To determine whether cyclic adenosine monophosphate influences active potassium transport in the rat colon, we studied the effect of dibutyryl cyclic adenosine monophosphate and theophylline on unidirectional transmural 42K fluxes across proximal colonic mucosa under short-circuited conditions. Active potassium secretion (-0.19 +/- 0.02 microEq/h X cm2) was present in animals maintained on a normal potassium diet. Both 0.5 mM dibutyryl cyclic adenosine monophosphate and 5 mM theophylline significantly increased net potassium secretion by 0.49 +/- 0.04 and 0.33 +/- 0.03 microEq/h X cm2, p less than 0.001, respectively; the stimulation of net potassium secretion was secondary to an increase in serosal-to-mucosal potassium transport without change in mucosal-to-serosal potassium movement. A similar increase in active potassium secretion (from -0.15 +/- 0.03 to -0.32 +/- 0.03 microEq/h X cm2, p less than 0.005) was produced by bethanechol, a cholinergic muscarinic agonist that alters sodium and chloride transport by a noncyclic adenosine monophosphate, calcium-dependent process. In animals maintained on a high potassium diet, active potassium secretion was significantly increased to -0.79 +/- 0.17 microEq/h X cm2 (p less than 0.001). In these potassium-loaded animals, theophylline produced a greater increase in active potassium secretion (0.91 +/- 0.10 vs. 0.33 +/- 0.03 microEq/h X cm2, p less than 0.001) than in animals fed a normal potassium diet. These studies demonstrate that cyclic adenosine monophosphate and noncyclic adenosine monophosphate mediated secretogogues stimulate active potassium secretion. We speculate that the mechanism by which cyclic adenosine monophosphate increases active potassium secretion is related to an increase in luminal potassium conductance.