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Endothelial dysfunction (ED) complicates hypertension and is a precursor of atherosclerosis. Reduced NO bioactivity, because of increased reduced NAD(P)H oxidase–derived reactive oxygen species (ROS), plays a critical role in ED. gp91 phox , predominantly expressed in the endothelium and adventitia, is a subunit of NAD(P)H oxidase important for its activation in response to angiotensin (Ang) II. Human atherosclerotic plaques are heavy laden with gp91 phox . We have shown that in Dahl salt-sensitive (DS) rats, a paradigm of low renin salt-sensitive (SS) hypertension in humans, Ang II receptor blockade normalizes ROS production and endothelium-dependent relaxation (EDR) without significantly affecting systolic blood pressure (SBP). To additionally elucidate the mechanisms involved in the functional association of Ang II in SS hypertension, we administered a cell-permeable inhibitor of the assembly of p47 phox with gp91 phox in NAD(P)H oxidase, gp91ds-tat (10 mg/kg body weight, 3 weeks by minipump), to DS rats fed a 4% salt diet. Control rats received either vehicle or an inactive scramb-tat peptide. Vehicle-treated DS developed hypertension (SBP 168±5 mm Hg), left ventricular hypertrophy (LVH), proteinuria, impaired EDR, and increased aortic ROS production (superoxide 115% and peroxynitrite 157%) and expression of the proatherogenic molecules LOX-1 (130%) and MCP-1 (166%). gp91ds-tat, but not scramb-tat, normalized ROS and EDR, as well as LOX-1 and MCP-1, despite nonsignificant effects on SBP (159±5 mm Hg; P >0.05), left ventricular hypertrophy, and proteinuria. Our findings support the notion that in SS hypertension, activation of NAD(P)H oxidase promotes ED and atherogenesis via decreased nitric oxide bioactivity and increased LOX-1 and MCP-1, independent of blood pressure.

The balance between endothelial nitric oxide (NO) and angiotensin II (Ang II) maintains the homeostasis of the cardiovascular and renal systems. We tested the hypothesis that increased oxidant stress linked to a functional imbalance between NO and Ang II might play a central pathogenetic role in salt-sensitive (SS) hypertension. We studied Dahl SS (DS) rats during the prehypertensive (5 days) and hypertensive (12 weeks) phases of a high-salt (4% NaCl) diet. Control rats received a normal-salt (0.5% NaCl, [NS]) diet. Prehypertensive DS rats (systolic blood pressure [SBP] 138±2 mm Hg) manifested a 35% increase ( P 2 − ) production without evidence of end-organ damage. Hypertensive DS rats (SBP 214±11 mm Hg) had impaired endothelium-dependent relaxation (EDR) and increased aortic O 2 − production (320%), urinary isoprostane excretion (83%), aortic (20%) and left ventricular (LVH, 21%) hypertrophy, and proteinuria (124%). In prehypertensive DS rats, candesartan (10 mg · kg −1 · d −1 ) an Ang II type 1 receptor blocker (ARB), normalized O 2 − production. In hypertensive DS rats, the ARB decreased aortic O 2 − production by 71% and normalized EDR without affecting SBP (212±8 mm Hg), aortic hypertrophy, LVH, or proteinuria. Switching hypertensive DS rats to an NS diet did not affect SBP (208±8 mm Hg), LVH, aortic hypertrophy, or proteinuria and had minimal effects on O 2 − and EDR. Concomitant ARB administration plus a switch to an NS diet normalized SBP (138±8 mm Hg) as well as end-organ damage. Dahl salt-resistant rats fed an HS diet for 12 weeks did not show hypertension or increased O 2 − production. Thus, SS hypertension might represent a specific vascular diathesis linked to functional upregulation of Ang II action (increased O 2 − synthesis) accompanied by insufficient NO bioavailability, which promotes severe endothelial dysfunction.