Nicholas Sean Tilford

5-HT2B receptors play a key role in mediating the excitatory effects of 5-HT in human colon in vitro

5‐Hydroxytryptamine (5‐HT) is known to produce a number of different effects in the gastrointestinal tract of various species, and has been proposed to play a key role in a number of intestinal disorders in man, including irritable bowel syndrome (IBS), although the receptors involved have yet to be established. The aim of the present study was to investigate the distribution and function of 5‐HT2B receptors in human colon, and to establish their possible role in the aetiology of IBS. The distribution of 5‐HT2B receptor mRNA and protein were investigated by quantitative RT – PCR, Western analysis and immunocytochemistry. High levels of both mRNA and protein for 5‐HT2B receptors were found throughout the human gastrointestinal tract, and in particular in colon, where 5‐HT2B receptors were found predominantly in the longitudinal and circular smooth muscle layers within the muscularis externa, and in the myenteric nerve plexus lying between these two layers. Electrical field stimulation of longitudinal muscle preparations of human colon mounted in organ baths resulted in neuronally‐mediated contractile responses, that were significantly potentiated by application of 5‐HT (up to 10−7 M), with a pEC50 of 8.2±0.1 (n=49 donors). The response to 5‐HT was inhibited by a number of selective 5‐HT2B receptor antagonists. This study has shown for the first time that, in contrast to animal studies, the excitatory effects of 5‐HT in human colon are mediated by 5‐HT2B receptors. It is proposed that these receptors contribute to the putative 5‐HT‐induced colonic smooth muscle hypersensitivity associated with IBS.

Mediation by 5-hydroxytryptamine2B receptors of endothelium-dependent relaxation in rat jugular vein.

1 An ‘atypical’ 5‐HT2 receptor which is located on the endothelium of rat jugular vein has been described. In the present study we have further defined the nature of the 5‐HT2 receptor subtype present in this preparation. 2 In experiments conducted in the presence of ketanserin to preclude involvement of 5‐HT2 receptors, the mixed 5‐HT2B/2C antagonist, SB 200646, acted as an antagonist of 5‐HT at the endothelial 5‐HT receptor (pA2 = 7.2). Yohimbine, which exhibits negligible affinity for rat 5‐HT2C receptors but has high 5‐HT2B receptor affinity, acted as a potent but non‐surmountable antagonist (pA2 ≥ 7.3) in rat jugular vein. Neither yohimbine nor SB 200646 affected endothelium‐dependent relaxations induced by carbachol. 3 Mianserin also acted as a surmountable antagonist (pA2 = 7.3) and the 5‐HT2B agonist, BW 723C86, acted as a potent partial agonist (pEC50 [95% C L], intrinsic activity ± s.e.mean = 7.9 [7.6–8.3], 0.84 ± 0.04). Responses to BW 723C86 were antagonized by SB 200646 (0.3 μm) yielding an ‘apparent’ pA2 [95% CL] of 7.03 [6.76–7.32]. 4 These data are consistent with the presence of 5‐HT2B receptors mediating endothelium‐dependent relaxation of rat jugular vein.