While previous studies have examined the effects of histamine on the permeability of the blood-brain barrier and reactivity of cerebral blood vessels, cellular mechanisms which account for histamine-induced affects on the cerebral microcirculation are not clear. The goals of this study were to determine the role of nitric oxide in histamine-induced increases in permeability of the blood-brain barrier and dilatation of pial arterioles. We examined the pial microcirculation in rats using intravital fluorescence microscopy. Permeability of the blood-brain barrier (clearance of fluorescent-labeled dextran; molecular weight 10,000 daltons; FITC-dextran-10K) and diameter of pial arterioles were measured in the absence and presence of histamine (10 and 100 microM). During superfusion with vehicle (saline), clearance of FITC-dextran-10K from pial vessels was minimal and diameter of pial arterioles remained constant. Topical application of histamine (10 and 100 microM) produced an increase in clearance of FITC-dextran-10K and diameter of pial arterioles. To determine a potential role for nitric oxide in histamine-induced increases in permeability of the blood-brain barrier and dilatation of pial arterioles, we examined the effects of NG-monomethyl-L-arginine (L-NMMA; 10 microM). L-NMMA inhibited histamine-induced increases in permeability of the blood-brain barrier and attenuated histamine-induced dilatation of cerebral arterioles. The findings of the present study suggest that histamine increases permeability of the blood-brain barrier and diameter of pial arterioles via the synthesis/release of nitric oxide or a nitric oxide containing compound.