ROLE OF PLASMA URIC ACID CONCENTRATION IN OXIDATIVE STRESS AND ANTIOXIDANT CAPACITY

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ROLE OF PLASMA URIC ACID CONCENTRATION IN OXIDATIVE STRESS AND ANTIOXIDANT CAPACITY.1Peter A. Hosick, 1Steven R. McAnulty, 2Lisa L. McAnulty, 1John S. Quindry, 1Matthew B. Hudson, 2Laura Still, 1John T. Owens, 1Adrianna DiBernardi, 1Dept. of Health, Leisure, and Exercise Science, 2Dept of Family and Consumer Sciences. Appalachian State University, Boone, NC 28608Acknowledgements: University Research Council (ASU) and the Vaughn Christian Research grant (ASU) Fischer/Nycom Laboratory.

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Oxidants Name Formula Radical ROS Superoxide radical O2- + + Singlet oxygen 1O2 + Hydrogen peroxide H2O2 + Hydroxyl radical OH. + + Alkyl radical R. + + Lipid Hydroperoxide ROOH + Nitric oxide NO. + +

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ROS AO Balance is key Introduction

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Outcomes of unchecked oxidative stress include Cancer (1) Diabetes (2) Alzheimer's (3) Cardiovascular disease (4) Macular degeneration (5) ROS AO Oxidative Stress increased

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Exogenous Antioxidants Supplementation with Vitamins A, C, E all have shown little if any protection when supplemented What about endogenous antioxidants? Marchioli 1999 (6)

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the final oxidation product of purine catabolism strong reducing substance abundant antioxidant in human serum and responsible for two thirds of all antioxidant capacity in blood (7) Squadrito et al. 2000 (8) Uric Acid

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An inverse relationship between uric acid level and amount of oxidative stress has been identified (9) Waring et al. 2003 (9)

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Hypothesis Decreased antioxidant capacity of plasma as a result of decreased plasma urate levels will result in increased oxidative stress. + ROS UA = Ox. Stress ?

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Methods Subjects - 15 endurance trained males Double blinded crossover - 2 trials following 5 days of probenicid or citric acid placebo with one week in between trials Ran at ~80% VO2max for 45 minutes on two separate occasions Blood sample taken at baseline, pre-exercise, and immediately post-exercise

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Blood sample analysis: Glucose Lactate Plasma Volume Shift Antioxidant Capacity (FRAP) Plasma Urate Concentration Total Nitrite F2-isoprostane

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Results Table 1. Baseline Characteristics of subject population (N=15) Characteristic Value Age (years) 24.3±7.3 Height (m) 1.78±0.05 Weight (kg) 69.46±5.12 Body fat (%) 8.2±3.0 Max. Heart Rate (bpm) 194.7±7.9 VO2max (ml/kg/min) 58.2±6.7 Values are means ± S.D.

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Table 2. Exercise Variables Variable PRO Trial PLA Trial P-value Ending HR (BPM) 185±12 182±13 P=0.05 Ending RPE 17.1±1.8 16.6±2.2 P=0.05 Ending VO2 (Rel.) 47.6±5.0 48.6±5.5 P=0.05 Ending RER 0.93±0.04 0.95±0.05 P=0.05 Ending Ve (L/min) 113.7±21.2 113.7±22.2 P=0.05 Values are means ± S.D.

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Table 3. Baseline and Trial Lactate and Glucose Values are means ±S.D. Variable PRO Trial PLA Trial P-value Pre Post Pre Post Treatment: Time: Interaction: Lactate (uM/L) 1.0±0.2 4.6±2.6 1.1±0.3 5.1±2.8 0.332 0.0001 0.398 Glucose (mg/dL) 93.3±10.6 135.4±41.7 100.8 ±13.9 141±38.0 0.436 0.0001 0.929

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Urate Fig. 1 Trt (P<0.004); Time (P=0.124); Trt x Time Interaction (P=0.179) * Denotes significant difference from baseline (p<0.05)

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FRAP Fig. 2 Trt (P<0.001); Time (P<0.001); Trt x Time Interaction (P=0.125) * Denotes significant difference from baseline (p<0.05)

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Nitrite Fig. 3 Trt (P=0.161); Time (P=0.203); Trt x Time Interaction (P=0.276)

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F2-Isoprostane Fig. 4 Trt (P=0.143); Time (P=0.102); Trt x Time Interaction (P=0.488)

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Conclusions Lowering urate levels in plasma does decrease antioxidant capacity of plasma. This did not affect plasma nitrite or F2-isprostane concentrations. Possible basal level needed for urate to function that present study did not achieve Other antioxidant systems adequate to compensate for oxidative stress despite decreased urate concentration Results may have been skewed by subject population

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References 1. Casimiro, C. Nutr. Hosp. 17:128-138, 2002. 2. Mayer-Davis EJ. et al. Diabetes Care. 25(12):2172-7, Dec. 2002. 3. Zandi, PP. et al. Expert. Opin. Pharmacother. 3:365-80, 2002. 4. Czernichow, S. et al. J. Nutr. Health Aging 5:188-95, 2001. 5. Fekrat, S. et al. Curr. Opin. Ophthalmol. 7:65-72, 1996. 6. Marchioli R. Pharm. Research 40(3): 227-38, 1999. 7. Maxwell SR. et al. Eur. J. Clin. Invest. 27(6):484-90, 1997 8. Squadrito GL. et al. Arch. Biochem. Biophys. 376: 333-7, 2000. 9. Waring, WS. et al. Clin. Sci. (Lond) 105:425-30, 2003.

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