Differential influences of dietary sodium on blood pressure regulation based on race and sex

Abstract

There are clear differences between men and women, and differences among races, in the incidence and prevalence of hypertension. Furthermore, there is extensive inter-individual variability among humans in the extent to which sodium ingestion alters blood pressure. Orthostatic intolerance and orthostatic hypotension are more common in women; these are often treated with a high salt diet, which has variable efficacy in increasing blood volume and blood pressure. Conversely, people with certain forms of hypertension are often counseled to decrease their sodium intake. Non-Hispanic Black men and women have higher rates of hypertension compared to non-Hispanic White men and women and other racial/ethnic groups. In aggregate, Black women appear to have better orthostatic tolerance than White women. In the present paper, we summarize and evaluate the current evidence for mechanisms of blood pressure regulation in men and women, as well as differences between Black and White groups, with a focus on cardiovascular responses to salt and differences among these groups. We also provide a brief review of factors that are not traditionally considered to be “biological” – such as socio-economic disparities resulting from historic and contemporary inequity across racial groups. These non-biological factors have direct and substantial influences on cardiovascular mechanisms, as well as implications for the influences of salt and sodium intake on blood pressure and cardiovascular health. We conclude that both biological and socio-economic factors provide critical modulating influences when considering the impacts of sodium on cardiovascular health as functions of race and sex.

Introduction

Sodium chloride (table salt) and sodium have central roles in the typical “Western” diet and in the regulation of blood volume and blood pressure in humans, respectively (1, 2). Sodium is ubiquitous in human physiology, and is central to cellular signaling pathways in neuronal, cardiovascular, renal and most other systems in the body. For the general population and specific patient populations (e.g., individuals with heart failure and hypertension) it is appropriate to recommend less sodium intake than what the populous consumes, however for other patient populations (individuals with orthostatic hypotension) more dietary sodium can be beneficial for blood pressure regulation (1–7). There is broadly a misconception in the lay public that salt is inherently “not good” in the context of blood pressure regulation, however the issue is quite nuanced. In fact, for many otherwise healthy people, changing sodium intake (within reason) has no influence on their resting blood pressure (i.e., “salt resistant” blood pressure). Furthermore, in certain contexts, such as long duration exercise in the heat, salt ingestion can help offset electrolytes lost through sweat (8).

There has been historically a “one-size-fits-all” mentality when it comes to research in blood pressure and cardiovascular diseases: the research that has led to most of the medical doctrine we have today comes from studies that were largely, or entirely, performed in non-Hispanic White men (9, 10). However, there are clearly differences between men and women, and differences among races, in the incidence and prevalence of hypertension (11–14), as well as documented differences in factors that contribute to hemodynamic regulation (e.g., fluid regulatory hormones and sympathetic nerve activity)(9, 15–17). The purpose of the present brief review is to summarize race and sex differences in the role of sodium in blood pressure regulation, and to discuss some of the factors contributing to these differences. Of note, we primarily focus on studies comparing Black and White adults as the overwhelmingly majority of published papers have focused on these two racial groups, but we recognize the need for future studies inclusive of other racial and ethnic groups.

Historical Perspective & Classic Studies

The regulation of blood pressure in humans is complex and multifactorial, including central roles for the sympathetic nervous system in its control of the heart, kidneys, and peripheral vasculature. Because of the key role of the sympathetic mechanisms, much early research on potential blood pressure lowering medications focused on manipulating the sympathetic nervous system (18, 19). With the many challenges associated with the management of such a multifactorial problem as hypertension, some treatment methods were quite extreme. One early surgical approach for severe resistant hypertension involved progressively interrupting all the spinal sympathetic ganglia (20, 21). This approach did decrease resting blood pressure, but there are also studies demonstrating sympathectomy interrupts normal baroreflex regulation, which can result in orthostatic hypotension and/or exercise intolerance (22–24).

