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

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Abstract
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.