**3. Effect of sodium intake reduction on pulse wave velocity**

Evidences suggest that salt intake plays an important role on blood pressure regulation, and it is also suggested a direct effect of salt on large artery wall that modulates vascular stiffness [14].

Pulse wave velocity is known to be associated with BP and age [26, 32, 33]. In a recent study where the authors have evaluated the effect of salt restriction on pulse wave velocity, no significant statistical differences were detected. Although sodium restriction reduced SBP and DBP in the combined analysis of all studies, results of the meta-regression analysis, however, indicated that the effect of salt restriction on arterial stiffness did not depend on changes in blood pressure. In fact, in one of the studies included in the meta-analysis, there was a significantly greater reduction in pulse wave velocity in black than white and Asian hypertensive patients, despite the fact that the three ethnic groups had similar reductions in blood pressure [34].

Another study evaluating the long-term sodium restriction showed an improvement in arterial stiffness independently of the changes in BP [35]. The authors did not detect a dose dependence in the pooled association between salt restriction and reduction of PWV. Accordingly, the lack of a dose-related effect in the range of salt reduction applied in the available studies might be the possible cause of these results.

In subgroup analyses of nine cohorts that evaluated the effect of sodium restriction on PWV including prehypertensive and/or hypertensive participants, whereas in the five cohorts that enrolled non-hypertensive individuals, an inverse trend was detected, but this difference was not statistically significant. A larger effect of sodium reduction on PWV was also seen in the three cohorts that included hypertensive patients under antihypertensive treatment (5.07%) than in the cohorts enrolling untreated normotensive or prehypertensive individuals (1.70%): again, however, this difference was not statistically significant [14].

More recently, a study using a hypothetical model to analyze the association between salt intake and PWV (carotid-femoral) through direct and mediating pathways that aimed to investigate whether the association between salt intake and arterial stiffness also has a sex-specific pattern has demonstrated that high salt intake has a direct and independent effect increasing on arterial stiffness regardless of sex. The authors also concluded that the association between salt intake and arterial stiffness is more dependent on BP in normotensive women than it is

in normotensive men. As stated by the authors, these results highlight the need for a sex-specific approach in the evaluation of cardiovascular risk associated with dietary habits [36].

Furthermore, Grigorova et al. [37] have demonstrated that high salt intake was associated with an increase in Na/K-ATPase inhibitor marinobufagenin (MBG) levels, and an activation of the transforming growth factor-beta (TGF-β) mediated pro-fibrotic pathway in the vasculature, leading to an increase of aortic stiffness without elevation of BP. MBG activated TGFβ1 pro-fibrotic pathway in cultural vascular smooth muscle cell (VSMC), indicating a fundamental role of MBG in the development of fibrosis via the Na/K-ATPase signaling function. The decrease in salt consumption restored the aortic elasticity through inactivation of the TGF-β pathway. Therefore, decreasing salt consumption can improve vascular elasticity and lower the risk of cardiovascular disease by MBG level reduction [37].

#### **4. Renal sodium handling, blood pressure, and vascular compliance**

The relationship between sodium intake and blood pressure regulation has been suggested through animal experiments indicating that a high-sodium diet, at their initial phase, leads to volume expansion and cardiac output increases. Based on experiments including mainly nephrectomized dogs that received a large amount of saline solution daily for 2 weeks, Guyton [7] suggested that the BP increases mainly through two mechanisms: (1) volume expansion and cardiac output increases and (2) an autoregulatory mechanism that affects the vessel resistance. Accordingly, the hypothetic mechanism on how dietary salt increases blood pressure includes Guyton's main theory that the increase in blood pressure is initially associated with an increase in extracellular fluid and blood volumes [7, 15, 26]. According to Guyton's hypothesis, in the hypertension pathophysiology, irrespective of the causal factor, the pressure-natriuresis relationship in the kidney is always involved, with higher blood pressures being required to eliminate a higher given sodium load [38]. However, it has never been demonstrated that measurements of extracellular fluid volume in hypertensive individuals are modified consistently. All of the authors found that the volumes of extracellular fluid and exchangeable sodium were normal in hypertensive individuals [39, 40].

