Salt Sensitivity of Blood Pressure in Blacks: the need to sort out ancestry versus epigenetic versus social determinants of its causation

Abstract

Race is a social construct, but self-identified Blacks are known to have higher prevalence and worse outcomes of hypertension than Whites. This may be partly due to the disproportionate incidence of salt sensitivity of blood pressure in Blacks, a cardiovascular risk factor that is independent of blood pressure and has no proven therapy. We review the multiple physiologic systems involved in regulation of blood pressure, discuss what, if anything is known about the differences between Blacks and Whites in these systems and how they affect salt sensitivity of blood pressure. The contributions of genetics, epigenetics, environment and social determinants of health are briefly touched on, with the hope of stimulating further work in the field.

Race is a social construct that identifies groups based upon history, culture, and phenotypic characteristics. In biomedical research, it is assigned by self-identification or by investigators who mostly studied the biology rather than social determinants of health. However, genetic variability is less between than within races^1,2 and there is ample genetic admixture in modern populations. Therefore, some argue that results of race-related research perpetuate institutional racism in health care and shouldn’t be used any longer (e.g., estimation of glomerular filtration rate in African Americans³). In contrast, others have warned against disregarding knowledge (regardless of its nature) that identifies targetable therapies because this may exacerbate rather than ameliorate inequities in health outcomes^4,5. Also, there is evidence that social determinants of health have epigenetic effects that may become inheritable⁶ adding a layer of complexity to the differential genetic vs social determinants of health between races.

In contrast to race, ancestry reflects the genetic origins of an individual, as determined by historical continental drifts of migrating populations. Modern technology permits its estimation by comparing genome-wide variation in autosomes, or Y-chromosomes, or mitochondrial DNA with reference maps of different geographic regions, using advanced computational algorithms or principal component analyses. In the SPRINT study, this approach demonstrated that the proportion of European genetic ancestry in American Black participants determines their risk for incident diabetes, confirming genetic causation in addition to the previously known social contributors⁷. Henceforth, we will use the term Blacks to refer to African-American people, unless otherwise specified.

Biological research has generated a large body of knowledge on differences between Whites and Blacks in the epidemiology, clinical features, mechanistic pathways, and results of therapies in hypertension (HTN). Although obtained with self-reported race, some findings are targetable with specific approaches, e.g., higher prevalence and severity of HTN, greater response to calcium channel blockers compared with other antihypertensive agents, especially blockers of the renin-angiotensin system in people of sub-Saharan African descent,⁸ and the specific effects of nitrates and hydralazine in congestive heart failure⁹ of Blacks. In this review, we summarize knowledge on salt sensitivity of blood pressure (SSBP) in Blacks, an untreatable cardiovascular risk factor that seems to affect them disproportionally. Myriad mechanistic differences between races have been described in SSBP, but the relative contributions of genetics, epigenetics and social determinants of health remain obscure. We hope to stimulate the use of recent advances in human genetics to dissect the contribution of these components, an approach that has become feasible in studying asthma of minority children¹⁰.

EPIDEMIOLOGY OF HTN AND SSBP IN BLACKS

SSBP

The 2016 AHA statement¹¹ defines SSBP as a trait of members of diverse species, including humans, in whom significant changes in blood pressure (BP) parallel changes in salt balance. Whereas rodents have been dichotomized into salt-sensitive (SS) and salt-resistant (SR) sub-strains by inbreeding, responses to salt loading or depletion in humans are normally distributed instead, requiring use of arbitrary cutoffs to classify subjects into SS and SR. The long-term dietary (days to weeks) or acute (salt infusion and diuretic-induced salt depletion) protocols that have been used for this classification are laborious, expensive, and time-consuming, hence, not useful for diagnosis of the phenotype in the clinic. No biomarker has been discovered for SSBP either, although some investigators are pursuing this^12–14. There is clear evidence that SS subjects (about 25% of the normotensive and 50% of the hypertensive population) have a more detrimental cardiovascular prognosis than their SR counterparts^15,16, hence lack of diagnostic tools is a problem because it precludes therapy.

