How Long Does Salt Stay In Your System To Increase Blood Pressure
Curr Hypertens Rep. 2018; 20(11): 94.
Skin Sodium and Hypertension: a Paradigm Shift?
Viknesh Selvarajah
Division of Experimental Medicine and Immunotherapeutics, University of Cambridge, Box 98, Addenbrookes Hospital, Cambridge, CB2 0QQ UK
Kathleen Connolly
Partition of Experimental Medicine and Immunotherapeutics, University of Cambridge, Box 98, Addenbrookes Hospital, Cambridge, CB2 0QQ U.k.
Carmel McEniery
Sectionalisation of Experimental Medicine and Immunotherapeutics, Academy of Cambridge, Box 98, Addenbrookes Infirmary, Cambridge, CB2 0QQ Uk
Ian Wilkinson
Partitioning of Experimental Medicine and Immunotherapeutics, University of Cambridge, Box 98, Addenbrookes Hospital, Cambridge, CB2 0QQ UK
Abstract
Purpose of Review
Dietary sodium is an of import trigger for hypertension and humans testify a heterogeneous blood force per unit area response to salt intake. The precise mechanisms for this have not been fully explained although renal sodium treatment has traditionally been considered to play a central function.
Recent Findings
Animal studies have shown that dietary salt loading results in non-osmotic sodium accumulation via glycosaminoglycans and lymphangiogenesis in skin mediated past vascular endothelial growth factor-C, both processes attenuating the ascension in BP. Studies in humans take shown that pare could be a buffer for sodium and that skin sodium could be a marker of hypertension and salt sensitivity.
Summary
Peel sodium storage could represent an additional system influencing the response to salt load and claret pressure level in humans.
Keywords: Blood force per unit area, Table salt, Skin, Sodium, VEGF-C
Introduction
Chronically elevated blood force per unit area, known equally hypertension, represents an imminent global health challenge. Hypertension is responsible for over 10 meg deaths annually and is one of the foremost modifiable gamble factors for stroke, heart failure, ischaemic middle disease and chronic kidney disease [1–3]. Hypertension currently affects nearly one 3rd of the population, and its prevalence is increasing worldwide [4]. Despite this pervasiveness, the precise origins of hypertension remain unclear, with inquiry primarily focused on the kidney, brain, heart and blood vessels. Large population studies propose that excessive dietary sodium, principally as the chloride salt, is an important trigger for hypertension, with the kidney considered to be the main organ regulating the haemodynamic response to salt intake [5, 6]. In this review, we examine emerging evidence supporting the role of the pare in sodium homeostasis and the regulation of claret pressure and novel extrarenal mechanisms involved in these.
Rethinking the Mechanisms for Salt Sensitivity of Blood Pressure (SSBP)
Salt sensitivity of blood pressure level (SSBP) refers to the physiological trait past which BP of certain individuals exhibits changes parallel to changes in salt intake, while individuals without this trait are termed salt resistant [7]. SSBP is more common with greater age, Afro-Caribbean descent and individuals with hypertension, diabetes mellitus and chronic kidney disease. The variability in this trait and the mechanisms by which sodium influences blood pressure are not fully understood [7, 8]. In the classical Guytonian model, sodium intake in excess of renal excretory chapters causes an osmotically driven expansion of the extracellular fluid volume. This leads to an increase in plasma volume, venous return, and cardiac output, which in turn produce a rise in systemic claret pressure [9]. Thus, in this traditional paradigm, a defect in renal sodium excretion is the basis for salt sensitivity; conversely, common salt-resistant individuals are protected from common salt-induced BP rises because they can rapidly excrete a salt load without retaining sodium [10]. Others have expanded on this model, suggesting that SSBP occurs with a subnormal decrease in renal and peripheral vascular resistance in response to a loftier salt intake, rather than an increase in sodium retentivity and cardiac output, with the kidney maintaining a central role [xi].
More contempo studies accept similarly challenged this view in humans. Schmidlin and Laffer et al. noted that both salt-resistant and salt-sensitive normotensive individuals underwent like degrees of body sodium memory with astute dietary common salt loading, demonstrating that in salt-resistant individuals, sodium retentiveness occurred without adverse furnishings on BP [12, 13, fourteen••].These studies revealed that table salt-resistant individuals tin can adapt to a table salt load via vasodilation concomitant to increased cardiac output, while this vasodilatory response is attenuated those who are in common salt sensitive [12, 13, 14••]. In general, these observations abnegate the view that salt sensitivity is solely due to deficiencies in renal excretion of sodium.
