One specific example reflecting the completity ofcardiovascular responses induced by serotonin(5-hydroxytryptamine;5-HT)and the progress achieved inthe pharmacological characterization of the receptorsinvolved can be ...One specific example reflecting the completity ofcardiovascular responses induced by serotonin(5-hydroxytryptamine;5-HT)and the progress achieved inthe pharmacological characterization of the receptorsinvolved can be illustrated by the effects of 5-HT on thecanine external carotid artery bed.Within thisframework,it has been shown that the external carotidvasoconstrictor response to 5-HT in the dog is mediatedby'5-HT_(1)-like'receptors,which being blocked by the5-HT_(1B/1D)receptor antagonist GR127935,resemble 5-HT_(1B/1D)(previously called 5-HT_(1B/1D))receptors.It was proposed that these receptors coilld belong to the 5-HT_(lB),rather than the 5-HT_(lD),subtype on the basis of their resistance to blockade by a high dose of ritanserin(a potential 5-HT_(lD)receptor antagomst and the presence of mRNA for 5-HT_(lB)(5-HT_(lDB))receptors,but not for 5-HT_(lD)(5-HT_(lD))receptors,in vascalar smooth muscle.With the advent of subtype-selective antagonists it was subsequently shown that the external carotid vasocenstriction to 5-HT and surmantriptan is dose-dependently antagonized by the selective 5-HT_(lB)receptor antagonist SB224289[2,3,6.7-telrahydro-I'-methyl-5-[2'-methyl-4(5-methyl-1,2,4-oxadiazol-3-y1)biphenyl-4-carbonyl]]furo[2,3-f]indole-3-spiro-4'-piperidine hydrochloride],whereas the selective 5-HT_(lD)receptor antagonist BRL15572[l(3-chloropheny1)-4-[3,3-diphenyl(2-(S,R)hydroxypropany1)piperazine]hydrochloride was inefective.These findings represent the first in vivo evidence showing that vascular constriction induced by 5-HT and sumatriptan is mediated primarily via 5-HT_(lB),but not 5-HT_(lD)receptors.The pharmacological profile of these receptors could be similar(isolated human temporal artery and porcine carotid arteriovenous anastomoses)to other putative 5-HT_(lB)receptors mediating vasoconstrictor responses.In view of the putative pathophysiologic role of external carotid(and extracerebral)vasodilation in migraine,the constriction of these blood vessels by sumatriptan via 5-HT_(lB)receptors may be,at least partly,responsible for its therapeutic efficacy in migraine.展开更多
基金Project supported by Consejo Nacional de Ciencia y Tecnologia(Mexico City)
文摘One specific example reflecting the completity ofcardiovascular responses induced by serotonin(5-hydroxytryptamine;5-HT)and the progress achieved inthe pharmacological characterization of the receptorsinvolved can be illustrated by the effects of 5-HT on thecanine external carotid artery bed.Within thisframework,it has been shown that the external carotidvasoconstrictor response to 5-HT in the dog is mediatedby'5-HT_(1)-like'receptors,which being blocked by the5-HT_(1B/1D)receptor antagonist GR127935,resemble 5-HT_(1B/1D)(previously called 5-HT_(1B/1D))receptors.It was proposed that these receptors coilld belong to the 5-HT_(lB),rather than the 5-HT_(lD),subtype on the basis of their resistance to blockade by a high dose of ritanserin(a potential 5-HT_(lD)receptor antagomst and the presence of mRNA for 5-HT_(lB)(5-HT_(lDB))receptors,but not for 5-HT_(lD)(5-HT_(lD))receptors,in vascalar smooth muscle.With the advent of subtype-selective antagonists it was subsequently shown that the external carotid vasocenstriction to 5-HT and surmantriptan is dose-dependently antagonized by the selective 5-HT_(lB)receptor antagonist SB224289[2,3,6.7-telrahydro-I'-methyl-5-[2'-methyl-4(5-methyl-1,2,4-oxadiazol-3-y1)biphenyl-4-carbonyl]]furo[2,3-f]indole-3-spiro-4'-piperidine hydrochloride],whereas the selective 5-HT_(lD)receptor antagonist BRL15572[l(3-chloropheny1)-4-[3,3-diphenyl(2-(S,R)hydroxypropany1)piperazine]hydrochloride was inefective.These findings represent the first in vivo evidence showing that vascular constriction induced by 5-HT and sumatriptan is mediated primarily via 5-HT_(lB),but not 5-HT_(lD)receptors.The pharmacological profile of these receptors could be similar(isolated human temporal artery and porcine carotid arteriovenous anastomoses)to other putative 5-HT_(lB)receptors mediating vasoconstrictor responses.In view of the putative pathophysiologic role of external carotid(and extracerebral)vasodilation in migraine,the constriction of these blood vessels by sumatriptan via 5-HT_(lB)receptors may be,at least partly,responsible for its therapeutic efficacy in migraine.
