Histamine has been shown previously to cause dose-dependent systemic hypotension and concurrent alterations in the permeability of the blood-brain barrier of rats. The purpose of the present study was to determine whether histamine-induced changes in cerebrovascular permeability were mediated by the histamine H2-receptor. Wistar-Kyoto (control) and spontaneously hypertensive rats were pretreated with the histamine H2-receptor antagonist cimetidine (10 mg/kg), followed by saline or histamine (1.25, 2.5 or 5.0 micrograms/kg). Premedication with cimetidine did not block histamine-induced systemic hypotension. The permeability of the blood-brain barrier was measured with 131I-labelled serum albumin (RISA) or with 99mTc-sodium pertechnetate (TcO4-). In both control and spontaneously hypertensive animals, cimetidine prevented histamine-induced changes in the permeability of the blood-brain barrier to either tracer. These findings suggest that the H2-receptor is the prime mediator of histamine-stimulated alterations in cerebrovascular permeability.