BACKGROUND:

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.

DESIGN NARRATIVE:

The 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- weeks duration in which a total of 300 African-American 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. The hypothesis predicts that lowering uric acid will enhance BP control, prevent endothelial dysfunction, reduce systemic inflammation, improve glucose tolerance and reduce hyperinsulinemia. In Aim 1 the investigators will test the hypothesis that prevention of chlorthalidone - induced hyperuricemia with allopurinol results in improved BP control. In Aim 2 they will 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 they will test the hypothesis that prevention of chlorthalidone induced hyperuricemia with allopurinol improves renal blood flow and glomerular filtration rate (GFR) and prevents microalbumineria. The primary endpoint of this study is the significant reduction in clinic blood pressure at the end of 8 weeks of treatment.

Inclusion criteria:

African-American (including black individuals born in the Caribbean, Africa, Canada, etc.) men or women between the ages of 18 and 50 years of age will be eligible to participate. an average sitting clinic BP of between 140/90 and 159/99 mm Hg; a random spot Urine protein/creatinine ratio of less than 0.15; a serum creatinine of less than 1.5 mg/dl; the subject must not be taking allopurinol, probenecid. antihypertensive medication or nonsteroidal anti-inflammatory drugs for at least one month prior to enrollment, the patient needs to be willing and have the ability to cooperate with the protocol; the patient also has to be willing to travel to the General Clinical Research Center (GCRC) at Shands Hospital on two separate occasions.

Exclusion criteria:

Exclusions include any patient currently on anti-hypertensive medication or has taken them within the last 3 months or any patient who in the past required more than one antihypertensive agent to control BP. Any patient who is using tobacco products, using a nicotine patch, or chewing nicotine gum will be excluded. Also excluded are any patients with a history of malignant or accelerated hypertension; a confirmed total white cell count of less than 2.500/ mm3; a known secondary cause of hypertension; a history of diabetes requiring blood sugar-lowering therapy; a history of heart failure; a history of clinical or renal biopsy evidence of renal parenchymal disease; known familial disorder of uric acid metabolism or uric acid nephrolithisasis; a history of gout; a history of drug abuse in the last 2 years, including narcotics, cocaine, or alcohol (>21 drinks/week); current use of HMG CoA reductase inhibitors; and patients with an arm circumference > 52 cm, which precludes measurement with a ''''thigh'''' BP cuff. Also excluded are patients who have a history of a reaction to allopurinol or chlorthalidone; who are pregnant, lactating, or who are planning to become pregnant during the study period; who have a history of noncompliance, are unable to comply with the study requirements, or who are currently participating in another study.