No evidence of racial disparities in blood pressure salt sensitivity when potassium intake exceeds levels recommended in the US dietary guidelines.

On average, black individuals are widely believed to be more sensitive than white individuals to blood pressure (BP) effects of changes in salt intake. However, few studies have directly compared the BP effects of changing salt intake in black versus white individuals. In this narrative review, we analyze those studies and note that when potassium intake substantially exceeds the recently recommended US dietary goal of 87 mmol/day, black adults do not appear more sensitive than white adults to BP effects of short-term or long-term increases in salt intake (from an intake ≤50 mmol/day up to 150 mmol/day or more). However, with lower potassium intakes, racial differences in salt sensitivity are observed. Mechanistic studies suggest that racial differences in salt sensitivity are related to differences in vascular resistance responses to changes in salt intake mediated by vasodilator and vasoconstrictor pathways. With respect to cause and prevention of racial disparities in salt sensitivity, it is noteworthy that 1) on average, black individuals consume less potassium than white individuals and 2) consuming supplemental potassium bicarbonate, or potassium rich foods can prevent racial disparities in salt sensitivity. However, the new US dietary guidelines reduced the dietary potassium goal well below the amount associated with preventing racial disparities in salt sensitivity. These observations should motivate research on the impact of the new dietary potassium guidelines on racial disparities in salt sensitivity, the risks and benefits of potassium-containing salt substitutes or supplements, and methods for increasing consumption of foods rich in nutrients that protect against salt-induced hypertension.

The pivotal role of renal vasodysfunction in salt sensitivity and the initiation of salt-induced hypertension.

PURPOSE OF REVIEW: For decades, it has been widely accepted that initiation of salt-induced hypertension involves a type of kidney dysfunction (natriuretic handicap), which causes salt-sensitive subjects to initially excrete less of a sodium load than normal subjects and undergo abnormal increases in cardiac output, and therefore blood pressure. Here we discuss emerging views that renal vasodysfunction, not natriuretic dysfunction (subnormal sodium excretion), is usually a critical factor initiating salt-induced hypertension. RECENT FINDINGS: Serious logical issues have been raised with arguments supporting historical views that natriuretic dysfunction initiates hypertension in response to increased salt intake. Most salt-sensitive humans do not have a 'natriuretic handicap' causing them to excrete a sodium load more slowly and retain more of it than salt-resistant normal subjects. Mounting evidence indicates that in most salt-sensitive subjects, renal vasodysfunction, defined as impaired renal vasodilation and abnormally increased renal vascular resistance in response to increased salt intake, in the absence of greater sodium retention than in salt-loaded normal subjects, is involved in initiation of salt-induced hypertension. SUMMARY: To advance discovery, prevention, and treatment of primary abnormalities causing salt-induced hypertension, greater research emphasis should be placed on identifying mechanisms mediating subnormal renal vasodilation and abnormally increased renal vascular resistance in response to high-salt diets.

An alternative hypothesis to the widely held view that renal excretion of sodium accounts for resistance to salt-induced hypertension.

It is widely held that in response to high salt diets, normal individuals are acutely and chronically resistant to salt-induced hypertension because they rapidly excrete salt and retain little of it so that their blood volume, and therefore blood pressure, does not increase. Conversely, it is also widely held that salt-sensitive individuals develop salt-induced hypertension because of an impaired renal capacity to excrete salt that causes greater salt retention and blood volume expansion than that which occurs in normal salt-resistant individuals. Here we review results of both acute and chronic salt-loading studies that have compared salt-induced changes in sodium retention and blood volume between normal subjects (salt-resistant normotensive control subjects) and salt-sensitive subjects. The results of properly controlled studies strongly support an alternative view: during acute or chronic increases in salt intake, normal salt-resistant subjects undergo substantial salt retention and do not excrete salt more rapidly, retain less sodium, or undergo lesser blood volume expansion than do salt-sensitive subjects. These observations: (i) directly conflict with the widely held view that renal excretion of sodium accounts for resistance to salt-induced hypertension, and (ii) have implications for contemporary understanding of how various genetic, immunologic, and other factors determine acute and chronic blood pressure responses to high salt diets.

Hypertension in Primary Aldosteronism Is Initiated by Salt-Induced Increases in Vascular Resistance With Reductions in Cardiac Output.

