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Journal of Hypertension:
doi: 10.1097/HJH.0b013e32835e8de1
Editorial Commentaries

Vascular effects of high-salt intake

Stier, Charles T.

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Department of Pharmacology, New York Medical College, Valhalla, New York, USA

Correspondence to Charles T. Stier, Jr., PhD, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA. Tel: +1 914 594 4138; fax: +1 914 594 4273; e-mail:

In the study by DuPont et al.[1] published in the present issue of the Journal of Hypertension the effect of high-salt intake for a 7-day period on endothelial function was examined. These studies are of significance as endothelial dysfunction has been shown to be a prognostic indicator of vascular events such as stroke and myocardial infarction. Fourteen otherwise healthy individuals were studied who, by definition, were salt-resistant as there was no discernible change in 24-h mean arterial pressure with salt loading. Endothelium-dependent dilation (EDD) measured at the end of the 1 week of study was slightly but significantly reduced when individuals were on a high-salt as compared with a low-salt intake. Interestingly, the reduction in EDD with salt loading occurred despite reductions in plasma renin activity (PRA), plasma angiotensin II (Ang II) and plasma aldosterone. These findings call attention to mechanisms other than increases in blood pressure and activation of the renin–angiotensin–aldosterone system (RAAS) in the detrimental effect of high-salt intake on vascular function. Farquharson and Struthers have shown that acute intravenous infusion of aldosterone can attenuate endothelium-dependent vasodilatation to acetylcholine compared with placebo [2] and the mineralocorticoid receptor antagonist spironolactone can increase flow-mediated dilation in the forearm of patients with chronic heart failure [3]. Further, studies by Nishizaka et al.[4] showed that flow-mediated vasodilation was impaired in hypertensive patients with hyperaldosteronism and that this difference was absent when patients were treated with spironolactone. Thus, in the present study suppression of the RAAS may have mitigated against what would have been an even greater intrinsic effect of high-salt intake to reduce EDD.

In support of the findings of DuPont et al., recent studies have shown that high-salt intake can produce acute reductions in vascular function in humans independent of changes in blood pressure [5,6]. In the former study, ingestion of a high-salt meal reduced flow-mediated vasodilation more so than ingestion of a low-salt meal at 30 and 60 min after consumption of the meal [5]. In the latter study, nitric oxide-dependent vasodilation to acetylcholine was severely impaired in young normotensive individuals placed on a short-term high-salt diet [6]. In another study, flow-mediated vasodilation was lower in normotensive salt-sensitive individuals than in normotensive salt-resistant ones during high-salt intervention (1 week) [7]. High-salt intake has also been associated with increases in serum uric acid [8]. Impaired EDD is characteristic of patients with hyperuricemia and hyperuricemia has been associated with an increased risk for cardiovascular disease and increased mortality [9].

Epidemiological studies relating high-salt intake to target organ damage have yielded heterogeneous results [10]. Some studies have reported that high-salt intake is associated with a significantly increased risk of stroke and total cardiovascular disease [11], whereas many other studies have reported no effect. Unlike the present study which provides information on the vascular effects of sodium loading under uniform conditions, epidemiological studies may not precisely control for sodium intake or the period of time over which high salt is applied. Also, blood pressure may or may not have been measured and in many epidemiological studies measurements of PRA, plasma Ang II and plasma aldosterone have not been performed. The latter information is of critical importance as sodium loading alone may not be responsible for target organ injury. Our own studies with stroke-prone spontaneously hypertensive rats (SHRSP) support this contention. SHRSP develop stroke, myocardial infarcts and malignant nephrosclerosis when maintained on high-salt intake for several weeks [12]. Treatment of these rats with angiotensin-converting enzyme inhibitors [12], AT1 receptor blockers [13] and mineralocorticoid receptor blockers [14] can prevent vascular injury and target organ damage in these rats despite maintenance of high levels of arterial pressure and continued and sustained high-salt intake. These studies support the notion that high-salt intake and/or increased arterial pressure are necessary but not sufficient for the production of severe vascular injury. Of importance in the SHRSP is the fact that although high-salt intake may initially suppress PRA [15,16] and aldosterone levels [17], this suppression is not sustained over time and paradoxical increases may occur despite continued salt loading. Likewise, salt loading of SHR has been reported to activate the local renal RAS [18], and to increase Ang II levels in the heart [19]. In view of the mutual potentiating effect of activation of the RAAS and high-salt intake to produce vascular injury, it would be important to know the extent to which high-salt intake suppresses the RAAS not only in the circulation but also at the tissue level. The present study specifically examined the effects of high-salt intake on forearm blood flow over a 1-week period. Certainly it would be important to know whether an increase in the extent and duration of high-salt intake would produce an even greater deficit in EDD. Further, it would be extremely important to know whether similar or even greater effects would be seen in the cardiac, cerebral and renal circulations as these changes may have a more direct bearing on heart attack, stroke and kidney dysfunction.

There are several possible mechanisms by which high-salt intake can reduce EDD. Salt loading may stimulate central sympathetic outflow creating a hyperadrenergic state [20]. Another mechanism by which high-salt intake can impair endothelial dysfunction is by suppression of nitric oxide formation. A reduction in nitric oxide is thought to be the hallmark of endothelial dysfunction. High-salt intake has been reported to stimulate the formation of reactive oxygen species [21] and this in turn can scavenge nitric oxide and reduce its bioavailability. There is also evidence that high-salt intake increases serum and interstitial sodium concentration. This increase can be as much as 3 mmol/l [5]. Increases in plasma sodium have been reported to increase vascular responses to Ang II. In these studies, Heistad et al.[22] found a direct correlation between serum sodium concentration and vasoconstrictor responses to Ang II in the human forearm circulation. Recent work suggests that high-salt intake may result in the nonosmotic storage of sodium in the body [23]. One such site is the endothelial glycocalyx [24] which when damaged may allow increased local concentrations of sodium within the vessel wall. The ability of aldosterone to stimulate the entry of sodium into human endothelial cells has been demonstrated using atomic force microscopy [25] and may form the cellular basis for why high-salt intake and aldosterone act in concert to produce severe vascular injury. The studies by DuPont et al.[1] provide clear evidence to demonstrate under controlled experimental conditions that high-salt intake has a detrimental effect on vascular function. However, whether and to what extent the above mechanisms may play a role in this action needs to be established. In future studies it will be important to learn how sodium interacts with components of the RAAS at the cellular level in blood vessels as this appears to be the basis for the production of severe vascular injury leading to end-organ damage.

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Conflicts of interest

There are no conflicts of interest.

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