- Email: [email protected]
Sodium surfeit and potassium deficit: Keys to the pathogenesis of hypertension
Journal of the American Society of Hypertension 8(3) (2014) 203–213
Review Article
Sodium surfeit and potassium deficit: Keys to the pathogenesis of hypertension Horacio J. Adrogue, MDa and Nicolaos E. Madias, MDb,* a
Department of Medicine, Baylor College of Medicine, Methodist Hospital, and Renal Section, Veterans Affairs Medical Center, Houston, TX; and b Department of Medicine, Tufts University School of Medicine and Division of Nephrology, St. Elizabeth’s Medical Center, Boston, MA Manuscript received August 19, 2013 and accepted September 22, 2013
Abstract The pathogenic role of Naþ in primary hypertension is widely recognized but that of Kþ remains unappreciated. Yet, extensive evidence indicates that together, the body’s dominant cations constitute the chief environmental factor in the pathogenesis of hypertension and its cardiovascular sequelae. In this Review, we provide a synthesis of the determinants of Naþ retention and Kþ loss developing in the body as the Naþ-rich and Kþ-poor modern diet interacts with kidneys intrinsically poised to conserve Naþ and excrete Kþ; and the molecular pathways utilized by these disturbances in the central nervous system and the periphery to increase sympathetic tone and vascular resistance, and establish hypertension. These fresh insights point to new directions for targeted pharmacotherapy of hypertension. The interdependency of Naþ and Kþ in the pathogenesis of hypertension indicates that Naþ restriction and increased Kþ intake are important strategies for the primary prevention and treatment of hypertension and its cardiovascular consequences. J Am Soc Hypertens 2014;8(3):203–213. Ó 2014 American Society of Hypertension. All rights reserved. Keywords: Sodium sensitivity; sympathetic activity; aldosterone; angiotensin II; endogenous ouabain; potassium channels; calcium signaling.
Introduction Contrary to isolated populations eating natural foods, contemporary societies are plagued by age-related increases in blood pressure and a lifetime risk of hypertension exceeding 90%. Such dramatic departure from normotension nowadays appears to arise largely from changes in environmental factors.1 Epidemiologic observations coupled with animal and human studies converge into the conclusion that Kþ deficiency augments the morbid impact of Naþ excess on the pathogenesis of hypertension and associated cardiovascular complications.2–5 Conversely, Kþ supplementation of animals or humans maintained on high Naþ diets decreases blood pressure, and reduces cardiovascular and renal No financial support has been provided for this article. The authors declare no conflicts of interest. *Corresponding author: Nicolaos E. Madias, MD, Department of Medicine, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. Tel.: 617-562-7502; fax: 617-562-7797. E-mail: [email protected]
injury.6–9 Indeed, in some studies, the vascular protection provided by Kþ was shown to be independent of its blood pressure-lowering effects.10 Several years ago, we juxtaposed the evidence implicating Naþ in the pathogenesis of hypertension with that for Kþ.1 On the strength of that analysis, we proposed that the chief environmental factor in the pathogenesis of primary hypertension and the associated cardiovascular disease is not an isolated surfeit of Naþ or deficit of Kþ in the body, but the combination of the two derangements. The root cause is the interplay between the modern diet–rich in Naþ and poor in Kþ–and nonadapted kidneys that are intrinsically poised to conserve Naþ and excrete Kþ. Since then, the proposal for a shared primacy of Naþ and þ K in the pathogenesis of primary hypertension and cardiovascular risk has been bolstered by novel insights on the manifold interactions of these electrolytes. Here we provide a synthesis of the determinants of Naþ retention and Kþ loss prevailing in consumers of the modern diet, and the molecular pathways utilized by these disturbances in the central nervous system and the periphery to increase vascular resistance and establish hypertension.
1933-1711/$ - see front matter Ó 2014 American Society of Hypertension. All rights reserved. http://dx.doi.org/10.1016/j.jash.2013.09.003
204
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
NaD Sensitivity and its Blockade by KD Linking Naþ intake to hypertension conceptualized Naþ sensitivity that refers to the blood pressure responsiveness to a short-term, sizable NaCl load or loss.11–13 It is observed in approximately one-third of normotensives, serving as a harbinger of hypertension, and two-thirds of hypertensives. Sodium-sensitive individuals consuming a high-Naþ diet appear to retain more Naþ than Naþ-resistant subjects, indicating impaired renal Naþ excretion. Declining glomerular filtration rate, aging, African descent, and obesity are associated with Naþ sensitivity. Dietary Kþ exerts a powerful, dose-dependent inhibitory effect on Naþ sensitivity. Strikingly, an increase in dietary Kþ can even abolish Naþ sensitivity in both normotensives and hypertensives.1,14,15 Blockade of Naþ sensitivity by Kþ reflects in part its natriuretic action. Sodium resistance in normotensives does not guarantee lasting normotension considering that over time, the vast majority of humans consuming a Naþ-rich and Kþ-poor diet develop hypertension.
Linkage of the Modern Diet to Hypertension Excess Naþ and a Kþ deficit in the body have been detected in hypertensive animals and humans.1,16–18 However, such reports have not been entirely consistent. Negative studies reflect several factors, including methodologic shortcomings, the altered distribution of Naþ and Kþ among tissues (eg, increased Naþ in vascular wall but reduced plasma Naþ owing to plasma-volume contraction), and the relatively modest Naþ gain and Kþ deficit in primary hypertension. Despite the early presence of hypertension-promoting mechanisms, primary hypertension might not develop until late in life. Remarkably, this occurs even in monogenic defects in Naþ excretion. Absent dietary adjustments, the delayed development of hypertension can reflect decline in renal function, diet and genome interactions (ie, epigenetic influences), and override of compensatory mechanisms with aging.19 The pressor effects of Naþ excess depend on the associated counter anion, as only NaCl, the usual form consumed, causes hypertension. As indicated by insufficient weight gain, the Naþ surplus must not obligate equivalent fluid retention. Retained Naþ replaces, in part, intracellular Kþ, which is then excreted as KCl in the urine. This Naþ-forKþ exchange is well documented in vascular smooth muscle (VSM) and skeletal muscle, most prominently in mineralocorticoid hypertension. Retained Naþ is also stored extracellularly in skin, cartilage, and bone. Mobilization of Naþ from extracellular stores can increase its level in body fluids and elicit a pressor response.20 The linkage of the Naþ-rich and Kþ-poor modern diet with the pathogenesis of hypertension is strongly supported by the blood pressure-lowering effects of diets with reverse cationic composition, that is, low in Naþ and high in Kþ.21–24
NaD Retention and KD Loss in Hypertension: Role of the Kidney In primary hypertension, Naþ-retentive kidneys in concert with a Naþ-rich diet generate Naþ excess. Concomitantly, ineffective Kþ conservation (renal and enteral) coupled with a Kþ-poor diet engenders Kþ deficit. Stimulation of Naþ transporters and the Naþ pump (Naþ, KþATPase) located at the luminal and basolateral membrane of the renal tubules, respectively, is key to these electrolyte deviations.1 Increased levels of sympathetic activity and angiotensin II as well as Kþ depletion stimulate Naþ reabsorption in the proximal tubule and the thick ascending limb of Henle’s loop by enhancing the activity of the luminal Naþ-Hþ exchanger.1,25 The Naþ-Clˉ cotransporter in the distal tubule, the epithelial Naþ channel (ENaC) in the collecting duct, and the ubiquitous Naþ pump are stimulated by the aldosterone excess of primary hypertension causing Naþ retention and Kþ loss.26 Angiotensin II, independent of aldosterone, increases ENaC activity in the distal nephron. Experimental models of Naþ-sensitive hypertension exhibit enhanced expression of ENaC in the renal medulla.1,27 The clinical effectiveness of thiazide diuretics in the management of hypertension attests to the pathogenic importance of Naþ surfeit. Importantly, the resulting hypokalemia discounts the antihypertensive effect of thiazides.28 Coadministration of Kþ-sparing diuretics augments the antihypertensive effect of thiazide diuretics both by inhibiting ENaC activity and most likely, by maintaining a higher serum Kþ level.29,30 Mutations and polymorphisms in the a-adducin gene also stimulate the Naþ pump. Contrary to their short-term actions, the long-term effects of Kþ depletion and increased levels of endogenous ouabain (EO) are to stimulate the activity and expression of the renal Naþ pump, thereby promoting Naþ retention. The WNK (With No lysine Kinase) proteins participate in the molecular pathways that control sodium and potassium excretion, and therefore blood pressure.31 Impaired release of corin, a serine protease produced by the cardiomyocyte that cleaves and activates atrial natriuretic peptide, causes Naþ retention. Corin-deficient mice exhibit impaired natriuresis, hypertension, and cardiac hypertrophy.32,33 Polymorphisms in the corin gene are associated with hypertension and heart failure in African Americans. Genetic factors might account for approximately onethird of blood-pressure variability in the general population and involve a growing number of mutations and polymorphisms.34 Variance in genes encoding proteins that alter renal Naþ and Kþ transport, vascular-wall reactivity, sympathetic activity, and other processes, might predispose humans to hypertension or, alternatively, prevent or delay its development35–41 (Table 1).