Although the idea that high salt intake contributes to hypertension has been around for more than half a century, it has never been unequivocal. Indeed, amongst healthy adults more people have salt-resistant blood pressure (i.e., blood pressure that does not change with dietary salt changes) than salt-sensitive blood pressure (i.e., blood pressure increases with higher salt intake and decreases with salt restriction) (25). An early meta-analysis of clinical trials demonstrated a high degree of heterogeneity among studies regarding sodium restriction and blood pressure (26). However, when the results of the 13 trials were pooled, there was a significant relation between dietary sodium and blood pressure. Moreover, it became clear that initial blood pressure and age were key contributors to the blood pressure lowering effect of lowering sodium in the diet. Interestingly, it is currently accepted that older age and hypertension predispose to a higher likelihood of salt sensitivity (25) and one of the earliest trials demonstrating a robust effect of sodium restriction on blood pressure was conducted in adults with hypertension (6).

The Dietary Approaches to Stop Hypertension (DASH)-Sodium study was a randomized 3-month feeding trial, which found that eating a diet high in fruits and vegetables, low in high-fat dairy products, and low in total and saturated fat and cholesterol significantly lowered blood pressure in individuals with- and without hypertension (27–29). Additionally, there is strong evidence that potassium content of foods has a negative relationship with blood pressure (1, 2). In the context of the present discussion, it is notable that most processed foods are high in sodium and often low in potassium. Furthermore, communities who suffer from poverty are more likely to have access to these processed foods (high in sodium) rather than to fresh fruits and vegetables (higher in potassium), which have routinely been associated with positive outcomes in cardiovascular health, including blood pressure (27, 29).

The classic Guytonian view of salt sensitivity of blood pressure holds that individuals with salt sensitivity of blood pressure demonstrate impaired renal function, characterized by impaired pressure natriuresis, causing greater salt retention and blood volume expansion than that which occurs in individuals with salt-resistant blood pressure (30). More recently, the Guytonian view of salt sensitivity has been challenged with computer simulations demonstrating the model does not predict sodium balance and hemodynamic responses of participants with normotensive blood pressure in response to increases in salt intake (31). Additionally, multiple studies have demonstrated that renal vascular dysfunction, rather than sodium retention, seems to be the predictive factor of salt sensitivity (32, 33). Taken together, these findings indicate that the kidneys likely play an important, but not exclusive, role in blood pressure regulation with sodium manipulation.

Overview of blood pressure regulation in humans

For the purpose of the present discussion, we focus on the roles of the sympathetic nervous system and renal volume regulating mechanisms in the regulation of arterial pressure, and the influences of salt intake on these mechanisms. We also direct the reader’s attention to a recent review on race and sex differences in autonomic blood pressure regulation with regard to obesity, hypertension and related issues (34). There are many other factors that contribute, including arterial stiffness and local endothelial mediators (nitric oxide, endothelin, etc.) (35–37).

The sympathetic nervous system is a key regulator of all the factors that contribute to the prevailing level of arterial blood pressure at any given moment (i.e., MAP = HR × SV × TPR). Cardiac sympathetic nerves innervate the sinoatrial and atrioventricular nodes to affect heart rate, as well as the myocardium, where they alter contractility to change stroke volume for a given preload and afterload. Peripheral vascular sympathetic nerves control the overall level of peripheral vasoconstrictor tone via release of norepinephrine (and co-transmitters), which acts primarily on alpha-adrenergic receptors in the vasculature to cause vasoconstriction (38, 39). Additionally, sympathetic innervation of the adrenal medulla leads to increased release of epinephrine and norepinephrine into the bloodstream. These catecholamines give circulating hormonal support to the neural sympathetic mechanisms in support of blood pressure. Although historically the role of the sympathetic nervous system was thought to be for short-term changes only (e.g., baroreflex responses to changes in posture) (40), more recent analyses have clarified that the sympathetic nervous system is central to the long-term regulation of arterial pressure as well (41, 42). For detailed discussion of sympathetic mechanisms in control of blood pressure, the reader is referred to several comprehensive reviews (39, 43, 44).

