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EFFECTS OF SELECTIVE M3 AND NON-SELECTIVE MUSCARINIC RECEPTOR ANTAGONISTS ON GASTROINTESTINAL TRANSIT AND BOWEL HABITS IN HUMANS.

Am J Physiol Gastrointest Liver Physiol. 2010 Apr 15;

Authors: Bharucha AE, Ravi K, Zinsmeister AR

While in vitro studies show that muscarinic M3 receptors primarily mediate the effects of acetylcholine on gastrointestinal contractility, the muscarinic receptor subtypes regulating gastrointestinal motor activity and transit in humans in vivo are unclear. We hypothesized that muscarinic M3-specific but not nonspecific receptor antagonists would delay gastrointestinal and colonic transit in humans. In this parallel-group study, gastric emptying, small intestinal, and colonic transit were assessed by scintigraphy on days 4-6 in 72 healthy subjects (49 women) who received placebo (n=16), the M3 antagonist, darifenacin ER (7.5 mg [n=20] or 15 mg daily [n=17]), or the non-specific antagonist tolterodine (4 mg daily [n=19]) for 6 days. Bowel habits were recorded by daily diaries. Darifenacin (15 mg) reduced (p<0.01) stool consistency versus tolterodine. Both doses of darifenacin substantially delayed (p<0.01 vs placebo [for both doses], p<0.01 vs tolterodine [for 15 mg]) small intestinal transit, i.e., colonic filling at 6h (placebo [59.6 +/- 6.4%, Mean +/- SEM], 7.5 mg ER [34.4 +/- 6.1%], 15 mg ER [20.4 +/- 6.3%]). Darifenacin (15 mg) also delayed (p < 0.01 versus placebo and tolterodine) t(half) for ascending colonic emptying (placebo [12.0 +/- 1.5h], 7.5 mg [18.6 +/- 1.9h], 15 mg [22.9 +/- 2.6h]) and colonic transit (geometric center) at 24 (placebo [2.8 +/- 0.2], 7.5 mg [2.4 +/- 0.2], 15 mg [1.9 +/- 0.2]) but not 48 hours. Darifenacin did not affect gastric emptying and tolterodine did not affect bowel habits or gastrointestinal transit. Using muscarinic antagonists at clinically-approved doses, these findings demonstrate that muscarinic M3 receptors regulate small intestinal and colonic transit in humans; colonic effects are more pronounced in the right than left colon. At doses which affect small and large intestinal transit, M3 antagonists do not affect gastric emptying in humans. The efficacy of darifenacin in diarrhea-predominant irritable bowel syndrome should be evaluated.

PMID: 20395537 [PubMed - as supplied by publisher]

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