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Quantification of different levels of 5-hydroxytryptamine(4) (5-HT(4)) receptor agonism expression across animal species as well as across organs within the same animal species offers substantial potential for the separation of desired gastrointestinal versus undesired cardiac pharmacological activity of compounds in development. Since a detailed investigation of such properties is lacking to date, we set out to quantify gastric and cardiac effects of 5-HT(4) receptor ligands in the pig, a model considered to be representative for the human situation. An in vitro test was developed to study the potentiating effect of 5-HT, prucalopride, tegaserod, R149402 (4-amino-5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid [3-hydroxy-1-(3-methoxy-propyl)-piperidin-4ylmethyl]-amide), and R199715 (4-amino-5-chloro-2,3-dihydro-benzofuran-7-carboxylic acid [3-hydroxy-1-(3-methoxy-propyl)-piperidin-4ylmethyl]-amide) on electrically induced cholinergic contractions in longitudinal muscle strips of the proximal stomach. The results were compared with inotropic and chronotropic effects of these compounds in the electrically paced left atrium and spontaneously beating right atrium, respectively. To quantify the observed tissue-dependent responses, a nonlinear mixed-effects model based on the operational model of agonism was developed and successfully fitted to the data. The model quantified the tissue-dependent partial agonism of the selective 5-HT(4) receptor agonists prucalopride, R149402, and R199715, whereas tegaserod and 5-HT were equiefficacious. The model was further extended to incorporate the responses to prucalopride in the presence of the 5-HT(4) receptor antagonist GR113808 ([1-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl-]methyl 1-methyl-1H-indole-3-carboxylate). The results indicate that these interactions do not follow a simple competitive pattern and that they differ between stomach and left atrium.

5‐HT4receptors mediate relaxation of human colon circular muscle. However, after 5‐HT4receptor blockade (SB 204070 10 nM), 5‐HT still induced a relaxation (pEC506.3). 5‐HT4receptors were sufficiently blocked, as the curves to 5‐HT obtained in the presence of 10 and 100 nMSB 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‐HT1or 5‐HT7receptors. Mesulergine, a 5‐HT7receptor antagonist at nanomolar concentrations, and a 5‐HT1receptor antagonist at micromolar concentrations, competitively antagonized the 5‐HT‐induced relaxation (pKB8.3) and antagonized the relaxation to 5‐CT. Methysergide antagonized the 5‐HT‐induced relaxation (pA27.6). It is concluded that the profile of the smooth muscle inhibitory 5‐HT receptor resembles that of the 5‐HT7receptor. These data provide the first evidence for functional human 5‐HT7receptors.

Vagal stimulation of the stomach induces a relaxation mediated via non-adrenergic, non-cholinergic (NANC) nerves. The neurotransmitter which is responsible for this relaxation is still unknown. To determine whether nitric oxide (NO) or a NO related substance mediates this relaxation, an intact guinea-pig stomach was mounted in an organ bath, with electrodes surrounding the vagal nerves.

In a previous study we showed that the relaxations induced after vagal stimulation of the guinea-pig stomach are mediated via nitric oxide (NO) or a NO-related substance. Intra-arterial injection (i.a.) of 5-hydroxytryptamine (5-HT) also induced relaxations in the guinea-pig stomach. Since it has been shown that in the guinea-pig colon 5-HT-induced relaxations are mediated via NO the aim of this study was to establish whether NO is involved in the 5-HT-induced relaxations in the guinea-pig stomach. Intra-arterial injection of 5-HT induced dose-dependent relaxations of the stomach. Since atropine and a- and ß-adrenoceptor blocking agents did not influence the relaxation and since tetrodotoxin (TTX) blocked the relaxations, this effect is mediated via NANC-neurons. Administration of a NO-synthase-inhibitor NG-nitro-l-arginine (L-NNA) concentration-dependently reduced the 5-HT-induced relaxations. Haemoglobin (a NO-scavanger) did not affect the relaxations to 5-HT, while addition of methylene blue, an inhibitor of soluble guanylate cyclase, reduced the relaxations by 50%. Addition of an opioid receptor agonist (loperamide), a 5-HT1 antagonist (methiothepin or metergoline) or a 5-HT4 receptor agonist (cisapride) or-antagonist (tropisetron in micromolar concentrations) inhibited the 5-HT-induced relaxations. Neither the 5-HT4 receptor agonist renzapride, nor the novel 5-HT4 receptor antagonist SDZ 205-557, affected the relaxations to 5-HT. These data indicate that 5-HT-induced relaxations of the guinea-pig stomach are mediated via NANC-inhibitory nerves on which inhibitory opioid-receptors are present. The use of selective agonists and antagonists indicates that 5-HT does not act via 5-HT2, 5-HT3 or 5-HT4 receptors. 5-HT may act via 5-HT1 receptors but the subtype involved, if any, has not yet been identified. The inhibitory neurotransmitter which is involved is NO or a NO-related substance.

In the guinea-pig proximal colon, 5-hydroxytryptamine (5-HT) relaxes the longitudinal muscle by stimulating neuronal 5-HT receptors, which induces the release of nitric oxide (NO). It was investigated whether the inhibitory neurotransmitters adenosine 5'-triphosphate (ATP) and/or vasoactive intestinal polypeptide (VIP) could be involved as well.

The purpose of this study was to investigate whether the effects of cisapride and its close structural analogue R 76186 on the isolated guinea-pig colon ascendens, are mediated through 5-HT4 receptors.