1 5-Hydroxytryptamine (5-HT) is known to produce a number of di erent e ects 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-HT 2B receptors in human colon, and to establish their possible role in the aetiology of IBS. 2 The distribution of 5-HT 2B receptor mRNA and protein were investigated by quantitative RT ± PCR, Western analysis and immunocytochemistry. High levels of both mRNA and protein for 5-HT 2B receptors were found throughout the human gastrointestinal tract, and in particular in colon, where 5-HT 2B 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.3 Electrical ®eld stimulation of longitudinal muscle preparations of human colon mounted in organ baths resulted in neuronally-mediated contractile responses, that were signi®cantly potentiated by application of 5-HT (up to 10 77 M), with a pEC 50 of 8.2+0.1 (n=49 donors). The response to 5-HT was inhibited by a number of selective 5-HT 2B receptor antagonists. 4 This study has shown for the ®rst time that, in contrast to animal studies, the excitatory e ects of 5-HT in human colon are mediated by 5-HT 2B receptors. It is proposed that these receptors contribute to the putative 5-HT-induced colonic smooth muscle hypersensitivity associated with IBS.

1 An 'atypical' 5-HT2 receptor which is located on the endothelium of rat jugular vein has been described. In the present study we 4 These data are consistent with the presence of 5-HT2B receptors mediating endothelium-dependent relaxation of rat jugular vein.

1 The pharmacology of a novel 5-HT4 receptor antagonist, SB204070 has been evaluated in the guinea-pig isolated distal colon longitudinal muscle-myenteric plexus (LMMP). 2 SB 204070 is a highly potent antagonist of 5-HT-evoked cholinergically-mediated contractions in the guinea-pig distal colon. Low concentrations (1O-100 pM) produced a shift to the right of the curve (apparent pA2 10.8 ± 0.1) with no significant effect on the maximum response. With higher concentrations of SB 204070 (300 pM and above), the maximum response to 5-HT was reduced. 3 When tested against the partial 5-HT4 receptor agonist, BIMU 1, SB 204070 was active at similar low concentrations (10 pM and above) but produced a reduction in maximum, with no prior shift to the right of the curve, at all concentrations tested (10-300 pM). 4 The antagonism seen with SB 204070 is unlikely to be due to a non-selective effect since high concentrations (10 nM and 1 9AM) of the compound had no effect on cholinergically-mediated contractions evoked by the nicotinic receptor agonist, DMPP, in the same preparation. SB 204070 is unlikely to be an irreversible antagonist since the effects of the compound could be reversed upon washing of the tissue. 5 Radioligand binding studies show that SB 204070 has a greater that 5000 fold selectivity for the 5-HT4 receptor over 5-HTIA, 5-HTID, 5-HTIE, 5-HT2A, 5-HT20, 5-HT3, GABAA, BDZ, TBPS, Al adenosine receptors, aC, a2, P, P2 adrenoceptors and DI, D2 and D3 dopamine receptors.6 SB 204070 is a highly potent, highly selective 5-HT4 receptor antagonist and as such is an important new tool in evaluating the functional role of the 5-HT4 receptor.

1 The pharmacology of a novel 5-HT4 receptor antagonist, SB 207266 has been evaluated in vitro in the guinea-pig distal colon longitudinal muscle myenteric plexus (LMMP) and in vivo in the dog Heidenhain pouch. 2 SB 207266 is a highly potent antagonist of 5-HT-evoked, cholinergically-mediated contractions in the guinea-pig distal colon. Low concentrations (0.1-10 nM) produced a parallel shift to the right of the concentration-effect curve (apparent pA2 10.6+0.1) with no significant effect on the maximum response. With higher concentrations of SB 207266 (30 nM and above) the maximum response to 5-HT was reduced. 3 The antagonism seen with SB 207266 cannot be attributed to a non-selective effect since high concentrations (1 tM) had no effect on cholinergically-mediated contractions evoked by the nicotinic receptor agonist DMPP in the same preparation. 4 SB 207266 is not an irreversible antagonist since the effects of the compound were reversible upon washing of the tissue. 5 In the dog Heidenhain pouch, oral (0.1-100 ,ug kg-') and intravenous (0.1-100 ,g kg-') administration of SB 207266 produced a dose-dependent antagonism of the contractions evoked by a bolus intravenous injection of 5-HT. An ID50 for SB 207266 of 1.3 Mg kg-' was obtained following i.v. administration and 9.6 Mg kg-' following oral administration. 6 The antagonistic effects of SB 207266 (0.1-100 yg kg-') in the dog Heidenhain pouch were long lasting since, following oral administration, the response to 5-HT was reduced for at least 135 min. 7 SB 207266 is a highly potent, highly selective and orally active 5-HT4 receptor antagonist. This compound is the first orally active amide to be identified in this class of antagonists and as such is an important new tool in the evaluation of 5-HT4 receptor function both in vitro and in vivo.

No abstract