The only similitudes were the lower ratio between intravascular and interstitial fluid volumes and smaller plasma volume, indicating unbalanced division in hypertensive patients [39]. Additionally, high levels of atrial natriuretic peptide hormone, lower levels of plasma renin, and an increased capacity of plasma to inhibit Na+/K+ - ATPase were observed in these patients [15, 41, 42]. In fact, all these apparent paradoxes can be easily understood when we observe that, in hypertensive patients, if total vascular compliance is reduced, a slight decrease in intravascular volume can be too large for the capacity of the corresponding vascular space [39].

Vascular compliance establishes the volume-pressure relationship or the volume within a vascular segment and the blood pressure that is generated by the presence of that blood volume. It is simply the basic concept of compliance applied to a vascular segment and represents a classic index of the elasticity of the intravascular compartment, from the slope of the curve plotting changes of blood volume (∆V) versus changes of intravascular pressure (∆P) [6].

Within a narrow range of volume and pressure changes, the linear relationship curve between both variables is used to define the compliance as the slope ∆V/∆P [6]. In a clustered circulation model, the vascular compliance expresses the sum of complacencies of all vascular segments, including arteries and veins [43]. Accordingly, Guyton [6] has defined "total" vascular compliance based on

#### *The Effect of Dietary Sodium Restriction on Vascular Stiffness in Hypertension DOI: http://dx.doi.org/10.5772/intechopen.93090*

experimental animal models as the relationship between the mean circulatory filling pressure (MCFP) and blood volume. The MCFP is the pressure that is registered throughout the entire circulatory system if the heart is suddenly stopped and the blood volume is redistributed entirely in the vascular system taking into account the capacity of the vessels. Vascular compliance is then defined as the product of volume change and mean circulatory filling pressure. However, as the MCFP measurement implies the presence of a non-beating heart, in humans, it cannot be measured. Therefore, an alternative index of the capacitance function had to be defined.

Evidence from studies in both animals and humans has shown that similar indices are observed in cases where the circulation is not interrupted between blood volume changes and pressures measured throughout the different parts of the venous system [6, 37]. For example, the relationship between rapid blood volume expansion (∆V) and central venous pressure (∆CVP) with a plasmatic expander such as dextran has the dimensions of compliance [39, 44]. The "true" vascular compliance measured from ∆V/∆MCFP ratio is also called "effective" total vascular compliance to differentiate it from the ∆V/∆MCFP ratio [39, 45].

Compared to the normotensive patients, the slope of the curve plotting blood-volume versus central venous pressure (∆V/∆CVP) is markedly lower in hypertensive subjects [39, 45]. On the other hand, there are no changes in curves of cardiac output versus blood volume expansion, indicating that the cardiac function is maintained despite cardiac structural modifications in hypertensive individuals. At these conditions, compared to non-hypertensive individuals, in hypertensive patients, the central venous pressure increases more, and the decrease in the effective compliance of the vascular bed is pointed out as the responsible factor for this phenomenon [46, 47].

Evidence suggests that renal sodium handling is the main factor influencing the level of intra- and extrarenal blood pressure and is regulated by complex physiological and inflammatory mediators, hormones, and the sympathetic nervous system [48]. Therefore, a compromised kidney capacity to eliminate sodium in response to increased blood pressure is a major factor for a sustained increase in blood pressure, irrespective of the primary cause.

The changes registered in plasma sodium levels exert their effects on the vascular system, affecting not only the small resistance arteries but also the large artery properties leading to an increase in arterial stiffness and consequent decrease in vascular compliance [49].

