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1 The 5-hydroxytryptamine (5-HT) receptor mediating contraction of endothelium denuded human basilar artery has been characterized in vitro. 2 5-HT and a variety of 5-HT agonists contracted human isolated basilar artery with a rank order of agonist potency, 5-carboxamidotryptamine (5-CT) > 5-HT methysergide > GR43175 > 8-OHDPAT > 2-methyl-5-HT. The maximum response produced by these agonists differed. 3 None of the agonists relaxed human basilar artery when tone was elevated with prostaglandin F2U,, indeed further contraction was seen.4 The contractile responses of human basilar artery to 5-HT and the selective 5-HT1-like agonist GR43175 were highly reproducible whilst those to 5-CT were not. 5 The contractile response to both 5-HT and GR43175 was resistant to antagonism by ketanserin and GR38032, thus excluding activation of 5-HT2 and 5-HT3 receptors. The contractile action of 5-HT and GR43175 was also not antagonized by (±)-cyanopindolol, excluding the activation of receptors similar to 5-HTlA and 5-HTlB recognition sites identified in ligand binding studies. 6 In marked contrast, methiothepin was a potent antagonist of the contractile actions of both 5-HT and GR43175, with a pA2 value of 8.8 against both agonists. Methiothepin (lOOnM) had no effect on the contractile response to the thromboxane A2-mimetic U46619. 7 We conclude that 5-HT and GR43175 contract the human isolated basilar artery by activating the same receptor type. This receptor appears identical to the 5-HT1-like receptor causing contraction of the dog isolated saphenous vein and cerebral blood vessels from the dog and primate.

There is a considerable literature to suggest that adenosine A1 receptor agonists may have anti-nociceptive effects, and we sought to explore the role of adenosine A1 receptors in a model of trigeminovascular nociceptive transmission. Cats were anaesthetized (alpha-chloralose 60 mg/kg, intraperitoneally), and prepared for physiological monitoring. The superior sagittal sinus (SSS) was stimulated electrically, and linked units were recorded in the trigeminocervical complex. Post-stimulus histograms were constructed to analyse the responses and the effect of drug administration. Blood was sampled from the external jugular vein to determine levels of calcitonin gene-related peptide (CGRP) release before and after drug administration. Intravenous administration of the highly selective adenosine A1 receptor agonist, GR79236 (3-100 microg/kg) had a dose-dependent inhibitory effect on SSS-evoked trigeminal activity. The maximal effect (80 +/- 6% reduction in probability of firing) was seen at 100 microg/kg. The neuronal inhibitory effect of GR79236 could be inhibited by the selective adenosine A1 receptor antagonist DPCPX (300 microg/kg; P < 0.05). SSS stimulation increased cranial CGRP levels from 33 +/- 2 pmol/l (n = 6) to 64 +/- 3 pmol/l, an effect substantially reduced by pre-treatment with GR79236 (30 microg/kg; P < 0.01). The selective low efficacy adenosine A1 receptor agonist, GR190178 (30-1000 microg/kg i.v.), also inhibited SSS-evoked neuronal activity in a dose-dependent fashion. In this model of trigeminovascular nociception, adenosine A1 receptor activation leads to neuronal inhibition without concomitant vasoconstriction, suggesting a novel avenue for the treatment of migraine and cluster headache.

1 The aim of this study was to characterize the 5-hydroxytryptamine (5-HT) receptor which mediates contraction of canine and primate isolated basilar artery by use of a variety of selective 5-HT agonists and antagonists. 2 5-HT, a-methyl 5-HT and the selective 5-HT1-like receptor agonists, GR43175 and 5-carboxamidotryptamine (5-CT), each caused contraction of canine and primate basilar artery with a rank order of agonist potency of 5-CT > 5-HT > GR43175 > a-methyl 5-HT. The 5-HT1-Iike receptor agonists, GR43175 and 5-CT, produced maximum effects which were less than that produced by 5-HT or a-methyl 5-HT. 3 In canine basilar artery, ketanserin (0.1-1 kM) caused some depression of the maximum effect of 5-HT but produced little or no shift of the concentration-effect curve. The contractile effects of GR43175 were not modified by ketanserin (1 M), MDL72222 (1 M) or cyanopindolol (1 pM). However, the effects of 5-HT and GR43175 were specifically antagonized by methiothepin (0.1 pM); the mean agonist concentration-ratios were 33 and 48 respectively. 4 In primate basilar artery, ketanserin (1 M) again caused a small depression of the 5-HT maximum response but had no effect against GR43175-induced contractions. In contrast, methiothepin (0.1 yM) antagonized both 5-HT-and GR43175-induced contractions; the mean agonist concentration-ratios were 35 for both. 5 These results demonstrate that a large component of the effects of 5-HT in canine and primate basilar artery is produced by stimulation of a 5-HT1-like receptor. This receptor can be characterized by the high potency of the novel, selective agonist, GR43175, and susceptibility to blockade by methiothepin. However, there also appears to be a population of 5-HT2 receptors in these prepAarations which contribute to the contractile effects of 5-HT.

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1 We have investigated the influence of endothelial damage on the cerebrovascular reactivity to 5-hydroxytryptamine (5-HT) and some selective 5-HT agonists in canine basilar artery. 2 5-HT, a-methyl 5-HT, GR 43175 (3-[2-dimethyl amino] ethyl-N-methyl-1H-indole-5-methane sulphonamide) and 5-carboxamidotryptamine (5-CT) produced concentration-dependent contractions of untreated dog basilar artery with a functional endothelium. Following endothelial damage by perfusion with Triton X-100 (0.1%), which abolished the relaxant response to substance P. the maximum contractile effect of 5-HT, a-methyl 5-HT, GR 43175 and 5-CT was markedly enhanced although there was little change in the EC50 values. Endothelial damage did not modify the vasoconstrictor effect of the thromboxane agonist, U46619, or potassium chloride. 3 Neither 5-HT nor 5-CT caused relaxation of untreated canine basilar arteries contracted with prostaglandin F2I, U46619, uridine triphosphate or potassium chloride. 4 These results suggest that canine basilar artery spontaneously releases endothelium-derived relaxing factor which can attenuate the vasoconstrictor effect of 5-HT and selective 5-HT agonists. This effect appeared to be specific since the vasoconstrictor response to U46619 was not modified. 5 These results demonstrate that the cerebrovascular endothelium can markedly influence the reactivity of the vascular smooth muscle of canine basilar artery to 5-HT and 5-HT1-like receptor agonists. However we could find no evidence that 5-HT receptor activation stimulates endothelial cell function as it does in some other blood vessels.