The AHA statement reviewed the multiplicity of abnormalities that have been putatively linked to the SS phenotype. There are two major lines of thought about its causation. One stems from the concept of the infinite gain of the pressure-natriuresis curve, derived from mathematical modeling by Guyton and coworkers¹⁷. It states that if all renal and systemic mechanisms that regulate renal Na⁺ excretion are intact, a salt load won’t produce sustained BP elevation, because they will bring salt balance back to baseline. Therefore, a sustained hypertensive response to salt would require impaired renal natriuresis. Experimental support for this view was obtained by producing SSBP by “clamping” antinatriuretic responses to salt depletion or natriuretic responses to salt loading with drugs or genetic manipulation¹⁸, and by identifying association of SSBP with variants of genes exclusively expressed in the kidney (uromodulin, UMOD)^19,20 or exclusively knocked out in the kidney (collectrin²¹).

Critics of this hypothesis state that in order to reach chronically elevated total peripheral resistance (TPR) with normal cardiac output (CO) (the most common hemodynamic pattern of HTN), autoregulation of organ blood flow would need to take place on initial differences in plasma volume (PV) and CO between salt-loaded SS and SR. However, only one study showed higher PV in Blacks than in Whites²², whereas most showed opposite results measuring PV surrogates such as left ventricular (LV) end diastolic volume, LV internal diameter at diastole, and N-terminal pro brain natriuretic peptide (NT-proBNP) in young Black Africans²³.

Upon salt loading, SR sustain immediate (as rapidly as 24 hrs²⁴) reduction of TPR and maintain normal BP, whereas SS fail to normally vasodilate and exhibit an increase in BP²⁵. Hence, the alternative hypothesis is that SSBP is primarily a vasodilatory defect²⁶. In Dahl-S rats, impaired salt-induced vasodilation includes the renal circulation²⁷, which may explain both hemodynamic and excretory renal contributions to SSBP. Possible causes for the putative excretory and vasodilatory defects in the SSBP of Blacks are discussed in the following sections.

HTN in Blacks

Blacks have higher prevalence^28,29, and severity³⁰ of HTN than Whites, with 40% of the former vs 25% of the latter exceeding a systolic BP (SBP) of 160 mmHg³⁰. HTN mortality in Blacks is double that of Whites³¹ owing to more frequent cerebral, cardiovascular and renal complications in the former^32–35. Middle-aged Blacks have a 4-fold increased risk of stroke (and a 3-fold risk for the same BP elevation in Whites³⁰), regardless of its type: extracranial or intracranial atherosclerotic and embolic lacunar strokes³⁶, small vessel disease (in South London)³⁷ and intracerebral hemorrhage³⁸. The last produces major disability in young (35 to 54 years) Blacks, owing to brain stem and deep cerebral bleeds³⁹. Only half this excess risk is attributable to BP or traditional risk factors, suggesting increased susceptibility linked to ancestry³⁰. Unraveling the cause of the racial stroke disparity is crucial because many types of stroke can be reduced significantly by intensifying therapy with personalized treatment algorithms^40–42 or systematic approaches to treatment inertia⁴³.

Black women have higher crude rates for peripartum cardiomyopathy, heart failure, acute renal failure, arrhythmias, preterm birth⁴⁴ and preeclampsia (adjusted odds ratio 1.45) compared to other races. Socioeconomic factors play a role because once treated as confounders, event rates were highest in Asian/Pacific Islander, not Black women⁴⁵. Finally, HTN is more resistant to treatment in US Blacks than in Whites, despite the fact that the former are more likely to have a diagnosis of HTN and to be aggressively treated^30,46.

Hypothetical factors causing the above differences between Blacks and Whites include environmental (salt and fructose intake and reduced potassium intake⁴⁷), social (access to care, adherence to treatment, stress)⁴⁸ and biological/genetic (Figure 1). Proponents of genetic causation have speculated that Na⁺ scarcity in hot climate regions of Africa exerted evolutionary pressure with drift towards renal Na⁺ retention gene variants, later exaggerated by the fitness for survival during passage to America on slave ships^49,50. Genetic drift is supported by increased risk for HTN in African Blacks than Whites. Also, the covariate-adjusted population systolic BP of South African Blacks is 9.7 mmHg higher than that of American Blacks and their cardiac and renal complications and resistance to treatment are worse than in White Africans^51,52. An effect of the bottleneck during passage to America is supported by genetic differences between African and US Blacks⁵³, and by higher prevalence of HTN among US-born than among foreign-born Black US residents^48,50.

Figure 1.

