The goal of this study was to determine the role of nitric oxide in disruption of the blood-brain barrier during acute hypertension. We examined the microcirculation of the cerebrum in vivo. Permeability of the blood-brain barrier was quantitated by the formation of venular leaky sites and clearance of fluorescent-labeled albumin (FITC-albumin) before and during phenylephrine-induced acute hypertension. We compared disruption of the blood-brain barrier during acute hypertension in untreated rats and in rats treated for 1 h with topical application of NG-monomethyl-L-arginine (L-NMMA; 100 microM) or NG-nitro-L-arginine methyl ester (L-NAME; 100 microM). Under control conditions, no venular leaky sites were visible and clearance of FITC-albumin was minimal in untreated rats and in rats treated with topical application of nitric oxide synthase inhibitors. Phenylephrine (20 micrograms/kg/min for 5 min) infusion increased systemic arterial pressure by a similar magnitude in all groups of rats and produced disruption of the blood-brain barrier in venules. However, the magnitude of disruption of the blood-brain barrier during acute hypertension was significantly less in rats treated with L-NMMA (52% reduction in the clearance of FITC-albumin) and L-NAME (47% reduction in clearance of FITC-albumin). The findings of the present study suggest that synthesis/release of nitric oxide contributes to disruption of the blood-brain barrier during acute hypertension.