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
205
Table 1 Genetic factors altering both Naþ and Kþ transport and blood pressure Mutated Protein
Condition
Functional Effect
Effect on Blood Pressure
ENaC WNK1, WNK4 NCCT
Liddle syndrome Gordon syndrome Primary hypertension
[ [ [
a-adducin
Primary hypertension
ENaC
Pseudohypoaldosteronism type 1 (recessive) Bartter syndrome type 1 (homozygous) General population (heterozygous carriers) Bartter syndrome type 2 (homozygous) General population (heterozygous carriers) Bartter syndrome type 3 Bartter syndrome type 4 Gitelman syndrome (homozygous) General population (heterozygous carriers) SeSAME syndrome General population
Overactive ENaC in renal CD Overactive NCCT in renal DCT Increased expression of NCCT in renal DCT Overactive renal Naþ pump. Increase in Naþ sensitivity Hypoactive ENaC in renal CD
NKCC2 NKCC2 Kþ channel ROMK Kþ channel ROMK Chloride channel CIC-Kb Barttin NCCT NCCT Kþ channel (Kir4.1) Ca2þ-sensing receptor Angiotensinogen Angiotensin-converting enzyme Angiotensin receptor 1 Kþ channel (KCNJ5) 11 b-hydroxylase 11a-hydroxylase/17,20-lyase Aldosterone synthase 11a-hydroxylase 11 b-hydroxysteroid dehydrogenase 11 b-hydroxysteroid dehydrogenase MR Natriuretic peptide Corin MR
Primary hypertension Primary hypertension Systolic hypertension Adrenal adenoma and bilateral adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia Glucocorticoid remediable aldosteronism Apparent mineralocorticoid excess syndrome Primary hypertension Hypertension exacerbated in pregnancy Primary hypertension African-American population Pseudohypoaldosteronism type 1 (dominant)
[ Y
Hypoactive NKCC2 in renal TALH Modestly hypoactive NKCC2 in renal TALH Hypoactive NKCC2 in renal TALH Modestly hypoactive NKCC2 in renal TALH Hypoactive NKCC2 in renal TALH Hypoactive NKCC2 in renal TALH Hypoactive NCCT in renal DCT Modestly hypoactive NCCT in renal DCT Hypoactive Naþ pump in distal nephron Inhibition of ROMK and hypoactive NKCC2 in renal TALH Stimulation of RAS Stimulation or depression of RAS Stimulation of RAS Excessive mineralocorticoid activity
Y Y
Excessive mineralocorticoid activity Excessive mineralocorticoid activity ACTH-dependent, excessive mineralocorticoid activity Activation of MR by cortisol
[ [ [
Modest activation of MR by cortisol
[
Excessive mineralocorticoid activity Hypoactive natriuretic peptide Hypoactive natriuretic peptide Modestly hypoactive ENaC in renal CD
[ [ [ Y
Y Y Y Y Y Y Y Y [ [Y [ [
[
CD, collecting duct; DCT, distal convoluted tubule; ENaC, epithelial sodium channel; MR, mineralocorticoid receptor; NCCT, sodiumchloride cotransporter; NKCC2, sodium-potassium-2 chloride cotransporter; ROMK, renal outer medullary Kþ channel; TALH, thick ascending limb of Henle’s loop; WNK, with no lysine Kinase. Upward arrows denote increases, and downward arrows denote decreases.
Increased Sympathetic Tone Dietary Naþ modulates adrenergic mechanisms resulting in changes in plasma catecholamines and adrenergic neuronal function.42 Alterations in Naþ intake affect inversely plasma catecholamines via exclusive adjustment of adrenalgland secretory activity. In stark contrast, adrenergic neuronal function varies directly with Naþ intake and evokes
directional changes in vascular resistance.43,44 The increased sympathetic tone caused by a Naþ-rich diet reflects activation of sensors surrounding the brain’s third ventricle. Alterations in dietary Kþ also impact sympathetic activity.45 Potassium administration to patients with primary aldosteronism, a condition of severe Kþ depletion, depresses sympathetic activity, corrects baroreceptor hyporesponsiveness, and reduces blood pressure, despite augmenting
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
206
aldosterone secretion. Conversely, Kþ depletion increases sympathetic tone and promotes vasoconstriction. Similar to Naþ, the effects of Kþ on sympathetic activity are mediated centrally. The Naþ-rich and Kþ-poor modern diet increases sympathetic tone owing to the converging effects of each of the resulting electrolyte deviations; as a consequence, peripheral vascular resistance increases. Yet, precise attribution of roles is obscured by the demonstration that in Kþ depletion, Naþ largely replaces the intracellular cationic deficit; conversely, Kþ replacement in Kþ-depleted subjects causes natriuresis and decreases intracellular Naþ. Potassiumdeficient diet appears to impact sympathetic tone more overtly in young hypertensives.
Altered NaD and KD Homeostasis and the ReninAngiotensin System (RAS) þ
animals. Highlighting the interplay between Kþ and Naþ, Kþ supplementation virtually prevents the blood-pressure rise of mineralocorticoids plus Naþ.45 As assessed in vascular rings, aldosterone acts both in endothelium and VSM.54–56 In endothelium, it elicits vasodilation via mineralocorticoid-receptor (MR) activation and nitric-oxide generation. By contrast, in endotheliumdenuded preparation, aldosterone causes vasoconstriction. In normal animals and humans, the dilatory and constrictor effects appear to be balanced. Conversely, in diseases characterized by endothelial dysfunction (eg, hypertension), aldosterone might largely exert constrictor effects, promoting vascular damage and organ failure.57,58 Injury to vascular endothelium initiated by body Naþ surfeit and Kþ deficit might be critical to the vasculotoxic effects of aldosterone in primary hypertension.
Endogenous Ouabain (EO)
þ
Altered Na and K stores can each impact the classic (circulating) and the local (tissue) RAS.46 Remarkably, the effects of either electrolyte abnormality on the two RAS components can be divergent. Thus, Naþ excess inhibits the classic RAS but stimulates the brain RAS; conversely, Kþ loading stimulates aldosterone secretion but inhibits the brain RAS.47–49 Angiotensin II acting through receptors in the kidney, brain, heart, vascular wall, and adrenals mediates the actions of RAS. Activation of RAS was critical to survival of our human ancestors maintained on a Naþ-poor and Kþ-rich natural diet. The reverse electrolyte composition of the modern diet would be expected to suppress the classic RAS. Far from it, RAS is fundamental to the pathogenesis of hypertension by increasing sympathetic tone, impairing natriuresis, and mediating direct vasoconstriction. The remarkable efficacy of angiotensin convertingenzyme inhibitors and angiotensin-receptor blockers in primary hypertension attests to the pathogenic importance of RAS.
Effects of Aldosterone Mineralocorticoid hypertension exemplifies Naþdependent hypertension: Naþ restriction obviates hypertension and the associated vascular and tissue damage.50–52 Indeed, the Yanomamo Indians, an isolated population of no-Naþ and high-Kþ intake, exhibit low blood pressure, virtual absence of age-related increases in blood pressure, and small cardiovascular risk, despite aldosterone levels dwarfing those of primary aldosteronism. Mineralocorticoids mediate hypertension by facilitating Naþ entry into the cells of many tissues, particularly the brain, via activation and recruitment of ENaCs.53 The Naþ surfeit and Kþ deficit resulting from co-administration of mineralocorticoids and Naþ largely account for the extensive vascular and tissue damage observed in experimental
Along with aldosterone, EO offers effective defense against extracellular-volume depletion and hypotension, a constant threat to humans on low-Naþ diet, since the two hormones induce Naþ retention and vasoconstriction.59 Proper adaptation to the high-Naþ and low-Kþ modern diet should have completely suppressed the adrenal secretion of both aldosterone and EO.26,60 However, high levels of both hormones are encountered in many hypertensives consuming the modern diet.26,61,62 EO inhibits the Naþ pump triggering activation of the Naþ-Ca2þ exchanger (NCX1); the resulting rise in cytosolic [Ca2þ] is responsible for the physiological effects of EO on brain, heart, and vascular wall.62,63 Were EO also to inhibit the renal Naþ pump, it would promote natriuresis. Yet, EO administration to normal subjects does not increase Naþ excretion. Rodents infused with ouabain develop Naþ retention and hypertension. In humans, the FENa was lower in the higher quartiles of circulating EO.59,60 Contrasting with other tissues, the long-term action of EO on the renal Naþ pump appears to be stimulatory.60,61 Neuronal Naþ pumps have various levels of affinity to circulating and locally produced ouabain; the a2 variant of Naþ pump participates in ouabain-induced hypertension in rodents.62 EO inhibits the neuronal Naþ pump in the hypothalamus and other brain regions, which in turn activates the cerebral RAS; together, these changes trigger sympathetic stimulation, baroreceptor hyporesponsiveness, and hypertension.
Mechanisms of Blood-pressure Effects of NaD and KD Early Focus on Plasma-volume Expansion Decades ago, it was proposed that retention of Naþ and water by the kidney would increase plasma volume, venous return, and cardiac output, hence blood pressure. It was
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
further theorized that high cardiac output would soon give way to increased vascular resistance reflecting adaptation of organ blood flow to metabolic needs (total body autoregulation).64 This ‘‘kidney-fluid mechanism’’ hypothesis was widely embraced by the scientific community. Notwithstanding, no support for that hypothesis was offered by mineralocorticoid-Naþ hypertension in animals or humans, the prototypical form of Naþ-dependent hypertension. Cardiac output is not increased consistently, and increases in exchangeable Naþ and plasma [Naþ], and a sizable Kþ deficit are the leading determinants of the severity of hypertension.51,65 Furthermore, plasma volume is decreased, not increased, in patients with borderline or established primary hypertension. The volume-expansion hypothesis essentially ignored a wealth of data countering its framework and the burgeoning evidence for an important role of Kþ in hypertension. In short, the validity of the ‘‘kidney-fluid mechanism’’
207
hypothesis has been challenged and alternative mechanisms that account for the pathogenic role of both Naþ and Kþ have been identified.1,51,65,66
Role of the Central Nervous System Experimental studies have demonstrated that a variety of signals, including changes in plasma/cerebrospinal fluid (CSF) [Naþ] and [Kþ] as well as peripherally-derived hormones (aldosterone, EO, angiotensin II), are detected by the brain evoking blood-pressure responses.62,67–70 Initial processing of signals occurs in hypothalamic nuclei that then transmit information to the nucleus tractus solitarius (NTS). In turn, NTS integrates this information along with input from other brain areas and the periphery, and regulates sympathetic and parasympathetic tone (Figure 1). The blood-pressure responses largely reflect changes in peripheral vascular resistance.
