Thiazide diuretics, endothelial function, and vascular oxidative stress.
OBJECTIVE
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% NaCl), high salt (4% NaCl), 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 (O2(-)) production, endothelium-dependent relaxation (EDR) to acetylcholine, and aortic angiotensin II type 1 (AT1) 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 O2(-) (106%), impaired EDR, and aortic upregulation of AT1 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 O2(-) production, AT1 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 pro-atherogenic molecules. We conclude that thiazide diuretics may not fully provide long-term global cardiovascular protection beyond lowering blood pressure.
Zhou
Ming-Sheng
MS
Nephrology and Hypertension Section, Veterans Affairs Medical Center, Miami, Florida 33125, USA.
Schulman
Ivonne Hernandez
IH
Jaimes
Edgar A
EA
Raij
Leopoldo
L
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D020303:Rats, Inbred Dahl; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000096:biosynthesis; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology*; D015854:Up-Regulation
D018932:Chemokine CCL2; C495137:OLR1 protein, human; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D049993:Sodium Chloride Symporter Inhibitors