BACKGROUND: Few studies have investigated the hemodynamic mechanism whereby primary aldosteronism causes hypertension. The traditional view holds that hyperaldosteronism initiates hypertension by amplifying salt-dependent increases in cardiac output (CO) by promoting increases in sodium retention and blood volume. Systemic vascular resistance (SVR) is said to increase only as a secondary consequence of the increased CO and blood pressure. However, mounting evidence indicates that aldosterone can influence multiple pathways regulating vascular tone. We investigated the primary hemodynamic mechanism whereby hyperaldosteronism promotes salt sensitivity and initiation of salt-dependent hypertension. METHODS: In unilaterally nephrectomized male Sprague-Dawley rats given infusions of aldosterone or vehicle, we used chronically implanted arterial pressure probes and Doppler ultrasonic flow probes to continuously monitor changes in mean arterial pressure, CO, and SVR 24 hours/day, 7 days/week in response to increases in salt intake. RESULTS: In vehicle-treated control rats, switching from a low-salt diet to a high-salt diet initiated modest increases in mean arterial pressure by increasing SVR while simultaneously decreasing heart rate and CO. In aldosterone-treated rats compared with control rats, switching from a low-salt diet to a high-salt diet initiated significantly greater increases in mean arterial pressure and SVR and significantly greater decreases in heart rate and CO. CONCLUSIONS: Aldosterone promoted salt sensitivity and initiation of salt-dependent hypertension by amplifying salt-induced increases in SVR while decreasing CO. Increases in CO are not required for the initiation or maintenance of hypertension. These findings challenge the traditional view of the hemodynamic mechanisms that cause hypertension in primary aldosteronism.

Small Amounts of Inorganic Nitrate or Beetroot Provide Substantial Protection From Salt-Induced Increases in Blood Pressure.

To reduce the risk of salt-induced hypertension, medical authorities have emphasized dietary guidelines promoting high intakes of potassium and low intakes of salt that provide molar ratios of potassium to salt of ≥1:1. However, during the past several decades, relatively few people have changed their eating habits sufficiently to reach the recommended dietary goals for salt and potassium. Thus, new strategies that reduce the risk of salt-induced hypertension without requiring major changes in dietary habits would be of considerable medical interest. In the current studies in a widely used model of salt-induced hypertension, the Dahl salt-sensitive rat, we found that supplemental dietary sodium nitrate confers substantial protection from initiation of salt-induced hypertension when the molar ratio of added nitrate to added salt is only ≈1:170. Provision of a low molar ratio of added nitrate to added salt of ≈1:110 by supplementing the diet with beetroot also conferred substantial protection against salt-induced increases in blood pressure. The results suggest that on a molar basis and a weight basis, dietary nitrate may be ≈100× more potent than dietary potassium with respect to providing substantial resistance to the pressor effects of increased salt intake. Given that leafy green and root vegetables contain large amounts of inorganic nitrate, these findings raise the possibility that fortification of salty food products with small amounts of a nitrate-rich vegetable concentrate may provide a simple method for reducing risk for salt-induced hypertension.

Changing views on the common physiologic abnormality that mediates salt sensitivity and initiation of salt-induced hypertension: Japanese research underpinning the vasodysfunction theory of salt sensitivity.

High-salt intake is one of the major dietary determinants of increased blood pressure and cardiovascular disease. Thus, there is scientific and medical interest in understanding the mechanistic abnormalities mediating the pressor effects of salt (salt sensitivity). According to historical theory, salt sensitivity stems from an impairment in renal function (referred to as "abnormal pressure natriuresis" or a "natriuretic handicap"), which causes salt-sensitive subjects to excrete a sodium load more slowly, and retain more of it than salt-resistant normotensive controls. However, this historical view has come under intense scrutiny because of growing awareness that in salt-sensitive subjects, acute salt loading does not usually induce greater increases in sodium balance and cardiac output than those induced by salt loading in salt-resistant normotensive controls. Here we highlight pioneering studies from Japan that challenge the historical thinking and provide insights into a contemporary theory of salt sensitivity termed the "vasodysfunction theory." According to this theory, initiation of salt-induced hypertension usually involves abnormal vascular resistance responses to increased salt intake, not greater renal retention of a salt load in salt-sensitive subjects than in normal subjects. By shifting the focus from the historical theory to a contemporary final common pathway for the pathogenesis of salt sensitivity, research from Japan is building the scientific foundation for more effective approaches to the prevention and treatment of salt-induced hypertension. Among the most promising approaches are dietary strategies for reducing the risk for salt-induced hypertension that do not depend on reducing salt consumption in the population.