Figure 1. Elements of the central nervous system involved in the effects of dietary Naþ and Kþ on blood pressure. The signals, sensors, integrative components, and effectors are illustrated. The nucleus tractus solitarius (NTS) in the brain stem processes input from the hypothalamus, other brain areas, and the periphery behaving as the switchboard that modulates the sympathetic and parasympathetic outflow to the heart and vascular wall. CSF, cerebrospinal fluid; DMN, dorsal motor nucleus; OVLT, organum vasculosum of the lamina terminalis; PON, preoptic nucleus; PVN, paraventricular nucleus; SFO, subfornical organ; SON, supraoptic nucleus.
208
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
Signals þ
A small increase in plasma and CSF [Na ] (1–3 mmol/L) caused by high dietary Naþ and the peripherally derived hormones constitute signals promoting a rise in blood pressure.71–73 A hypertensive response is also evoked by both hypokalemia and minor reductions in CSF [Kþ] (0.1–0.3 mmol/L). Low dietary Kþ causes hypokalemia but only small or undetectable decreases in CSF [Kþ]. The intracerebroventricular (ICV) infusion of aldosterone (at doses not eliciting systemic effects) decreases CSF [Kþ] and augments blood pressure; both events are prevented by the ICV co-administration of a mineralocorticoid antagonist, an ENaC blocker, or Kþ.74–76 Simulating the central effects of adrenal EO, the ICV infusion of EO acts as a signal that increases blood pressure, a response inhibited by the central infusion of Kþ.
Sensors The signals noted above are detected by sensors residing in the neuronal arrangement of the circumventricular
organs seated anteroventral to the third ventricle, that is, the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO). Animal studies have identified CSF-contacting neurons in these organs with somas located in the periventricular area or exposed to the lumen and projecting dendrites into the cavity; other neurons project their axons toward the ventricular lumen and have synapses on ependymal cells.77,78 The ICV-infusion studies suggest that the central sensors have a multifaceted nature that comprises the functions of ENaC, MR, angiotensin II receptor 1 (AT1R), Kþ sensor, and Naþ pump67,79–81 (Figure 2A). Increased expression of brain ENaC might participate in the pathogenesis of Liddle syndrome. The CSF-Kþ sensor has not been identified but might involve transient receptor protein channels (TRPC). The TRPCs are non-selective cation channels present in various brain regions, including the hypothalamic paraventricular nucleus (PVN); they sense changes in CSF-electrolyte composition and elicit sympathetic responses.79–83 Increases in CSF [Kþ] might activate TRPCS evoking sympathetic inhibition.
Figure 2. Molecular mechanisms implicated in the central-nervous-system regulation of blood pressure by dietary Naþ and Kþ. A, The signals generated by dietary Naþ and Kþ, and the molecular functions incorporated by the circumventricular sensors. B, The molecular pathways involved in translating Naþ surfeit in the body into increased sympathetic nerve activity and blood pressure, and Kþ feeding into decreased sympathetic activity and blood pressure. Upward arrows denote increases, and downward arrows denote decreases. Ang II, angiotensin II; AT1R, angiotensin receptor 1; ENaC, epithelial sodium channel; EO, endogenous ouabain; MR, mineralocorticoid receptor.
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
Pathways and Integration The neuron axons of the central sensors reach hypothalamic nuclei, including the preoptic nucleus (PON), the supraoptic nucleus (SON), and PVN (Figure 1). Additionally, the magnocellular neurons of the PVN project dendritic processes that reach the ependymal cells and the dendritic terminals of CSF-contacting cells.78,81 Thus, the neural network surrounding the third ventricle allows cross-talk between the CSF and the hypothalamus. Information regarding the electrolytic and hormonal composition of the plasma and CSF is recorded by the SON,
209
which projects efferent routes to neurosecretory areas of the hypothalamus, yielding altered synthesis and secretion of aldosterone, EO, and angiotensin II. Also, the brain sensors relay information to the PVN, with subsequent activation or deactivation of the brain RAS. Input reflecting these changes is communicated to the NTS, where further integration occurs and eventual translation into altered sympathetic activity60,67,79,82,83 (Figure 1). Figure 2B highlights the current understanding of the central molecular pathways involved in translating a Naþ surfeit in the body into a pressor response. A similar
Table 2 Impact of a low- or high-Kþ intake on the blood-pressure effects and cardiovascular risk of a high-Naþ diet* High-Naþ Diet Low-Kþ intake General Aggravation of primary and mineralocorticoid hypertension Increase in Naþ sensitivity Promotion of positive Naþ balance (decreased natriuresis) Partial intracellular replacement of lost Kþ by retained Naþ Stimulation of circulating and tissue RAS Depression of baroreceptor sensitivity Organ-specific Kidney Augmentation of renin release (direct action) Increase in renal vascular resistance Reduction in glomerular filtration rate Promotion of kidney damage: glomerular and arteriolar lesions Promotion of inflammatory pathways of fibrosis Brain Inhibition of neuronal Naþ pump Increase in sympathetic nerve activity Augmentation of central effects of aldosterone Augmentation of central effects of EO Increase risk of cerebrovascular accident Heart and circulatory beds Promotion of cardiac hypertrophy and fibrosis Vasoconstriction (cerebral, coronary, renal, mesenteric, and limb vascular beds) Reduction in aortic compliance Promotion of atherogenesis Vascular wall Inhibition of Naþ pump Depression of inward rectifier Kþ channels (KIR channels) and Kþ ATP channels Inhibition of endothelium-dependent vasodilation Stimulation of vascular-smooth-muscle proliferation Augmentation of the pressor response to angiotensin II Adrenal cortex Inhibition of aldosterone secretion (direct action) Stimulation of EO secretion and action EO, endogenous ouabain; RAS, renin-angiotensin system. * Listed effects are derived from animal and human studies.
High-Kþ intake Prevention/amelioration of primary and mineralocorticoid hypertension Reduction in need for antihypertensive medication Inhibition of Naþ sensitivity Promotion of negative Naþ balance (increased natriuresis) Displacement of intracellular Naþ by retained Kþ Suppression of circulating and tissue RAS Restoration of baroreceptor sensitivity
Suppression of renin release (direct action) Reduction in renal vascular resistance Increase in glomerular filtration rate Protection from kidney damage Suppression of inflammatory pathways of fibrosis Stimulation of neuronal Naþ pump Depression of sympathetic nerve activity Suppression of central effects of aldosterone Depression of central effects of EO Protection from cerebrovascular accident Protection from cardiac hypertrophy and fibrosis Vasodilation (cerebral, coronary, renal, mesenteric, and limb vascular beds) Enhancement of aortic compliance Antiatherogenic effects Stimulation of Naþ pump Activation of inward rectifier Kþ channels (KIR channels) and Kþ ATP channels Promotion of endothelium-dependent vasodilation Inhibition of vascular-smooth-muscle proliferation Decrease in the pressor response to angiotensin II Stimulation of aldosterone secretion (direct action) Inhibition of EO secretion and action
210
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
cascade of steps, but with opposite molecular effects, is traversed in evoking the depressor response to Kþ supplementation69,74,75 (Figure 2B). The release and actions of central EO are inhibited by Kþ feeding. Remarkably, long-term ICV infusion of KCl prevents development of deoycorticosterone-Naþ hypertension.74 Conversely, Kþ depletion stimulates the brain RAS, and raises sympathetic activity and blood pressure.
Role of the Periphery Beyond generating the Naþ excess and Kþ deficit in hypertension, the kidney and the adrenal cortex provide input to the central modulation of sympathetic activity, and contribute directly to increasing vascular resistance via the actions of circulating RAS, and adrenal aldosterone and EO. The vasoconstrictor actions of EO reflect both stimulation of VSM and inhibition of endothelial vasodilation. Sodium retention and Kþ depletion have direct effects on the arterial-wall endothelium and VSM, culminating in vasoconstriction.84–87 Vascular endothelial cells exhibit high sensitivity to changes in the extracellular [Naþ] and [Kþ].57,58,88 Within minutes from an increase in extracellular [Naþ], cultured vascular endothelial cells stiffen, a response strongly dependent on aldosterone; increasing extracellular [Kþ] decreases endothelial stiffness. Additionally, Naþ retention decreases the endothelial synthesis of nitric oxide and increases the plasma level of asymmetric dimethyl Larginine, an endogenous inhibitor of nitric acid production.89–92 Sodium restriction and a high-Kþ diet exert the opposite effects. Endothelium-dependent vasodilation is defective in primary hypertension. Experimental Kþ depletion inhibits endothelium-dependent vasodilation.91 The VSM Naþ pump possesses activation sites with high affinity for extracellular [Kþ]; hypokalemia depresses the Naþ pump causing membrane depolarization and vasoconstriction, whereas hyperkalemia has the opposite effects. A deficit of body Kþ or hypokalemia inhibits Kþ channels causing membrane depolarization and vasoconstriction. Downregulation of large conductance Kþ channels in VSM contributes to the increased vascular tone in primary hypertension.
