Beneficial effects of the synthetic antioxidant tert-butyl bisphenol on the hepatic microcirculation in a rat model of diabetes mellitus.

Diabetes mellitus is associated with oxidative injury to the vasculature. Here, the link between oxidative stress and ultrastructural changes in the hepatic microcirculation was investigated as well as the effects of a synthetic antioxidant, tert-butyl bisphenol (tBP). The study focused on the impact of experimental diabetes on liver sinusoidal endothelial cell (LSEC) fenestrations, which are pores in the liver endothelium that facilitate substrate transfer between blood and hepatocytes. Adult male rats were rendered diabetic using streptozotocin (60 mg/kg) and administered 1-2 IU insulin daily. After 8 weeks, animals received either 100 mg/kg tBP or vehicle alone, on 2 consecutive days. Livers were harvested 24 h later under isofluorane anaesthesia (5% v/v in O2(g) by inhalation) and fixed for scanning electron microscopy to evaluate fenestrations or for immuno-histochemical assessment of nitrotyrosine, a marker of nitrosative stress. Median fenestration diameter increased significantly following 8 weeks of diabetes (80 nm vs. 70 nm controls; P < 0.001). LSEC porosity increased by ~50% (P < 0.001). Treatment with tBP reversed these changes completely. Periportal nitrotyrosine staining was increased in diabetic livers, and this was abrogated by tBP, indicating that tBP reduced nitrosative stress in the liver. Early diabetes caused an increase in fenestration diameter and porosity. This was reversed by acute treatment with tBP, suggesting a link between nitrosative stress and regulation of liver endothelial fenestrations, and indicates that antioxidant therapy may protect the liver microvasculature against the effects of diabetes mellitus.