Dysfunctional renal nitric oxide synthase as a determinant of salt-sensitive hypertension: Mechanisms of renal artery endothelial dysfunction and role of endothelin for vascular hypertrophy and glomerulosclerosis

This study investigated the role of renal nitric oxide synthase (NOS), endo thelin, and possible mechanisms of renovascular dysfunction in salt-sensiti ve hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated for 8 wk with high salt diet (4% NaCl) alone or in combination wit h the ETA receptor antagonist LU135252 (60 mg/kg per d). Salt loading marke dly increased NOS activity (pmol citrulline/mg protein per min) in renal co rtex and medulla in DR but not in DS rats by 270 and 246%, respectively. Hy pertension in DS rats was associated with renal artery hypertrophy, increas ed vascular and renal endothelin-1 (ET-1) protein content, and glomeruloscl erosis. in the renal artery but not in the aorta of hypertensive DS rats, e ndothelium-dependent relaxation to acetylcholine was unchanged; however, en dothelial dysfunction due to enhanced prostanoid-mediated, endothelium-depe ndent contractions and attenuation of basal nitric oxide release was presen t. Treatment with LU135252 reduced hypertension in part, but completely pre vented activation of tissue ET-I without affecting ET-3 levels. This was as sociated with a slight increase of renal NOS activity, normalization of end othelial dysfunction and renal artery hypertrophy, and marked attenuation o f glomerulosclerosis. Thus, DS rats fail to increase NOS activity in respon se to salt loading. This abnormality may predispose to activation of the ti ssue ET-1 system, abnormal renal vasoconstriction, and renal injury. Chroni c ETA receptor blockade normalized salt-induced changes in the renal artery and reduced glomerular injury, suggesting therapeutic potential for ET ant agonists in salt-sensitive forms of hypertension.