi: 10.1016/j.lfs.2006.01.003. Epub 2006 Feb 3.
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.
尽管对偏头痛病理生理学的理解仍不完整，但几乎毫无疑问，包括脑膜动脉在内的颅血管扩张参与了偏头痛的头痛阶段。由于降钙素基因相关肽（CGRP）与这种血管舒张有关，本研究旨在比较内源性配体h-αCGRP和[乙酰胺 - Cys(2,7)]h-αCGRP（[Cys(Et)(2,7)]h-αCGRP），一种CGRP(2)受体激动剂，对用氯化钾预收缩的人离体脑膜中动脉段的舒张作用。使用经典的Schild图分析法，以BIBN4096BS和h-αCGRP(8 - 37)作为拮抗剂来表征该动脉中的受体群体。h-αCGRP比[Cys(Et)(2,7)]h-αCGRP更有效地舒张动脉段（pEC(50)分别为8.51±0.16和7.48±0.24），而对这些激动剂的最大反应没有显著差异。BIBN4096BS以约10的pA(2)等效地阻断了两种激动剂诱导的舒张，且Schild图斜率与1无显著差异。h-αCGRP(8 - 37)也以6.46±0.16的pA(2)拮抗对h-αCGRP的反应，且Schild图斜率与1无差异。此外，RT-PCR研究结果证实了这些动脉中存在功能性CGRP(1)受体所需的所有必需成分。考虑到BIBN4096BS的高拮抗效力，以及[Cys (Et)(2,7)]h-αCGRP较低的激动剂效力，有理由认为CGRP(1)受体在人脑膜中动脉中起主要作用。Schild图分析强化了这一观点，该分析在所有实验中均显示斜率为1，进一步证明了该血管制剂中CGRP受体群体的同质性。
