An improved method of evaluation of drug-evoked changes in gastric emptying in mice

Abstract

Introduction: The increased availability of transgenic mice prompts a need for the adaptation to mice of whole-animal assays traditionally performed in larger laboratory animals. Gastric emptying studies are frequently conducted in dogs and rats. Mouse-based gastric emptying models currently available often use inert, nonnutrient liquid meals containing nonabsorbable markers or radionuclides. We have developed a mouse gastric emptying assay that features a favorable throughput and the use of a semisolid, high-calorie meal.

Methods: A carbohydrate- and protein-rich semisolid test meal was prepared from common laboratory reagents. Gastric emptying was determined by subtracting the mass of test meal remaining in the stomach from the mass of test meal administered. A time-course study of basal emptying of a semisolid, paste-like test meal high in carbohydrate and protein from the stomachs of overnight-fasted mice was conducted. Agents known to either inhibit (propantheline, 0.3-10 mg/kg sc; corticotropin-releasing factor [CRF], 3-100 nmol/kg ip) or accelerate (metoclopramide, 1-10 mg/kg ip; bethanechol, 1-30 mg/kg ip) gastric emptying were tested. A single time-point variation of the assay can be used for quickly screening compounds for effects on gastric emptying.

Results: In time-course studies, the test meal emptied from the stomach with a half-emptying time of 30.6 min (95% CI: 27.3-34.7). The gastric emptying data were successfully modeled by a two-parameter exponential decay function. No lag phase was observed, indicating that the meal empties from the stomach as a liquid. The anticholinergic agent propantheline increased gastric half-emptying time (t(1/2)) approximately threefold, while metoclopramide decreased gastric half-emptying time approximately twofold compared to basal emptying. Single time-point screening studies correctly detected the gastrokinetic activity of bethanechol and the inhibitory effect of CRF.

Discussion: The mouse gastric emptying assay reported here is simple, inexpensive, and not labor-intensive. It is capable of detecting either stimulation or inhibition of gastric motor activity. This assay should prove useful for identifying drug-evoked changes in gastric emptying as well as for assessing the gastric motility effects of altered gene expression in genetically modified mice.