Adverse effects of sodium chloride on bone in the aging human population resulting from habitual consumption of typical American diets.

A typical American diet contains amounts of sodium chloride far above evolutionary norms and potassium far below those norms. It also contains larger amounts of foods that are metabolized to noncarbonic acids than to organic bases. At baseline, in a steady state, diets that contain substantial sodium chloride and diets that are net acid producing each independently induce and sustain increased acidity of body fluid. With increasing age, the kidney's ability to excrete daily net acid loads declines, invoking homeostatically increased utilization of base stores (bone, skeletal muscle) on a daily basis to mitigate the otherwise increasing baseline metabolic acidosis, which results in increased calciuria and net losses of body calcium. Those effects of net acid production and its attendant increased body fluid acidity may contribute to development of osteoporosis and renal stones, loss of muscle mass, and age-related renal insufficiency. The inverted ratio of potassium to sodium in the diet compared with preagricultural diets affects cardiovascular function adversely and contributes to hypertension and stroke. The diet can return to its evolutionary norms of net base production inducing low-grade metabolic alkalosis and a high potassium-to-sodium ratio by 1) greatly reducing content of energy-dense nutrient-poor foods and potassium-poor acid-producing cereal grains, which would entail increasing consumption of potassium-rich net base-producing fruits and vegetables for maintenance of energy balance, and 2) greatly reducing sodium chloride consumption. Increasingly, evidence supports the health benefits of reestablishing evolutionary norms of dietary net base loads and high potassium and low sodium chloride loads. We focus here on the American diet's potential effects on bone through its superphysiologic content of sodium chloride.

Postulating the major environmental condition resulting in the expression of essential hypertension and its associated cardiovascular diseases: Dietary imprudence in daily selection of foods in respect of their potassium and sodium content resulting in oxidative stress-induced dysfunction of the vascular endothelium, vascular smooth muscle, and perivascular tissues.

We hypothesize that the major environmental determinant of the expression of essential hypertension in America and other Westernized countries is dietary imprudence in respect of the consumption of daily combinations of foods containing suboptimal amounts of potassium and blood pressure-lowering phytochemicals, and supraphysiological amounts of sodium. We offer as premise that Americans on average consume suboptimal amounts of potassium and blood pressure-lowering phytochemicals, and physiologically excessive amounts of sodium, and that such dietary imprudence leads to essential hypertension through oxidative stress-induced vascular endothelial and smooth muscle dysfunction. Such dysfunctions restrict nitric oxide bioavailability, impairing endothelial cell-mediated relaxation of the underlying vascular smooth muscle, initiating and maintaining inappropriately increased peripheral and renal vascular resistance. The biochemical steps from oxidative stress to vascular endothelial dysfunction and its pernicious cardiovascular consequences are well established and generally accepted. The unique aspect of our hypothesis resides in the contention that Americans' habitual consumption of foods resulting in suboptimal dietary intake of potassium and supraphysiological intake of sodium result in oxidative stress, the degree of which, we suggest, will correlate with the degree of deviation of potassium and sodium intake from optimal. Because suboptimal intakes of potassium reflect suboptimal intakes of fruits and vegetables, associated contributors to oxidative stress include suboptimal intakes of magnesium, nitrate, polyphenols, carotenoids, and other phytochemical antioxidants for which fruits and vegetables contain abundant amounts. Currently Americans consume potassium-to-sodium in molar ratios of less than or close to 1.0 and the Institute of Medicine (IOM) recommends a molar ratio of 1.2. Ancestral diets to which we are physiologically adapted range from molar ratios of 5.0 to 10.0 or higher. Accordingly, we suggest that the average American is usually afflicted with oxidative stress-induced vascular endothelial dysfunction, and therefore the standards for normal blood pressure and pre-hypertension often reflect a degree of clinically significant hypertension. In this article, we provide support for those contentions, and indicate the findings that the hypothesis predicts.