A '3-Compartment Model' of Torso Sodium
Total body water (TBW) has historically been divided into two compartments, the intracellular fluid (ICF) and the extracellular fluid (ECF), with this latter compartment comprising the intravascular and interstitial spaces. Total body sodium (TBNa) has been similarly compartmentalised [15].While intracellular sodium and fluid volume are tightly regulated to protect cells against detrimental volume changes, the intravascular and interstitial spaces are generally believed to exist in equilibrium.
Post-obit an increase in dietary table salt intake, sodium accumulates in the extracellular infinite. In theory, each 140 mmol of additional sodium must exist coupled with the accumulation of ~ 1 50 of water in the extracellular fluid to maintain osmolality. Yet, four carefully conducted longer-term sodium balance studies in good for you humans take shown that big amounts of sodium can accumulate without commensurate water [xvi–19]. Of these studies, the Mars 500 study, which investigated sodium metabolism at constant common salt intake under controlled conditions for either 105 or 250 days, showed that sodium is rhythmically stored and released independent of common salt intake, and that BP, trunk weight and extracellular water were not coupled to urine sodium excretion as expected [19]. A further study, which assessed sodium and water excretion in healthy humans later on infusion with hypertonic saline, found that sodium recovery in the urine was simply half of the expected amount, indicating that some of the infused sodium was retained in an osmotically inactivated form [20••]. These observations back up the beingness of non-osmotic storage of excess sodium (sodium accumulation without commensurate water retention) in an additional third compartment, suggesting the existence of 'extra-renal' mechanisms for sodium homeostasis.
The Skin as a '3rd Compartment' of Body Sodium and Relevance to BP
The skin is the largest organ in the human torso, comprising 6% of trunk weight and forming a significant component of the interstitium [21, 22]. The peel consists of two tissue layers: the epidermis, the external layer consisting of not-stratified epithelial cells and the dermis, which consists mainly of connective tissue [22]. The epidermis is approximately 50–200 μm thick and acts as a physical barrier against microorganisms and water loss, while the dermis is relatively acellular, comprised of fibroblasts, claret vessels, lymphatics and nerves in an extracellular matrix of collagen, elastin and glycosaminoglycans [22, 23]. The skin is a rich source of nitric oxide, a major regulator of vascular tone, containing 10 times the levels in the circulation [24]. Blood menses in the skin is dynamic, ranging from as low every bit 1% in common cold temperatures to every bit high equally sixty% in erythroderma and heat stress [25, 26••]. These backdrop of the skin would suggest the potential for influencing systemic BP [25, 26••].
From equally early as 1909, directly chemic measurements indicated that the skin is a depot for sodium, chloride and water, although the exact relevance of skin electrolytes was non known [27–30]. In 1978, Ivanova et al. showed that skin sodium in white rats increased with dietary salt loading and observed that this was associated with an increment in sulphated glycosaminoglycans [31]. Glycosaminoglycans (GAGs) are linear polysaccharide bondage of variable length consisting of repeating disaccharide units [32, 33]. Due to the presence of carboxyl and sulphate functional groups on the disaccharide units, GAGs possess significant negative charge densities capable of facilitating the non-osmotic storage of sodium in the interstitium, as described in a recent comprehensive review [34••]. It should be noted that the skin is non the simply place with high glycosaminoglycan content, and not-osmotic sodium storage can occur elsewhere in the interstitium.
In 2002, Titze et al. first proposed the connection between skin sodium, GAGs and BP following a series of rat experiments [35–39]. Work by this group revealed that GAG polymerisation facilitates osmotically inactive sodium storage in the skin, enabling skin sodium concentrations to rise as much as 180–190 mmol/fifty without commensurate increases in peel water content. This osmotically inactive sodium storage could therefore serve as a machinery for buffering volume and blood pressure following changes in common salt intake [36–39].
