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Background: Nitric oxide (NO), a potent vasodilator produced by endothelial cells, is reduced in patients with peripheral arterial disease (PAD), but the mechanism has not been fully elucidated. Because NO is rapidly inactivated by superoxide anion, we speculated that enhanced oxidative stress could lower NO generation. The aim of our study was to investigate if an imbalance between oxidative stress and NO does exist in patients with PAD and if an increase of NO formation could be achieved by an antioxidant treatment., Methods: In a first study, serum levels of nitrite and nitrate (NOx), markers of NO generation, and 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative stress and maximal walking distance (MWD), were measured in 40 PAD patients and 40 controls. In a second study, 10 PAD patients were randomly allocated in a crossover design to intravenous propionyl-L-carnitine (6 g/day) or placebo for 7 days, with a washout of 30 days between the two phases of the trial. Serum levels of NOx and 8-OHdG were measured before and after the study., Results: Compared with controls, serum levels of 8-OHdG (mean +/- SD) were significantly increased in PAD patients (4.4 +/- 3.1 ng/mL vs 2.4 +/- 1.2 ng/mL; P < .001), and serum levels of NOx were significantly decreased (11.6 +/- 6 microM vs 17 +/- 6.1 microM; P < .001). Levels of 8-OHdG and NOx were inversely correlated (r = -0.879; P < .001). Serum levels 8-OHdG were inversely correlated with MWD (r = -0.48, P = .002). The interventional trial showed no changes in the patients given placebo. Patients treated with propionyl-L-carnitine showed a significant increase of MWD from 101 +/- 31 meters to 129 +/- 35 meters (P = .007) and in NOx from 14.5 +/- 4.5 microM to 17.1 +/- 3.8 microM (P = .007). A significant decrease of 8-OHdG from 3.6 +/- 1.1 ng/mL to 2.6 +/- 1 ng/mL was also found (P = .005.), Conclusions: This study suggests that in PAD patients, the reduction of NO generation could be dependent upon enhanced oxidative stress.