Functional foods for augmenting nitric oxide activity and reducing the risk for salt-induced hypertension and cardiovascular disease in Japan.

High salt intake is one of the major dietary determinants of hypertension and cardiovascular disease in Japan and throughout the world. Although dietary salt restriction may be of clinical benefit in salt-sensitive individuals, many individuals may not wish, or be able to, reduce their intake of salt. Thus, identification of functional foods that can help protect against mechanistic abnormalities mediating salt-induced hypertension is an issue of considerable medical and scientific interest. According to the "vasodysfunction" theory of salt-induced hypertension, the hemodynamic abnormality initiating salt-induced increases in blood pressure usually involves subnormal vasodilation and abnormally increased vascular resistance in response to increased salt intake. Because disturbances in nitric oxide activity can contribute to subnormal vasodilator responses to increased salt intake that often mediate blood pressure salt sensitivity, increased intake of functional foods that support nitric oxide activity may help to reduce the risk for salt-induced hypertension. Mounting evidence indicates that increased consumption of traditional Japanese vegetables and other vegetables with high nitrate content such as table beets and kale can promote the formation of nitric oxide through an endothelial independent pathway that involves reduction of dietary nitrate to nitrite and nitric oxide. In addition, recent studies in animal models have demonstrated that modest increases in nitrate intake can protect against the initiation of salt-induced hypertension. These observations are: (1) consistent with the view that increased intake of many traditional Japanese vegetables and other nitrate rich vegetables, and of functional foods derived from such vegetables, may help maintain healthy blood pressure despite a high salt diet; (2) support government recommendations to increase vegetable intake in the Japanese population.

Testing Computer Models Predicting Human Responses to a High-Salt Diet.

Recently, mathematical models of human integrative physiology, derived from Guyton's classic 1972 model of the circulation, have been used to investigate potential mechanistic abnormalities mediating salt sensitivity and salt-induced hypertension. We performed validation testing of 2 of the most evolved derivatives of Guyton's 1972 model, Quantitative Cardiovascular Physiology-2005 and HumMod-3.0.4, to determine whether the models accurately predict sodium balance and hemodynamic responses of normal subjects to increases in salt intake within the real-life range of salt intake in humans. Neither model, nor the 1972 Guyton model, accurately predicts the usual changes in sodium balance, cardiac output, and systemic vascular resistance that normally occur in response to clinically realistic increases in salt intake. Furthermore, although both contemporary models are extensions of the 1972 Guyton model, testing revealed major inconsistencies between model predictions with respect to sodium balance and hemodynamic responses of normal subjects to short-term and long-term salt loading. These results demonstrate significant limitations with the hypotheses inherent in the Guyton models regarding the usual regulation of sodium balance, cardiac output, and vascular resistance in response to increased salt intake in normal salt-resistant humans. Accurate understanding of the normal responses to salt loading is a prerequisite for accurately establishing abnormal responses to salt loading. Accordingly, the present results raise concerns about the interpretation of studies of salt sensitivity with the various Guyton models. These findings indicate a need for continuing development of alternative models that incorporate mechanistic concepts of blood pressure regulation fundamentally different from those in the 1972 Guyton model and its contemporary derivatives.

The American Heart Association Scientific Statement on salt sensitivity of blood pressure: Prompting consideration of alternative conceptual frameworks for the pathogenesis of salt sensitivity?

: Recently, the American Heart Association (AHA) published a scientific statement on salt sensitivity of blood pressure which emphasized a decades old conceptual framework for the pathogenesis of this common disorder. Here we examine the extent to which the conceptual framework for salt sensitivity emphasized in the AHA Statement accommodates contemporary findings and views of the broader scientific community on the pathogenesis of salt sensitivity. In addition, we highlight alternative conceptual frameworks and important contemporary theories of salt sensitivity that are little discussed in the AHA Statement. We suggest that greater consideration of conceptual frameworks and theories for salt sensitivity beyond those emphasized in the AHA Statement may help to advance understanding of the pathogenesis of salt-induced increases in blood pressure and, in consequence, may lead to improved approaches to preventing and treating this common disorder.