Hormonal Regulation of Blood Volume & Pressure

The renin–angiotensin–aldosterone system (RAAS) is the key endocrine system involved in the regulation of blood pressure (i.e., negative feedback loop) by regulating fluid and electrolyte balance (45, 46). Briefly, renin, released by the kidneys, initiates a cascade of events leading to increased circulating levels of the peptide angiotensin II (Ang II). Subsequently, Ang II elicits vasoconstriction, resulting in increased peripheral resistance and elevated blood pressure, and also acts at the kidney to increase sodium reabsorption (47, 48). The renin-angiotensin cascade also stimulates release of aldosterone from the adrenal cortices; aldosterone also increases reabsorption of sodium and water by the kidney (49) as well as vascular epithelial sodium channels (50).

Increased sodium and water reabsorption increase blood volume, eliciting an increase in cardiac output – which, if nothing else changes, results in increased blood pressure (i.e., ↑CO × ↔TPR = ↑MAP). However, an acute increase in blood volume elicits reflex changes in sympathetic neural control – specifically increased venous return elicits a reflex decrease in peripheral vascular resistance to minimize or “buffer” large swings in blood pressure. Also important is that there is a high degree of inter-individual variability in the effectiveness of these counter-regulatory mechanisms (51–53). In response to high dietary sodium, there is a normal suppression of RAAS hormones (see Figure 1) (49, 54).

Figure 1.

High salt influences sympathetic and renal regulation of blood pressure.

High dietary salt typically results in increased extracellular volume resulting in suppression of sympathetic nerve activity (SNA) (98) and the renin angiotensin aldosterone system (RAAS) (64). There is limited evidence demonstrating that low dietary salt decreases neurovascular sympathetic transduction compared to recommended (99) and high salt (98). Multiple studies have demonstrated that increased renal vascular resistance and/or insufficient reductions in total peripheral resistance contribute to salt sensitivity (32, 132). Taken together, these integrative responses play a role in maintained or increased blood pressure with high dietary salt. Some studies have demonstrated salt sensitivity of blood pressure is more prevalent in women and in Black adults (25, 28) but additional data are needed, particularly regarding sex or race differences in neurovascular sympathetic transduction or vasodilation dysfunction as a result of high dietary salt. Figure made with biorender.com

Another important hormonal regulator of blood volume and pressure is arginine vasopressin (AVP), also known as anti-diuretic hormone. Consuming a high sodium diet may elicit an increase in serum sodium and plasma osmolality, both of which stimulate the hypothalamus to cause AVP release from the posterior pituitary (55, 56). AVP causes aquaporin channels to be inserted into the apical membrane of the collecting duct, increasing water reabsorption and potentially plasma volume (57). AVP can also be released in response to low plasma volume, and can act in the peripheral vasculature to cause vasoconstriction (58). AVP can also be stimulated by circulating Ang II and sympathetic stimulation (58, 59).

Dysregulation of arterial pressure - orthostatic intolerance and hypertension

Despite the many physiological systems involved in maintaining blood pressure, disorders in blood pressure regulation are not uncommon. Orthostatic intolerance (OI) is defined as the development of symptoms such as dizziness, lightheadedness, headache or fatigue with upright posture. OI is sometimes, but not always, associated with hypotension upon assumption of the upright posture (i.e., orthostatic hypotension). Upon standing, there is a translocation of blood from the core to the lower limbs due to gravitational stress (60, 61). Indeed, as much as 700 mL of blood shifts to the lower extremity (60, 61). Initially, neural reflexes such as the baroreflex act to increase heart rate and cause sympathetic vasoconstriction to the peripheral blood vessels so that blood will not pool in the lower limbs; the maintenance of upright posture is dependent on blood circulating back to the heart to ultimately maintain perfusion of the brain. Contraction of skeletal muscle in the lower legs acts as a second pump to restore central blood volume (muscle pump). Over several minutes of standing, additional hormonal mechanisms are activated (such as RAAS and AVP) to help maintain blood pressure (62).