Hypothesized mechanisms contributing to greater salt-sensitivity of blood pressure in Blacks. Several factors including genetic, epigenetic, environmental/social determinants and diet have been implicated in renal, neural and vascular mechanisms leading to salt-sensitive hypertension. ADMA: asymmetric dimethyl arginine; NO: nitric oxide; H3K4me1: methylation of fourth lysine of histone H3; LSD1: lysine-specific histone demethylase 1A; PGE2: prostaglandin E2; UNaV: urinary sodium excretion

SSBP in Blacks

Prevalence of SSBP is higher in Blacks than in Whites^54,55, reaching ~75% particularly after development of HTN⁵⁶, and associates with a low-renin phenotype^57,58. Although the reason for this is unknown, estimated heritability of SSBP (74%) is higher than that for HTN⁵⁹ and the trait is observed in 22% of healthy adolescent Blacks⁶⁰, both supporting a role for ancestry. The slavery hypothesis also applies to SSBP because it deals with a genetic enhancement of Na⁺ reabsorption^49,61,62. Excretion of urine cations is similar in Blacks and Whites^63,64, whereas urine Na⁺ is highly heritable in Blacks, both suggesting intake-independent, genetic regulation⁶⁵. Delayed excretion of a water load in Blacks compared to Whites supports differences in the time-course of the hemodynamic consequences of salt and water loading between races⁶⁶.

The pressor effect of salt is greater in Blacks than in Whites, independent of baseline BP^67–69, and exaggerated by total calorie⁷⁰ and K⁺ intake deficiencies^67,71. The depressor response to salt depletion was also greater in Blacks than in Whites in large trials such as DASH⁷² and TOHP⁷³. Increased erythrocyte Na⁺/K⁺ and Ca²⁺/Mg²⁺ ratios, concomitant to exaggerated BP responses to salt in Black women, stimulated investigation on cation pump and transporters genes as a possible cause of SSBP⁷⁴. However, urine K⁺ excretion is lower in Blacks than Whites and it is not known whether this reflects lower K⁺ intake or different renal or fecal K⁺ disposition^75,76. Nonetheless, SSBP is attenuated by K⁺ replacement⁷⁷, which erases the differences in its prevalence between races⁷⁸ and supports environmental causation.

The major mechanisms involved in control of blood pressure, with differences between Blacks and Whites, are delineated in Table 1. (For fuller discussion, including sources, see the Supplement.) Those that potentially contribute to racial differences in SSBP are shown in Figure 2 and include: lower plasma levels of aldosterone with enhanced responses to amiloride and paradoxical increases in response to salt; higher expression of SGK1, resulting in decreased ubiquitination of the epithelial sodium channel (ENaC) and enhanced blood pressure response to salt; diminished PGE2 urine excretion in salt-sensitive hypertensive Black women; paradoxical salt-induced decreases in plasma atrial natriuretic peptides in salt-sensitive Blacks; lower Na⁺-K⁺-ATPase activity in Blacks with resultant higher erythrocyte Na⁺ which correlates with salt-sensitivity, and is inhibited by endogenous ouabain in salt-sensitive Blacks; and more frequent estrogen receptor minor allele variants in Blacks which are associated with SSBP.

Table 1.

Mechanisms Potentially Contributing to Salt Sensitivity of Blood Pressure (BP) and Differences Between Blacks and Whites

