1. Permeability of pial venular capillaries to Lucifer Yellow (PLY) was measured using the single microvessel occlusion technique. 2. PLY was extremely low, when measured shortly after the removal of the meninges, consistent with an intact blood-brain barrier, but rose spontaneously to (1.65 +/- 0.60) x 10(-6) cm s-1 (mean +/- S.D.) within 20-60 min. This first phase of spontaneous disruption lasted 44-164 min. A second phase started when PLY rose sharply, and was characterized by rapid permeability fluctuations with a mean of (12.31 +/- 15.14) x 10(-6) cm s-1. 3. The first phase could be mimicked by applying the divalent cation ionophore A23187 in the presence of Ca2+, when PLY rose by (1.47 +/- 0.25) x 10(-6) cm s-1 (mean +/- S.E.M.). Application of histamine (10 microM) to tight vessels increased PLY by (2.41 +/- 0.22) x 10(-6) cm s-1. 4. Substances that raised intraendothelial cAMP of vessels during the first phase of disruption reduced PLY to the initial blood-brain barrier level. 5. The second phase could be prevented by applying catalase. Similar high and fluctuating PLY values could be produced reversibly by applying arachidonic acid or NH4Cl. 6. This is the first report of two distinct types of permeability increase in the cerebral microvasculature, and reasons for this are discussed.