A61603-induced contractions of the porcine meningeal artery are mediated by alpha1- and alpha2-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 alpha(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 alpha-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 alpha(1)-(probably alpha(1A)) and, to a lesser extent, alpha(2)-adrenoceptors, involving the adenylyl cyclase, but not the diacylglycerol pathway.
Mehrotra
Suneet
S
Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Gupta
Saurabh
S
Centurión
David
D
Villalón
Carlos M
CM
Saxena
Pramod R
PR
VandenBrink
Antoinette Maassen
AM
D058646:Adrenergic alpha-1 Receptor Agonists; D058647:Adrenergic alpha-2 Receptor Agonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005544:Forecasting; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008576:Meningeal Arteries / Q000187:drug effects* / Q000502:physiology; D008719:Methiothepin / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D016713:Ritanserin / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013552:Swine; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
C094643:A 61603; D058646:Adrenergic alpha-1 Receptor Agonists; D058647:Adrenergic alpha-2 Receptor Agonists; D000317:Adrenergic alpha-Antagonists; D000470:Alkaloids; D053119:Benzophenanthridines; D007093:Imidazoles; D010069:Oxadiazoles; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D016713:Ritanserin; D005576:Colforsin; D010656:Phenylephrine; C090701:GR 127935; D015016:Yohimbine; D008719:Methiothepin; D011189:Potassium Chloride; C016299:chelerythrine; D011493:Protein Kinase C; D009638:Norepinephrine; D011224:Prazosin