Hormone or Factor	Gene / observation	Racial Differences Black v White
Renin-angiotensin system
Renin	Multiple observations	Lower renin levels and blunted response to salt depletion (correlates with depressor response); associated with lower angiotensin (Ang) I / II, and angiotensinogen levels (without volume expansion); genes do not relate to BP or renal disease (do in Whites)
Glutamyl Aminopeptidase A	(AP-A) Converts Ang II to III	Decreased in hypertensives (vasoconstrictive) but no difference in BP response to central inhibitor between Blacks and Whites
Alanyl Aminopeptidase N	(AP-N) Converts Ang III to IV	Increased (less natriuresis) in hypertensives but not known to differ by race
Mineralocorticoids
Aldosterone	Adrenal adenomas / hyperplasia, or obesity	Lower plasma levels with enhanced responses to amiloride; paradoxical increases in response to salt; higher ratio to renin (ARR) in hypertensive Blacks; inappropriately high in Blacks with resistant hypertension, with more adrenal hyperplasia and response to mineralocorticoid receptor blockers
Serum- and glucocorticoid-inducible kinase 1 (SGK1)	Ancestral variant	More frequent in African Blacks, with increased expression enhancing BP response to salt (Figure 2)
11-β hydroxysteroid dehydrogenase 2	11βHSD2 variants + epigenetics	Loss of function variants associate with low renin hypertension in Blacks
Sympathetic nervous system
Norepinephrine	Overactive SNS	Augmented responses in Blacks, with greater responses to orthostasis
Phenylethanolamine N-methyltransferase	Converts epi- to norepi-nephrine	Does not associate with hypertension in Blacks despite variant that diminishes expression and activity
Neuropeptide Y (NPY)	Variants	Associate with increase in BP on high-fat diet in Blacks
NPY receptors	Variants	Associate with left ventricular mass in Blacks and autonomic dysfunction in both races
Endothelin (ET) system
ET-1	Variants	Overall higher plasma levels in Blacks, which decrease in response to normalization of BP; carriers of minor allele have increased ARR and blunted dipping of nocturnal BP
ETA receptor	Vasoconstrictor	Higher vasoconstrictor tone, with greater response to ETA blockers
Arginine Vasopressin (AVP)
AVP	(controversial)	Higher plasma levels, with greater response to type V1 receptor antagonists
Prostaglandins (PG)
PGE2	Vasodilator	Urine excretion lower in SS hypertensive than normotensive Black women
Kinins
Kallikrein	Natriuretic	Diminished urinary kallikrein excretion, but not related to SSBP (is in Europeans)
Bradykinin	BK-B2 receptor variants	Different allelic frequencies, with associated impaired vascular responsiveness in some
Natriuretic peptides (NP)
Atrial NP	Intronic SNP varies	Plasma levels paradoxically decreased in response to high salt in SS (v SR or Whites)
Corin	Variant	More prevalent and associates with severity of hypertension in Blacks
CYP450 enzymes, eicosanoids and soluble epoxide hydrolase
20-hydroxyeicosatetranoic acid (20-HETE)	Vasoconstrictor and natriuretic	Natriuresis disrupted in SS, variable relationship to BP; not studied in SSBP of Blacks
CYP4A11 monooxygenase	20-HETE synthase; diminishes epoxygenases	Variants enhance response to amiloride and synthesis of epoxyeicosatrienoic acids (EETs: normally down regulate ENaC); minor allele more frequent in both races and associated with SSBP
soluble Epoxide Hydrolase	Inactivates EETs	EPHX2 variants associated with coronary artery calcification but not BP in Blacks
Nitric oxide (NO) system
Endothelial NO Synthase	NOS3 variant	More prevalent in Blacks, increases expression of T cell inflammation and cytokines
Asymmetric Dimethyl Arginine (ADMA)	Inhibits NO production	Higher levels in Blacks correlate with higher central BP and lower pulse wave velocity
Oxidative stress
Oxidative stress	In human umbilical vein endothelium	Higher in Blacks, with increased intracellular hydrogen peroxide in PBMCs
Nuclear factor erythroid 2-Related Factor2	Inhibitor of NLRP3 inflammasome	Variant in Blacks associated with lower forearm blood flow and higher vascular resistance (not in Whites)
Angiogenesis factors and Immunity
Tonicity-responsive Enhancer-Binding Protein	TonEBP	Dietary salt increases Na+ storage in the skin, stimulating TonEBP, which increases production of VEGF-C and its receptor, facilitating extrusion of Na. Although not directly studied in SSBP, Blacks on dialysis have higher skin Na+ than Whites, which has been shown to relate to production of inflammatory isolevuglandins in immune cells
Vascular Endothelial Growth Factor	VEGF
Renal transporters: Na + -K + -ATPase and regulatory molecules
Na+-K+-ATPase	ubiquitous	Lower activity in Blacks with resultant higher erythrocyte Na+ which correlates with SSBP; inhibition by endogenous ouabain in SS Blacks
-β1subunit	ATP1B1	Variant associates with BP in Blacks
α-adducin	ADD1	Variant stimulates ATPase activity but does not associate with BP in Blacks
Renal transporters: Na+H− exchangers (NHE)
NHE	Variant	Higher exchange rates in hypertensive Blacks; although variant in renal isoform is more common in Blacks, it does not associate with BP or renin in either race
Renal transporters: Na+K+2Cl− cotransporter (NKCC)
NKCC2	Renal isoform	Hyperactive in Blacks; not directly studied in SS
Uromodulin	Stimulates NKCC2	Variants associate with low-renin resistant hypertension in Blacks
Renal transporters: Thiazide-Sensitive Sodium-Chloride Cotransporter (NCC) and its regulator
With-No-Lysine Kinase (WNK)1	Regulates NCC activity	Interaction between WNK1 and environmental stressors determines systolic BP in Blacks; no direct study of NCC SNPs in Black populations.
Renal transporters: CL− channel (CLCNK)
CLCNKB	Gain-of-function	More prevalent and associated with BP in Blacks; not directly studied in SS
Renal transporters: Na+ bicarbonate− cotransporter (SLC)
SLC4A5	Variants	Associated with BP in Blacks; not directly studied in SS
Renal transporters: Epithelial Sodium Channel (ENaC) and its regulatory molecules
ENaC	(also immune cells)	Hyperactivity associated with lower urine aldosterone/K+ ratios in Blacks
-β subunit	Variants	Higher frequency in Blacks, with enhanced response to amiloride over spironolactone
NEDD4 (E3 ubiquitin-protein ligase)	Regulator of ENaC degradation	Higher frequency of variants associated with worse cardiovascular prognosis in Blacks
Renal dopaminergic natriuretic system
G-protein-coupled Receptor Kinase-4 (GRK4)	Stimulates renal AT1R expression	Variant associates with low-renin, low-aldosterone hypertension in Blacks; + epigenetics
Klotho (KL, mainly expressed in kidney, levels decrease with aging)
KL gene and protein	Variants	Increased protein expression and delayed onset of nondiabetic renal disease in Blacks.
Metabolic factors
Insulin Resistance	Impairs PI3 Kinase pathway	Correlates with severity of SSBP, worsened by salt depletion in SR; in Blacks may mediate effects of obesity
Insulin Receptor Substrate 1	Variants	Associate with IR in Blacks but not known to with SSBP (does in Whites)
Ghrelin	Natriuretic in kidney via NOS1	Decreased by salt depletion in Black women, which relates to SSBP; variants associate with hypertension in Whites, not studied in Blacks
Leptin	Multiple variants	Higher levels in Blacks, which predict incidence and severity of hypertension
Adiponectin	Paradoxical, + epigenetics	Lower levels in Black women (independent of BMI), predicting diabetes and hypertension
Peroxisome proliferator-activated receptors (PPARs)	Minor allele of PPARγ	Carriers have higher plasma renin in both Whites and Blacks, resulting in higher BP in Blacks (but not Whites)
Estrogen
Estrogen	Multiple mechanisms	SSBP more prevalent in women especially after menopause, estrogen-replacement reduces their SSBP; not directly studied in Blacks
Estrogen Receptor	ER2 variants	Minor allele more frequent in Blacks and associated with SSBP

