Histamine levels are elevated in inflammatory bowel disease. We investigated the mechanism by which histamine affects electrolyte transport in the mouse cecum. Using the Ussing-chamber voltage clamp technique, histamine was found to cause a transient concentration-dependent increase in short-circuit current, a measure of total ion transport across the epithelial tissue. This increase was not affected by amiloride pretreatment, but was significantly inhibited by bumetanide and completely inhibited when chloride was substituted in the bathing buffer by gluconate. A histamine-induced increase in short-circuit current was also significantly reduced by inhibitors of the cyclooxygenase pathway indicating the involvement of prostaglandin E2 in its action. Prostaglandin E2 levels were increased in histamine treated tissue and this increase was reversed by indomethacin. These data suggest that histamine causes its effect on mouse cecum largely through increasing arachidonic acid metabolism resulting in increased levels of prostaglandins which in turn increase Cl- secretion in the epithelial cells.