Evidence for 5-HT7 receptors mediating relaxation of human colonic circular smooth muscle

5-HT4 receptors mediate relaxation of human colon circular muscle. However, after 5-HT4 receptor blockade (SB 204070 10 nM), 5-HT still induced a rela xation (pEC(50) 6.3). 5-HT4 receptors were sufficiently blocked, as the cur ves to 5-HT obtained in the presence of 10 and 100 nM SE 204070 were indist inguishable. This 5-HT-induced relaxation was tetrodotoxin-insensitive, ind icative of a smooth muscle relaxant 5-HT receptor. This, and the rank order of potency (5-CT = 5-MeOT = 5-HT) suggested involvement of 5-HT1 or 5-HT7 receptors. Mesulergine, a 5-HT7 receptor antagonist at nanomolar concentrat ions, and a 5-HT1 receptor antagonist at micromolar concentrations, competi tively antagonized the 5-HT-induced relaxation (pK(B) 8.3) and antagonized the relaxation to 5-CT. Methysergide antagonized the 5-HT-induced relaxatio n (pA(2) 7.6). It is concluded that the profile of the smooth muscle inhibi tory 5-HT receptor resembles that of the 5-HT7 receptor. These data provide the first evidence for functional human 5-HT7 receptors.