5-HT receptors mediating external carotid vasoconstriction in vagosympathectomized dogs

One specific example reflecting the complexity of cardiovascular responses induced by serotonin (5-hydroxytryptamine; 5-HT) and the progress achieved in the pharmacological characterization of the receptors involved can be il lustrated by the effects of 5-HT on the canine external carotid artery bed. Within this framework, it has been shown that the external carotid vasocon strictor response to 5-HT in the dog is mediated by '5-HT1-like' receptors, which being blocked by the 5-HT1B/1D receptor antagonist GR127935, resembl e 5-HT1B/1D (previously called 5-HT1D beta/1D alpha) receptors. It was prop osed that these receptors could belong to the 5-HT1B, rather than the 5-HT1 D, subtype on the basis of their resistance to blockade by a high dose of r itanserin (a potential 5-HT1D receptor antagonist) and the presence of mRNA for 5-HT1B (5-HT1D beta) receptors, but not for 5-HT1D(5-HT1D alpha) recep tors, in vascular smooth muscle. With the advent of subtype-selective antag onists it was subsequently shown that the external carotid vasoconstriction to 5-HT and sumatriptan is dose-dependently antagonized by the selective 5 -HT1B receptor antagonist SB224289 {2,3,6,7-tetrahydro-1'-methyl-5-[2'-meth yl-4' (5-methyl-1,2,4-oxadiazol-3-yl) biphenyl-4-carbonyl] furo [2,3-f] ind ole-3-spiro-4'-piperidine hydrochloride}, whereas the selective 5-HT1D rece ptor antagonist BRL15572 {1-(3-chlorophenyl)-4-[3, 3-diphenyl (2-(S, R)hydr oxypropanyl) piperazine] hydrochloride} was ineffective. These findings represent the first in vivo evidence showing that vascular c onstriction induced by 5-HT and sumatriptan is mediated primarily via 5-HT1 B, but not 5-HT1D receptors. The pharmacological profile of these receptors could be similar (isolated human temporal artery and porcine carotid arter iovenous anastomoses) to other putative 5-HT1B receptors mediating vasocons trictor responses. In view of the putative pathophysiologic role of externa l carotid (and extracerebral) vasodilation in migraine, the constriction of these blood vessels by sumatriptan via 5-HT1B receptors may be, at least p artly, responsible for its therapeutic efficacy in migraine.