Effects of a serotonin 5-HT4 receptor antagonist SE-207266 on gastrointestinal motor and sensory function in humans

Background-Serotonin 5-HT4 receptors are located on enteric cholinergic neu rones and may regulate peristalsis. 5-HT4 receptors on primary afferent neu rones have been postulated to modulate visceral sensation. While 5-HT4 agon ists are used as prokinetic agents, the physiological role of 5-HT4 recepto rs in the human gut is unknown. Aims-Our aim was to characterise the role of 5-HT4 receptors in regulating gastrointestinal motor and sensory function in healthy subjects under basel ine and stimulated conditions with a 5-HT4 receptor antagonist. Methods-Part A compared the effects of placebo to four doses of a 5-HT4 rec eptor antagonist (SB-207266) on the cisapride mediated increase in plasma a ldosterone (a 5-HT4 mediated response) and orocaecal transit in 18 subjects . In part B, 52 healthy subjects received placebo, or 0.05, 0.5, or 5 mg of SB-207266 for 10-12 days; gastric, small bowel, and colonic transit were m easured by scintigraphy on days 7-9, and fasting and postprandial colonic m otor function, compliance, and sensation during distensions were assessed o n day 12. Results-Part A: 0.5, 5, and 20 mg doses of SB-207266 had significant and qu antitatively similar effects, antagonising the cisapride mediated increase in plasma aldosterone and acceleration of orocaecal transit. Part B: SB-207 266 tended to delay colonic transit (geometric centre of isotope at 24 (p=0 .06) and 48 hours (p=0.08)), but did not have dose related effects on trans it, fasting or postprandial colonic motor activity, compliance, or sensatio n. Conclusion-5-HT4 receptors are involved in the regulation of cisapride stim ulated orocaecal transit; SB 207266 tends to modulate colonic transit but n ot sensory functions or compliance in healthy human subjects.