The effects of tegaserod, a 5-HT4 receptor agonist, on gastric emptying in a murine model of diabetes mellitus

The C57BLKS/J db/db transgenic mouse is a model of diabetes mellitus that has been shown to have delayed gastric emptying. We assessed gastric emptying rates in C57BLKS/J mice, and determined the effects of tegaserod, a new selective 5-HT4 receptor partial agonist, on gastric emptying. Methods: Gastric emptying rates of a 20% glucose test meal were determined in 12-20-week-old female db/db mice and control littermates. The effects of tegaserod (0.1-2.0 mg kg(-1), i.p.) on gastric transit were tested in a second group of db/db mice. Pretreatment with GR11308, a specific 5-HT4 antagonist, was used to confirm the mechanism of action of tegaserod on gastric emptying. Results: Gastric emptying of glucose was significantly slower in db/db mice than in control littermates. Tegaserod (0.1 mg kg-1) significantly accelerated the gastric emptying rate of glucose in db/db mice, reducing the fraction of the meal remaining in the stomach at 30 min by 80%. GR11308 blocked the gastrokinetic effects of tegaserod. Conclusions: Gastric emptying was impaired in db/db mice. Low dose tegaserod improved gastric emptying rates in this model of gastroparesis through the activation of 5-HT4 receptors. These findings suggest that 5-HT4 receptor agonists may prove useful for improving delayed gastric emptying in gastroparesis.