Perspective Current evidence indicates that the pathogenesis of hypertension is critically dependent on brain responses to Naþ surfeit and Kþ deficit. Changes in plasma/CSF [Naþ] and [Kþ], complemented by the circulating levels of angiotensin II, aldosterone, and EO (that are conditioned by the altered cationic homeostasis), are detected by circumventricular sensors that relay input to hypothalamic nuclei. The latter evoke responses to the NTS in the brain stem culminating in increased sympathetic activity and
hypertension. Peripheral effects on the vascular wall of the Naþ surfeit and Kþ deficit themselves as well as the circulating RAS, aldosterone, and EO contribute to the hypertension phenotype. These fresh insights point to new avenues for targeted pharmacotherapy of hypertension.1,60 The body’s dominant cations, Naþ and Kþ, are intertwined regarding dietary intake, body stores, physiological roles, and vascular effects. This interdependency points to natural means for preventing and treating hypertension and its cardiovascular sequelae. Age-related increases in blood pressure and primary hypertension are largely observed in societies consuming >100 mmol of Naþ per day. Efforts at decreasing daily consumption of Naþ is an important strategy toward this goal.1,22 The totality of the experimental and clinical evidence indicates that Kþ is a powerful, natural antidote for the pernicious effects of Naþ excess and its accomplices, namely angiotensin II, aldosterone, and EO, on blood pressure and cardiovascular risk. Table 2 juxtaposes the adverse effects of Kþ depletion with the salutary effects of Kþ administration on blood pressure and cardiovascular events.1,87,93 Therefore, a second strategy for the primary prevention and treatment of hypertension is to increase Kþ intake.22 This strategy is equally important as Naþ restriction and trumps it in terms of ease of implementation. Acknowledgments The authors wish to acknowledge Geri Tasby for her skillful assistance in the preparation of the manuscript.
References 1. Adrogue HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007;356: 1966–78. 2. Langford HG, Watson RL. Electrolytes and hypertension. In: Paul O, editor. Epidemiology and control of hypertension. New York: Stratton; 1975. P. 119–30. 3. Luft FC, Weinberger MH. Sodium intake and essential hypertension. Hypertension 1982;4(sup III):III-14–9. 4. Kirkendall AM, Connor WE, Abboud F, Rastogi SP, Anderson TA, Fry M. The effect of dietary sodium chloride on blood pressure, body fluids, electrolytes, renal function, and serum lipids of normotensive man. J Lab Clin Med 1976;87:411–34. 5. Whelton PK. Potassium and blood pressure. In: Izzo JL Jr, Black HR, editors. Hypertension primer. 3rd ed. Dallas: American Heart Association/Council on High Blood Pressure Research; 2003. P. 280–2. 6. He FJ, MacGregor GA. Beneficial effects of potassium. BMJ 2001;323:497–501. 7. Intersalt Cooperative Research Group. Intersalt: an international study of electrolyte excretion and blood
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
pressure: results for 24-hour urinary sodium and potassium excretion. BMJ 1988;297:319–28. 8. Meneely GR, Ball COT, Youmans JB. Chronic sodium chloride toxity: the protective effect of added potassium chloride. Ann Intern Med 1957;47:263–73. 9. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approches to Stop Hypertension (DASH) diet. N Engl J Med 2001;344:3–10. 10. Tobian L, Lange J, Ulm K, Wold L, Iwai J. Potassium reduces cerebral hemorrhage and death rate in hypertensive rats, even when blood pressure is not lowered. Hypertension 1985;7:1110–4. 11. Simpson FO. Blood pressure and sodium intake. Handbook of Hypertension, Vol 20: Epidemiology of Hypertension. C.J. Bulpitt, ed. Amsterdam: Elsevier Science B.V., 2000; 274–295. 12. Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension 1996;27:481–90. 13. Richardson SI, Freedman BI, Ellison DH, Rodriguez CJ. Salt sensitivity: a review with focus on non-Hispanic blacks and Hispanics. J Am Soc Hypertens 2013;7:170–9. 14. Morris RC Jr, Sebastian A, Forman A, Tanaka M, Schmidlin O. Normotensive salt sensitivity: effects of race and dietary potassium. Hypertension 1999;33:18–23. 15. Bulpitt CJ. Blood pressure and potassium consumption. Handbook of Hypertension, Vol. 20: Epidemiology of Hypertension. C.J. Bulpitt, ed. Amsterdam: Elsevier Science B.V., 2000;296–312. 16. Hansen J. Blood volume and exchangeable sodium in essential hypertension. Acta Med Scand 1968;184: 517–23. 17. Lever AF, Beretta-Piccoli C, Brown JJ, Davies DL, Fraser R, Robertson JIS. Sodium and potassium in essential hypertension. Br Med J (Clin Res Ed) 1981; 283:463–8. 18. Kopp C, Linz P, Wachsmuth L, Dahlmann A, Horbach T, Sch€ ofl C, et al. Na magnetic resonance imaging of tissue sodium. Hypertension 2012;59:167–72. 19. Millis RM. Epigenetics and hypertension. Curr Hyperten Rep 2011;13:21–8. 20. Bhave G, Neilson EG. Body fluid dynamics: Back to the future. J Am Soc Nephrol 2011;22:2166–81. 21. Cook NR, Obarzanek E, Cutler JA, Buring JE, Rexrode KM, Kumanyika SK, et al. Joint effects of sodium and potassium intake on subsequent cardiovascular disease. The Trials of Hypertension Prevention Follow-up Study. Arch Intern Med 2009;169:32–40. 22. Adrogue HJ, Madias NE. Shared primacy of sodium and potassium on cardiovascular risk. Am J Kidney Dis 2009;54:598–601. 23. O’Donnell MJ, Salim Y, Mente A, Gao P, Mann JF, Teo K, et al. Urinary sodium and potassium excretion and risk of cardiovascular events. JAMA 2011;306:2229–38.
211
24. Yang Q, Liu T, Kuklina EV, Flanders WD, Hong Y, Gillespie C, et al. Sodium and potassium intake and mortality among US adults. Prospective data from the third National Health and Nutrition Examination Survey. Arch Intern Med 2011;171:1183–91. 25. Liu J, Yan Y, Liu L, Xie Z, Malhotra D, Joe B, et al. Impairment of Na/K-ATPase signaling in renal proximal tubule contributes to Dahl salt-sensitive hypertension. J Biol Chem 2011;286:22806–13. 26. Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N, et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med 2004;351:33–41. 27. Amin MS, Reza E, El-Shahat E, Wang HW, Tesson F, Leenen FH. Enhanced expression of epithelial sodium channels in the renal medulla of Dahl S rats. Can J Physiol Pharmacol 2011;89:159–68. 28. Kaplan NM, Carnegie A, Raskin P, Heller JA, Simmons M. Potassium supplementation in hypertensive patients with diuretic-induced hypokalemia. N Engl J Med 1985;312:746–9. 29. Pratt JH. Central role for ENaC in development of hypertension. J Am Soc Nephrol 2005;16:3154–9. 30. Ellison DH, Hoorn EJ, Schrier RW. Mechanisms of diuretic action. In: Coffman TM, Molitoris BA, Falk RJ, Neilson EG, Schrier RW, editors. Schrier’s Diseases of the Kidney. 9th Ed. Philadelphia: Lippincott Williams & Wilkins; 2013. P. 1906–37. 31. Hoorn EJ, Nelson JH, McCormick JA, Ellison DH. The WNK kinase network regulating sodium, potassium, and blood pressure. J Am Soc Nephrol 2011;22:605–14. 32. Wang W, Shen J, Cui Y, Jiang J, Chen S, Peng J, et al. Impaired sodium excretion and salt-sensitive hypertension in corin-deficient mice. Kidney Int 2012;82:26–33. 33. Bouley R. Corin: a key protein of an adaptive renal mechanism to respond to salt variation? Kidney Int 2012;82:7–8. 34. Vehaskari VM. Heritable forms of hypertension. Pediatr Nephrol 2009;24:1929–37. 35. Choi M, Scholl UI, Yue P, Bj€orklund P, Zhao B, Nelson-Williams C, et al. Kþ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011;331:768–72. 36. Meneton P, Oh YS, Warnock DG. Genetic disorders of renal apical Naþ transporters. In: Dubose TD Jr, Hamm LL, editors. Acid-base and electrolyte disorders: a companion to Brenner & Rector’s The Kidney. Philadelphia: Elsevier Science (Saunders); 2002. P. 335–46. 37. Ji W, Foo JN, O’Roak BJ, Zhao H, Larson MG, Simon DB, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nature Genetics 2008;40:592–9. 38. Fang L, Li D, Welling PA. Hypertension resistance polymorphisms in ROMK (Kir1.1) alter channel
212
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
function by different mechanisms. Am J Physiol Renal Physiol 2010;299:F1359–64. Monette MY, Rinehart J, Lifton RP, Forbush B. Rare mutations in the human Na-K-Cl cotransporter (NKCC2) associated with lower blood pressure exhibit impaired processing and transport function. Am J Physiol Renal Physiol 2011;300:F840–7. Subramanya AR, Welling PA. Toward an understanding of hypertension resistance. Am J Physiol Renal Physiol 2011;300:F838–9. Acu~ na R, Martinez-de-la-Maza L, Ponce-Coria J, Vazquez N, Ortal-Vite P, Pacheco-Alvarez D, et al. Rare mutations in SLC12A1 and SLC12A3 protect against hypertension by reducing the activity of renal salt cotransporters. J Hypertens 2011;29:475–83. Vlahakos D, Gavras H. Central sympathetic stimulation produced by sline application into the nucleus tractus solitarii area of conscious rats. Neurosci Lett 1988; 92:335–40. de Leeuw PW, Birkenh€ager WH. Sodium and adrenergic mechanisms. Handbook of Hypertension, Vol 8: Pathophysiology of Hypertension - Regulatory Mechanisms. A. Zanchetti, R.C. Tarazi, eds. Amsterdam: Elsevier Science B.V., 1986;203–215. Schlaich MP, Lambert E, Kaye DM. Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine uptake, and angiotensin neuromodulation. Hypertension 2004;43:169–75. Sato Y, Fujita T. Suppression of renal sympathetic activity with potassium supplement in DOCA-salt rats. Jpn Heart J 1984;25:253–61. Crowley SD, Gurley SB, Oliverio MI, Pazmino AK, Griffiths R, Flannery PJ, et al. Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. J Clin Invest 2005;115:1092–9. Ferrario CM, Ueno Y, Diz DI, Barnes KL. The reninangiotensin system: physiological actions on the central nervous system. Handbook of Hypertension, Vol 8: Pathophysiology of Hypertension - Regulatory Mechanisms. A. Zanchetti, R.C. Tarazi, eds. Amsterdam: Elsevier Science B.V., 1986;431–454. Huang BS, Zheng H, Tan J, Patel KP, Leenen FHH. Regulation of hypothalamic renin-angiotensin system and oxidative stress by aldosterone. Exp Physiol 2011;96:1028–38. Huang BS, Cheung WJ, Wang H, Tan J, White RA, Leenen FHH. Activation of brain renin-angiotensinaldosterone system by central sodium in Wistar rats. Am J Physiol Heart Circ Physiol 2006;291: H1109–17. Wang Q, Clement S, Gabbiana G, Horisberger JD, Burnier M, Rossier BC, et al. Chronic hyperaldosteronism in a transgenic mouse model fails to induce cardiac remodeling and fibrosis under a normal-salt diet. Am J Physiol Renal Physiol 2004;286:F1178–84.
