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. 2000 Nov;47(5):667–674. doi: 10.1136/gut.47.5.667

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

A Bharucha 1, M Camilleri 1, S Haydock 1, I Ferber 1, D Burton 1, S Cooper 1, D Tompson 1, K Fitzpatrick 1, R Higgins 1, A Zinsmeister 1
PMCID: PMC1728108  PMID: 11034583

Abstract

BACKGROUND—Serotonin 5-HT4 receptors are located on enteric cholinergic neurones and may regulate peristalsis. 5-HT4 receptors on primary afferent neurones have been postulated to modulate visceral sensation. While 5-HT4 agonists are used as prokinetic agents, the physiological role of 5-HT4 receptors 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 baseline and stimulated conditions with a 5-HT4 receptor antagonist.
METHODS—Part A compared the effects of placebo to four doses of a 5-HT4 receptor antagonist (SB-207266) on the cisapride mediated increase in plasma aldosterone (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 measured by scintigraphy on days 7-9, and fasting and postprandial colonic motor function, compliance, and sensation during distensions were assessed on day 12.
RESULTS—Part A: 0.5, 5, and 20 mg doses of SB-207266 had significant and quantitatively similar effects, antagonising the cisapride mediated increase in plasma aldosterone and acceleration of orocaecal transit. Part B: SB-207266 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 transit, fasting or postprandial colonic motor activity, compliance, or sensation.
CONCLUSION—5-HT4 receptors are involved in the regulation of cisapride stimulated orocaecal transit; SB 207266 tends to modulate colonic transit but not sensory functions or compliance in healthy human subjects.


Keywords: 5-HT4 receptors; colon transit; gastrointestinal motor function; gastrointestinal sensory function

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Figure 1  .

Figure 1  

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Experimental design for part A. On each study day, volunteers received placebo or one of four doses of SB-207266. *Breath hydrogen samples were collected every 10 minutes until three consecutive samples with readings ⩾15 ppm above baseline were attained.

Figure 2  .

Figure 2  

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Experimental design for colonic barostat-manometric study. Equil., equilibration periods; Comp./sens., assessment of colonic compliance and sensation.

Figure 3  .

Figure 3  

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Effect of SB-207266 on cisapride induced increases in plasma aldosterone. SB-207266 (0.5, 5, and 20 mg) significantly inhibited the cisapride induced increase in plasma aldosterone levels.

Figure 4  .

Figure 4  

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Effect of drugs on colonic transit expressed as the geometric centre of colonic transit at 24 (GC24) and 48 (GC48) hours. Main figure shows data for each subject with dose mean. Insert depicts anatomical location of GC 0-5.

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