Titze et al. calculated that osmotically inactive sodium storage in table salt-resistant rats was threefold higher than in salt-sensitive rats, based on body sodium and body h2o measurements [35]. They further demonstrated that male rats had a college capacity for osmotically inactive skin sodium storage compared to fertile female rats, while ovariectomised rats had no capacity for osmotically inactive sodium accumulation [36]. The above findings led to the conclusion that the pare functions a '3rd compartment' of body sodium, with a dynamic capacity for sodium storage and buffering volume and claret pressure changes with salt intake.
Tissue Macrophages and the Lymphatics Influence Sodium Balance, Interstitial Volume and Claret Pressure level
In recent years, information technology has go apparent that cells of the innate and adaptive immune system play a role in hypertension and cardiovascular disease [twoscore]. Work in rodent skin has showed that macrophages mediate an additional adaptive mechanism that functions during periods of high table salt intake (Fig.1) [38, 39, 41]. Post-obit salt challenge, pare sodium concentration increased and the resultant hypertonicity caused recruitment of macrophages which activated tonicity-responsive enhancer binding protein (TonEBP). TonEBP increased the expression of vascular endothelial growth gene C (VEGF-C) cistron via autocrine signalling. By mediating VEGF-C, the macrophage response restructured the interstitial lymphatic network, enabling drainage of water and electrolytes from the skin into the systemic circulation. VEGF-C as well and induced expression of endothelial nitric oxide synthase (eNOS), causing vasodilation via nitric oxide (NO) production. These processes evidently serve to buffer the haemodynamic effects to salt loading [38]. VEGF-C and TonEBP animosity and genetic deletion and consistent disruption of the in a higher place pathway caused salt sensitivity in these rodents [38, 39, 41].
A novel extra-renal mechanism for buffering dietary salt. Under normal atmospheric condition, Na+ binds to negatively charged GAGs in the dermal interstitium, without commensurate water, allowing loftier concentrations of Na+ to accumulate in the skin. During salt loading, the Na+-binding chapters of GAGs is exceeded and interstitial hypertonicity develops. This leads to an influx of macrophages, which release an osmosensitive transcription factor (TonEBP). This induces the secretion of VEGF-C in an autocrine manner, leading to lymphangiogenesis. The enhanced lymphatic network increases Na+ transport back into the apportionment, for eventual removal by the kidneys, preventing a blood pressure rise with table salt loading (Adapted from Marvar et al. [42]. Illustrated by Gökçen Ackali)
In summary, macrophages exert a homeostatic part in the skin via TonEBP and VEGF-C, regulating clearance of osmotically inactive stored common salt via cutaneous lymphatic vessels, buffering the haemodynamic response to dietary salt. In this process, the lymphatics serve as a connection between pare equally a 'third compartment' of body sodium and the circulation and this appears to be mediated by VEGF-C.
Recent Evidence for the Office of the Skin in Sodium Homeostasis and BP Regulation in Humans
Most of the novel mechanisms described above linking dietary salt, peel sodium, and BP were examined in rodent models. The balance of this review will focus on recent studies examining skin sodium in humans, its relevance to man sodium homeostasis and BP regulation and possible mechanisms linking these.
Insights from Sodium MRI of the Skin in Humans
For over 30 years, the employ of 23Na-MRI spectroscopy has enabled non-invasive in vivo cess of sodium concentrations in human being tissue [43]. Recently, researchers accept begun using 23Na-MRI spectroscopy to measure sodium in calf skin and musculus alongside h2o measurements using traditional proton MRI [44, 45, 46••, 47, 48, 49••].
Initial experiments showed that skin sodium was positively correlated with age, and that men had higher skin sodium than women later on decision-making for both historic period and BMI [44, 45, 48]. In cross-sectional studies on normotensives and hypertensives, Kopp et al. have shown that pare sodium was positively associated with BP, patients with refractory hypertension had increased tissue Na+ content compared to controls, and at that place was a trend for increased skin sodium in individuals with hyperaldosteronism [44, 45].
