The duodenal epithelium is regularly exposed to contents of varying osmolality, ranging from 50 to over 700 mosmol/kg H₂O. This constitutes a potential threat to the epithelial integrity and maintenance of the intracellular environment. As the content moves along the duodenum the osmolality is approaching that of blood plasma. The osmolality-adjusting capability of the duodenal epithelium has long been attributed to its 'leakiness' meaning that a significant part of transepithelial movement of ions and water occurs passively and between cells, i.e., paracellularly. However, recent findings in our laboratory indicate that the osmolality-adjusting process in the rat duodenum is more complex than that. It has been shown that perfusion of the duodenum with hypotonic solutions, ranging from 100 to 0 mM NaCl, induce osmolality-dependent and reversible increases in mucosal permeability to ⁵¹Cr-EDTA. Furthermore, there is an excellent linear correlation between the increase in ⁵¹Cr-EDTA permeability and the capability to increase luminal osmolality possibly suggesting that changes in mucosal permeability take part in the osmolality-adjusting process. Interestingly, the hypotonicity-induced increase in mucosal permeability seems to be physiologically regulated by the enteric nervous system, prostaglandins and serotonin since nerve blockers, vasoactive intestinal peptide, COX inhibitors and 5-HT₃ receptor antagonists affect it. Distortion of the activity in ENS, that occurs in response to an abdominal operation and which involves increased production of prostaglandins, markedly depresses the capability of the duodenum to respond with an increase in permeability and to adjust osmolality when exposed to a hypotonic content.