Thiazide diuretics are associated with many metabolic side effects including hyperuricemia, gout, insulin resistance, and hyperlipidemia. These very conditions are already highly prevalent in African-Americans. We and others have generated a large body of epidemiologic, animal model, cell culture, and preliminary data in patients that suggests that uric acid is itself a mediator of hypertension, endotheliai dysfunction, and systemic inflammation. In our animal models elevated uric acid leads to increased blood pressure (BP) and lowering uric acid decreases BP. Furthermore, our study of hypertensive young adults suggests that allopurinol treatment leads to a decrease in uric acid associated with a lower BP. Our hypothesis is that thiazide-induced hyperuricemia decreases the efficacy of thiazides in controlling BP, leads to endothelial dysfunction, and increases the incidence of insulin resistance and impaired glucose tolerance. This hypothesis will be tested in a randomized double-blind placebo-controlled 2x2 factorial clinical trial of 8- week duration in which a total of 300 African-Americans patients with stage 1 hypertension (BP: 140-159/90- 99 mm Hg) will be assigned to one of four regimens: 1) a thiazide-like diuretic, chlorthalidone 25 mg/day, and a xanthine oxidase inhibitor, allopurinol; 2) chlorthalidone 25 mg/day and placebo; 3) placebo or 4) allopurinol. All subjects will receive a low-sodium diet. Our hypothesis predicts that lowering uric acid will enhance BP control, prevent endothelial dysfunction, reduce systemic inflammation, improve g.ucose tolerance and reduce hyperinsulinemia.
In Aim 1 we test the hypothesis that prevention of chlorthalidone - induced hyperuricemia with allopurinol results in improved BP control.
In Aim 2 we test the hypothesis that prevention of chlorthalidone-induced increase in serum uric acid by allopurinol improves endothelial function and reduces systemic inflammation.
In Aim 3 we test the hypothesis that prevention of chlorthalidone induced hyperuricemia with allopurinol improves renal blood flow and GFR and prevents microalbumineria. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079352-04
Application #
7413657
Study Section
Special Emphasis Panel (ZRG1-CICS (01))
Program Officer
Einhorn, Paula
Project Start
2005-08-01
Project End
2011-04-30
Budget Start
2008-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$671,612
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Segal, Mark S; Srinivas, Titte R; Mohandas, Rajesh et al. (2015) The effect of the addition of allopurinol on blood pressure control in African Americans treated with a thiazide-like diuretic. J Am Soc Hypertens 9:610-619.e1
Mohandas, Rajesh; Sautina, Laura; Beem, Elaine et al. (2014) Uric acid inhibition of dipeptidyl peptidase IV in vitro is dependent on the intracellular formation of triuret. Exp Cell Res 326:136-42
Beem, Elaine; Segal, Mark S (2013) Evaluation of stability and sensitivity of cell fluorescent labels when used for cell migration. J Fluoresc 23:975-87
Mazali, Fernanda Cristina; Johnson, Richard J; Mazzali, Marilda (2012) Use of uric acid-lowering agents limits experimental cyclosporine nephropathy. Nephron Exp Nephrol 120:e12-9
Nakagawa, Takahiko; Johnson, Richard J (2010) Hypertension: Is there a dark side to thiazide therapy for hypertension? Nat Rev Nephrol 6:564-6
Kim, Kyung Mee; Henderson, George N; Frye, Reginald F et al. (2009) Simultaneous determination of uric acid metabolites allantoin, 6-aminouracil, and triuret in human urine using liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 877:65-70
Kim, Kyung Mee; Henderson, George N; Ouyang, Xiaosen et al. (2009) A sensitive and specific liquid chromatography-tandem mass spectrometry method for the determination of intracellular and extracellular uric acid. J Chromatogr B Analyt Technol Biomed Life Sci 877:2032-8
Mohandas, Rajesh; Johnson, Richard J (2008) Uric acid levels increase risk for new-onset kidney disease. J Am Soc Nephrol 19:2251-3
Johnson, Richard J; Feig, Dan I; Nakagawa, Takahiko et al. (2008) Pathogenesis of essential hypertension: historical paradigms and modern insights. J Hypertens 26:381-91
Johnson, Richard J; Gaucher, Eric A; Sautin, Yuri Y et al. (2008) The planetary biology of ascorbate and uric acid and their relationship with the epidemic of obesity and cardiovascular disease. Med Hypotheses 71:22-31

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