Second messengers, such as cyclic adenosine 3',5'-monophosphate (cAMP), have been shown to take part in the regulation of blood-brain barrier permeability. In the present study, elevation of cAMP levels decreased sucrose (mol. wt, 342) and inulin (mol. wt, 5000) permeability across monolayers of bovine brain capillary endothelial cells as early as 1 h after exposure. Since both tracers use predominantly a paracellular pathway, we assume that cAMP may increase the tightness of the tight junctions through protein phosphorylation.