Figure 2.

Racial differences in mechanisms of blood pressure control that contribute to salt-sensitivity of blood pressure in Blacks. Lower plasma levels of aldosterone with elevated ratio to renin (A/R), enhanced responses to amiloride and paradoxical increases in response to salt; higher expression of SGK1 (serum- and glucocorticoid-inducible kinase) leading to reduced ubiquitination (U) of ENaC (epithelial sodium channel, which is regulated by the mineralocorticoid receptor, MR) by NEDD4-2 (ubiquitin-protein ligase) and enhanced blood pressure response to salt; lower Na⁺-K⁺-ATPase activity, inhibited by endogenous ouabain, resulting in higher erythrocyte Na; paradoxical salt-induced decreases in plasma atrial natriuretic peptide (ANP); and, in Black women, diminished urinary excretion of prostaglandin E2 and increased frequency of minor estrogen receptor variants have all been implicated in greater salt-sensitivity of blood pressure in Blacks. For details see the Supplement.

EPIGENETICs

The Table includes putative factors that may participate in the pathogenesis of SSBP (such as 11βHSD2, GRK4, adiponectin and leptin) via epigenetic mechanisms (see Supplement).

More recently, epigenetic effects of different diets were deemed responsible for the more severe phenotype (HTN and renal damage) present in the Dahl-S rat from Medical College of Wisconsin (fed a purified diet), compared with a genetically almost identical strain fed a commercial grain chow⁷⁹. T cells isolated from kidneys of rats on the purified diet responded to a high salt challenge with an increase in methylated regions and preferential hypermethylation compared to those fed the grain diet. The phenotype was associated with suppressed gene expression and could be reversed with inhibition of DNA methyltransferases.

