96 The Structure and Function of the Gastro-Esophageal Junction in Health and Reflux Disease Assessed By Magnetic Resonance Imaging and High Resolution Manometry

Abstract

nitrate, and during acid reflux, generation of NO is shifted to the distal esophagus. We have demonstrated that high concentrations of luminal NO can impair the gastric mucosal barrier function by disrupting the tight junction (Gut 2008). We hypothesized that NO generated luminally during acid reflux could disrupt the esophageal barrier function and provoke DIS. Aim: To investigate the direct effects of luminal NO on the esophageal barrier function using an ex vivo chamber model. Design and Setting: A chamber model in which the rat esophageal mucosal membrane was mounted between the two halves of a chamber was designed to simulate the microenvironment of the lumen and the adjacent mucosa of the esophagus. On the mucosal side of the chamber, NO was generated by the acidification of physiologic concentrations of sodium nitrite. The epithelial barrier function was evaluated by electrophysiological transmembrane resistance (R) and membrane permeability with 3H-mannitol flux in four groups; Krebs buffer, acid alone (pH 1.5), acid + sodium nitrite 5.0 mM, and acid + sodium nitrite 1.0 mM. Intercellular space diameters were measured on transmission electron microscopy photomicrographs. Results: In all groups except for Krebs buffer, the R decreased rapidly within the initial 15 minutes, followed by gradual decrease thereafter. At 180 minutes, the R decreased by 34% in acid alone group, by 39% in acid + nitrite 1.0 mM group, by 45% in acid + nitrite 5.0 mM group by 55%. Consequently, the administration of acidified nitrite (1.0 mM or 5.0 mM) to the mucosal side significantly decreased the R compared with that of the acid alone (p<0.01). While epithelial permeability with 3Hmannitol slightly increased at 180 minutes in acid alone group, it remarkably increased in acid + nitrite 5.0 mM group. Thus, the administration of acidified nitrite to the mucosal side significantly increased epithelial permeability compared with the acid alone group (p<0.05). DIS was observed in the nitrite groups but not in the acid alone group. Conclusions: The NO generated luminally via acidification of nitrite disrupted the barrier function of the esophageal epithelium and provoked DIS, suggesting that NO generated luminally contributes to DIS observed in GERD patients and plays an important role in the pathophysiology of GERD.