Thiazide diuretics, endothelial function, and vascular oxidative stress

Objectives Increased endothelial production of reactive oxygen species and decreased nitric oxide bioactivity, associated with the upregulation of monocyte chemoattractant protein (MCP)-1 and lectin-like oxidized low-density lipoprotein receptor (LOX)-1, link hypertension with atherogenesis. We investigated whether the beneficial effects of thiazide diuretics are exclusively related to a reduction in the biomechanical stress of hypertension or are also endowed with pleiotropic vasculoprotective effects that are independent of their effect upon blood pressure. Methods Dahl salt-sensitive (DSS) rats, a paradigm of human salt-sensitive hypertension, were given a diet with normal salt (0.5% NaCI), high salt (4% NaCI), or a high salt diet plus either hydrochlorothiazide 75 mg/l, chlorthalidone 37 or 75 mg/l in their drinking water for 6 weeks. We determined systolic blood pressure (SBP), left ventricular hypertrophy (LVH), proteinuria, aortic superoxide anion (O 2 - ) production, endothelium-dependent relaxation (EDR) to acetylcholine, and aortic angiotensin II type 1 (AT 1 ) receptor, LOX-1, and MCP-1 messenger RNA expression (by real-time polymerase chain reaction). Results DSS rats on a high salt diet developed hypertension, LVH, proteinuria, increased production of aortic O 2 - (106%), impaired EDR, and aortic upregulation of AT 1 receptor (198%), LOX-1 (135%), and MCP-1 (145%). Hydrochlorothiazide as well as the high and low dose of chlorthalidone reduced SBP, LVH, and proteinuria, but did not reduce O 2 - production, AT 1 receptor, LOX-1, or MCP-1 expression, or improved EDR. Conclusions This study demonstrates that thiazide diuretics do not reduce oxidative stress, improve endothelial function, or prevent the expression of proatherogenic molecules. We conclude that thiazide diuretics may not fully provide long-term global cardiovascular protection beyond lowering blood pressure..