In 2014, Dahlmann et al. investigated the role of the pare as a sodium buffer using 23Na-MRI in 24 haemodialysis patients before and after a unmarried dialysis. Pare sodium was reduced past nineteen% following dialysis, and patients with higher serum VEGF-C levels had better dialytic Na+ removal [46••]. Skin sodium was too higher in haemodialysis patients compared to healthy controls, and they noted an age-related ascension in skin Na+ which corresponded to a pass up in serum VEGF-C. The authors ended that skin Na+ stores can exist mobilised by haemodialysis, and VEGF-C facilitates Na+ catamenia between the interstitium and systemic apportionment in humans, supporting earlier work in rodents [38, 46••]. More recently, Kopp et al. showed that type two diabetics on haemodialysis had significantly higher skin sodium compared with their not-diabetic counterparts [50••].
Schneider et al. used Na MRI to investigate the potential role of skin Na+ as a biomarker for hypertensive target-organ damage, further demonstrating that skin sodium content positively correlated with systolic BP and was a potent, independent predictor of left ventricular mass (LVM) in 89 participants with mild renal damage [49••]. In these patients, peel sodium was contained of sex, summit, SBP and trunk hydration every bit measured by bioimpedence.
In summary, cross-sectional information from 23Na-MRI studies in humans show that higher skin sodium storage is associated with college BP and target organ harm. Skin sodium appears to exist college in older individuals, hypertensives, haemodialysis patients and diabetics—all groups previously known to have the SSBP trait. Skin sodium changes during dialysis support its office as a buffer for trunk sodium. VEGF-C appears to determine peel sodium in humans, potentially via lymphangiogenesis facilitating the efflux of sodium. Sexual activity-specific differences in skin Na+ are interesting, just their relevance is currently unclear. Thus, it can be seen that 23Na MRI has provided important insights into the relevance of pare Na+ in humans.
Insights from Direct Chemical Analysis of the Skin Sodium in Humans
Although MRI data were confirmed by direct ashing of human cadaveric samples, they take not yet been confirmed by direct chemical analysis of skin electrolytes in humans [44]. In the by year, two studies have evaluated skin electrolytes in humans using inductively coupled plasma optical emission spectrometry (ICP-OES), a highly sensitive analytical tool capable of simultaneous multi-elemental determinations down to the sub-parts-per-billion level [51, 52••, 53••]. Fischereder et al. measured tissue Na+ and GAG content in pare and arterial samples taken from renal transplant donors and recipients [52••]. They showed that skin and arterial Na+ concentration correlated with GAG content, suggesting that interstitial Na+ storage is regulated by GAGs in humans, and this could function in the buffering of dietary salt. They as well constitute that skin Na+ correlated well with arterial Na+, indicating a possible link between the systemic vasculature and the skin with regard to sodium homeostasis.
We recently assessed pare electrolytes, claret pressure and plasma VEGF-C in 48 healthy participants (24 men) taking placebo (70 mmol sodium/day) and tiresome sodium (200 mmol/solar day) for vii days in a double-blind, randomised, cantankerous-over study [53••]. Skin Na+, expressed equally the ratio Na+:K+, was 8% college following the slow sodium phase. Post hoc analysis revealed a sex-specific issue, wherein men experienced a meaning 11.two% increment in pare Na+:K+ following the slow sodium phase while women did not (4%). Women showed a pregnant increment in 24-h mean arterial claret pressure and body weight with table salt loading while men did not. We concluded that skin sodium increases with dietary salt loading and this may be influenced by sex. Women showed a trend for less skin Na+ accumulation of salt loading and greater table salt sensitivity of BP, in keeping with previous studies in rodents showing the skin functions equally a buffer for dietary sodium [35–39]. We hypothesised that the sex differences observed could be due to sexual activity-specific peel structural differences in thickness and GAG content and men having a greater capacity for passage of Na+ through the skin than women [54, 55]. In this report, skin Na+:K+ positively correlated with BP and peripheral vascular resistance (PVR), in support of contempo 23Na MRI data showing a positive correlation between BP and skin Na+ [45, 49]. This was seen in men only, possibly due to variability in pare Chiliad+ and hence the Na+:K+ ratio with contraceptive treatment in women [53••]. No meaning changes in plasma VEGF-C were observed between placebo and ho-hum sodium phases to support a clear involvement of Ton-EBP or VEGF-C activation in this study.
