Oxidative stress plays an important role in the development of atherosclerosis and contributes to tissue damage that occurs as a consequence, particularly in myocardial infarction and acute stroke. Antioxidant properties of uric acid have long been recognized and, as a result of its comparatively high serum concentrations, it is the most abundant scavenger of free radicals in humans. Elevation of serum uric acid concentration occurs as a physiologic response to increased oxidative stress-for example, during acute exercise-thus providing a counter-regulatory increase in antioxidant defenses. In view of its antioxidant properties, uric acid may have potentially important and beneficial effects within the cardiovascular system. We wished to investigate whether administration of uric acid was feasible and if it could have an impact on antioxidant function in vivo. We have, therefore, performed a randomized, placebo-controlled double-blind study of the effects of systemic administration of uric acid, 1,000 mg, in healthy volunteers, compared with vitamin C, 1,000 mg. We observed a significant increase in serum free-radical scavenging capacity from baseline during uric acid and vitamin C infusion, using two methodologically distinct antioxidant assays. The effect of uric acid was substantially greater than that of vitamin C.

Uric acid (UA) possesses free-radical-scavenging properties, and systemic administration is known to increase serum antioxidant capacity. However, it is not known whether this protects against oxidative stress. The effects of raising UA concentration were studied during acute aerobic physical exercise in healthy subjects, as a model of oxidative stress characterized by increased circulating 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) concentrations. Twenty healthy subjects were recruited to a randomized double-blind placebo-controlled crossover study, and underwent systemic administration of 0.5 g of UA in 250 ml of 0.1% lithium carbonate/4% dextrose vehicle or vehicle alone as control. Subjects performed high-intensity aerobic exercise for 20 min to induce oxidative stress. Plasma 8-iso-PGF2alpha concentrations were determined at baseline, after exercise and after recovery for 20 min. A single bout of high-intensity exercise caused a significant increase in plasma 8-iso-PGF2alpha concentrations from 35.0 +/- 4.7 pg/ml to 45.6 +/- 6.7 pg/ml (P<0.01). UA administration raised serum urate concentration from 293 +/- 16 to 487 +/- 16 micromol/l (P<0.001), accompanied by increased serum antioxidant capacity from 1786+/-39 to 1899 +/- 45 micromol/l (P<0.01). UA administration abolished the exercise-induced elevation of plasma 8-iso-PGF2alpha concentrations. High UA concentrations are associated with increased serum antioxidant capacity and reduced oxidative stress during acute physical exercise in healthy subjects. These findings indicate that the antioxidant properties of UA are of biological importance in vivo.

Endothelial dysfunction is a characteristic finding in both patients with type 1 diabetes and in regular smokers and is an important precursor to atherosclerosis. The urate molecule has antioxidant properties, which could influence endothelial function. The impact of acutely raising uric acid concentrations on endothelial function was studied in eight men with type 1 diabetes, eight healthy regular smokers, and eight age-matched healthy control subjects in a randomized, four-way, double-blind, placebo-controlled study. Subjects received 1,000 mg uric acid i.v. in vehicle, 1,000 mg vitamin C as a control antioxidant, vehicle alone, or 0.9% saline on separate occasions over 1 h. Forearm blood flow responses to intrabrachial acetylcholine and sodium nitroprusside were assessed using venous occlusion plethysmography. Responses to acetylcholine, but not sodium nitroprusside, were impaired in patients with diabetes (P < 0.001) and in smokers (P < 0.005) compared with control subjects. Administration of uric acid and vitamin C selectively improved acetylcholine responses in patients with type 1 diabetes (P < 0.01) and in regular smokers (P < 0.05). Uric acid administration improved endothelial function in the forearm vascular bed of patients with type 1 diabetes and smokers, suggesting that high uric acid concentrations in vivo might serve a protective role in these and other conditions associated with increased cardiovascular risk. Diabetes 55:3127-3132, 2006