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

Abstract

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.