The symptoms associated with OI can be debilitating and affect at least a half a million Americans (3, 4). As such, increased salt intake is a common therapeutic recommendation from physicians for those experiencing symptoms related to orthostatic intolerance. A recent systematic review and meta-analysis examining the scientific evidence for these guidelines demonstrated that increasing salt intake improved time to pre-syncope by ~2 minutes, increased systolic blood pressure during upright posture (either standing or during tilt testing) by ~12 mmHg, and improved overall symptoms of orthostasis in 62% of study participants (63). Interestingly, resting supine systolic BP increased only 1mmHg with increased salt intake. Additional data in young healthy adults (without orthostatic hypotension) also suggest that consuming a high salt diet over several days does not alter blood pressure variability (64). It is important to note that 60% of the study participants in the meta-analysis were women, but race was not reported. However, only 14 studies were included in the meta-analysis, and the authors noted that there were no clinical trials found to support the recommended level of salt and water intake. Although most guidelines recommend somewhere between 6–9g of salt, this can vary across societies (63). Finally, while increased salt intake in the short-term may help improve symptoms and support blood pressure, the long-term consequences are not known (63).

In contrast to OI and “hypotensive” disorders, at the other end of the blood pressure spectrum is hypertension. According to the most recent statistics, almost 50% of the adult population in the United States has hypertension (11), and hypertension disproportionately affects Black Americans more than White Americans. Despite experiencing similar or sometimes higher levels of awareness and treatment, hypertension in Black Americans is not as well controlled compared to White Americans and other racial/ethnic groups (11). Mechanisms contributing to hypertension include activation of the sympathetic nervous system, activation of RAAS, as well as activation of local factors such as endothelin-1. Given the prominent role the sympathetic nervous system to regulate blood pressure at the level of the kidney, renal denervation showed great initial promise for treating resistant hypertension (65). However, subsequent clinical trials did not show a benefit over standard therapy (66). This may have been due to the specifics of the surgical technique used to ablate the renal arteries (67); thus, renal denervation may still prove to be a useful therapeutic tool to treat hypertension.

While ~90% of cases of hypertension occur due to an unknown origin (as opposed to secondary hypertension related to kidney disease, obesity, or diabetes) clinical treatment recommendations have remained largely the same over many decades. Recommendations include reduction in salt intake as well as lifestyle modifications such as exercise, whereas therapeutic guidelines include usage of angiotensin converting enzyme inhibitors or angiotensin receptor blockers to suppress the production and/or vasoconstrictor effects of Ang II, calcium channel blockers, or diuretics to reduce volume and ultimately blood pressure. Despite potential differences in pathophysiology that may cluster based on race and sex, treatment guidelines have not yet factored in sex. Although more recent pharmacological guidelines to treat hypertension do factor in race (68), this has been met with some controversy (69). However, data showing that Black adults are ~3x more likely to develop edema from ACE-inhibitors (70) is an example of the crucial fact that hypertension treatment should not be approached as ‘one size fits all’.

Differences in blood pressure regulation based on race and sex

Women and men experience a dysregulation of BP at varying points across the lifespan. For example, young women generally have lower blood pressure and lower muscle sympathetic nerve activity (MSNA) compared to younger men (Figure 2) (16). In fact, orthostatic intolerance and/or hypotension are disorders that primarily affect younger women. Approximately 40% of women have at least one syncopal episode in their lifetime (71). Although the reason(s) women have greater rates of orthostatic intolerance is not completely understood, laboratory studies using tilt table testing or lower body negative pressure demonstrate that women have lower stroke volume and reduced cardiac filling compared to men (72). However, changes in muscle sympathetic nerve activity (MSNA) or norepinephrine were not different between women and men in these trials (73, 74).

