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

• Published in: British journal of pharmacology Vol. 127; no. 3; pp. 609 - 616
• Main Authors: TERRON, J. A, FALCON-NERI, A
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.1999; Nature Publishing
• Subjects: 5‐HT7 receptor; 5‐hydroxytryptamine; Animals; Basilar artery; Basilar Artery - drug effects; Basilar Artery - physiology; Biological and medical sciences; Blood vessels and receptors; Cerebral Arteries - drug effects; Cerebral Arteries - physiology; Dinoprost - pharmacology; Dogs; Endothelium, Vascular - physiology; Female; Fundamental and applied biological sciences. Psychology; In Vitro Techniques; Male; middle cerebral artery; migraine; Muscle Relaxation - drug effects; Muscle Relaxation - physiology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Receptors, Serotonin - physiology; relaxation; Serotonin - analogs & derivatives; Serotonin - pharmacology; Serotonin Receptor Agonists - pharmacology; Spiperone - pharmacology; Sumatriptan - pharmacology; vascular smooth muscle; Vertebrates: cardiovascular system; Fissipedia; Carnivora; Serotonin; Smooth muscle; Serotonine receptor; Cerebral artery; In vitro; Vasodilation; Muscular relaxation; Vertebrata; Mammalia; Neuromediator; Blood vessel; Animal; Circulatory system; Dog
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0702580

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‐HT7 receptor. In arterial rings deprived of endothelium and pre‐contracted with prostaglandin F2α (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‐HT1B/1D and 5‐HT2A 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>>sumatriptanα‐methyl‐5‐HT. In dog basilar artery, pre‐incubated with GR127935 (1 μM) and ketanserin (0.1 μM) and pre‐contracted with prostaglandin F2α (2 μM), the 5‐HT7 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 (Emax), whilst the other drugs behaved as competitive antagonists with affinity values (pKB) that significantly correlated with their binding affinity (pKi) at recombinant 5‐HT7 receptors. These data disclosing the involvement of the 5‐HT7 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‐HT7 receptor affinity of migraine prophylactic 5‐HT antagonists. British Journal of Pharmacology (1999) 127, 609–616; doi:10.1038/sj.bjp.0702580