, Volume 374, Issue 3, pp 163-175
Date: 14 Nov 2006

Effects of current and prospective antimigraine drugs on the porcine isolated meningeal artery

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Abstract

Vasoconstriction to agonists at serotonin (5-hydroxytryptamine; 5-HT) receptors and α-adrenoceptors, as well as vasodilatation induced by α-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-HT2A receptor antagonist ketanserin, whilst those to noradrenaline were antagonized by α1-(prazosin), α2-(rauwolscine and yohimbine) and α2C/2B-(OPC-28326) adrenoceptor antagonists. Whilst dobutamine and salbutamol were ineffective, α-CGRP produced concentration-dependent relaxations that were antagonized by the CGRP1 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-HT1B, 5-HT1D, 5-HT1F, 5-HT2A and 5-HT7) and adrenoceptors (α1A, α1B, α1D, α2A, α2B, α2C, β1 and β2), as well as that for the calcitonin receptor like receptor, a component of the CGRP1 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-HT1B receptor and β1- and β2-adrenoceptors are probably unstable, or that their density is too low for being translated as receptor protein in sufficient quantities.