Changes in extracellular osmolarity lead to alteration in cellular volume. In the study, we examined the effects of hyperosmolarity on short-circuit currents (I-sc) in the rat ileum using the Ussing chamber technique. Mucosal exposure to 20 mM glucose evoked a decrease of I-sc in the rat ileum, which was antagonized by the stretch-activated channel blocker GdCl3, TTX and atropine, respectively. In contrast, it was not blocked by phlorizin, a Na+-glucose cotransporter SGLT1 inhibitor. Furthermore, the unabsorbed substances, such as sucrose, lactulose or urea, also induced a decrease of I-sc in rat ileum. ELISA results revealed that 20 mM glucose stimulated the release of histamine from rat ileum mucosa, which was attenuated by TTX. In addition, the glucose-induced Isc was depressed by pyrilamine, a histamine H-1 receptor blocker (H-1 antagonist) whereas it was not affected by ranitidine (H-2 antagonist), clobenpropit (H-3 antagonists) or JNj7777120 (H-4 antagonist), respectively. The ion substitution experiments suggest that the changes of Na+ and HCO(3) over bar ion flux underlie the glucose-induced I-Sc. In conclusion, osmotic stimulus decreased the basal I-sc of rat ileum by evoking histamine release from ileum mucosa. The changes of Na+ and HCO(3) over bar ion transport are involved in the glucose-evoked decrease of basal I-sc. (C) 2017 Elsevier Inc. All rights reserved.