Both observational and longitudinal studies have suggested that lower sodium intake is associated with lower wave pulse velocity. Evidence suggests that in hypertensive patients, a low sodium intake is associated with a larger brachial artery diameter than that seen with a high sodium intake [50]. A sodium overload reduces arterial distensibility and compliance irrespective of blood pressure changes in hypertension in the elderly and in severe hypertension patients with end-stage renal disease [51].

#### **5. Sodium-induced change in arterial stiffness and BP**

A considerable body of evidence has shown major links along with cause-andeffect relationships between salt intake and BP [15, 16, 52]. In many studies, both SBP and DBP had a similar effect regarding their action on the arterial wall, regardless of the presence of a high-sodium diet or not. Remarkably, many observational studies suggest a special role of systolic blood pressure, which, until recently, was rarely considered.

Evidence from studies of genetic models of animal hypertension suggested that long-term high sodium intake is associated with increased intima-media thickness due to the extracellular matrix (ECM) development and aortic hypertrophy regardless of blood pressure. These changes caused by high sodium consumption and often associated with increased arterial stiffness and changes in smooth vascular cells properties are reversed by reducing sodium and/or giving diuretics [16, 53].

Hormonal counterregulatory mechanisms that modulate arterial changes act chronically in the presence of a high-sodium diet because bradykinin β2-receptor blockage by Hoe-140 (selective B2 bradykinin receptor antagonist that suppresses the effects of bradykinin) produces more carotid hypertrophy, while in case of normal sodium intake, less aortic collagen accumulates due to AngII-specific type 1 receptor activity [54, 55].

Several studies have consistently established an independent correlation between sodium dietary intake, arterial stiffness, and blood pressure, regardless of whether systemic, regional, or local determinations were present [16, 56]. In a study addressing the relationship between sodium intake and arterial stiffness based on the Chinese populations, Avolio et al. [57] have found that sodium intake has an independent effect on arteriolar tone and arterial wall properties, with the former indirectly and the later directly contributing to increased arterial stiffness with age. In the same study, the comparison of salt intake between urban and rural subjects, as determined by urinary sodium excretion, was greater in the urban subjects (13.3 g NaCl/day) than in rural ones (7.3 g NaCl/day). This difference was related to higher arterial stiffness and hypertension prevalence and lesser vascular compliance in urban subjects. Salt intake had, therefore, an independent effect on arterial structural and functional properties, with the arterial wall directly and arterial tone indirectly contributing to increased PWV with age [16]. Another study from Australia involving young and middle-aged (20–66 years old) normotensive subjects on a low-salt diet who were compared with age- and BP-matched subjects on a normal-sodium diet showed adult subjects on a low-sodium diet have lower arterial stiffness independent of blood pressure [35].

On the other hand, the benefits of a low-salt diet on blood pressure seem to be greater in hypertensive patients than in normotensive ones. A systematic review carried out by Graudal et al. [58] that included 185 randomized controlled trials found that sodium reduction from an average high usual sodium intake level (201 mmol/day) to an average level of 66 mmol/day, which is below the recommended upper level of 100 mmol/day (5.8 g salt), resulted in a small decrease (1/0 mmHg) in systolic and diastolic BP in white normotensive patients and a decrease in systolic and diastolic BP of 5.5/2.9 mmHg in white hypertensive patients. The decrease of blood pressure was even greater in black and Asian populations.

Moore et al. [59] in their study addressing the effect of low sodium intake on the blood pressure levels among Framingham Offspring Study adults even found paradoxical results. These authors analyzed dietary data from 2632 subjects (normotensive men and women) aged 30–64 years old who were part of the Framingham Offspring Study. Over 16 years of follow-up, systolic and diastolic blood pressures decreased with increasing sodium intake (≥2.5 g). Mean systolic and diastolic blood pressures of 129.5 mmHg and 75.6 mmHg, respectively, were seen among subjects in the high-sodium and high-potassium (≥2.3 g) groups compared with 135.4 mmHg and 79.0 mmHg, respectively, among people in the low-sodium (<2.5 g) and low-potassium (<2.3 g) groups.
