Presence of vasoconstrictor 5HT1‐like receptors revealed by precontraction of rabbit isolated mesenteric artery

• Published in: British journal of pharmacology 1995-01, Vol.114 (2), p.309-314
• Main Authors: Choppin, A., O'Connor, S.E.
• Format: Article
• Language: English
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 5‐carboxamidotryptamine (5‐CT); 5‐HT1D receptors; 5‐HT1‐like receptors; 5‐hydroxytryptamine (5‐HT); Animals; Biological and medical sciences; Blood vessels and receptors; Fundamental and applied biological sciences. Psychology; In Vitro Techniques; Male; Mesenteric Arteries - drug effects; Mesenteric Arteries - physiology; Muscle Contraction - drug effects; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Potassium Chloride - pharmacology; Prostaglandin Endoperoxides, Synthetic - pharmacology; rabbit isolated mesenteric arteries; Rabbits; Receptors, Serotonin - drug effects; Receptors, Serotonin - physiology; Serotonin - analogs & derivatives; Serotonin - pharmacology; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology; sumatriptan; Sumatriptan - pharmacology; Thromboxane A2 - analogs & derivatives; Thromboxane A2 - pharmacology; vasoconstriction; Vasoconstriction - drug effects; Vasoconstriction - physiology; Vasoconstrictor Agents - pharmacology; vasoconstrictor synergy; Vertebrates: cardiovascular system
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1995.tb13228.x

1 A series of 5‐hydroxytryptamine (5‐HT) receptor agonists including 5‐HT, 5‐carboxamidotryptamine (5‐CT) and sumatriptan produced little or no contraction of rabbit isolated mesenteric arteries under resting tone conditions, even at concentrations up to 10−4m. 2 When the same agonists were retested in mesenteric artery preparations pre‐contracted with the thromboxane‐mimetic, U46619, each demonstrated concentration‐related vasoconstrictor activity. 5‐CT and 5‐HT were especially potent and effective in this model giving EC50 values of 4.3 times 10−9 m and 1.6 times 10−8 m respectively and maximum effects equivalent to those of KC1 80 mm. In preparations precontracted by U46619 (conditions retained throughout the rest of the study) the order of agonist potency was 5‐CT>5‐HT>RU 24969 = sumatriptan>8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OHDPAT) > cisapride. 3 The vasoconstrictor effects of 5‐CT were competitively antagonized by methiothepin (pA2 8.20) but resistant to antagonism by a range of other 5‐HT receptor antagonists, i.e. pindolol (5‐HT1A/5‐HT1B), propranolol (5‐HT1B), spiperone (5‐HT2A), ondansetron (5‐HT3), ICS 205930 (5‐HT3/5‐HT4) and SDZ 205557 (5‐HT4). 5‐CT responses were slightly antagonized by a high concentration of ritanserin (5‐HT2A/5‐HT2C). Responses to 5‐HT and sumatriptan were also antagonized by methiothepin with similar affinity (pA2/pKB values ⋍ 8.0). 4 Metergoline and rauwolscine (10−7 −10−6m) antagonized the effects of 5‐CT in a non‐competitive fashion giving pKBapp values of 7.13 (metergoline) and 6.86 (rauwolscine). 5 Vasoconstrictor responses to 5‐HT were not modified in the presence of ritanserin (3 times 10−7 m) or spiperone (3 times 10−7m) and only modestly antagonized by ketanserin (10−6m) suggesting that 5‐HT2A receptors do not make a significant contribution in this model. 6 Hence, precontraction of rabbit mesenteric arteries reveals potent vasoconstrictor effects of 5‐HT and related agonists. Based on the agonist potency order and the antagonist studies performed, the receptor subtype responsible has the characteristics of a 5‐HT1‐like (probably 5‐HT1D) receptor. This study therefore demonstrates a particularly striking example of vasoconstrictor synergy involving 5‐HT1‐like receptors.