5‐HT1‐like receptors requiring functional cyclo‐oxygenase and 5‐HT2 receptors independent of cyclo‐oxygenase mediate contraction of the human umbilical artery

1 The interactions between 5‐hydroxytryptamine (5‐HT) and the antagonists ketanserin, methysergide and phentolamine were studied in isolated preparations of human umbilical artery (HUA) at physiological oxygen tension (Po2 ∽ 15 mmHg) and at high Po2 (∽ 120 mmHg). 2 At physiological Po2 ketanserin, methysergide and phentolamine behaved as silent competitive antagonists of the 5‐HT‐induced contraction of HUA. pA2 values calculated by Schild analysis were 8.92, 8.52 and 6.37, respectively. 3 At high Po2, 5‐HT‐induced contractions were antagonised in a biphasic manner by ketanserin (0.1 μm); the response to low but not to high concentrations of 5‐HT was resistant to blockade by ketanserin. The ketanserin‐resistant component was abolished following cyclo‐oxygenase inhibition by indomethacin (1 μm). 4 At high Po2, methysergide behaved as a partial agonist. Methysergide‐induced contractions were inhibited but not abolished by indomethacin, and resistant to 5‐HT2 receptor and α1‐adrenoceptor blockade. 5 At high Po2 the component of the response to 5‐HT mediated by the ketanserin‐resistant receptor was mimicked by the selective 5‐HT1‐like receptor agonist 5‐carboxamidotryptamine (5‐CT): 5‐CT was 7 fold more potent than 5‐HT. 6 At high Po2 the component of the response to 5‐HT mediated by the ketanserin‐resistant receptor was antagonised by phentolamine and the selective α2‐adrenoceptor antagonist Wy 26703. 7 These results suggest that (i) at physiological Po2 5‐HT2 receptors almost exclusively mediate contractions induced by 5‐HT, and (ii) at high Po2 the agonist potency order of 5‐CT > 5‐HT > methysergide suggests that ketanserin‐resistant responses are mediated by 5‐HT1‐like receptors which require functional cyclo‐oxygenase.