The effect of histamine, bradykinin and serotonin on blood-brain barrier permeability was investigated using in situ measurement of transendothelial electrical resistance in pial microvessels of anaesthetized rats. Mean resistance of vessels superfused with artificial cerebrospinal fluid was 1800 omega cm2, indicating a tight barrier with extremely low ion permeability. In paired experiments from continuous measurements in single vessels, addition of 10(-3) M serotonin to the solution bathing the brain had no marked effect on resistance; whereas both histamine and bradykinin, applied at a concentration of 10(-4) M, caused a rapid and reversible decrease in resistance. Mean resistance was 408 and 505 omega cm2 in 10(-4) M histamine and bradykinin, respectively, and approximately 50% of vessels had a resistance less than 250 omega cm2, compared to 12% in controls, indicating a leaky blood-brain barrier that is not capable of normal brain ion homeostasis. Histamine and bradykinin had similar dose-response relations, and a maximal effect was observed between 20 and 50 microM. Thus, histamine and bradykinin act at the abluminal (brain-facing) membranes of the cerebral endothelium to mediate blood-brain barrier opening. These results support a role for histamine and bradykinin in brain oedema formation.