Figure 2.

Muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate from 260 women (red) and 398 men (black) between the ages of 18 and ~80 yrs.

Notably, in women, MSNA declines from age 20–30 yrs compared to men. After age 30 yrs, MSNA increases in both men and women until ~age 50yrs, where MSNA then becomes higher in women compared to men later in life. Importantly, the age-related increases in MSNA is much greater in women compared to men. Systolic blood pressure increased in both women and men until age 50yrs; thereafter, systolic blood pressure declined in men but continued to increase with age in women. A similar trend was demonstrated for heart rate. Data in this cohort of otherwise healthy adults demonstrates the important sex differences in MSNA and blood pressure with aging. Figure from Keir et al (16). Obtained with permission from Hypertension, Wolters Kluwer Health, Inc.

Tolerance to orthostatic stress differs within women, and sensitivity to fluctuations in sex hormones like estrogen and progesterone play an important role in contributing to orthostatic intolerance (75, 76). Although orthostatic intolerance largely impacts women, there is evidence that Black women, on average, have a higher tolerance to orthostatic stress (i.e., lower body negative pressure) compared to White women (77) (Figure 3). This increase in orthostatic tolerance was accompanied by a greater increase in norepinephrine and plasma renin activity (PRA) in Black compared to White women (77). In another investigation young Black women demonstrated similar blood pressures and increases in MSNA compared to White women response to head-up tilt (78). However, renal-adrenal system responses (i.e., greater Δ blood aldosterone concentration) appeared to regulate blood pressure responses during head up tilt to a greater extent in Black women (78). During various perturbations (e.g., exercise and the cold pressor test), blood pressure reactivity is greater in Black adults (79–81). However, during mental stressors (e.g., videogames and mental arithmetic), there have been mixed findings regarding racial differences in blood pressure reactivity (82, 83). Interestingly, resting MSNA is not different between young Black and White adults; however, sympathetic vascular transduction (increases in blood pressure that follow bursts of sympathetic outflow) is greater in Black compared to White adults (84, 85), as is total peripheral resistance and blood pressure variability (86). It remains unclear if these factors contribute to the greater prevalence of hypertension in Black adults later in life.

Figure 3.

Survival curve demonstrating that Black women have higher tolerance to orthostatic stress compared to white women.

During a lower body negative pressure test (LBNP), it took longer for Black women to experience signs of pre-syncope such that Black women had an 86% chance of becoming pre-syncopal at a later stage / later time compared to White women. Figure from Hinds and Stachenfeld (77). Obtained with permission from Hypertension, Wolters Kluwer Health, Inc.

Aging is associated with increases in blood pressure in both women and men, which is accompanied by concomitant changes in MSNA. (Figure 2) (16). However, postmenopausal women are more likely to have higher blood pressure and MSNA compared to men of similar age (16), and also experience higher rates of hypertension (87). This is likely attributable to menopause condition (lack of female hormones after years of having them) and aging having separate, and perhaps additive adverse effects on BP regulation in aging women (14). A recent pooled study of several cohort studies using sex-specific analyses also indicated that increased cardiovascular disease risk beginning at lower thresholds of systolic blood pressure for women than for men (88). In young adults, women typically have lower MSNA compared to men. After the 4^th decade of life, the age-related increase in MSNA is greater in women compared to men (89). Moreover, older women with hypertension display altered firing patterns of sympathetic action potentials and greater increases in total peripheral resistance when assuming an upright posture via tilt testing (90). Regardless of sex, Black men and women have a higher prevalence of hypertension compared to White individuals (11). As has been seen in young adults, resting MSNA is similar between elderly Black and White adults (91). Beat-to-beat sympathetic transduction is blunted with aging (92) but there have not been any studies comparing potential racial differences in neurovascular sympathetic transduction in older adults.

