Pharmacological evidence for the 5-HT(7) receptor mediating smooth muscle relaxation in canine cerebral arteries

1. We investigated in the present study whether 5-HT is able to exert direct relaxant responses in canine basilar and middle cerebral arteries via the 5-HT(7) receptor. 2. In arterial rings deprived of endothelium and pre-contracted with prostaglandin F(2α) (2 μM), 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine, sumatriptan or α-methyl-5-HT produced further increase in tone and/or slight relaxation. Blockade of 5-HT(1B/1D) and 5-HT(2A) receptors with GR127935 (1 μM) and ketanserin (0.1 μM), respectively, antagonized the vasoconstrictor component of the response and unmasked a concentration-dependent relaxation to 5-HT, 5-CT and 5-methoxytryptamine; sumatriptan and α-methyl-5-HT remained inactive as relaxant agonists. The rank order of agonist potency in both arteries was 5-CT>5-HT>5-methoxytryptamine>>sumatriptan⩾α-methyl-5-HT. 3. In dog basilar artery, pre-incubated with GR127935 (1 μM) and ketanserin (0.1 μM) and pre-contracted with prostaglandin F(2α) (2 μM), the 5-HT(7) ligands, clozapine (1 μM), mesulergine (0.3 μM), methiothepin (3 nM), risperidone (3 nM), spiperone (1 μM) and LY215840 (10–100 nM), produced significant rightward shifts of the concentration-response curves for 5-HT and 5-CT. Only methiothepin and risperidone reduced significantly the maximum relaxant response (E(max)), whilst the other drugs behaved as competitive antagonists with affinity values (pK(B)) that significantly correlated with their binding affinity (pK(i)) at recombinant 5-HT(7) receptors. 4. These data disclosing the involvement of the 5-HT(7) receptor in cerebrovascular relaxation may be strongly relevant in the light of : (1) the involvement of 5-HT in migraine; (2) the putative linkage between cephalovascular vasodilatation and migraine headache; and (3) the relatively high 5-HT(7) receptor affinity of migraine prophylactic 5-HT antagonists