A61603-induced vasoconstriction in porcine carotid vasculature: involvement of a non-adrenergic mechanism.
It has recently been shown that the pharmacological profile of alpha(1)-adrenoceptors mediating constriction of porcine carotid arteriovenous anastomoses resembles that of alpha(1A)- and alpha(1B)-adrenoceptor subtypes. In an attempt to verify the involvement of alpha(1A)-adrenoceptors, we used the potent alpha(1A)-adrenoceptor agonist N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl]methane sulphonamide (A61603) and found that intracarotid (i.c.) administration of A61603 (0.3-10 microg kg(-1)) dose-dependently decreased porcine carotid blood flow and vascular conductance. This decrease was exclusively due to a constriction of carotid arteriovenous anastomoses; the capillary blood flow and conductance remained unchanged. Surprisingly, the responses to A61603 were little modified by prior i.v. treatment with 5-methylurapidil (1000 microg kg(-1)), prazosin (100 microg kg(-1)) or a combination of prazosin and rauwolscine (100 and 300 microg kg(-1), respectively). The 5-HT(1B/1D) receptor antagonist 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 hydrochloride monohydrate (GR127935; 500 microg kg(-1)) and ketanserin (500 microg kg(-1)) also failed to modify carotid vascular responses to A61603, but, interestingly, methiothepin (3000 microg kg(-1)) proved to be an effective antagonist. Taken together, the present results show that A61603 is a relatively poor agonist at the alpha(1A)-adrenoceptor in anaesthetised pigs and that the carotid vasoconstriction produced by A61603 is mediated by a novel non-adrenergic mechanism.
Willems
E W
EW
Department of Pharmacology, Dutch Migraine Research Group and Cardiovascular Research Institute "COEUR", Faculty of Medicine and Health Science, Erasmus University Medical Centre Rotterdam "EMCR", P.O. Box 1738, 3000 DR Rotterdam, Netherlands.
Heiligers
J P
JP
De Vries
P
P
Tom
B
B
Kapoor
K
K
Villalón
C M
CM
Saxena
P R
PR
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
C094643:A 61603; D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D013764:Tetrahydronaphthalenes