Alterations in cardiovascular sympathetic transduction may be related to sex, age, and race-related changes in adrenergic receptor sensitivity. Young women have reduced alpha-adrenergic receptor sensitivity and greater beta-adrenergic mediated vasodilation compared to men, which may explain (in part) their lower blood pressure (93, 94). However, this beta-adrenergic receptor mediated dilation is lost after menopause, and MSNA is positively associated with total peripheral resistance (17), potentially explaining the higher rates of hypertension in older, compared to younger, women. A more in-depth discussion can be found in this review (17). Racial differences in adrenergic receptor sensitivity have also been reported, showing greater alpha-adrenergic vasoconstriction in black compared to White men (95). A more recent study including both men and women support these findings, but also demonstrate that, on average, Black adults display reduced beta-adrenergic receptor responsiveness (96). Taken together, the greater hypertension prevalence in Black adults may be, in part, related to the alterations in alpha- and beta- adrenergic receptors and sympathetic transduction to elicit aberrant blood pressure responses.

A recent study in healthy adults demonstrated that sodium restriction reduces sympathetic vascular transduction (97). Another recent investigation in premenopausal women demonstrated that compared to low salt intake, high intake reduced sympathetic nerve activity and increased neurovascular sympathetic transduction (98). Both of these recent controlled salt feeding studies (98, 99) assessing neurovascular sympathetic transduction were conducted in salt-resistant cohorts. Therefore, future trials are needed to determine if high salt elicits even greater changes in neurovascular sympathetic transduction in patients with hypertension and/or salt-sensitive blood pressure. While it is unclear if exaggerated sympathetic vascular transduction plays a role in renovascular dysfunction in the context of salt sensitivity, these and other data (51, 100, 101) suggest that individual differences in the interplay between renal, sympathetic, and vascular factors in the control of arterial pressure may have implications for the extent of salt-sensitivity of blood pressure in a given individual (See Figure 1).

Differences in prevalence of salt sensitivity

There are some data documenting sex and racial differences in the incidence of salt-sensitivity of blood pressure, such as that women and Black Americans may be more likely to exhibit salt sensitivity of blood pressure. However, there is controversy as to whether these findings are due to unique differences in physiology per se, or are a result of issues such as sodium density in controlled feeding study diets (102), concomitant potassium intake (1), and racial differences in biological “weathering” due to psychosocial stressors related to inequitable socio-environmental conditions faced by Black Americans (see Figure 4B) (10, 103, 104).

Figure 4.

Non-physiological factors that may contribute to sex and racial differences in salt-sensitivity and blood pressure.

(A) Many previous controlled feeding studies have not controlled for body mass or Caloric intake when assigning sodium loads in the diet. Taking this approach may result in women participants consuming a disproportionately higher sodium density, despite consuming the same absolute sodium load, which could lead to a greater incidence of salt sensitivity (102). (B) Black Americans are more likely to experience poverty (134, 135), live in disadvantaged neighborhoods with greater adverse environmental pollution exposure (136) and have fewer opportunities to obtain healthful foods (137). These factors likely contribute to documented disparities in sleep (138–140) and dietary potassium intake (1), all of which may culminate in higher hypertension prevalence and altered blood pressure regulation. Figure made with biorender.com and images from 123rf.com

