Pharmacological evidence for the 5‐HT₇ receptor mediating smooth muscle relaxation in canine cerebral arteries

Abstract

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 2a (2 mM), 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine, sumatriptan or a-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 mM) and ketanserin (0.1 mM), respectively, antagonized the vasoconstrictor component of the response and unmasked a concentration-dependent relaxation to 5-HT, 5-CT and 5-methoxytryptamine; sumatriptan and a-methyl-5-HT remained inactive as relaxant agonists. The rank order of agonist potency in both arteries was 5-CT45-HT45-methoxytryptamine44sumatriptan5a-methyl-5-HT. 3 In dog basilar artery, pre-incubated with GR127935 (1 mM) and ketanserin (0.1 mM) and precontracted with prostaglandin F 2a (2 mM), the 5-HT 7 ligands, clozapine (1 mM), mesulergine (0.3 mM), methiothepin (3 nM), risperidone (3 nM), spiperone (1 mM) and LY215840 (10 ± 100 nM), produced signi®cant rightward shifts of the concentration-response curves for 5-HT and 5-CT. Only methiothepin and risperidone reduced signi®cantly the maximum relaxant response (E max ), whilst the other drugs behaved as competitive antagonists with a nity values (pK B ) that signi®cantly correlated with their binding a nity (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 a nity of migraine prophylactic 5-HT antagonists.

5-HT7 receptor-mediated dilatation in the middle meningeal artery of anesthetized rats

“…These data might provide support to the contention that 5-HT promotes cranial dilatation and migraine via activation of 5-HT 7 receptors (Terrón and Falcón-Neri, 1999;Terrón, 2002). Effect of the topical administration of 5-CT on conductance in the middle meningeal artery of anesthetized rats pretreated either with physiological saline (A), GR-127935 (B), SB-269970 (C), or GR-127935 + SB-269970 (GR + SB; D).…”

“…On the basis of these and other observations, it was postulated that the 5-HT 7 receptor could be a target of endogenous 5-HT to promote cranial vasodilatation during migraine attacks (Terrón and Falcón-Neri, 1999;Terrón, 2002). The present study in anesthetized rats provides evidence that such a dilator mechanism involving the 5-HT 7 receptor may operate in the middle meningeal artery and therefore be of relevance in the pathogenesis and treatment of migraine.…”

“…It has been demonstrated that activation of the 5-HT 7 receptor mediates dilatation in cranial vessels, including the dog basilar and middle cerebral artery (Terrón and Falcón-Neri, 1999), the porcine pial vein (Ishine et al, 2000) and the canine carotid circulation (Villalón et al, 1997). On the basis of these and other observations, it was postulated that the 5-HT 7 receptor could be a target of endogenous 5-HT to promote cranial vasodilatation during migraine attacks (Terrón and Falcón-Neri, 1999;Terrón, 2002).…”

“…However, a key issue to be resolved is how such increased levels of 5-HT could promote dilatation of cranial vessels. In this regard, our group demonstrated for the first time that 5-HT is actually capable of producing vasodilatation in cranial vessels via the activation of 5-HT 7 receptors (Terrón and Falcón-Neri, 1999), a finding which could explain, at least in part, the beneficial effects of migraine prophylactic 5-HT receptor antagonists (Terrón, 2002).…”

“…Evidence has been provided that cranial vasodilatation may be an important mechanism in migraine (Saxena and Ferrari, 1989;Terrón and Falcón-Neri, 1999) and that attacks could be evoked by a massive release of 5-HT in the brain (Fozard and Kalkman, 1994;Hamel and Saxena, 2000;Humphrey, 1991). However, a key issue to be resolved is how such increased levels of 5-HT could promote dilatation of cranial vessels.…”