No abstract

The G protein-coupled receptors, GPR41 and GPR43, are activated by short-chain fatty acids (SCFAs), with distinct rank order potencies. This study investigated the possibility that SCFAs modulate intestinal motility via these receptors. Luminal SCFA concentrations within the rat intestine were greatest in the caecum (c. 115 mmol L(-1)) and proximal colon. Using similar concentrations (0.1-100 mmol L(-1)), SCFAs were found to inhibit electrically evoked, neuronally mediated contractions of rat distal colon, possibly via a prejunctional site of action; this activity was independent of the presence or absence of the mucosa. By contrast, SCFAs reduced the amplitude but also reduced the threshold and increased the frequency of peristaltic contractions in guinea-pig terminal ileum. In each model, the rank-order of activity was acetate (C2) approximately propionate (C3) approximately butyrate (C4) > pentanoate (C5) approximately formate (C1), consistent with activity at the GPR43 receptor. GPR43 mRNA was expressed throughout the rat gut, with highest levels in the colon. However, the ability of SCFAs to inhibit neuronally mediated contractions of the colon was similar in tissues from wild-type and GPR43 gene knockout mice, with identical rank-orders of potency. In conclusion, SCFAs can modulate intestinal motility, but these effects can be independent of the GPR43 receptor.

Previous studies have demonstrated mixed inhibitory and facilitatory effects of 5-hydroxytryptamine-4 (5-HT(4)) receptor agonists on electrical field stimulation (EFS)-induced responses in human isolated colon. Here we report three types of responses to EFS in human isolated colon circular muscle: monophasic cholinergic contraction during EFS, biphasic response (nitrergic relaxation during EFS followed by cholinergic contraction after termination of EFS) and triphasic response (cholinergic contraction followed by nitrergic relaxation during EFS and a tachykininergic contraction after EFS). The effects of two 5-HT(4) receptor agonists, prucalopride and tegaserod were then investigated on monophasic responses only. Each compound inhibited contractions during EFS in a concentration-dependent manner. In the presence of N(omega)-nitro-l-arginine methyl ester (l-NAME) however, prucalopride and tegaserod enhanced the contractions in a concentration-dependent manner. In strips where the tone was elevated with substance-P and treated with scopolamine, EFS-induced relaxations were enhanced by the two agonists. The above observed effects by the two agonists were abolished by 5-HT(4) receptor antagonist SB-204070. The two agonists did not alter the tone raised by substance-P in the presence of scopolamine and l-NAME and did not affect carbachol-induced contractions in the presence of tetrodotoxin. These results suggest that in the circular muscle of human colon, 5-HT(4) receptor agonists simultaneously facilitate the activity of neurones which release the inhibitory and excitatory neurotransmitters, nitric oxide and acetylcholine respectively.

1 Following identification of the human motilin receptor, we isolated the rabbit orthologue by PCR amplification and found this to be 85% identical to the open reading frame of the human receptor. The protein encoded was 84% identical to the human polypeptide. ]-motilin faded rapidly during its continual presence. Rat or human ghrelin 0.01 -10 mM were without activity. 4 Erythromycin 30 -3000 nM and 10 mM, respectively, increased neuronal activity and muscle tension in rabbit stomach. Unlike [Nle 13 ]-motilin, the increase in neuronal activity did not fade during continual presence of submaximally-effective concentrations of erythromycin; some fade was observed at higher concentrations. 5 We conclude that the pharmacology of the rabbit motilin receptor is similar to the human orthologue and, when expressed as a recombinant, comparable to the native receptor. However, in terms of their ability to increase neuronal activity in rabbit stomach, [Nle 13 ]-motilin and erythromycin are distinguished by different response kinetics, reflecting different rates of ligand degradation and/or interaction with the receptor.