Hyperosmolarity evokes histamine release from ileum mucosa by stimulating a cholinergic pathway

Changes in extracellular osmolarity lead to alteration in cellular volume. In the study, we examined the effects of hyperosmolarity on short-circuit currents (Isc) 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 I_SC was depressed by pyrilamine, a histamine H₁ receptor blocker (H₁ antagonist) whereas it was not affected by ranitidine (H₂ antagonist), clobenpropit (H₃ antagonists) or JNJ7777120 (H₄ antagonist), respectively. The ion substitution experiments suggest that the changes of Na⁺ and HCO₃^- 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 HCO₃^- ion transport are involved in the glucose-evoked decrease of basal I_SC.