It has recently been shown that A61603 (N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methane sulphonamide), a potent α 1A -adrenoceptor agonist, decreased carotid artery conductance in anaesthetized pigs by a novel non-adrenergic mechanism. In this study, we set out to pharmacologically characterize A61603-induced contractions of the porcine isolated meningeal artery. While the maximum contractile responses of the artery were similar, A61603 (E max : 183 ± 23% of 100 mM KCl; pEC 50 : 7.25 ± 0.18) was more potent than noradrenaline (E max : 156 ± 16%; pEC 50 : 5.75 ± 0.17) or phenylephrine (E max : 163 ± 20%; pEC 50 : 5.63 ± 0.02). Prazosin (pA 2 : 9.36 ± 0.23) and, to a lesser extent, rauwolscine (pK b : 6.36 ± 0.38) and yohimbine (pK b : 7.30 ± 0.15) antagonised the contractions to A61603. The 5-HT 1B (GR127935; N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide) and 5-HT 2 (ritanserin) receptor antagonists failed to affect the responses to A61603, but methiothepin, which, in addition, has a high affinity for α-adrenoceptors, proved an effective antagonist. The A61603-induced responses were suppressed by the cAMP stimulator forskolin, but not by the protein kinase C inhibitor chelerythrine. Our results suggest that the contraction of porcine isolated meningeal artery by A61603 is mediated via mainly α 1 -(probably α 1A ) and, to a lesser extent, α 2 -adrenoceptors, involving the adenylyl cyclase, but not the diacylglycerol pathway.Acutely acting antimigraine drugs (triptans [1-3] and ergot alkaloids [4]) potently and selectively constrict cephalic arteriovenous anastomoses in anaesthetized pigs. Yet, sumatriptan, ergotamine and dihydroergotamine fail to constrict the porcine isolated meningeal artery [5]. These drugs have an agonist action at the 5-HT 1B receptor [6,7], but the ergot alkaloids also act at α-adrenoceptors [2,8-10]. Both α 1 -and α 2 -adrenoceptors have been identified to mediate constriction of porcine cephalic arteriovenous anastomoses [11] and their subtypes are proposed as targets for novel antimigraine action [12,13].A61603 (N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methane sulphonamide) is a potent and selective α 1A -adrenoceptor agonist [14,15] which, like triptans and ergot alkaloids, constricted porcine cephalic arteriovenous anastomoses [16]. This effect of A61603 was, however, poorly modified by the adrenoceptor antagonists, 5-methylurapidil (α 1A ) and prazosin (α 1 ), either alone or in combination with rauwolscine (α 2 ), suggesting the involvement of a novel non-adrenergic mechanism [16]. The present study in the porcine isolated meningeal artery was designed to further characterize the mechanism of the contractile action of A61603 by using: (i) antagonists at α 1 -(prazosin) and (table 1); and (ii) the protein kinase C inhibitor chelerythrine [17,18] as well as the cAMP stimulator forskolin [19,20].
Materials and MethodsCompounds....