In the DASH-Sodium study women demonstrated a greater reduction in blood pressure with salt restriction compared to men (29). In other smaller trials using less moderate approaches to sodium manipulation (e.g., comparing 50 mM to >250mM of sodium per day), there are data demonstrating women are more likely to exhibit salt-sensitivity of blood pressure (105), although others have shown no difference (106–108). Importantly, most of this work has been done in patients with hypertension, so additional data is needed in participants in the normotensive blood pressure range. Furthermore, all of these studies (except DASH-sodium) provided men and women similar absolute amounts of dietary sodium. An important consideration for studies demonstrating sex differences in salt sensitivity is sodium density in the diet (see Figure 4A). Giving men and women similar absolute sodium loads without considering sex differences in energy intake or body weight, could lead to potentially spurious conclusions regarding salt sensitivity. Data from NHANES clearly illustrate that sodium density is similar between men and women (~1.7 mg sodium per Calorie) but that women eat less absolute sodium (2900 mg vs 4000 mg sodium per day) because they consume fewer Calories than men (109). These data illustrate the importance of accounting for divergent energy intake among participants with different Caloric needs (e.g., men vs women) in future controlled sodium feeding trials.

Studies using hypertonic saline infusion, alone or in combination with dietary salt, have demonstrated evidence of differences between races in sodium handling and blood pressure regulation (52, 110, 111). A recent meta-analysis demonstrated blood pressure was reduced to a greater extent in non-White compared to White adults with sodium restriction (112). For the sake of this review, we focus our attention on controlled feeding trials. In these trials, where racial comparisons in salt sensitivity have been made, the findings have been mixed. For example, some studies reported no apparent differences in salt sensitivity (113–115), some have reported differences (28, 29, 49, 116), and still others found differences but they varied depending on whether the participants had hypertension, or normotensive blood pressure (117–119). Importantly, there is not a universal consensus for the definition of salt sensitivity. Some the papers cited used a categorical definition (e.g., > 5 mmHg for mean arterial pressure) and some used a comparison of blood pressure as a continuous variable.

In the DASH-Sodium trial, Black adults demonstrated a greater reduction in blood pressure with modest sodium restriction compared to other participants but only on the control diet and not the DASH diet. These data suggest the DASH diet may minimize racial differences in blood pressure responses to sodium manipulation (28, 29). In addition, Morris et al (33) demonstrated that adding high dietary potassium (4700mg) to a moderately high salt diet (5750 mg of sodium per day) attenuated racial differences in the frequency of salt sensitivity, and decreased the average increase (delta) in blood pressure. The findings by Morris et al indicate that the high potassium content in fruits and vegetables may be part of the reason why the DASH diet attenuated racial differences in blood pressure responses to sodium manipulation. Taken together, these findings demonstrate the importance of background diet, and not just sodium in the diet. While most Americans, irrespective of racial or ethnic group, fail to attain optimal intake of dietary potassium, there are racial disparities in dietary potassium intake (1, 120). Specifically, Black Americans consume less than other racial/ethnic groups (1). A recent review has covered racial differences in salt sensitivity of BP, and the role of potassium in attenuating the disparity at length (121).

Hormonal differences

The impact of sex and sex hormones on hormonal regulation of fluid balance and blood pressure control has been reviewed previously (122–124). Both estrogen and progesterone increase plasma volume (125). Estrogen also shifts the osmotic threshold for AVP release to a lower plasma osmolality (126). However, men have a greater increase in AVP release to an osmotic stimulus compared to women (127). AVP was also found to be higher in Black, compared to White, adults with hypertension (128). To date, studies comparing sex hormone effects or sex differences within Black adults related to AVP and osmotic regulation of AVP on blood pressure have not been conducted, but are an important area for future investigation.

Several (49, 110, 129, 130) but not all (115, 117) studies have demonstrated that Black individuals have lower basal PRA and aldosterone levels compared to other racial and ethnic groups. Although there are some data demonstrating the magnitude of RAAS suppression is not a predictor of salt sensitivity of blood pressure (107), a preponderance of studies demonstrating a lower basal RAAS activity in Black adults has led many scientists to speculate that reduced ability to suppress RAAS with high salt intake may potentially contribute to a greater prevalence of salt sensitivity in Black individuals (49, 129). Interestingly, potassium supplementation increases PRA in Black individuals (131), suggesting that a potential mechanism by which potassium is protective is via alterations in volume regulatory hormones. Interestingly, another study of potassium supplementation within Black adults demonstrated that potassium prevented high salt-induced reductions in renal blood flow and increased renal vascular resistance among salt-sensitive Black adults, presumably facilitating a reduction in TPR and CO. Additionally, as noted above, Morris and colleagues demonstrated that renal vascular dysfunction appears to be an important factor regulating salt sensitivity of blood pressure in Black adults as opposed to sodium retention (32, 33, 116, 132). Unfortunately, many studies assessing potential physiological differences between racial groups have failed to consider social factors that may potentially underlie physiological differences and health disparities.

