Modulation of Intestinal Gas Dynamics in Healthy Human Volunteers by the 5-HT4Receptor Agonist Tegaserod

Abstract

Bloating in irritable bowel syndrome (IBS) may result from impaired intestinal gas transit and is reduced by the 5-HT4 agonist tegaserod. Abnormal serotonergic function underlies many IBS symptoms, but the role of 5-HT4 pathways in regulating gas dynamics under healthy conditions is unexplored. We hypothesized that 5-HT4 activation by tegaserod stimulates gas transit in healthy individuals. Sixteen normal volunteers underwent jejunal perfusion of gas mixtures (88% N2, 5.5% O2, 6.5% CO2) at 11.2 mL/min x 3 h under control conditions and 3 h after oral tegaserod 6 mg on separate days. Gas collected from an intrarectal catheter was quantified using a barostat. Under control conditions, gas evacuation after a lag period (1,959 +/- 428 s) was predominantly pulsatile with expulsion of 1,984 +/- 90 mL. A mean of 29 +/- 2 boluses with volumes of 72 +/- 5 mL were expelled. In 10 subjects with physiologic degrees of gas retention in control studies (248 +/- 73 mL), tegaserod increased expulsion from 1,768 +/- 73 to 1,973 +/- 37 mL and decreased retention to 43 +/- 37 mL (p < 0.05). Total volumes expelled as boluses were greater after tegaserod (1,708 +/- 73 vs 1,846 +/- 59 mL, p < 0.05) from increased bolus numbers in four subjects and increased bolus volumes in seven. Nonpulsatile continuous flow tended to increase with tegaserod (43 +/- 7 vs 126 +/- 43 mL, p= 0.10). Tegaserod did not increase evacuation in individuals without physiologic gas retention. The 5-HT4 agonist tegaserod promotes evacuation of jejunally perfused gas mixtures in healthy humans. These findings provide the foundation for future investigations into use of 5-HT4 agonists in conditions of pathologic gas retention.