Effects of Thiazide Diuretics on Sympathetic Nervous System in Hypertension

Thiazide medications, including chlorthalidone, are commonly prescribed for individuals with
high blood pressure because they are inexpensive, effective at lowering blood pressure, and
able to reduce the risk of heart failure and stroke. Despite these advantages, research has
shown that thiazide medications may increase an individual's risk of developing diabetes. The
exact mechanism that causes this remains unknown. Thiazide appears to increase sympathetic
nervous system activity, thereby decreasing glucose reuptake and metabolism by skeletal
muscle tissues. In turn, this tends to contribute to glucose intolerance and the development
of diabetes. More research, however, is needed to confirm this link. Spironolactone, another
blood pressure medication, does not pose the same risk for developing diabetes and may prove
beneficial as a primary treatment for high blood pressure. The purpose of this study is to
determine the role of the sympathetic nervous system in glucose metabolism in individuals
with high blood pressure, as well as compare the effectiveness of thiazide, spironolactone,
and other antihypertensive medications in reducing blood pressure. Results from this study
may initiate the development of future clinical trials involving spironolactone as a primary
treatment for reducing blood pressure.

This study will enroll individuals with high blood pressure. Study# 1: All subjects were
randomized to receive 3 months chlorthalidone (12.5-25 mg/d) or spironolactone (50-75 mg/d),
using a single-blind 2-phase crossover design without washout between treatments. Each
subject was followed every 4 wk for measurement of 24-h ambulatory BP and serum potassium
(K). The doses of chlorthalidone and spironolactone were titrated to achieve 24-h ambulatory
BP of less than 130/80mmHg in the same subject. During chlorthalidone treatment period,
subject was given oral K supplementation according to a sliding scale to maintain serum K
from 4.0-4.5 mmol/liter. Then, sympathetic nerve activity (SNA) is measured after 3 months of
chlorthalidone and after 3 months of spironolactone. Arterial baroreflex sensitivity,
glucose, and insulin are measured at baseline, after 3 months of chlorthalidone, and after 3
months of spironolactone. Insulin sensitivity will be measured using HOMA-IR. Study #2: All
subjects are randomized to 3 months of fixed-dose Chlorthalidone 25 mg once daily alone,
fixed-dose Chlorthalidone 25 mg once daily plus fixed-dose Spironolactone 25 mg once daily,
and fixed-dose Chlorthalidone 25 mg once daily plus fixed-dose Irbesartan 150 mg once daily,
using a single-blind 3-phase crossover design without washout between treatments. Then, SNA ,
Arterial baroreflex sensitivity, glucose, and insulin are measured after 3 months of each
treatment phase.

Inclusion Criteria:

- Untreated stage 1 primary hypertension (systolic blood pressure between 140 to 159 mm
Hg and diastolic blood pressure between 90 to 99 mm Hg)

Exclusion Criteria:

- Cardiopulmonary disease, as determined by medical history or by physical examination

- Serum creatinine greater than or equal to 1.5 mg/dL

- Diabetes mellitus or other systemic illness

- Left ventricular hypertrophy by echocardiography or ECG

- Hypersensitivity to chlorthalidone, spironolactone, eplerenone, angiotensin converting
enzyme (ACE) inhibitors, angiotensin receptor blocker, insulin, Evans blue dye, or
clonidine

- History of substance abuse (other than tobacco)

- History of gouty arthritis

- History of ACE inhibitor-induced cough or angioedema

- Evidence of secondary hypertension

- Pregnant