Social factors

There is a large body of literature demonstrating racial disparities in resting blood pressure and hypertension prevalence (12, 133). Specifically, the cumulative incidence of hypertension by age 55 years is 76% in both Black men and women, 55% in White men, and 40% in White women (12, 133). Hypertension is associated with salt sensitivity of blood pressure (25, 107, 112). Thus, it is not surprising that Black Americans, in aggregate, are statistically more likely to exhibit salt sensitivity. We have also highlighted the role of background diet, particularly potassium, in influencing salt-sensitivity of blood pressure and that there are racial disparities in potassium intake. Differences in socioeconomic status and health behaviors are likely major contributors to the differences in potassium intake and other factors that may predispose Black adults to hypertension.

Due to the United States’ history of chattel slavery, Jim Crow era policies, redlining, and other forms of discrimination, contemporary Black Americans face substantial wealth inequality, are more likely to experience poverty (134, 135), live in disadvantaged neighborhoods with greater adverse environmental pollution exposure (136) and have fewer opportunities to obtain healthful foods (137). Neighborhood disadvantage is also a contributor to documented racial differences in sleep duration and quality (138–140). Importantly, increasing evidence points to strong links among neighborhood environments, blood pressure and cardiovascular health in general (141, 142). Thus, there are several financial and environmental barriers, in addition to limitations in factors such as patient education and implementation counseling for healthy lifestyles. Any of these factors (or combinations thereof) likely make it exceedingly difficult for many Black Americans to adopt health-promoting behaviors, such as incorporating a DASH type of eating pattern, that could help reduce their inequitable burden of hypertension and other cardiovascular diseases (143). When considering physiological and pathophysiological differences between racial groups, these factors create important context and ultimately influence the physiology we are trying to understand.

Conclusion

The complex, integrative mechanisms involved in human blood pressure regulation include important interactions between sympathetic neural control of the circulation, renal volume regulatory mechanisms, and circulating sodium. As discussed here, there are clinically and physiologically important differences among individuals in the influences of sodium or sodium ingestion on cardiovascular function and arterial pressure. Although there is clearly inter-individual variability within a given race or sex, there are important differences between men and women, and between Black people and non-Hispanic White people, in the effects of sodium on blood pressure. These require further study to be more completely understood. In general, women appear to increase their blood pressure less than men, and Black people tend to have more of an increase in pressure to a given sodium load compared to White people. These differences between races and between sexes appear to be due in part to biological mechanisms (e.g., influences of reproductive hormones on AVP signaling). Additionally, key non-biological (societal, economic) factors have important implications for observed racial differences in blood pressure regulation in general, and the role of sodium in particular. This is an exciting area for continuing to broaden our understanding of integrative mechanisms of cardiovascular regulation in humans. We encourage future researchers in this area to incorporate broad, comprehensive analyses of both biological and societal factors affecting cardiovascular regulation across our diverse population.

Abbreviation & Acronyms:

Ang II

angiotensin II

AVP

arginine vasopressin

DASH

dietary approaches to stop hypertension

HR

heart rate

MAP

mean arterial pressure

MSNA

muscle sympathetic nerve activity

OI

orthostatic intolerance

PRA

plasma renin activity

RAAS

renin angiotensin aldosterone system

SV

stroke volume

TPR

total peripheral resistance