The evolution-informed optimal dietary potassium intake of human beings greatly exceeds current and recommended intakes.

An organism best fits the environment described by its genes, an environment that prevailed during the time period (millions of years) when evolution naturally selected the genes of its ancestors-those who survived to pass on their genes. When an organism's current environment differs from its ancestral one, the environment's mismatch with the organism's genome may result in functional disadvantages for the organism. The genetically conditioned nutritional requirements of human beings established themselves over millions of years in which ancestral hominins, living as hunter-gatherers, ate a diet markedly different from that of agriculturally dependent contemporary human beings. In that context, we sought to quantify the ancestral-contemporary dietary difference with respect to the supply of one of the body's major mineral nutrients: potassium. In 159 retrojected Stone Age diets, human potassium intake averaged 400 +/- 125 mEq/d, which exceeds current and recommended intakes by more than a factor of 4. We accounted for the transition to the relatively potassium-poor modern diet by the fact that the modern diet has substantially replaced Stone Age amounts of potassium-rich plant foods (especially fruits, leafy greens, vegetable fruits, roots, and tubers), with energy-dense nutrient-poor foods (separated fats, oils, refined sugars, and refined grains), and with potassium-poor energy-rich plant foods (especially cereal grains) introduced by agriculture (circa 10,000 years ago). Given the fundamental physiologic importance of potassium, such a large magnitude of change in potassium intake invites the consideration in human beings of whether the quantitative values of potassium-influenced physiologic phenomena (eg, blood pressure, insulin and aldosterone secretion rates, and intracellular pH) currently viewed as normal, in fact disaccord with genetically conditioned norms. We discuss the potential implications of our findings in respect to human health and disease.

Logical Issues With the Pressure Natriuresis Theory of Chronic Hypertension.

The term "abnormal pressure natriuresis" refers to a subnormal effect of a given level of blood pressure (BP) on sodium excretion. It is widely believed that abnormal pressure natriuresis causes an initial increase in BP to be sustained. We refer to this view as the "pressure natriuresis theory of chronic hypertension." The proponents of the theory contend that all forms of chronic hypertension are sustained by abnormal pressure natriuresis, irrespective of how hypertension is initiated. This theory would appear to follow from "the three laws of long-term arterial pressure regulation" stated by Guyton and Coleman more than 3 decades ago. These "laws" articulate the concept that for a given level of salt intake, the relationship between arterial pressure and sodium excretion determines the chronic level of BP. Here, we review and examine the recent assertion by Beard that these "laws" of long-term BP control amount to nothing more than a series of tautologies. Our analysis supports Beard's assertion, and also indicates that contemporary investigators often use tautological reasoning in support of the pressure natriuresis theory of chronic hypertension. Although the theory itself is not a tautology, it does not appear to be testable because it holds that abnormal pressure natriuresis causes salt-induced hypertension to be sustained through abnormal increases in cardiac output that are too small to be detected.

Long-term persistence of the urine calcium-lowering effect of potassium bicarbonate in postmenopausal women.

Potassium bicarbonate (KBC) potently reduces urine calcium excretion in adult humans, including patients with hypertension or calcium urolithiasis, and postmenopausal women. In the latter, who have substantial risk of calcium deficiency, it remains unknown whether the observed short-term urine calcium-lowering effect of KBC persists over years. We studied 170 postmenopausal women randomized to KBC 30, 60, or 90 mmol/d (KBC treatment), or placebo, for up to 36 months. Each received a multivitamin with 400 IU vitamin D, and calcium carbonate as needed to produce a total dietary calcium intake of at least 30 mmol daily. Daily urine calcium excretion (UCaV) did not differ among groups at baseline (all-groups mean +/- SD, 155 +/- 83 mg/d). From 1-36 months of KBC treatment, adjusting UCaV for creatinine (Cr) excretion, each dose of KBC reduced UCaV (P < 0.01) with a dose-dependent trend (P = 0.05). The reduced UCaV/Cr persisted throughout the KBC treatment period (up to 36 months) in all KBC, and the greatest reductions occurred in the subjects with greatest baseline UCaV/Cr (Delta UCaV/Cr vs. baseline UCaV/Cr; P < 0.001). Twenty-eight percent of the subjects had high baseline calciuria (UCaV/Cr > 200 mg Ca/1000 mg Cr). With baseline UCaV/Cr of 250 mg/1000 mg Cr, KBC 60 mmol decreased UCaV/Cr by 55.8 mg/1000 mg Cr, a potential daily calcium retention that over a 36-month period would accumulate up to 55,845 mg of calcium, nearly 5% of bone calcium content. KBC treatment induced a dose-dependent decrease in UCaV/Cr that persisted up to 36 months, with the greatest decreases occurring in those women with the greatest baseline UCaV, nearly a third of whom had high baseline calciuria. Thus, one can preselect postmenopausal women most likely to have the urine calcium-lowering effect of KBC and predict their potential bone calcium increase.