Potential Mechanisms Linking Peel Sodium and Blood Pressure level
The exact footing for the relationship between peel sodium and BP is unknown. These parameters could be linked to a mutual nevertheless unknown aetiological cistron. Alternatively, skin sodium could mediate changes in haemodynamics either straight or through other substances. The Ton-EBP-VEGF-C axis has been shown to mediate BP in dietary salt loading. Several other mechanisms could explain the link between skin sodium and haemodynamics.
Peel capillary rarefaction, the reduction in the density of capillaries, and has been associated with hypertension [56–58]. Capillary rarefaction is believed to exist structural in origin, associated with either impaired angiogenesis or capillary attrition and is believed to mediate BP changes by altering PVR [57]. He et al. showed that in hypertensive humans, a modest reduction in salt intake improves dermal capillary density as assessed by capillaroscopy [58]. This trend was seen beyond unlike racial groups and suggests that salt intake is linked to microvascular rarefaction. The verbal mechanisms whereby salt affects the microcirculation remain unclear, with contempo work in rats suggesting that skin sodium aggregating during loftier table salt intake increases vasoreactivity in the skin [59].
The hypoxia inducible factor (HIF) transcription system, acting via the heterodimeric transcription factors HIF-1α and HIF-2α, plays a cardinal role in the cellular response to hypoxia [sixty]. Recent prove suggests that the HIF-1α:HIF-2α ratio in the skin affects synthesis of nitric oxide synthase 2(NOS ii), a key regulator of vascular tone [61]. HIF-1α and HIF-2a act antagonistically—HIF-1a promotes nitric oxide production past keratinocytes via NOS 2 while HIF-2α promotes keratinocyte arginase expression and urea production [62]. Cowburn et al. recently showed that mice with keratinocyte HIF-1α deletion had increased vascular tone and elevated systemic BP. Conversely, deletion of HIF-2α activeness in keratinocytes resulted in increased peel NO levels and reduced systemic BP [61]. In accordance with this, they showed decreased epidermal expression of HIF-1α and increased epidermal HIF-2α expression in hypertensive humans correlated significantly with increased hateful blood pressure. These findings provide a novel mechanism for systemic BP regulation by the skin. Recent testify in rodents suggests that HIF metabolism may also be influenced past dietary salt. In the renal medulla dietary salt suppresses HIF prolyl-hydroxylase ii (PHD2), which degrades HIF-1α and HIF-2α, increasing natriuresis [63, 64]. If high table salt intake could similarly alter levels of HIF isomers in the pare, this would potentially influence PVR. This would need to be explored in farther piece of work.
Movement of Dietary Sodium into the Pare—How and Why Does It Go There?
To reach the skin, dietary sodium must start transit through the intestine, the blood stream and then out into the dermal interstitium (Fig.2). Sodium absorption beyond the apical membrane of enterocytes and colonocytes is broadly facilitated past three mechanisms: (1) sugar and phosphate co-transport via SGLT1, GLUT and NaPi2b; (two) electroneutral proton exchange via NHE-2, NHE-3, and NHE-viii and (3) passive improvidence via the sodium channel ENaC [65–69]. This latter mechanism is predominantly localised to the colon.
Movement of sodium from the intestinal lumen to the pare. [one] Intestinal sodium assimilation across the upmost membrane of enterocytes is facilitated by (i) Na-H exchange (NHE-ii, NHE-three, NHE-eight), (two) cotransport with sugars and phosphates (SGLT-1, Overabundance, NaPi2b) and (iii) diffusion through endothelial Na channels (ENaC). Chloride send occurs via bicarbonate exchange (DRA) and paracellular diffusion. [2] Intracellular sodium is actively pumped across the basal membrane of the intestine past Na-Grand ATPases. [3] Once in the interstitium, sodium diffuses into the intestinal capillaries for transport through the vasculature. [iv] Sodium can diffuse paracellularly into the peel under low salt weather condition. Consuming excessive amounts of salt can exaggerate this process by causing harm to the endothelial glycocalyx and reducing barrier effectiveness
In contrast, chloride absorption is largely mediated by paracellular improvidence and apical bicarbonate exchange via downregulated-in-adenoma (DRA) proteins. This bicarbonate commutation is coupled to NHE-mediated sodium absorption, effectively marrying Na+/H+ and Cl−/HCO3 − exchange [70]. Intracellular chloride tin can diffuse out of enterocytes through chloride channels.
