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We hypothesized that the femoral I/R vein will exhibit increased levels of H2O2 in the blood when compared to the sham vein in the same anesthetized rat. Moreover, we predict that there will be a concurrent decrease in levels of NO released in the femoral I/R vein compared to the sham vein. When mitoQ or SS-31 is given at reperfusion, we expect that the I/R limbs will show decreased H2O2 blood levels and increased NO blood levels compared to the non-drug treated saline controls. As a result, there will be a decrease in ROS and I/R injury. When mitoQ or SS-31 is given at the beginning of reperfusion, there is a significant reduction of blood H2O2 and a significant increase in endothelial-derived NO bioavailablity compared to saline controls. The results of this study support our hypothesis that mitochondria-targeted antioxidant agents can significantly attenuate reperfusion induced ROS release and lead to an increase in NO bioavailability. Collectively, the data suggests that mitoQ or SS-31 can be effective tools in the clinical setting for attenuating post-ischemic insult and endothelial dysfunction. The results also suggest that mitochondrial derived ROS significantly contributes to increased blood H2O2 levels and decreased NO blood levels during reperfusion. Moreover, the mitochondria-targeted antioxidant agents mitoQ or SS-31 were able to attenuate the changes in blood H2O2 and NO levels suggesting that mitochondrial derived ROS are major contributors to oxidative stress in I/R injury. Male Sprague-Dawley (SD) rats (275-325 grams, Charles River, Springfield, MA) were anesthetized with an induction dose of 60mg/kg and maintenance dose 30mg/kg of sodium pentobarbital intraperitoneally (i.p.). The rats also received sodium heparin (1000 USP units/mL) i.p. to act as an anticoagulant. We measured blood H2O2 or NO release from femoral veins in real-time: one vein was subjected to I/R while the other was used as a non-ischemic sham control. The H2O2 or NO microsensors (100 μm, WPI Inc., Sarasota, FL) were connected to a free radical analyzer (Apollo 4000, WPI Inc.) and were inserted into a catheter placed in each femoral vein. Ischemia was induced by clamping the femoral artery/vein of one limb for 30 min followed by 45 min of reperfusion. MitoQ (2 mg/kg), SS-31 (2.5 mg/kg), or saline (for non-drug control group) was administered as a bolus injection via the jugular vein at the beginning of reperfusion. We continuously recorded the H2O2 or NO release and collected the data at 5 min intervals during a 15 min baseline period, 30 min ischemia and 45 min reperfusion. The changes in H2O2 or NO release during reperfusion (in picoamps) are expressed as relative change to baseline after correction to the calibration curve of H2O2 (μM) or NO (nM) microsensors. Experimental groups were compared with Student‘s t-test or ANOVA using post hoc analysis with the Student-Newman-Keuls test.

Effects of Mitochondrial-Targeted Antioxidants on Real-Time Nitric Oxide and Hydrogen Peroxide Release in Hind Limb Ischemia and Reperfusion (I/R)