Uric Acid and Hypertension in African Americans

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
100 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. 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.

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.

Inclusion Criteria:

- African American (including black individuals born in the Caribbean, Africa, Canada,
etc.)

- Are either untreated with any antihypertensive agent, with an average sitting clinic
BP of between 140/90 and 159/99 mm Hg OR subjects with hypertension controlled (i.e.
BP less than 140/90) or no higher than stage 1 hypertension (i.e., less than 160/100)
on a single antihypertensive agent or two antihypertensive agents (individuals on
fixed dose ARB-diuretic or ACEI-diuretic combinations will also be considered as being
on monotherapy for purposes of the study. Individuals on beta blockade or calcium
channel blockade for coronary artery disease and/or arrhythmia will not be eligible
for the study)

- Random spot urine protein/creatinine ratio of less than 0.5 (approximates a 24-hour
urinary protein excretion of 500 mg/day)

- Calculated MDRD GFR of greater than or equal to 60 ml/min/1.73/m^2

- No allopurinol or probenecid intake for at least one month prior to study entry

- Willing and able to cooperate with study procedures

- Willing to travel to the GCRC at Shands Hospital for overnight inpatient stays on two
separate occasions

Exclusion Criteria:

- History of malignant or accelerated hypertension

- Confirmed total white cell count of less than 2,500/mm^3, anemia, or thrombocytopenia

- Known history of liver disease

- Known secondary cause of hypertension

- Known presence of diabetes or fasting blood glucose greater than or equal to 126 mg/dL

- History of heart failure, acute myocardial infarction, or stroke or on a β-blocker or
calcium channel blocker for cardiovascular indications other than for lowering blood
pressure

- Abnormal EKG requiring medical intervention

- History of clinical or renal biopsy or evidence of renal parenchymal disease

- Acute gout attack within 2 weeks of study entry

- History of drug abuse in the last 2 years, including narcotics, cocaine, or alcohol
(greater than 21 drinks/week)

- Arm circumference of greater than 52 cm, which precludes measurement with a 'thigh' BP
cuff

- History of a reaction to allopurinol or chlorthalidone

- Pregnant or planning to become pregnant during the study, or breastfeeding

- History of noncompliance, are unable to comply with the study requirements, or who are
currently participating in another study

- Not fasting prior to obtaining screening laboratory data. If a participant has clearly
not fasted, we will exclude those individuals with casual blood glucose levels of
greater than or equal to 200 mg/dL. In the event that a fasting blood sugar exceeds
126 mg/dL, it will be reconfirmed on a blood glucose measurement obtained on a
subsequent day, per American Diabetes Association criteria