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.

R01HL079352

2005-08-01

2010-04-30