Molecular-based mechanisms of Mendelian forms of salt-dependent hypertension: questioning the prevailing theory.

This critical review directly challenges the prevailing theory that a transient increase in cardiac output caused by genetically mediated increases in activity of the ENaC in the aldosterone sensitive distal nephron, or of the NCC in the distal convoluted tubule, accounts entirely for the hemodynamic initiation of all Mendelian forms of salt-dependent hypertension (Figure 1). The prevailing theory of how genetic mutations enable salt to hemodynamically initiate Mendelian forms of salt-dependent hypertension in humans (Figure 1) depends on the results of salt-loading studies of cardiac output and systemic vascular resistance in nongenetic models of hypertension that lack appropriate normal controls. The theory is inconsistent with the results of studies that include measurements of the initial hemodynamic changes induced by salt loading in normal, salt-resistant controls. The present analysis, which takes into account the results of salt-loading studies that include the requisite normal controls, indicates that mutation-induced increases in the renal tubular activity of ENaC or NCC that lead to transient increases in cardiac output will generally not be sufficient to enable increases in salt intake to initiate the increased BP that characterizes Mendelian forms of salt-dependent hypertension (Table). The present analysis also raises questions about whether mutation-dependent increases in renal tubular activity of ENaC or NCC are even necessary to account for increased risk for salt-dependent hypertension in most patients with such mutations. We propose that for the genetic alterations underlying Mendelian forms of salt-dependent hypertension to enable increases in salt intake to initiate the increased BP, they must often cause vasodysfunction, ie, an inability to normally vasodilate and decrease systemic vascular resistance in response to increases in salt intake within dietary ranges typically observed in most modern societies. A subnormal ability to vasodilate in response to salt loading could be caused by mutation-related disturbances originating in the vasculature itself or in sites outside the vasculature (eg, brain or adrenal glands) that have the capacity to affect vascular function.

Estimation of the net acid load of the diet of ancestral preagricultural Homo sapiens and their hominid ancestors.

BACKGROUND: Natural selection has had < 1% of hominid evolutionary time to eliminate the inevitable maladaptations consequent to the profound transformation of the human diet resulting from the inventions of agriculture and animal husbandry. OBJECTIVE: The objective was to estimate the net systemic load of acid (net endogenous acid production; NEAP) from retrojected ancestral preagricultural diets and to compare it with that of contemporary diets, which are characterized by an imbalance of nutrient precursors of hydrogen and bicarbonate ions that induces a lifelong, low-grade, pathogenically significant systemic metabolic acidosis. DESIGN: Using established computational methods, we computed NEAP for a large number of retrojected ancestral preagricultural diets and compared them with computed and measured values for typical American diets. RESULTS: The mean (+/- SD) NEAP for 159 retrojected preagricultural diets was -88 +/- 82 mEq/d; 87% were net base-producing. The computational model predicted NEAP for the average American diet (as recorded in the third National Health and Nutrition Examination Survey) as 48 mEq/d, within a few percentage points of published measured values for free-living Americans; the model, therefore, was not biased toward generating negative NEAP values. The historical shift from negative to positive NEAP was accounted for by the displacement of high-bicarbonate-yielding plant foods in the ancestral diet by cereal grains and energy-dense, nutrient-poor foods in the contemporary diet-neither of which are net base-producing. CONCLUSIONS: The findings suggest that diet-induced metabolic acidosis and its sequelae in humans eating contemporary diets reflect a mismatch between the nutrient composition of the diet and genetically determined nutritional requirements for optimal systemic acid-base status.