Low-dose L-NAME induces salt sensitivity associated with sustained increased blood volume and sodium-chloride cotransporter activity in rodents

Abstract

To investigate the cause of salt sensitivity in a normotensive animal model, we treated rats with a low-dose of the nitric oxide synthase inhibitor, L-NAME, that does not elevate blood pressure per se or induce kidney fibrosis. A high salt diet increased the circulating blood volume both in L-NAMEtreated and nontreated animals for the first 24 hours. Thereafter, the blood volume increase persisted only in the L-NAME-treated rats. Blood pressure was higher in the L-NAMEtreated group from the start of high salt diet exposure. Within the first 24 hours of salt loading, the L-NAME treated animals failed to show vasodilation and maintained high systemic vascular resistance in response to blood volume expansion. After four weeks on the high salt diet, the slope of the pressure-natriuresis curve was blunted in the L-NAME-treated group. An increase in natriuresis was observed after treatment with hydrochlorothiazide, but not amiloride, a change observed in parallel with increased phosphorylated sodium-chloride cotransporter (NCC). In contrast, a change in blood pressure was not observed in L-NAME-treated NCCdeficient mice fed a high salt diet. Moreover, direct L-NAMEinduced NCC activation was demonstrated in cells of the mouse distal convoluted tubule. The vasodilatator, sodium nitroprusside, downregulated phosphorylated NCC expression. The effect of L-NAME on phosphorylated NCC was blocked by both the SPAK inhibitor STOCK2S-26016 and the superoxide dismutase mimetic TEMPO which also attenuated salt-induced hypertension. These results suggest that the initiation of salt sensitivity in normotensive rodents could be due to hyporeactivity of the vasculature and that maintaining blood pressure could result in a high circulating volume due to inappropriate NCC activity in the low-dose L-NAME model. Thus, even slightly impaired nitric oxide production may be important in salt sensitivity regulation in healthy rodents.

The Sweet and Salty Dietary Face of Hypertension and Cardiovascular Disease in Lebanon

“…Nitric Oxide (NO) is a potent vasodilator proposed to be a key regulator of vascular tone in salt sensitivity (Bech et al, 1998). In this regard, an important model of salt sensitivity that has been widely used includes a low dose of the nitric oxide synthase inhibitor, L-NAME, that does not elevate blood pressure per se, followed by a high salt diet (Itani et al, 2016;Van Beusecum et al, 2019;Wang et al, 2020). This model demonstrated increased blood pressure in response to salt intake due to subnormal vasodilatory responses combined with a normal saltand salt-induced hypervolemia.…”

“…This model demonstrated increased blood pressure in response to salt intake due to subnormal vasodilatory responses combined with a normal saltand salt-induced hypervolemia. Interestingly, controls' blood volume reductions were associated with elevated urinary sodium excretion, indicating that high blood pressure, sodium retention, and hypervolemia are necessary (Wang et al, 2020).…”

Pathophysiology and genetics of salt-sensitive hypertension

“…Moreover, NO prevents lipid peroxidation and inhibits the formation of lipid peroxidation products like isoprostanes and isoketals, which are immunogenic in DCs. Another important pathogenic event resulting from low-dose L-NAME is vascular dysfunction ( Wang et al, 2020 ). In that regard, rats treated with a low dose of L-NAME demonstrated Subnormal vasodilation and elevated BP in response to a salt load ( Wang et al, 2020 ).…”

“…Another important pathogenic event resulting from low-dose L-NAME is vascular dysfunction ( Wang et al, 2020 ). In that regard, rats treated with a low dose of L-NAME demonstrated Subnormal vasodilation and elevated BP in response to a salt load ( Wang et al, 2020 ). Interestingly, in that study, volume expansion was comparable between the two groups on day 1, suggesting that vascular dysfunction was responsible for the initiation of salt-sensitive HTN.…”

A Novel Ferroptosis-Related lncRNA Signature for Prognosis Prediction in Patients with Papillary Renal Cell Carcinoma

“…7 Long non-coding RNAs (lncRNAs) are a subset of non-coding RNA molecules of about 200 nt, and studies have shown that lncRNAs play important roles in many life processes such as epigenetic regulation, cell cycle regulation, and cell differentiation regulation. [8][9][10] LncRNAs are involved in tumorigenesis, development, and metastasis processes. 11,12 Currently, studies on iron death-related lncRNAs are limited.…”