1. It has previously been shown that the antimigraine drug, sumatriptan, a putative 5-HT1D receptor agonist, decreases porcine common carotid and arteriovenous anastomotic blood flows, but slightly increases the arteriolar (capillary) blood flow to the skin and ears. Interestingly, such responses, being mediated by 5-HT1-like receptors, are resistant to blockade by metergoline, which, in addition to displaying a very high affinity for (and occasionally intrinsic efficacy at) the 5-HT1D receptor subtypes, blocks (with lower potency than methiothepin) some 5-HT1D receptor-mediated vascular responses. These findings raise doubts whether sumatriptan-sensitive 5-HT1-like receptors mediating changes in the distribution of porcine carotid blood flow are identical to cloned 5-HT1D receptors. With the recent advent of the potent and selective 5-HT1D receptor antagonist, GR127935, we have examined in the present study whether the carotid vascular effects of sumatriptan in the pig are amenable to blockade by GR127935. 2. In animals pretreated with saline, sumatriptan (30, 100 and 300 micrograms kg-1, i.v.) reduced the total carotid and arteriovenous anastomotic blood flows in a dose dependent manner. In contrast, sumatriptan increased blood flow to the skin, ears and fat, although the total capillary fraction was not significantly affected. 3. While GR127935 pretreatment (0.25 and 0.5 mg kg-1) itself slightly reduced the total carotid and arteriovenous anastomotic blood flows, carotid vasoconstrictor responses to sumatriptan were either partly (0.25 mg kg-1) or completely (0.5 mg kg-1) blocked by the compound. In GR127935 pretreated animals, the sumatriptan-induced increases in blood flow to the skin, ears and fat were also attenuated. 4. Taken together, the results suggest that arteriovenous anastomotic constriction and, possibly, arteriolar dilatation in the skin, ears and fat by sumatriptan are mediated by 5-HT1D receptors. Therefore, vascular 5-HT1-like receptors in the porcine carotid bed appear to be identical to 5-HT1D receptors.

Intravenous boluslinjections of 5-hydroxytryptamine (5-HT; 3, 10 and 30pgkg-'), 5-methoxytryptamine (5-MeO-T; 3, 10 and 30,ugkg-1), renzapride (BRL 24924; 3, 10, 30 and lOO1ugkg-1) and isoprenaline (0.03, 0.1 and 0.34ugkg-1) to anaesthetized pigs increased heart rate by, respectively, 22 + 3, 44 + 3 and 65 + 4 beatsmin -(5-HT; n = 17); 12 + 1, 26 + 2 and 44 + 4 beatsmin 1 (5-MeO-T; n = 15), 5 + 2, 11 ± 2, 18 + 4 and 37 + 5 beatsmin -(renzapride; n = 8) and 17 ± 2, 46 + 3 and 75 + 3 beatsmin -(isoprenaline; n = 13). The responses to 5-HT, 5-MeO-T and renzapride were antagonized by ICS 205-930 (1 and 3mg kg 1, i.v.), which did not modify the increases in heart rate by isoprenaline. Renzapride showed tachyphylaxis and attenuated the responses to 5-HT. These findings indicate that 5-HT elicits tachycardia in the pig by acting on a novel receptor, either similar or identical to the 5-HT4 receptor identified in mouse brain colliculi.

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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.