The epithelium from the porcine distal colon was mounted in Ussing chambers and bathed in plasma-like Ringer's solution. Histamine produced increases in current which were not affected by pretreatment with the neural conduction blocker tetrodotoxin. Both the H1-histamine antagonist pyrilamine and the cyclooxygenase inhibitor indomethacin produced dextral shifts in the histamine concentration-response curve. Replacement of Cl with gluconate or HCO3 with tris(hydroxymethyl)aminomethane(tris)-N-2- hydroxyethylpiperazine-N'-2-ethanesulfonic acid in the bathing solution inhibited the mucosal response to histamine by 74 and 23%, respectively. In addition, histamine increased the serosal-to-mucosal Na and Cl fluxes and inhibited the mucosal-to-serosal Na flux, resulting in a reduction of net Na and Cl absorption. Prostaglandin E2 also produced increases in short-circuit current which remained unaffected by tetrodotoxin. Replacement of either Cl or HCO3 inhibited these increases by 85%. Prostaglandin E2 inhibited the mucosal-to-serosal and net Cl fluxes. Leukotriene C4 produced oscillating increases in the short-circuit current which were completely blocked by tetrodotoxin. These increases in current were attributed to an increase in the serosal-to-mucosal Cl flux which resulted in a decrease in net Cl absorption. From these data it was concluded that: 1) histamine interacts with H1-receptors to increase Na and Cl secretion and inhibit Cl absorption; 2) prostaglandin E2 inhibits a HCO3-dependent Cl absorptive pathway, possibly involving Cl/HCO3 exchange and 3) leukotriene C4 acts on enteric nerves to stimulate Cl secretion.