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The novel enterokinetic drug prucalopride was tested at various intravenous and oral doses in fasted dogs to assess: (i) the effects on colonic contractile motility patterns; and (ii) the mediation of these effects by 5-hydroxytryptamine (5-HT4) receptors. Colonic motility patterns were assessed in conscious dogs with four chronically implanted strain-gauge force transducers that were sutured on the serosal side of the colon. Prucalopride altered colonic contractile motility patterns in a dose-dependent fashion by stimulating high-amplitude clustered contractions in the proximal colon and by inhibiting contractile activity in the distal colon. Prucalopride was equipotent after oral and intravenous administration, as reflected by the values for the effective dose that induced 50% of maximum effect (95% confidence limits): 0.04 mg kg(-1) p.o. (0.01-0.1 mg kg(-1)) and 0.01 mg kg(-1) i.v. (0.006-0.04 mg kg(-1)). Prucalopride also caused a dose-dependent decrease in the time to the first giant migrating contraction (GMC); at higher doses of prucalopride, the first GMC generally occurred within the first half-hour after treatment. Subcutaneous pretreatment with the 5-HT4 receptor antagonist GR125487 (40 microg kg(-1) bodyweight) completely prevented the effects of orally administered prucalopride (0.31 mg kg(-1) bodyweight). Prucalopride, given orally or intravenously, alters colonic motility in the fasted conscious dog in a dose-dependent fashion. It induces GMCs and causes proximal colon stimulation and distal colon inhibition of contractile motility patterns by stimulating 5-HT4 receptors.

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.

1 This study aimed to characterize for the ®rst time in vitro 5-HT 4 receptors in the canine gastrointestinal tract. For this purpose, we used circular muscle strips of the canine isolated rectum. 2 In the presence of methysergide (60 mM), 5-HT induced relaxation of methacholine (1 mM)-precontracted muscle strips, yielding a monophasic sigmoidal concentration-relaxation curve (pEC 50 7.2+0.07). 3 Tetrodotoxin (0.3 mM) did not a ect the curve to 5-HT, suggesting the inhibitory 5-HT receptor is located on the smooth muscle. Granisetron (0.3 mM) did also not a ect the curve to 5-HT, which excludes the 5-HT 3 receptor mediating the relaxation to 5-HT. The presence of methysergide rules out the involvement of 5-HT 1 , 5-HT 2 or 5-HT 7 receptors. 4 5-HT, the selective 5-HT 4 receptor agonists R076186, prucalopride (R093877) and SDZ HTF-919 and the 5-HT 4 receptor agonists cisapride and 5-MeOT relaxed the muscle strips with a rank order of potency R076186=5-HT4cisapride4prucalopride5SDZ HTF-91945-MeOT. 5 The selective 5-HT 4 receptor antagonists GR 125487, RS 39604 and GR 113808 competitively antagonized the relaxations to 5-HT, yielding pK B estimates of 9.7, 7.9 and 9.1, respectively. The selective 5-HT 4 receptor antagonist SB 204070 shifted the curve to 5-HT rightward and depressed the maximal response (apparent pA 2 10.6). GR 113808 (10 nM) produced a parallel rightward shift of the curve to the selective 5-HT 4 receptor agonists R076186 (pA 2 8.8). 6 It is concluded that 5-HT induces relaxation of the canine rectum circular muscle through stimulation of a single population of smooth muscle 5-HT 4 receptors. For the ®rst time, a nonhuman species was shown to exhibit relaxant 5-HT 4 receptors in the large intestine.

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