In normal human colon, water and sodium (Na+) absorption are directly related. Defective Na+ absorption may therefore be an important factor in the pathogenesis of diarrhea in ulcerative colitis (UC). Electrophysiological studies have revealed profound decreases in channel-mediated apical Na+ entry and Na(+)-K(+)-ATPase-mediated basolateral Na+ extrusion in surface epithelial cells in inflamed human distal colon. Recent molecular biological studies indicate that mucosal inflammation in UC leads to significant decreases in Na+ channel beta- and gamma-subunit expression in the apical membrane of surface colonocytes, with a marked reduction in the levels of beta- and gamma-subunit-specific mRNAs. In addition, basolateral expression of the Na(+)-K(+)-ATPase alpha 1-isoform is reduced along the surface cell-crypt cell axis in UC, although there is no change in the level of the corresponding mRNA. Diarrhea in ulcerative colitis is therefore related, at least in part, to a major defect in electrogenic Na+ absorption, which reflects changes in the levels of expression of critical subunits of both the apical Na+ channel and basolateral Na(+)-K(+)-ATPase.