5-HT 4 receptors mediate relaxation of human colon circular muscle. However, after 5-HT 4 receptor blockade (SB 204070 10 nM), 5-HT still induced a relaxation (pEC 50 6.3). 5-HT 4 receptors were suciently blocked, as the curves to 5-HT obtained in the presence of 10 and 100 nM SB 204070 were indistinguishable. This 5-HT-induced relaxation was tetrodotoxin-insensitive, indicative 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-HT 1 or 5-HT 7 receptors. Mesulergine, a 5-HT 7 receptor antagonist at nanomolar concentrations, and a 5-HT 1 receptor antagonist at micromolar concentrations, competitively antagonized the 5-HT-induced relaxation (pK B 8.3) and antagonized the relaxation to 5-CT. Methysergide antagonized the 5-HT-induced relaxation (pA 2 7.6). It is concluded that the pro®le of the smooth muscle inhibitory 5-HT receptor resembles that of the 5-HT 7 receptor. These data provide the ®rst evidence for functional human 5-HT 7 receptors. Keywords: 5-HT 7 receptors; 5-HT; human; colon; circular muscle . However, the 5-HT-induced relaxation could not be ascribed to a homogeneous 5-HT 4 receptor population. The selective 5-HT 4 receptor antagonist GR113808 shifted the response curve to 5-HT rightward at nanomolar concentrations, but at higher concentrations, GR113808 did not shift the curve to 5-HT further, which was re¯ected in a decrease in pA 2 estimates with increasing concentrations of antagonist Tam et al., 1995). This suggests that the 5-HT-induced relaxation also involved a non-5-HT 4 receptor mechanism.Interestingly, we found that in the presence of 5-HT 4 receptor blockade (induced by SB 204070), 5-HT was still able to relax the carbachol-contracted tissue and in the current study we describe the characterization of this non-5-HT 4 receptor-mediated relaxation of human colonic circular muscle.

1Cisapride stimulates gastrointestinal motility, probably by enhancing the release of acetylcholine from myenteric nerve endings. Such an effect could be mediated via presynaptic muscarinic (Ml)-receptors. Our aim was to determine whether cisapride could antagonize the inhibitory effects of a M1-agonist, or mimic the effects of a M,-antagonist, pirenzepine.2 Longitudinal segments were suspended in Krebs solution (95% 02, 5% CG2, 37.5C) for isometric tension recording (preload 1 g) during electrical transmural stimulation (0.1 Hz, 1 ms, sub-or supramaximal current). 3 McN-A-343 (2.0 x 10-6M) reduced the contractile response to supramaximal stimulation (EC50 = 1.6 x 10-6 M), but had no effect on the contractions induced by exogenous acetylcholine. 4 The inhibitory effect of McN-A-343 on the contractile response to electrical stimulation could be reversed by pirenzepine (ECQ0 = 1.6 x 10-8M) but not by atropine. At these concentrations pirenzepine itself did not modify the contractile response to electrical stimulation. However, at 50 times higher concentrations pirenzepine inhibited the response to electrical stimulation as well as the response to exogenous acetylcholine (ECQ0 = 8.5 x 10-7 M).