In humans, two weeks of salt depletion produced methylation changes in T cells and arterioles, which correlated with a concomitant BP reduction of −8/−4 mmHg and with improvement in flow-mediated vasodilation. T-cell DNA was more methylated than arteriole DNA; the differentially methylated regions involved 188 genes, four of which were present in both cell types. Many of the differentially methylated genes were common to humans and the Medical College of Wisconsin Dahl-S rat model described above. In summary, sodium restriction affects DNA methylation in a manner related to the BP effect with overlap between tissues and species⁸⁰. Sodium loading for one week also affected DNA methylation in a Chinese study, but its results differed in that only SS subjects exhibited changes. These consisted of salt-induced increases in serum H3K4me1 (methylation of fourth lysine of histone H3, a marker of epigenetic methylation), and in histone methyltransferase Set7⁸¹ (the enzyme that monomethylates it).

Most importantly, a study of whole blood DNA methylation in Black subjects uncovered methylation regions that were associated with the 24-hr BP phenotypes (SBP, DBP, MAP and PP) of the subjects but not with their clinic BPs. The findings were confirmed in a validation study in another cohort. The identified methylation regions accounted for more of the variability of 24-hr SBP than that accounted for by age, sex, and BMI⁸².

Lysine-specific histone demethylase 1A (LSD1), a human monoamine oxidase, was the first histone demethylase described. It demethylates mono- and di-methylated lysines⁸³ so it is a major regulator of epigenetic DNA modification. Mice heterozygous for LSD1 knockout develop low-renin, low aldosterone HTN, which is different from that of humans because ENaC activity is diminished. The phenotype is vascular, with diminished expression of NOS3 and guanylate cyclase, decreased endothelium-dependent relaxation, and decreased responses to exogenous NO⁸⁴.

It is therefore important that the minor allele of a LSD1 SNP was linked to SSBP in Blacks of the HyperPath cohort, but not in Whites, suggesting that non-genetic factors may have determined SSBP a long time ago in this population, whereas the consequent altered gene expression became inherited by ensuing generations as an epigenetic, not a genetic phenomenon. These hypertensive subjects had low renin and aldosterone levels and blunted renal blood flow responses to salt-loading⁸⁵. It is not known, however, whether their phenotype resembles the Liddle-like phenotype observed in Africa or the vascular one described in mice.

VASCULAR ABNORMALITIES IN SS HTN OF BLACKS

Several experimental and clinical findings support the possibility that SSBP may primarily reflect a vascular abnormality. A meal containing a typical amount of salt, given to healthy volunteers, impairs endothelial function in 30 minutes⁸⁶, increases BP in one hour⁸⁷ and conduit artery stiffness within 2 hours⁸⁸, all intervals too short to invoke hemodynamic autoregulatory mechanisms.

Even in healthy subjects with the SR phenotype, high-salt administration is capable of impairing brachial artery flow-mediated dilation in one week⁸⁹, more severely in males than females⁹⁰, by switching vasodilation to non-NO-dependent mechanisms⁹¹.

More than 40 years ago, the seminal observation was made that Dahl-R rats responded to the increased CO produced by a 3-day salt load with a decrease in TPR and maintenance of normal BP, whereas Dahl-S rats with the same increase in CO were unable to vasodilate and sustained instead a pressor response. This pattern persisted once salt balance equilibrated in one week, leading to chronic BP elevation in the Dahl-S strain⁹². This observation was repeated several times and attributed to different mechanisms. For example, Dahl-S rats have an abnormal endothelial ENaC, non-suppressible by salt, the overactivity of which produces endothelial stiffness in Liddle and in aging mice⁹³. Also, indirect pressor effects by the sympathetic nervous system, AVP, and vascular inflammation are triggered by overactive ENaCs in the brain, renal nerves, and antigen-presenting cells (see Supplement). Others have described vascular Ang II-induced oxidative stress, even during low-salt diet⁹⁴, which is reversible with antioxidants⁹⁵, salt-induced suppression of Ang II AT2 receptor vasodilatation⁹⁶, deficient PPARγ⁹⁷, excessive 20-HETE⁹⁸, overactivity of the vascular ETA receptor⁹⁹, increased vascular responsiveness to Ang II and NE¹⁰⁰, and to oxygen, loss of NO availability, and accelerated NO degradation by reactive oxygen species¹⁰¹. The role of an NO deficit in Dahl-S rats was confirmed by attenuation of their SS HTN when given dietary nitrate supplementation¹⁰². Finally, a high salt intake produces rarefaction of skin and other microcapillary networks in UK Blacks¹⁰³, adding a structural component to microvascular dysfunction that may precede changes in BP.