51. Conway J. Hemodynamics in mineralocorticoid hypertension. Handbook of Hypertension, Vol 7: Pathophysiology of Hypertension-Cardiovascular Aspects. A. Zanchetti, R.C. Tarazi, eds. Amsterdam: Elsevier Science B.V., 1986;217–224. 52. Gomez-Sanchez EP. Central mineralocorticoid receptors and cardiovascular disease. In: Koch CA, Chrousos GP, editors. Endocrine Hypertension: Underlying Mechanisms and Therapy. Contemporary Endocrinology. New York: Springer New York; 2013. P. 289–309. 53. Funder JW. Minireview: aldosterone and mineralocorticoid receptors: past, present, and future. Endocrinology 2010;151:5098–102. 54. Kusche-Vihrog K, Callis C, Fels J, Oberleithner H. The epithelial sodium channel (ENaC): Mediator of the aldosterone response in the vascular endothelium? Steroids 2010;75:544–9. 55. Nguyen Dinh Cat A, Griol-Charhbili V, Loufrani L, Labat C, Benjamin L, Farman N, et al. The endothelial mineralocorticoid receptor regulates vasoconstrictor tone and blood pressure. FASEB J 2010;24:2454–63. 56. Gros R, Ding Q, Armstrong S, O’Neil C, Pickering JG, Feldman RD. Rapid effects of aldosterone on clonal human vascular smooth muscle cells. Am J Physiol Cell Physiol 2007;292:C788–94. 57. Adler GK, Williams GH. Aldosterone – villain or protector? Hypertension 2007;50:31–2. 58. Ritz E, Tomaschitz A. Aldosterone, a vasculotoxic agent – novel functions for an old hormone. Nephrol Dial Transplant 2009;24:2302–5. 59. Manunta P, Messaggio E, Casamassima N, Gatti G, Carpini SD, Zagato L, et al. Endogenous ouabain in renal Naþ handling and related diseases. Biochimica et Biophysica Acta 2010;1802:1214–8. 60. Manunta P, Hamlyn JM, Simonini M, Messaggio E, Lanzani C, Bracale M, et al. Endogenous ouabain and the renin-angiotensin-aldosterone system: distinct effects on Na handling and blood pressure in human hypertension. J Hypertens 2011;29:349–56. 61. Hamlyn JM, Manunta P. Endogenous Ouabain: A link between sodium intake and hypertension. Curr Hypertens Rep 2011;13:14–20. 62. Blaustein MP, Leenen FHH, Chen L, Golovina VA, Hamlyn JM, Pallone TL, et al. How NaCl raises blood pressure: a new paradigm for the pathogenesis of saltdependent hypertension. Am J Physiol Heart Circ Physiol 2012;302:H1031–49. 63. Iwamoto T. Vascular Naþ/Ca2þ exchanger: implications for the pathogenesis and therapy of saltdependent hypertension. Am J Physiol Regul Integr Comp Physiol 2006;290:R536–45. 64. Guyton AC. Blood pressure control - special role of the kidneys and body fluids. Science 1991;252:1813–6. 65. Gavras I, Gavras H. ‘‘Volume-expanded’’ hypertension: the effect of fluid overload and the role of the
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
66.
67.
68.
69.
70.
71.
72.
73. 74.
75.
76.
77.
78.
79.
sympathetic nervous system in salt-dependent hypertension. J Hypertens 2012;30:655–9. Villamil MF, Amorena C, Ponce-Hornos J, M€ uller A, Taquini AC. Role of extracellular volume expansion in the development of DOC-salt hypertension in the rat. Hypertension 1982;4:620–4. Huang BS, Amin S, Leenen FHH. The central role of the brain in salt-sensitive hypertension. Curr Opin Cardiol 2006;21:295–304. Shah J, Jandhyala BS. Studies on the role(s) of cerebrospinal fluid osmolality and chloride ion in the centrally mediated pressor responses of sodium chloride. Clin Exp Hypertens A 1991;13:297–312. Shah J, Jandhyala BS. Role of Naþ, Kþ-ATPase in the centrally mediated hypotensive effects of potassium in anaesthetized rats. J Hypertens 1991;9: 167–70. Sun Y, Zhang J, Zhao D, Wang QS, Gu YC, Ma HP, et al. Role of the epithelial sodium channel in saltsensitive hypertension. Acta Pharmacologica Sinica 2011;32:789–97. He FJ, Markandu ND, Sagnella GA, de Wardener HE, MacGregor GA. Plasma sodium, ignored and underestimated. Hypertension 2005;45:98–102. Suckling RJ, He FJ, Markandu ND, MacGregor GA. Dietary salt influences postprandial plasma sodium concentration and systolic blood pressure. Kidney Int 2012;81:407–11. Oberleithner H, de Wardener HE. Sodium: a wolf in sheep’s clothing. Blood Purif 2011;31:82–5. Klarr SA, Keep RF, Betz AL. Chronic central potassium infusion prevents deoxycorticosterone-salt hypertension in rats. Am J Physiol 1995;268: H646–52. Atarashi K, Matsuoka H, Takagi M, Yamada K, Hirata Y, Hayakawa H, et al. Effects of intracerebroventricular infusion of aldosterone on blood pressure and sodium and potassium concentrations in cerebral spinal fluid in rats. Clin Exp Hypertens A 1988;10: 317–22. Gomez-Sanchez EP, Gomez-Sanchez CE. Effect of central amiloride infusion on mineralocorticoid hypertension. Am J Physiol 1994;267:E754–8. Vigh-Teichmann I, Vigh B. The system of cerebrospinal fluid-contacting neurons. Arch Histol Jpn 1983; 46:427–68. Korf HW, Viglietti-Panzica C, Panzica GC. A golgi study on the cerebrospinal fluid (CSF)-contacting neurons in the paraventricular nucleus of the Pekin duck. Cell Tissue Res 1983;288:149–63. Blaustein MP, Hamlyn JM. Signaling mechanisms that link salt retention to hypertension: Endogenous ouabain, the Naþ pump, the Naþ/Ca2þ exchanger and TRPC proteins. Biochimica et Biophysica Acta 2010; 1802:1219–29.
213
80. Ciura S, Liedtke W, Bourque CW. Hypertonicity sensing in organum vasculosum lamina terminalis neurons: a mechanical process involving TRPV1 but not TRPV4. J Neurosci 2011;31:14669–76. 81. Gabor A, Leenen FHH. Mechanisms in the PVN mediating local and central sodium-induced hypertension in Wistar rats. Am J Physiol Regul Integr Comp Physiol 2009;296:R618–30. 82. Takahashi H, Yoshika M, Komiyama Y, Nishimura M. The central mechanism underlying hypertension: a review of the roles of sodium ions, epithelial sodium channels, the renin-angiotensin-aldosterone system, oxidative stress and endogenous digitalis in the brain. Hypertens Res 2011;34:1147–60. 83. Leenen FH. The central role of the brain aldosterone‘‘ouabain’’ pathway in salt-sensitive hypertension. Biochimica et Biophysica Acta 2010;1802:1132–9. 84. Dolson GM, Ellis KJ, Bernardo MV, Prakash R, Adrogue HJ. Acute decreases in serum potassium augment blood pressure. Am J Kidney Dis 1995;26:321–6. 85. Dolson GM, Adrogue HJ. Low dialysate [Kþ] decreases efficiency of hemodialysis and increases urea rebound. J Am Soc Nephrol 1998;9:2124–8. 86. Dolson GM, Wesson DE, Adrogue HJ. Vascular relaxation probably mediates the antihypertensive effect of a high potassium diet. A role for enhanced vascular Na-K ATPase activity. J Hypertens 1995;13(12 Pt 1):1433–9. 87. McCabe RD, Young DB. Potassium inhibits cultured vascular smooth muscle cell proliferation. Am J Hypertens 1994;7(4 Pt 1):346–50. 88. Oberleithner H, Callies C, Kusche-Vihrog K, Schillers H, Shahin V, Riethm€uller C, et al. Potassium softens vascular endothelium and increases nitric oxide release. Proc Nat Acad Sci USA 2009;106:2829–34. 89. Panza JA, Quyyumi AA, Brush JB Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990;323:22–7. 90. Fujiwara N, Osanai T, Kamada T, Katoh T, Takahashi K, Okumura K. Study on the relationship between plasma nitrite and nitrate level and salt sensitivity in human hypertension: modulation of nitrite oxide synthesis by salt intake. Circulation 2000;101:856–61. 91. Haddy FJ, Vanhoutte PM, Feletou M. Role of potassium in regulating blood flow and blood pressure. Am J Physiol Regul Integr Comp Physiol 2006;290:R546–52. 92. Amberg GC, Bonev AD, Rossow CF, Nelson MT, Santana LF. Modulation of the molecular composition of large conductance, Caþþ activated Kþ channels in vascular smooth muscle during hypertension. J Clin Invest 2003;112:717–24. 93. Wang W, Soltero L, Zhang P, Huang XR, Lan HY, Adrogue HJ. Renal inflammation is modulated by potassium in chronic kidney disease: possible role of Smad7. Am J Physiol Renal Physiol 2007;293:F1123–30.
