Blockade of porcine carotid vascular responses to sumatriptan by GR127935, a selective 5‐HT_1D receptor antagonist

Abstract

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.

Investigations with GMC2021 in experimental models predictive of antimigraine activity and coronary side-effect potential

“…The effects of GMC2021 were qualitatively similar to, but less than those observed with sumatriptan in the same experimental model ( Fig. 3; see also Den Boer et al, 1991a;De Vries et al, 1996). The EDs0 of GMC2021 and sumatriptan in decreasing arteriovenous anastomotic blood flow were, respectively, 1.1 + 0.3 txmol • kg -1 (present experiments) and 0.16___ 0.04 Ixmol • kg-~ .…”

“…has often been reported with sumatriptan Den Boer et al, 1991a, 1992De Vries et al, 1996); in similar experiments no changes in heart rate occurred after four consecutive bolus injections of saline (Den Boer et al, 1991a). The mechanism involved in the rather small decrease in heart rate by sumatriptan (or GMC2021) is not clear, but may be related to presynaptic inhibition of sympathetic neurons (Humphrey et al, 1988(Humphrey et al, , 1990 or central 5-HT m receptor activation (Dreteler et al, 1989;Saxena and Villalrn, 1990).…”

“…3). The partial blockade of the vasoconstrictor effect of GMC2021 cannot be explained by the decrease in the baseline value (see Table 2), due to the agonist action of GR127935 (Pauwels and Colpaert, 1995;Watson et al, 1995;De Vries et al, 1996). While this decrease in the baseline will tend to exaggerate the effects of GMC2021 expressed as percentage change from baseline, the effect expressed in absolute values (i.e.…”

“…The EDs0 of GMC2021 in decreasing arteriovenous anastomotic blood flow in the 6 saline-pre-treated animals was found to be 467 _ 128 txg • kg -] (1.1 _ 0.3 Ixmol" kg -1) and with the highest dose (1000 txg • kg-J ) the decrease amounted to be 67 __+ 4%. In animals pre-treated with GR127935 (0.5 mg • kg-1), where the baseline values of arteriovenous anastomotic blood flow were less than in saline-pre-treated animals due to its partial agonist action (see De Vries et al, 1996), the GMC2021-induced decreases in the total carotid blood flow and its arteriovenous anastomotic fraction were reduced (the decrease in arteriovenous anastomotic blood flow by the highest dose was 29 + 8%) and the GMC2021-induced increase in the capillary blood flow was completely blocked (see Fig. 3; upper panels).…”

“…Evidence is now emerging that this vascular 5-HTl-like receptor may be identical to the recombinant 5-HTtD, most probably 5-HT1Dt3 , receptor. Thus, the mRNA for the 5-HT~D ~, but not that for 5-HT1D~, receptor is present in cranial blood vessels (Hamel et al, 1993) and the vasoconstriction by sumatriptan, which has a high affinity for 5-HT m receptors (Peroutka and McCarthy, 1989;Beattie et al, 1994), is antagonized by GR127935, a selective I H 5-HTID receptor antagonist (Skingle et al, 1993;Clitherow et al, 1994;De Vries et al, 1996).…”