A61603-induced contractions of the porcine meningeal artery are mediated by α1- and α2-adrenoceptors

It has recently been shown that A61603 (N-[5-(4,5-dihydro-1H-imidazol-2yl)- 2-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl]methane sulphonamide), a potent α1A-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 (Emax: 183 ± 23% of 100 mM KCl; pEC50: 7.25 ± 0.18) was more potent than noradrenaline (Emax: 156 ± 16%; pEC50: 5.75 ± 0.17) or phenylephrine (Emax: 163 ± 20%; pEC50: 5.63 ± 0.02). Prazosin (pA2: 9.36 ± 0.23) and, to a lesser extent, rauwolscine (pKb: 6.36 ± 0.38) and yohimbine (pK b: 7.30 ± 0.15) antagonised the contractions to A61603. The 5-HT1B (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-HT2 (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 α1-(probably α1A) and, to a lesser extent, α2-adrenoceptors, involving the adenylyl cyclase, but not the diacylglycerol pathway.

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