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We hypothesized that acute hyperglycemia (200 mg/dL) would increase H2O2 and decrease NO release in blood relative to saline control. By contrast, gp91ds-tat (RKKRRQRRR-CSTRIRRQL-Amide, MW=2452 g/mol, 1.2 mg/kg, Genemed Synthesis Inc., San Antonio, Tx), a cell-permeable peptide that selectively inhibits NADPH oxidase assembly/activation, would attenuate acute hyperglycemia-induced vascular dysfunction. Furthermore apocynin (MW=166 g/mol, Sigma Chemicals), another type of NADPH oxidase inhibitor, should have similar effects on H2O2 and NO blood levels as gp91ds-tat compared to hyperglycemia control, attenuating acute hyperglycemia-induced vascular dysfunction. We found that acute hyperglycemia significantly reduced blood NO compared to saline control. The addition of gp91ds-tat or apocynin with hyperglycemia significantly improved blood NO levels, similar to saline control. Meanwhile we found acute hyperglycemia maintained a higher level of H2O2 in blood compared to saline control. By contrast, gp91ds-tat or apocynin with hyperglycemia reduced blood H2O2 levels significantly compared to hyperglycemia. These results suggest that NADPH oxidase is a significant source of ROS overproduction and vascular endothelial dysfunction under acute hyperglycemic conditions, and that supplementation with gp91ds-tat or apocynin may be beneficial to attenuate hyperglycemia induced vascular endothelial dysfunction. Moreover, blood H2O2 levels in gp91ds-tat or apocynin treated groups were still significantly higher compared to that in saline groups. This may indicate that other sources of ROS exist such as in mitochondria, which will be further investigated. Results Male Sprague-Dawley rats (275 to 325g, Charles River, Springfield, MA) were anesthetized with 60 mg/kg of pentobarbital sodium with 1000 unit heparin via intraperitoneal (i.p.) injections. The jugular vein is catheterized in order to infuse intravenously with saline, 20% D-glucose, 20% D-glucose with 1.2 mg/kg gp91ds-tat, or 20% D-glucose with 14 mg/kg apocynin (see figure 3). The continuous infusion of 20% D-glucose solution is to maintain hyperglycemia at 200 mg/dL for about 180 min. gp91ds-tat and apocynin will be added to 20% glucose to reach approximately 20 μM and 1 mM in blood, respectively. Both femoral veins will be exposed and catheterized in order to place the calibrated NO and H2O2 microsensors (100μm, WPI Inc., Sarasota, FL) at random into each femoral vein (see figure 4). These microsensors will then be connected to the Apollo 4000 free radical analyzer (WPI Inc., Sarasota, FL) to measure for blood NO and H2O2 levels in real-time. NO, H2O2, and glucose levels will then be recorded at baseline and every 20 minutes intervals throughout 180 minutes infusion period. The changes of blood NO and H2O2 levels will be expressed as the relative change to the baseline. Blood NO and H2O2 recording in picoAmps pA will be converted to the concentration (nM for NO and μM for H2O2) according to the corresponding calibration curve. All the data are represented as a mean ± SEM. The data was then analyzed by ANOVA using post hoc analysis with the Student Newman Keuls. P<0.05 was considered as significant.

Effects of Selective NADPH Oxidase Inhibitors on Real-Time Blood Nitric Oxide and Hydrogen Peroxide Release in Acute Hyperglycemia