Review Article
Sodium surfeit and potassium deficit: Keys to the pathogenesis of hypertension Horacio J. Adrogue, MDa and Nicolaos E. Madias, MDb,* a
Department of Medicine, Baylor College of Medicine, Methodist Hospital, and Renal Section, Veterans Affairs Medical Center, Houston, TX; and b Department of Medicine, Tufts University School of Medicine and Division of Nephrology, St. Elizabeth’s Medical Center, Boston, MA Manuscript received August 19, 2013 and accepted September 22, 2013
Abstract The pathogenic role of Naþ in primary hypertension is widely recognized but that of Kþ remains unappreciated. Yet, extensive evidence indicates that together, the body’s dominant cations constitute the chief environmental factor in the pathogenesis of hypertension and its cardiovascular sequelae. In this Review, we provide a synthesis of the determinants of Naþ retention and Kþ loss developing in the body as the Naþ-rich and Kþ-poor modern diet interacts with kidneys intrinsically poised to conserve Naþ and excrete Kþ; and the molecular pathways utilized by these disturbances in the central nervous system and the periphery to increase sympathetic tone and vascular resistance, and establish hypertension. These fresh insights point to new directions for targeted pharmacotherapy of hypertension. The interdependency of Naþ and Kþ in the pathogenesis of hypertension indicates that Naþ restriction and increased Kþ intake are important strategies for the primary prevention and treatment of hypertension and its cardiovascular consequences. J Am Soc Hypertens 2014;8(3):203–213. Ó 2014 American Society of Hypertension. All rights reserved. Keywords: Sodium sensitivity; sympathetic activity; aldosterone; angiotensin II; endogenous ouabain; potassium channels; calcium signaling.
Introduction Contrary to isolated populations eating natural foods, contemporary societies are plagued by age-related increases in blood pressure and a lifetime risk of hypertension exceeding 90%. Such dramatic departure from normotension nowadays appears to arise largely from changes in environmental factors.1 Epidemiologic observations coupled with animal and human studies converge into the conclusion that Kþ deficiency augments the morbid impact of Naþ excess on the pathogenesis of hypertension and associated cardiovascular complications.2–5 Conversely, Kþ supplementation of animals or humans maintained on high Naþ diets decreases blood pressure, and reduces cardiovascular and renal No financial support has been provided for this article. The authors declare no conflicts of interest. *Corresponding author: Nicolaos E. Madias, MD, Department of Medicine, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. Tel.: 617-562-7502; fax: 617-562-7797. E-mail: [email protected]
injury.6–9 Indeed, in some studies, the vascular protection provided by Kþ was shown to be independent of its blood pressure-lowering effects.10 Several years ago, we juxtaposed the evidence implicating Naþ in the pathogenesis of hypertension with that for Kþ.1 On the strength of that analysis, we proposed that the chief environmental factor in the pathogenesis of primary hypertension and the associated cardiovascular disease is not an isolated surfeit of Naþ or deficit of Kþ in the body, but the combination of the two derangements. The root cause is the interplay between the modern diet–rich in Naþ and poor in Kþ–and nonadapted kidneys that are intrinsically poised to conserve Naþ and excrete Kþ. Since then, the proposal for a shared primacy of Naþ and þ K in the pathogenesis of primary hypertension and cardiovascular risk has been bolstered by novel insights on the manifold interactions of these electrolytes. Here we provide a synthesis of the determinants of Naþ retention and Kþ loss prevailing in consumers of the modern diet, and the molecular pathways utilized by these disturbances in the central nervous system and the periphery to increase vascular resistance and establish hypertension.
1933-1711/$ - see front matter Ó 2014 American Society of Hypertension. All rights reserved. http://dx.doi.org/10.1016/j.jash.2013.09.003
204
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
NaD Sensitivity and its Blockade by KD Linking Naþ intake to hypertension conceptualized Naþ sensitivity that refers to the blood pressure responsiveness to a short-term, sizable NaCl load or loss.11–13 It is observed in approximately one-third of normotensives, serving as a harbinger of hypertension, and two-thirds of hypertensives. Sodium-sensitive individuals consuming a high-Naþ diet appear to retain more Naþ than Naþ-resistant subjects, indicating impaired renal Naþ excretion. Declining glomerular filtration rate, aging, African descent, and obesity are associated with Naþ sensitivity. Dietary Kþ exerts a powerful, dose-dependent inhibitory effect on Naþ sensitivity. Strikingly, an increase in dietary Kþ can even abolish Naþ sensitivity in both normotensives and hypertensives.1,14,15 Blockade of Naþ sensitivity by Kþ reflects in part its natriuretic action. Sodium resistance in normotensives does not guarantee lasting normotension considering that over time, the vast majority of humans consuming a Naþ-rich and Kþ-poor diet develop hypertension.
Linkage of the Modern Diet to Hypertension Excess Naþ and a Kþ deficit in the body have been detected in hypertensive animals and humans.1,16–18 However, such reports have not been entirely consistent. Negative studies reflect several factors, including methodologic shortcomings, the altered distribution of Naþ and Kþ among tissues (eg, increased Naþ in vascular wall but reduced plasma Naþ owing to plasma-volume contraction), and the relatively modest Naþ gain and Kþ deficit in primary hypertension. Despite the early presence of hypertension-promoting mechanisms, primary hypertension might not develop until late in life. Remarkably, this occurs even in monogenic defects in Naþ excretion. Absent dietary adjustments, the delayed development of hypertension can reflect decline in renal function, diet and genome interactions (ie, epigenetic influences), and override of compensatory mechanisms with aging.19 The pressor effects of Naþ excess depend on the associated counter anion, as only NaCl, the usual form consumed, causes hypertension. As indicated by insufficient weight gain, the Naþ surplus must not obligate equivalent fluid retention. Retained Naþ replaces, in part, intracellular Kþ, which is then excreted as KCl in the urine. This Naþ-forKþ exchange is well documented in vascular smooth muscle (VSM) and skeletal muscle, most prominently in mineralocorticoid hypertension. Retained Naþ is also stored extracellularly in skin, cartilage, and bone. Mobilization of Naþ from extracellular stores can increase its level in body fluids and elicit a pressor response.20 The linkage of the Naþ-rich and Kþ-poor modern diet with the pathogenesis of hypertension is strongly supported by the blood pressure-lowering effects of diets with reverse cationic composition, that is, low in Naþ and high in Kþ.21–24
NaD Retention and KD Loss in Hypertension: Role of the Kidney In primary hypertension, Naþ-retentive kidneys in concert with a Naþ-rich diet generate Naþ excess. Concomitantly, ineffective Kþ conservation (renal and enteral) coupled with a Kþ-poor diet engenders Kþ deficit. Stimulation of Naþ transporters and the Naþ pump (Naþ, KþATPase) located at the luminal and basolateral membrane of the renal tubules, respectively, is key to these electrolyte deviations.1 Increased levels of sympathetic activity and angiotensin II as well as Kþ depletion stimulate Naþ reabsorption in the proximal tubule and the thick ascending limb of Henle’s loop by enhancing the activity of the luminal Naþ-Hþ exchanger.1,25 The Naþ-Clˉ cotransporter in the distal tubule, the epithelial Naþ channel (ENaC) in the collecting duct, and the ubiquitous Naþ pump are stimulated by the aldosterone excess of primary hypertension causing Naþ retention and Kþ loss.26 Angiotensin II, independent of aldosterone, increases ENaC activity in the distal nephron. Experimental models of Naþ-sensitive hypertension exhibit enhanced expression of ENaC in the renal medulla.1,27 The clinical effectiveness of thiazide diuretics in the management of hypertension attests to the pathogenic importance of Naþ surfeit. Importantly, the resulting hypokalemia discounts the antihypertensive effect of thiazides.28 Coadministration of Kþ-sparing diuretics augments the antihypertensive effect of thiazide diuretics both by inhibiting ENaC activity and most likely, by maintaining a higher serum Kþ level.29,30 Mutations and polymorphisms in the a-adducin gene also stimulate the Naþ pump. Contrary to their short-term actions, the long-term effects of Kþ depletion and increased levels of endogenous ouabain (EO) are to stimulate the activity and expression of the renal Naþ pump, thereby promoting Naþ retention. The WNK (With No lysine Kinase) proteins participate in the molecular pathways that control sodium and potassium excretion, and therefore blood pressure.31 Impaired release of corin, a serine protease produced by the cardiomyocyte that cleaves and activates atrial natriuretic peptide, causes Naþ retention. Corin-deficient mice exhibit impaired natriuresis, hypertension, and cardiac hypertrophy.32,33 Polymorphisms in the corin gene are associated with hypertension and heart failure in African Americans. Genetic factors might account for approximately onethird of blood-pressure variability in the general population and involve a growing number of mutations and polymorphisms.34 Variance in genes encoding proteins that alter renal Naþ and Kþ transport, vascular-wall reactivity, sympathetic activity, and other processes, might predispose humans to hypertension or, alternatively, prevent or delay its development35–41 (Table 1).
