Tissue plasminogen activator enhances the hypoxia/reoxygenation-induced impairment of the blood-brain barrier in a primary culture of rat brain endothelial cells.

Hemorrhagic transformation is a major complication associated with tissue plasminogen activator (tPA) therapy for ischemic stroke. We studied the effect of tPA on the blood-brain barrier (BBB) function with our in vitro monolayer model generated using rat brain microvascular endothelial cells subjected either to normoxia or to hypoxia/reoxygenation (H/R) with or without the administration of tPA. The barrier function was evaluated by the transendothelial electrical resistance (TEER), the permeability of sodium fluorescein and Evans' blue-albumin (EBA), and the uptake of lucifer yellow (LY). The permeability of sodium fluorescein and EBA was used as an index of paracellular and transcellular transport, respectively. The administration of tPA increased the permeability of EBA and the uptake of LY under normoxia. It enhanced the increase in the permeability of both sodium fluorescein and EBA, the decrease in the TEER, and the disruption in the expression of ZO-1 under H/R conditions. Administration of tPA could cause an increase in the transcellular transport under normoxia, and both the transcellular and paracellular transport of the BBB under H/R conditions in vitro. Even in humans, tPA may lead to an opening of the BBB under non-ischemic conditions and have an additional effect on the ischemia-induced BBB disruption.

Contrast media increase vascular endothelial permeability by inhibiting nitric-oxide production.

RATIONALE AND OBJECTIVES: Contrast media induce adverse effects including edema of the face, glottis, or lung. The endothelial function is maintained by nitric oxide (NO). The present study was designed to elucidate the role of NO in mediating endothelium-related adverse effects of contrast media. METHODS: Human microvascular endothelial cells grown on a Transwell membrane were incubated with iohexol or ioxaglate in the absence or presence of N(G)-monomethyl-L-arginine or sodium nitroprusside. After washing cells, the permeability of sodium fluorescein or Evans blue albumin and the accumulation of NO(2)(-) was examined. RESULTS: Contrast media (50-150 mgI/mL) dose-dependently increased the permeability coefficient by 30% to 230% and inhibited the formation of NO(2)(-) by 40% to 80%. Sodium nitroprusside and N(G)-monomethyl-L-arginine produced protective and aggravating effects on contrast media-increased permeability, respectively. CONCLUSIONS: The present study suggested that contrast media increase vascular endothelial permeability by inhibiting NO production, leading to vascular endothelium-related adverse effects of contrast media.