Inhibitory effect of BIBN4096BS, CGRP8-37, a CGRP antibody and an RNA-Spiegelmer on CGRP induced vasodilatation in the perfused and non-perfused rat middle cerebral artery
Inhibitory effect of BIBN4096BS, CGRP8-37, a CGRP antibody and an RNA-Spiegelmer on CGRP induced vasodilatation in the perfused and non-perfused rat middle cerebral artery
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DOI：
10.1038/sj.bjp.0707134
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发表时间：
2007-03-01
影响因子：
7.3
通讯作者：
Jansen-Olesen, I.
中科院分区：
文献类型：
--
作者：
Edvinsson, L.;Nilsson, E.;Jansen-Olesen, I.
背景和目的：通过使用CGRP抗体或CGRP结合的RNA-Spiegelmer(NOX-C89)与CGRP分子本身相互作用，形成了抑制CGRP信号转导的新概念。我们比较了这些CGRP清除剂和两种已知的受体拮抗剂(CGRP8-37和BIBN4096BS)对CGRP引起的大鼠大脑中动脉(MCA)的松弛作用。此外，我们还研究了内皮屏障的作用。实验方法：我们在动脉造影中使用了亮度灌流的大脑中动脉，加压到85 mm Hg，并对大脑中动脉的分离环段进行了肌图研究。关键结果：在肌图研究中和在动脉灌注系统中，α-CGRP和β-CGRP诱导的MCA呈浓度依赖性的扩张。给药后，两种多肽都不是显着的血管扩张剂。肾上腺髓质素和胰淀素引起微弱的扩张。在肌图实验中，4种CGRP阻断剂(CGRP8-37、BIBN4096BS、CGRP抗体和NOX-C89)均可阻断α-CGRP的松弛作用。在肺灌流实验中，这些药物不同程度地阻止了对α-CGRP的松弛反应。腔内CGRP8-37、BIBN4096BS、CGRP抗体或NOX-C89均不能抑制α-CGRP所致的扩张作用。结论：α-或β-CGRP作用于大鼠大脑中动脉平滑肌细胞的CGRP受体，并可通过内皮屏障有效地阻止其作用于该受体。降钙素基因相关肽阻滞剂显著抑制α-降钙素基因相关肽引起的松弛，但也被动脉内皮细胞阻止到达降钙素基因相关肽受体。
Background and purpose: A new concept for the inhibition of CGRP signalling has been developed by interaction with the CGRP molecule per se by using a CGRP antibody or a CGRP binding RNA-Spiegelmer (NOX-C89). We have compared these CGRP scavengers with two known receptor antagonists (CGRP8-37 and BIBN4096BS) on CGRP-induced relaxations in the rat middle cerebral artery (MCA). Furthermore, the role of the endothelial barrier has been studied.Experimental approach: We used the luminally perfused MCA in an arteriograph, pressurized to 85mm Hg and myograph studies of isolated ring segments of the MCA.Key results: In myograph studies and in the perfusion system during abluminal application, alpha CGRP and beta CGRP induced concentration-dependent dilatation of the MCA. Given luminally neither peptide was significantly vasodilator. Adrenomedullin and amylin induced weak dilatations. In myograph experiments, relaxation induced by a alpha CGRP was prevented by the four CGRP blockers (CGRP8-37, BIBN4096BS, the CGRP antibody and NOX-C89.). In abluminal perfusion experiments, the relaxant response to alpha CGRP was prevented by these agents to a varying degree. Dilatation induced by abluminal application of alpha CGRP was inhibited by luminal CGRP8-37 but not by luminal BIBN4096BS, CGRP antibody or NOX-C89.Conclusions and Implications: alpha or beta CGRP acted on smooth muscle cell CGRP receptors in rat MCA and were effectively prevented from reaching these receptors by the endothelial barrier. The CGRP blockers significantly inhibited alpha CGRP induced relaxation but were also prevented from reaching the CGRP receptors by the arterial endothelium.