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
205
Table 1 Genetic factors altering both Naþ and Kþ transport and blood pressure Mutated Protein
Condition
Functional Effect
Effect on Blood Pressure
ENaC WNK1, WNK4 NCCT
Liddle syndrome Gordon syndrome Primary hypertension
[ [ [
a-adducin
Primary hypertension
ENaC
Pseudohypoaldosteronism type 1 (recessive) Bartter syndrome type 1 (homozygous) General population (heterozygous carriers) Bartter syndrome type 2 (homozygous) General population (heterozygous carriers) Bartter syndrome type 3 Bartter syndrome type 4 Gitelman syndrome (homozygous) General population (heterozygous carriers) SeSAME syndrome General population
Overactive ENaC in renal CD Overactive NCCT in renal DCT Increased expression of NCCT in renal DCT Overactive renal Naþ pump. Increase in Naþ sensitivity Hypoactive ENaC in renal CD
NKCC2 NKCC2 Kþ channel ROMK Kþ channel ROMK Chloride channel CIC-Kb Barttin NCCT NCCT Kþ channel (Kir4.1) Ca2þ-sensing receptor Angiotensinogen Angiotensin-converting enzyme Angiotensin receptor 1 Kþ channel (KCNJ5) 11 b-hydroxylase 11a-hydroxylase/17,20-lyase Aldosterone synthase 11a-hydroxylase 11 b-hydroxysteroid dehydrogenase 11 b-hydroxysteroid dehydrogenase MR Natriuretic peptide Corin MR
Primary hypertension Primary hypertension Systolic hypertension Adrenal adenoma and bilateral adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia Glucocorticoid remediable aldosteronism Apparent mineralocorticoid excess syndrome Primary hypertension Hypertension exacerbated in pregnancy Primary hypertension African-American population Pseudohypoaldosteronism type 1 (dominant)
[ Y
Hypoactive NKCC2 in renal TALH Modestly hypoactive NKCC2 in renal TALH Hypoactive NKCC2 in renal TALH Modestly hypoactive NKCC2 in renal TALH Hypoactive NKCC2 in renal TALH Hypoactive NKCC2 in renal TALH Hypoactive NCCT in renal DCT Modestly hypoactive NCCT in renal DCT Hypoactive Naþ pump in distal nephron Inhibition of ROMK and hypoactive NKCC2 in renal TALH Stimulation of RAS Stimulation or depression of RAS Stimulation of RAS Excessive mineralocorticoid activity
Y Y
Excessive mineralocorticoid activity Excessive mineralocorticoid activity ACTH-dependent, excessive mineralocorticoid activity Activation of MR by cortisol
[ [ [
Modest activation of MR by cortisol
[
Excessive mineralocorticoid activity Hypoactive natriuretic peptide Hypoactive natriuretic peptide Modestly hypoactive ENaC in renal CD
[ [ [ Y
Y Y Y Y Y Y Y Y [ [Y [ [
[
CD, collecting duct; DCT, distal convoluted tubule; ENaC, epithelial sodium channel; MR, mineralocorticoid receptor; NCCT, sodiumchloride cotransporter; NKCC2, sodium-potassium-2 chloride cotransporter; ROMK, renal outer medullary Kþ channel; TALH, thick ascending limb of Henle’s loop; WNK, with no lysine Kinase. Upward arrows denote increases, and downward arrows denote decreases.
Increased Sympathetic Tone Dietary Naþ modulates adrenergic mechanisms resulting in changes in plasma catecholamines and adrenergic neuronal function.42 Alterations in Naþ intake affect inversely plasma catecholamines via exclusive adjustment of adrenalgland secretory activity. In stark contrast, adrenergic neuronal function varies directly with Naþ intake and evokes
directional changes in vascular resistance.43,44 The increased sympathetic tone caused by a Naþ-rich diet reflects activation of sensors surrounding the brain’s third ventricle. Alterations in dietary Kþ also impact sympathetic activity.45 Potassium administration to patients with primary aldosteronism, a condition of severe Kþ depletion, depresses sympathetic activity, corrects baroreceptor hyporesponsiveness, and reduces blood pressure, despite augmenting
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
206
aldosterone secretion. Conversely, Kþ depletion increases sympathetic tone and promotes vasoconstriction. Similar to Naþ, the effects of Kþ on sympathetic activity are mediated centrally. The Naþ-rich and Kþ-poor modern diet increases sympathetic tone owing to the converging effects of each of the resulting electrolyte deviations; as a consequence, peripheral vascular resistance increases. Yet, precise attribution of roles is obscured by the demonstration that in Kþ depletion, Naþ largely replaces the intracellular cationic deficit; conversely, Kþ replacement in Kþ-depleted subjects causes natriuresis and decreases intracellular Naþ. Potassiumdeficient diet appears to impact sympathetic tone more overtly in young hypertensives.
Altered NaD and KD Homeostasis and the ReninAngiotensin System (RAS) þ
animals. Highlighting the interplay between Kþ and Naþ, Kþ supplementation virtually prevents the blood-pressure rise of mineralocorticoids plus Naþ.45 As assessed in vascular rings, aldosterone acts both in endothelium and VSM.54–56 In endothelium, it elicits vasodilation via mineralocorticoid-receptor (MR) activation and nitric-oxide generation. By contrast, in endotheliumdenuded preparation, aldosterone causes vasoconstriction. In normal animals and humans, the dilatory and constrictor effects appear to be balanced. Conversely, in diseases characterized by endothelial dysfunction (eg, hypertension), aldosterone might largely exert constrictor effects, promoting vascular damage and organ failure.57,58 Injury to vascular endothelium initiated by body Naþ surfeit and Kþ deficit might be critical to the vasculotoxic effects of aldosterone in primary hypertension.
Endogenous Ouabain (EO)
þ
Altered Na and K stores can each impact the classic (circulating) and the local (tissue) RAS.46 Remarkably, the effects of either electrolyte abnormality on the two RAS components can be divergent. Thus, Naþ excess inhibits the classic RAS but stimulates the brain RAS; conversely, Kþ loading stimulates aldosterone secretion but inhibits the brain RAS.47–49 Angiotensin II acting through receptors in the kidney, brain, heart, vascular wall, and adrenals mediates the actions of RAS. Activation of RAS was critical to survival of our human ancestors maintained on a Naþ-poor and Kþ-rich natural diet. The reverse electrolyte composition of the modern diet would be expected to suppress the classic RAS. Far from it, RAS is fundamental to the pathogenesis of hypertension by increasing sympathetic tone, impairing natriuresis, and mediating direct vasoconstriction. The remarkable efficacy of angiotensin convertingenzyme inhibitors and angiotensin-receptor blockers in primary hypertension attests to the pathogenic importance of RAS.
Effects of Aldosterone Mineralocorticoid hypertension exemplifies Naþdependent hypertension: Naþ restriction obviates hypertension and the associated vascular and tissue damage.50–52 Indeed, the Yanomamo Indians, an isolated population of no-Naþ and high-Kþ intake, exhibit low blood pressure, virtual absence of age-related increases in blood pressure, and small cardiovascular risk, despite aldosterone levels dwarfing those of primary aldosteronism. Mineralocorticoids mediate hypertension by facilitating Naþ entry into the cells of many tissues, particularly the brain, via activation and recruitment of ENaCs.53 The Naþ surfeit and Kþ deficit resulting from co-administration of mineralocorticoids and Naþ largely account for the extensive vascular and tissue damage observed in experimental
Along with aldosterone, EO offers effective defense against extracellular-volume depletion and hypotension, a constant threat to humans on low-Naþ diet, since the two hormones induce Naþ retention and vasoconstriction.59 Proper adaptation to the high-Naþ and low-Kþ modern diet should have completely suppressed the adrenal secretion of both aldosterone and EO.26,60 However, high levels of both hormones are encountered in many hypertensives consuming the modern diet.26,61,62 EO inhibits the Naþ pump triggering activation of the Naþ-Ca2þ exchanger (NCX1); the resulting rise in cytosolic [Ca2þ] is responsible for the physiological effects of EO on brain, heart, and vascular wall.62,63 Were EO also to inhibit the renal Naþ pump, it would promote natriuresis. Yet, EO administration to normal subjects does not increase Naþ excretion. Rodents infused with ouabain develop Naþ retention and hypertension. In humans, the FENa was lower in the higher quartiles of circulating EO.59,60 Contrasting with other tissues, the long-term action of EO on the renal Naþ pump appears to be stimulatory.60,61 Neuronal Naþ pumps have various levels of affinity to circulating and locally produced ouabain; the a2 variant of Naþ pump participates in ouabain-induced hypertension in rodents.62 EO inhibits the neuronal Naþ pump in the hypothalamus and other brain regions, which in turn activates the cerebral RAS; together, these changes trigger sympathetic stimulation, baroreceptor hyporesponsiveness, and hypertension.
