Ground squirrels were used to study the effects of fasting and hibernation on small intestinal secretory function. Muscle-stripped sheets of jejunum set up in flux chambers were challenged with a variety of secretory agonists, and changes in short-circuit current (I(sc)) were recorded. Mucosal wet weights per centimeter and crypt dimensions were not affected by a 3-day fast in active squirrels, but villus height and area were significantly reduced in hibernators that had not eaten for over 6 wk. Tissue conductance was significantly greater in fasted and hibernating squirrels compared with fed animals. Maximal changes in I(sc) evoked by electrical stimulation of submucosal neurons, normalized to serosal surface area, were greater in fasted compared with fed or hibernating squirrels. When responses were normalized to crypt area, neurally evoked changes in I(sc) were greatest in the hibernators. Carbachol and serotonin evoked dose-dependent changes in I(sc) that were greater in fasted compared with fed squirrels at all concentrations. Histamine (100 muM) and theophylline (1 mM) also produced greater increases in I(sc) in fasted than in fed squirrels. The results suggest that a 3-day fast, or the extended fast of hibernation, results in enhanced secretory capacity in the ground squirrel jejunum.