Dysfunctional Renal Nitric Oxide Synthase as a Determinant of Salt-Sensitive Hypertension

Abstract

Abstract. This study investigated the role of renal nitric oxide synthase (NOS), endothelin, and possible mechanisms of renovascular dysfunction in salt-sensitive 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 with the ETA receptor antagonist LU135252 (60 mg/kg per d). Salt loading markedly increased NOS activity (pmol citrulline/mg protein per min) in renal cortex and medulla in DR but not in DS rats by 270 and 246%, respectively. Hypertension in DS rats was associated with renal artery hypertrophy, increased vascular and renal endothelin-1 (ET-1) protein content, and glomerulosclerosis. In the renal artery but not in the aorta of hypertensive DS rats, endothelium-dependent relaxation to acetylcholine was unchanged; however, endothelial dysfunction due to enhanced prostanoid-mediated, endothelium-dependent contractions and attenuation of basal nitric oxide release was present. Treatment with LU135252 reduced hypertension in part, but completely prevented activation of tissue ET-1 without affecting ET-3 levels. This was associated with a slight increase of renal NOS activity, normalization of endothelial dysfunction and renal artery hypertrophy, and marked attenuation of glomerulosclerosis. Thus, DS rats fail to increase NOS activity in response to salt loading. This abnormality may predispose to activation of the tissue ET-1 system, abnormal renal vasoconstriction, and renal injury. Chronic ETA receptor blockade normalized salt-induced changes in the renal artery and reduced glomerular injury, suggesting therapeutic potential for ET antagonists in salt-sensitive forms of hypertension.

Salt Sensitivity: Causes, Consequences, and Recent Advances

“…These volume effects were observed in both the Dahl salt-sensitive rats and nonsalt-sensitive control animals, with no differences between the 2; however, in the former, salt intake induced hypertension, and this was attributed to a failure of peripheral vascular resistance to fall as salt intake increased. 45 Mechanistically, the hemodynamic dysfunction could be intrinsic to the arterial vasculature: defects in nitric oxide production by the endothelial cell 46 and abnormalities in soluble guanylate cyclase signaling in the vascular smooth muscle cell 47 are both reported. Nevertheless, many factors impact vascular resistance and the list of modifying factors that respond abnormally in a salt-sensitive paradigm include the sympathetic nervous system, endocrine factors, such as the renin-angiotensin-aldosterone system, and the milieu of paracrine agents (eg, endothelin-1) that can influence both endothelial and vascular smooth muscle cell biology.…”

Challenges in the evaluation of endothelial cell dysfunction: a statement from the European Society of Hypertension Working Group on Endothelin and Endothelial Factors

“…The renal artery is at least one order of magnitude more sensitive to contractions evoked by ET-1 than other conduit arteries [39]. It is also highly sensitive to EDCF/TxA 2 -evoked endothelium-dependent contractions [40], which are augmented by hypertension [40,41] despite endothelium-dependent relaxations being still intact, thus resulting in net vasoconstriction [41]. In patients with hypertension, the excretion of the TxA 2 metabolite TxB 2 is increased, even in the absence of renal artery stenosis [42], indicating activation of endothelium-dependent contractions as a mechanism underlying increased vascular tone in hypertension.…”

“…Endothelial overexpression of the preproET-1 gene also increases systemic inflammation [53], the first step in CKD development ultimately leading to fibrosis and loss of functional renal tissue [55]. Accordingly, activation of intrarenal tissue ET-1 contributes to hypertensive CKD associated with salt-sensitivity [41] as well as to focal-segmental glomerulosclerosis, which are both sensitive to treatment with ET A -selective ERAs [41,56].…”

“…Indeed, in rodents, but not in humans, contractions to ET-1 in conduit arteries are mediated by EDCF (TxA 2 /PGH 2 ), as cyclooxygenase inhibitors block contractile responses to ET-1 [44]. Likewise, chronic treatment with the ET A -selective endothelin receptor antagonist (ERA) darusentan completely prevents the augmented renal artery vasoconstriction in models of hypertensive CKD [41], consistent with a functional cross-talk between COX-derived vasoconstrictor prostanoids and the ET system. Moreover, Ang II stimulates the production of ET-1 [45], while conversely ET-1 increases the production of Ang II from Ang I [46].…”

“…Moreover, constitutively produced tissue ET-1 contributes to basal vascular tone [62] as well as to enhanced vasoconstriction seen in patients with arterial hypertension with or without CKD [63,64]. ET Aselective ERAs, similar to RAAS inhibitors [32], reduce tissue vascular and renal ET-1 levels [41], partly restore glomerular filter function and structure of injured podocytes [65], and block EDCF-mediated endothelium-dependent contractions. Given these therapeutic effects, ERAs hold the potential to slow down or even induce remission of renal injury in patients with CKD or renovascular hypertension undergoing renal artery angioplasty.…”