Analogous to observations in the Dahl-R rat, young normotensive volunteers exposed to high salt acutely (days) or chronically (12 months) compensate sustained increases in CO with a decrease in TPR of about 30%¹⁰⁴. In contrast, an inability to undergo this compensatory vasodilation has been described in SS young normotensive populations (European Whites¹⁰⁵ using BP waveform analysis, Americans of both races²⁴ using echocardiography, and American Blacks²⁵ using impedance cardiography). The mechanism for this vascular abnormality has not been firmly established. In SS Blacks it is associated with salt-induced increases in ADMA¹⁰⁶, hyperresponsiveness to the vasodilator effect of L-arginine¹⁰⁷, and with paradoxical inhibition of urine nitrates¹⁰⁸ and ANP after a salt load¹⁰⁹, suggesting a deficit of NO or natriuretic peptide vasodilation. Potassium supplementation improves SS HTN and renal hemodynamics in hypertensive Blacks^71,110, indicating that environmental factors such as a low K⁺ intake may play a role.

Other mechanisms invoked in the causation of vascular abnormalities in SS HTN of Blacks include a tilt in the ratio between peroxynitrite and NO, favoring oxidative stress in their human umbilical vein endothelial cells^111,112, paradoxical hyperresponsiveness to NE and Ang II during a high salt diet¹¹³, enhanced aldosterone-induced endothelial dysfunction¹¹⁴, hyperreactivity to sympathetic stimulation (e.g., cold pressor test in Nigerian Blacks¹¹⁵), early vascular aging in South African Black, compared with White children¹¹⁶, and early endothelial dysfunction in young African Blacks,¹¹⁷ probably a consequence of early life events such as fetal undernutrition and low birth weight.

In summary, the evidence reviewed here suggests the presence of inherited, epigenetically determined, and environmental causes for the abnormalities observed in the SS HTN of Blacks. Sorting them out by future studies linked to ancestry, rather than race, may permit targeting of therapy to the predominant mechanism in individual subjects.

Non-standard Abbreviations and Acronyms:

ACE

angiotensin converting enzyme

ADMA

asymmetric dimethyl arginine

AGT

angiotensinogen

α2AR

α2-adrenergic receptor

Ang

angiotensin

ANP

atrial natriuretic peptide

ANS

autonomic nervous system

AP-A

glutamyl aminopeptidase

APC

antigen presenting cell

AT1R

angiotensin type I receptor

AVP

arginine vasopressin

11bHSD2

11 β-Hydroxysteroid Dehydrogenase Type 2

BP

blood pressure

cGMP

cyclic guanosine monophosphate

CO

cardiac output

COX

cyclooxygenase

EET

epoxyeicosatrienoic acid

ENaC

epithelial sodium channel

ET1

endothelin 1

ETA

endothelin type A receptor

ETB

endothelin type B receptor

GRK4

G protein-coupled receptor kinase 4

20-HETE

20-hydroxyeicosatetranoic acid

HTN

hypertension

IL

interleukin

LSD1

lysine-specific histone demethylase 1A

LV

left ventricular

NADPH

nicotinamide-adenine-dinucleotide phosphate

Na⁺K⁺ATPase

sodium-potassium-ATPase

NCC

Thiazide-Sensitive Sodium-Chloride Cotransporter

NEDD4

E3 ubiquitin-protein ligase

NHE3

sodium–hydrogen exchanger 3

NKCC

Na⁺K⁺2Cl⁻ Cotransporter

NOS

nitric oxide synthase

NPY

neuropeptide Y

NT-proBNP

N-terminal pro brain natriuretic peptide

PGE2

prostaglandin E2

PKC

protein kinase C

PPAR

peroxisome proliferator-activated receptor

PV

plasma volume

RAAS

renin-angiotensin-aldosterone system

SBP

systolic BP

SGK1

serum- and glucocorticoid-inducible kinase 1

sEH

soluble epoxide hydrolase

SLC

Na⁺-bicarbonate cotransporter

SR

salt resistant

SS

salt sensitive

SSBP

salt sensitivity of blood pressure

TAL

thick ascending limb

TPR

total peripheral resistance

UMOD

uromodulin