1 Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive trigeminal sensory nerves, seems to be involved in the pathogenesis of migraine. Hence, CGRP receptor antagonists may serve as a novel treatment for migraine. This study was therefore designed to investigate the effects of BIBN4096BS (100, 300 and 1000 mg kg À1 , i.v.), a potent and selective CGRP receptor antagonist, on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Both vagosympathetic trunks were cut and phenylephrine was infused into the carotid artery (i.c.) to support carotid vascular tone. 2 Infusions of capsaicin (0.3, 1, 3 and 10 mg kg À1 min À1 , i.c.) did not alter the heart rate, but dosedependently increased the mean arterial blood pressure. This moderate hypertensive effect was not modified by BIBN4096BS. 3 Capsaicin infusion (10 mg kg À1 min À1 , i.c.) increased total carotid, arteriovenous anastomotic and tissue blood flows and conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dosedependently blocked by BIBN4096BS. 4 Capsaicin infusion (10 mg kg À1 min À1 , i.c.) more than doubled the jugular venous plasma concentration of CGRP. This effect was not blocked, but rather increased, by BIBN4096BS. 5 The above results show that BIBN4096BS behaves as a potent antagonist of capsaicin-induced carotid haemodynamic changes that are mediated via the release of CGRP. Therefore, this compound may prove effective in the treatment of migraine.

1 Vasoconstriction of carotid arteriovenous anastomoses may be involved in the therapeutic action of acutely acting antimigraine agents, including the triptans and ergot alkaloids. While 5-HT 1B/1D receptors mediate the e ect of triptans, ergotamine and dihydroergotamine also interact with aadrenoceptors. In the present study, we investigated the potential role of a 1 -and a 2 -adrenoceptors in mediating vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. 2 Ten minute intracarotid infusions of phenylephrine (1, 3 and 10 mg kg 71 min 71 ) or BHT 933 (3, 10 and 30 mg kg 71 min 71 ) produced dose-dependent decreases in total carotid and arteriovenous anastomotic conductances; no changes were observed in the capillary fraction. 3 The carotid vascular e ects of phenylephrine and BHT 933 were selectively abolished by prazosin (100 mg kg 71 , i.v.) and rauwolscine (300 mg kg 71 , i.v.), respectively. The responses to phenylephrine and BHT 933 were not a ected by the selective 5-HT 1B/1D receptor antagonist GR127935 (500 mg kg 71 , i.v.). 4 These results show that both a 1 -and a 2 -adrenoceptors can mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Since vasoconstrictor activity in this in vivo model is predictive of anti-migraine activity, an agonist activity at particularly the a 2 -adrenoceptor subtypes, in view of their less ubiquitous nature, could provide migraine abortive potential. Thus, the present results may aid further understanding of the mode of action of some current antimigraine agents and may eventually be helpful in the development of future treatment in migraine. Keywords: a-Adrenoceptors; arteriovenous anastomoses; BHT 933; carotid artery; migraine; phenylephrine; pig; prazosin; rauwolscine; shunts Abbreviations: AVA, arteriovenous anastomotic; A-VSO 2 , di erence between arterial and jugular venous oxygen saturation; BHT 933,6,7, azepin-2-amine dihydrochloride; GR127935, N-[methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide hydrochloride; 5-HT, 5-Hydroxytryptamine

1 It has previously been shown that the antimigraine drug sumatriptan constricts porcine carotid arteriovenous anastomoses via 5-HT 1 -like receptors, identical to 5-HT 1B/1D receptors. The recent availability of silent antagonists selective for the 5-HT 1B (SB224289) and 5-HT 1D (BRL15572) receptor led us to further analyse the nature of receptors involved.

1 It has recently been shown that both a 1 -and a 2 -adrenoceptors mediate vasoconstriction in the canine external carotid circulation. The present study set out to identify the speci®c subtypes (a 1A , a 1B and a 1D as well as a 2A , a 2B and a 2C ) mediating the above response. 2 Consecutive 1 min intracarotid infusions of phenylephrine (a 1 -adrenoceptor agonist) and BHT933 (a 2 -adrenoceptor agonist) produced dose-dependent decreases in external carotid blood ow, without aecting mean arterial blood pressure or heart rate. 3 The responses to phenylephrine were selectively antagonized by the antagonists, 5-methylurapidil (a 1A ) or BMY7378 (a 1D ), but not by L-765,314 (a 1B ), BRL44408 (a 2A ), imiloxan (a 2B ) or MK912 (a 2C ). In contrast, only BRL44408 or MK912 aected the responses to BHT933. 4 The above results support our contention that mainly the a 1A , a 1D , a 2A and a 2C -adrenoceptor subtypes mediate vasoconstriction in the canine external carotid circulation.