A61603-Induced Contractions of the Porcine Meningeal Artery Are Mediated by α1- and α2-Adrenoceptors
Suneet Mehrotra
Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, and
Search for more papers by this authorSaurabh Gupta
Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, and
Search for more papers by this authorDavid Centurión
Department of Pharmacobiology, Cinvestav-Coapa, México DF, México
Search for more papers by this authorCarlos M. Villalón
Department of Pharmacobiology, Cinvestav-Coapa, México DF, México
Search for more papers by this authorPramod R. Saxena
Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, and
Search for more papers by this authorAntoinette Maassen VandenBrink
Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, and
Search for more papers by this authorSuneet Mehrotra
Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, and
Search for more papers by this authorSaurabh Gupta
Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, and
Search for more papers by this authorDavid Centurión
Department of Pharmacobiology, Cinvestav-Coapa, México DF, México
Search for more papers by this authorCarlos M. Villalón
Department of Pharmacobiology, Cinvestav-Coapa, México DF, México
Search for more papers by this authorPramod R. Saxena
Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, and
Search for more papers by this authorAntoinette Maassen VandenBrink
Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, and
Search for more papers by this authorAbstract
Abstract: 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 (pKb: 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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