• Significant reduction in blood pressure [ Time Frame: Measured at 8-10 weeks on allopurinol / placebo ] [ Designated as safety issue: No ]
  

• Endothelial function [ Time Frame: Measured at 8-10 weeks on allopurinol ] [ Designated as safety issue: No ]
  
• Systemic inflammation [ Time Frame: Measured at 8-10 weeks on allopurinol / placebo ] [ Designated as safety issue: No ]
  
• Insulin resistance [ Time Frame: Measured at 8-10 weeks on allopurinol / placebo ] [ Designated as safety issue: No ]
  

Thiazide diuretics when used in the treatment of hypertension are associated with many metabolic side effects, including hyperuricemia, gout, insulin resistance, and hyperlipidemia. Each of these conditions is already highly prevalent in African Americans. 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 clinical trial of 8-10 weeks duration in which a total of 220 African American patients with hypertension will be enrolled, randomized, and treated as follows:

1. Subjects with untreated stage I hypertension will receive chlorthalidone (25 mg/day) and potassium chloride (40 mEq/day) for 4 weeks. They will then be randomized to add-on allopurinol (300 mg/day) or placebo. Treatment will continue for 8-10 weeks with the chlorthalidone, potassium chloride, and allopurinol/placebo regimen.
2. Subjects with hypertension controlled (i.e. BP <140/90) or no higher than stage 1 hypertension (i.e., <160/100) on a single antihypertensive agent or two antihypertensive agents will be switched from their prior antihypertensive agent to chlorthalidone 25 mg/day, and potassium chloride (40mEq/day) for 4 weeks. Serum potassium levels will be obtained after four weeks on chlorthalidone. If the level is below 3.5 mEg/L, a bolus of 40 mEq potassium 2 to 3 times daily will be given for 2 to 3 days, or as clinically indicated. A maintenance dose of 50 mEq will be initiated. After at least 7 days, they will then be randomized to add-on allopurinol (300 mg/day) or placebo. Treatment will continue for 8-10 weeks with the chlorthalidone, potassium chloride, and allopurinol/placebo regimen.

The allopurinol (or placebo) dose will be adjusted to achieve serum uric acid levels between 4 and 5.5 mg/dL after 2 weeks on drug. All subjects will receive a low-sodium diet. The primary endpoint is reduction in systolic BP. Secondary endpoints measure endothelial function, ambulatory blood pressure, body composition, systemic inflammation, metabolic parameters, oxidant stress, and renal hemodynamics.