BLOCKADE OF PORCINE CAROTID VASCULAR-RESPONSES TO SUMATRIPTAN BY GR127935, A SELECTIVE 5-HT1D RECEPTOR ANTAGONIST

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 resistan t 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 doub ts whether sumatriptan-sensitive 5-HT1-like receptors mediating change s in the distribution of porcine carotid blood flow are identical to c loned 5-HT1D receptors. With the recent advent of the potent and selec tive 5-HT1D receptor antagonist, GR127935, we have examined in the pre sent 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 mu g kg(-1), i.v.) reduced the t otal carotid and arteriovenous anastomotic blood flows in a dose depen dent manner. In contrast, sumatriptan increased blood flow to the skin , ears and fat, although the total capillary fraction was not signific antly affected. 3 While GR127935 pretreatment (0.25 and 0.5 mg kg(-1)) itself slightly reduced the total carotid and arteriovenous anastomot ic blood flows, carotid vasoconstrictor responses to sumatriptan were either partly (0.25 mg kg(-1)) or completely (0.5 mg kg(-1)) blocked b y the compound. In GR127935 pretreated animals, the sumatriptan-induce d increases in blood flow to the skin, ears and fat were also attenuat ed. 4 Taken together, the results suggest that arteriovenous anastomot ic constriction and, possibly, arteriolar dilatation in the skin, ears and fat by sumatriptan are mediated by 5-HT,, receptors. Therefore, v ascular 5-HT1-like receptors in the porcine carotid bed appear to be i dentical to 5-HT1D receptors.