Intracellular sodium is actively pumped across the basolateral membrane and into the extracellular space by sodium-potassium ATPases, which consign three sodium ions from the cell in exchange for 2 potassium ions. The requisite extracellular potassium concentrations are maintained past diffusion of intracellular potassium through basolateral potassium channels. Afterwards concentration in the extracellular space, sodium tin can diffuse into the intestinal capillaries for ship throughout the trunk. Information technology is not articulate whether these various sodium, chloride and potassium transporters play a role in sodium sensitivity.
What drives sodium out of vasculature and into the skin specifically is not well understood, and the transit route from vascular lumen to dermis is besides speculative. When transitioning out of the vascular lumen, sodium first encounters the endothelial glycocalyx. Comprised primarily of heparan sulphate proteoglycans (HSPGs), this frail layer varies in thickness from 0.five to iv.5 μm [71]. The anionic character of this glycocalyx facilitates smooth red blood cell movement, inhibits white blood cell adhesion, scavenges oxygen complimentary radicals and can assist detect small changes in blood pressure and trigger a vasodilatory response [71, 72].
Excessive dietary sodium consumption may damage this glycocalyx and promote sodium 'leakage'. In vitro experiments have shown that chronic exposure of endothelial cells to 150 mM sodium decreased glycocalyx HSPGs by 68% and caused endothelial stiffening [73, 74]. This damaged glycocalyx could facilitate excessive sodium movement into the interstitium via paracellular diffusion and increased exposure to or increased activation of vascular ENaC channels [75]. Additionally, glycocalyx damage and endothelial stiffening may increase leucocyte adhesion and infiltration, further damaging the vessel wall [73, 75, 76].
From current information, it is not immediately clear whether the skin acts every bit a pre-emptive reservoir for excessive sodium, removing it from circulation before information technology tin can induce agin cardiovascular effects, or if the skin functions as an overflow reservoir one time the excessive sodium has caused sufficient vascular damage to 'leak' into the surrounding tissue. Regardless, in one case in the skin, the positively charged sodium is osmotically inactivated through association with anionic GAGs. The presence of high concentrations of sodium can stimulate increased GAG synthesis, expanding the storage capacity of this osmotically inactive tertiary compartment.
Conclusions and Future Directions
The pare acts as a third compartment for sodium, capable of non-osmotic sodium storage and mediating a vasodilatory response via VEGF-C. This appears to constitute an extra-renal mechanism controlling claret pressure during high salt intake. Incorporating this model into the traditional paradigm of sodium homeostasis, the skin may act as a buffer also every bit a reservoir for sodium, while the kidney controls sodium excretion and reabsorption, controlling serum osmolality and total body h2o. It is conceivable that people predisposed to salt-sensitive hypertension take defects in the pathways described to a higher place. What is less understood is why peel sodium aggregating with short-term dietary salt loading appears to protect from a rise in BP rise, but long-term high pare sodium is associated with college BP and the propensity for SSBP. A potential explanation could be that impaired VEGF-C-induced lymphangiogenesis in these individuals reduces efflux of sodium from the skin to the systemic circulation and attenuates the vasodilatory response to salt loading. Further work is needed to explore this and other mechanisms that could be involved. The verbal mechanisms underlying the movement of dietary sodium from the gut to the vasculature and the peel are however unclear. Hereafter challenges include ascertaining how different antihypertensive agents impact the distribution of sodium and h2o between the skin and the intravascular infinite and how this arrangement interacts with other organs that modulate BP like the kidney and encephalon.
Funding Information
VS has been funded past the British Heart Foundation and Addenbrookes Charitable Trust. IBW is funded by the British Heart Foundation and NIHR.
Notes
Conflict of Interest
The authors declare that they have no conflicts of interest.
Human being and Animal Rights and Informed Consent
VS, CM and IBW were involved in a study involving humans (Reference 55). Ethical approval for the written report was obtained from a National Inquiry Ethics Committee (REC Reference 11/H0304/003) and was performed according to Good Clinical Practice and according to the principles of the Proclamation of Helsinki.
Footnotes
This article is part of the Topical Collection on Blood Pressure Monitoring and Management
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153561/
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