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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 Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E 2 (PGE 2 ) occur in the blood, plasma and saliva of migraineurs during an attack, suggestive of a contributory role. In the present study, we have characterised the prostanoid receptors involved in the relaxation and contraction of human middle cerebral arteries in vitro. 2 In the presence of indomethacin (3 mM) and the TP receptor antagonist GR32191 (1 mM), PGE 2 was found to relax phenylephrine precontracted cerebral arterial rings in a concentration-dependent manner (mean pEC 50 8.070.1, n ¼ 5). 3 Establishment of a rank order of potency using the EP 4 4EP 2 agonist 11-deoxy PGE 1 , and the EP 2 4EP 4 agonist PGE 1 -OH (mean pEC 50 of 7.670.1 (n ¼ 6) and 6.470.1 (n ¼ 4), respectively), suggested the presence of functional EP 4 receptors. Furthermore, the selective EP 2 receptor agonist butaprost at concentrations o1 mM failed to relax the tissues. 4 Blockade of EP 4 receptors with the EP 4 receptor antagonists AH23848 and EP 4 A caused significant rightward displacements in PGE 2 concentration-response curves, exhibiting pA 2 and pK B values of 5.770.1, n ¼ 3, and 8.4, n ¼ 3, respectively. 5 The IP receptor agonists iloprost and cicaprost relaxed phenylephrine precontracted cerebral arterial rings (mean pEC 50 values 8.370.1 (n ¼ 4) and 8.170.1 (n ¼ 9), respectively). In contrast, the DP and FP receptor agonists PGD 2 and PGF 2a failed to cause appreciable relaxation or contraction at concentrations of up to 30 mM. In the absence of phenylephrine contraction and GR32191, the TP receptor agonist U46619 caused concentration-dependent contraction of cerebral artery (mean pEC 50 7.470.3, n ¼ 3). 6 These data demonstrate the presence of prostanoid EP 4 receptors mediating PGE 2 vasodilatation of human middle cerebral artery. IP receptors mediating relaxation and TP receptors mediating contraction were also functionally demonstrated.

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