Mehrotra Suneet, Gupta Saurabh, Garrelds Ingrid M, Villalón Carlos M, Saxena Pramod R, Bogers Ad J J C, Maassenvandenbrink Antoinette
Department of Pharmacology, Cardiovascular Research Institute COEUR, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.
Naunyn Schmiedebergs Arch Pharmacol. 2006 Dec;374(3):163-75. doi: 10.1007/s00210-006-0108-8. Epub 2006 Nov 14.
Vasoconstriction to agonists at serotonin (5-hydroxytryptamine; 5-HT) receptors and alpha-adrenoceptors, as well as vasodilatation induced by alpha-CGRP, have been well described in the porcine carotid circulation in vivo. The present study sets out to investigate the effects of current and prospective antimigraine drugs on porcine meningeal artery segments in vitro. Sumatriptan, ergotamine, dihydroergotamine, isometheptene and clonidine failed to contract the meningeal artery, but 5-HT, noradrenaline and phenylephrine induced concentration-dependent contractions. The contractions to 5-HT were competitively antagonized by the 5-HT(2A) receptor antagonist ketanserin, whilst those to noradrenaline were antagonized by alpha(1)-(prazosin), alpha(2)-(rauwolscine and yohimbine) and alpha(2C/2B)-(OPC-28326) adrenoceptor antagonists. Whilst dobutamine and salbutamol were ineffective, alpha-CGRP produced concentration-dependent relaxations that were antagonized by the CGRP(1) receptor antagonist olcegepant. In agreement with their lack of contractile effect, sumatriptan and ergotamine failed to influence forskolin-stimulated cyclic AMP accumulation in the porcine meningeal artery; in contrast, both compounds decreased forskolin-stimulated cyclic AMP accumulation in the human isolated saphenous vein, where they induced contractions. Finally, using RT-PCR, we could demonstrate the presence of mRNAs encoding for several 5-HT receptors (5-HT(1B), 5-HT(1D), 5-HT(1F), 5-HT(2A) and 5-HT(7)) and adrenoceptors (alpha(1A), alpha(1B), alpha(1D), alpha(2A), alpha(2B), alpha(2C), beta(1) and beta(2)), as well as that for the calcitonin receptor like receptor, a component of the CGRP(1) receptor. These results suggest that: (i) the porcine meningeal artery may not be involved in the vasoconstriction of the carotid vascular bed elicited by antimigraine drugs in anaesthetized pigs, and (ii) the mismatch between the presence of receptor mRNA and the lack of response to sumatriptan, dobutamine and salbutamol implies that mRNAs for the 5-HT(1B) receptor and beta(1)- and beta(2)-adrenoceptors are probably unstable, or that their density is too low for being translated as receptor protein in sufficient quantities.
在猪的颈动脉循环体内，5-羟色胺（5-ht）受体和α-肾上腺素受体激动剂引起的血管收缩，以及α-CGRP诱导的血管舒张，均已得到充分描述。本研究旨在体外研究当前和未来抗偏头痛药物对猪脑膜动脉段的影响。舒马曲坦、麦角胺、双氢麦角胺、异美汀和可乐定未能使脑膜动脉收缩，但5-ht、去甲肾上腺素和去氧肾上腺素可引起浓度依赖性收缩。5-ht（2A）受体拮抗剂酮色林竞争性拮抗5-ht引起的收缩，而去甲肾上腺素引起的收缩则被α（1）-（哌唑嗪）、α（2）-（萝芙木碱和育亨宾）和α（2C/2B）-（OPC-28326）肾上腺素受体拮抗剂拮抗。虽然多巴酚丁胺和沙丁胺醇无效，但α-CGRP产生浓度依赖性舒张，CGRP（1）受体拮抗剂olcegepant可拮抗这种舒张。与它们缺乏收缩作用一致，舒马曲坦和麦角胺未能影响福斯高林刺激的猪脑膜动脉中环磷酸腺苷（cAMP）的积累；相反，这两种化合物在人离体大隐静脉中均可降低福斯高林刺激的cAMP积累，在该静脉中它们可引起收缩。最后，通过逆转录-聚合酶链反应（RT-PCR），我们可以证明存在编码几种5-ht受体（5-ht（1B）、5-ht（1D）、5-ht（1F）、5-ht（2A）和5-ht（7））和肾上腺素受体（α（1A）、α（1B）、α（1D）、α（2A）、α（2B）、α（2C）、β（1）和β（2））的信使核糖核酸（mRNA），以及降钙素受体样受体（CGRP（1）受体的一个组成部分）的mRNA。这些结果表明：（i）猪脑膜动脉可能不参与麻醉猪中抗偏头痛药物引起的颈动脉血管床的血管收缩，（ii）受体mRNA的存在与对舒马曲坦、多巴酚丁胺和沙丁胺醇缺乏反应之间的不匹配意味着5-ht（1B）受体以及β（1）和β（2）肾上腺素受体的mRNA可能不稳定，或者其密度过低，无法大量翻译成受体蛋白。