Mechanisms of Blood-pressure Effects of NaD and KD Early Focus on Plasma-volume Expansion Decades ago, it was proposed that retention of Naþ and water by the kidney would increase plasma volume, venous return, and cardiac output, hence blood pressure. It was
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
further theorized that high cardiac output would soon give way to increased vascular resistance reflecting adaptation of organ blood flow to metabolic needs (total body autoregulation).64 This ‘‘kidney-fluid mechanism’’ hypothesis was widely embraced by the scientific community. Notwithstanding, no support for that hypothesis was offered by mineralocorticoid-Naþ hypertension in animals or humans, the prototypical form of Naþ-dependent hypertension. Cardiac output is not increased consistently, and increases in exchangeable Naþ and plasma [Naþ], and a sizable Kþ deficit are the leading determinants of the severity of hypertension.51,65 Furthermore, plasma volume is decreased, not increased, in patients with borderline or established primary hypertension. The volume-expansion hypothesis essentially ignored a wealth of data countering its framework and the burgeoning evidence for an important role of Kþ in hypertension. In short, the validity of the ‘‘kidney-fluid mechanism’’
207
hypothesis has been challenged and alternative mechanisms that account for the pathogenic role of both Naþ and Kþ have been identified.1,51,65,66
Role of the Central Nervous System Experimental studies have demonstrated that a variety of signals, including changes in plasma/cerebrospinal fluid (CSF) [Naþ] and [Kþ] as well as peripherally-derived hormones (aldosterone, EO, angiotensin II), are detected by the brain evoking blood-pressure responses.62,67–70 Initial processing of signals occurs in hypothalamic nuclei that then transmit information to the nucleus tractus solitarius (NTS). In turn, NTS integrates this information along with input from other brain areas and the periphery, and regulates sympathetic and parasympathetic tone (Figure 1). The blood-pressure responses largely reflect changes in peripheral vascular resistance.
Figure 1. Elements of the central nervous system involved in the effects of dietary Naþ and Kþ on blood pressure. The signals, sensors, integrative components, and effectors are illustrated. The nucleus tractus solitarius (NTS) in the brain stem processes input from the hypothalamus, other brain areas, and the periphery behaving as the switchboard that modulates the sympathetic and parasympathetic outflow to the heart and vascular wall. CSF, cerebrospinal fluid; DMN, dorsal motor nucleus; OVLT, organum vasculosum of the lamina terminalis; PON, preoptic nucleus; PVN, paraventricular nucleus; SFO, subfornical organ; SON, supraoptic nucleus.
208
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
Signals þ
A small increase in plasma and CSF [Na ] (1–3 mmol/L) caused by high dietary Naþ and the peripherally derived hormones constitute signals promoting a rise in blood pressure.71–73 A hypertensive response is also evoked by both hypokalemia and minor reductions in CSF [Kþ] (0.1–0.3 mmol/L). Low dietary Kþ causes hypokalemia but only small or undetectable decreases in CSF [Kþ]. The intracerebroventricular (ICV) infusion of aldosterone (at doses not eliciting systemic effects) decreases CSF [Kþ] and augments blood pressure; both events are prevented by the ICV co-administration of a mineralocorticoid antagonist, an ENaC blocker, or Kþ.74–76 Simulating the central effects of adrenal EO, the ICV infusion of EO acts as a signal that increases blood pressure, a response inhibited by the central infusion of Kþ.
Sensors The signals noted above are detected by sensors residing in the neuronal arrangement of the circumventricular
organs seated anteroventral to the third ventricle, that is, the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO). Animal studies have identified CSF-contacting neurons in these organs with somas located in the periventricular area or exposed to the lumen and projecting dendrites into the cavity; other neurons project their axons toward the ventricular lumen and have synapses on ependymal cells.77,78 The ICV-infusion studies suggest that the central sensors have a multifaceted nature that comprises the functions of ENaC, MR, angiotensin II receptor 1 (AT1R), Kþ sensor, and Naþ pump67,79–81 (Figure 2A). Increased expression of brain ENaC might participate in the pathogenesis of Liddle syndrome. The CSF-Kþ sensor has not been identified but might involve transient receptor protein channels (TRPC). The TRPCs are non-selective cation channels present in various brain regions, including the hypothalamic paraventricular nucleus (PVN); they sense changes in CSF-electrolyte composition and elicit sympathetic responses.79–83 Increases in CSF [Kþ] might activate TRPCS evoking sympathetic inhibition.
Figure 2. Molecular mechanisms implicated in the central-nervous-system regulation of blood pressure by dietary Naþ and Kþ. A, The signals generated by dietary Naþ and Kþ, and the molecular functions incorporated by the circumventricular sensors. B, The molecular pathways involved in translating Naþ surfeit in the body into increased sympathetic nerve activity and blood pressure, and Kþ feeding into decreased sympathetic activity and blood pressure. Upward arrows denote increases, and downward arrows denote decreases. Ang II, angiotensin II; AT1R, angiotensin receptor 1; ENaC, epithelial sodium channel; EO, endogenous ouabain; MR, mineralocorticoid receptor.
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
Pathways and Integration The neuron axons of the central sensors reach hypothalamic nuclei, including the preoptic nucleus (PON), the supraoptic nucleus (SON), and PVN (Figure 1). Additionally, the magnocellular neurons of the PVN project dendritic processes that reach the ependymal cells and the dendritic terminals of CSF-contacting cells.78,81 Thus, the neural network surrounding the third ventricle allows cross-talk between the CSF and the hypothalamus. Information regarding the electrolytic and hormonal composition of the plasma and CSF is recorded by the SON,
209
which projects efferent routes to neurosecretory areas of the hypothalamus, yielding altered synthesis and secretion of aldosterone, EO, and angiotensin II. Also, the brain sensors relay information to the PVN, with subsequent activation or deactivation of the brain RAS. Input reflecting these changes is communicated to the NTS, where further integration occurs and eventual translation into altered sympathetic activity60,67,79,82,83 (Figure 1). Figure 2B highlights the current understanding of the central molecular pathways involved in translating a Naþ surfeit in the body into a pressor response. A similar
Table 2 Impact of a low- or high-Kþ intake on the blood-pressure effects and cardiovascular risk of a high-Naþ diet* High-Naþ Diet Low-Kþ intake General Aggravation of primary and mineralocorticoid hypertension Increase in Naþ sensitivity Promotion of positive Naþ balance (decreased natriuresis) Partial intracellular replacement of lost Kþ by retained Naþ Stimulation of circulating and tissue RAS Depression of baroreceptor sensitivity Organ-specific Kidney Augmentation of renin release (direct action) Increase in renal vascular resistance Reduction in glomerular filtration rate Promotion of kidney damage: glomerular and arteriolar lesions Promotion of inflammatory pathways of fibrosis Brain Inhibition of neuronal Naþ pump Increase in sympathetic nerve activity Augmentation of central effects of aldosterone Augmentation of central effects of EO Increase risk of cerebrovascular accident Heart and circulatory beds Promotion of cardiac hypertrophy and fibrosis Vasoconstriction (cerebral, coronary, renal, mesenteric, and limb vascular beds) Reduction in aortic compliance Promotion of atherogenesis Vascular wall Inhibition of Naþ pump Depression of inward rectifier Kþ channels (KIR channels) and Kþ ATP channels Inhibition of endothelium-dependent vasodilation Stimulation of vascular-smooth-muscle proliferation Augmentation of the pressor response to angiotensin II Adrenal cortex Inhibition of aldosterone secretion (direct action) Stimulation of EO secretion and action EO, endogenous ouabain; RAS, renin-angiotensin system. * Listed effects are derived from animal and human studies.
High-Kþ intake Prevention/amelioration of primary and mineralocorticoid hypertension Reduction in need for antihypertensive medication Inhibition of Naþ sensitivity Promotion of negative Naþ balance (increased natriuresis) Displacement of intracellular Naþ by retained Kþ Suppression of circulating and tissue RAS Restoration of baroreceptor sensitivity
Suppression of renin release (direct action) Reduction in renal vascular resistance Increase in glomerular filtration rate Protection from kidney damage Suppression of inflammatory pathways of fibrosis Stimulation of neuronal Naþ pump Depression of sympathetic nerve activity Suppression of central effects of aldosterone Depression of central effects of EO Protection from cerebrovascular accident Protection from cardiac hypertrophy and fibrosis Vasodilation (cerebral, coronary, renal, mesenteric, and limb vascular beds) Enhancement of aortic compliance Antiatherogenic effects Stimulation of Naþ pump Activation of inward rectifier Kþ channels (KIR channels) and Kþ ATP channels Promotion of endothelium-dependent vasodilation Inhibition of vascular-smooth-muscle proliferation Decrease in the pressor response to angiotensin II Stimulation of aldosterone secretion (direct action) Inhibition of EO secretion and action
210
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
cascade of steps, but with opposite molecular effects, is traversed in evoking the depressor response to Kþ supplementation69,74,75 (Figure 2B). The release and actions of central EO are inhibited by Kþ feeding. Remarkably, long-term ICV infusion of KCl prevents development of deoycorticosterone-Naþ hypertension.74 Conversely, Kþ depletion stimulates the brain RAS, and raises sympathetic activity and blood pressure.
Role of the Periphery Beyond generating the Naþ excess and Kþ deficit in hypertension, the kidney and the adrenal cortex provide input to the central modulation of sympathetic activity, and contribute directly to increasing vascular resistance via the actions of circulating RAS, and adrenal aldosterone and EO. The vasoconstrictor actions of EO reflect both stimulation of VSM and inhibition of endothelial vasodilation. Sodium retention and Kþ depletion have direct effects on the arterial-wall endothelium and VSM, culminating in vasoconstriction.84–87 Vascular endothelial cells exhibit high sensitivity to changes in the extracellular [Naþ] and [Kþ].57,58,88 Within minutes from an increase in extracellular [Naþ], cultured vascular endothelial cells stiffen, a response strongly dependent on aldosterone; increasing extracellular [Kþ] decreases endothelial stiffness. Additionally, Naþ retention decreases the endothelial synthesis of nitric oxide and increases the plasma level of asymmetric dimethyl Larginine, an endogenous inhibitor of nitric acid production.89–92 Sodium restriction and a high-Kþ diet exert the opposite effects. Endothelium-dependent vasodilation is defective in primary hypertension. Experimental Kþ depletion inhibits endothelium-dependent vasodilation.91 The VSM Naþ pump possesses activation sites with high affinity for extracellular [Kþ]; hypokalemia depresses the Naþ pump causing membrane depolarization and vasoconstriction, whereas hyperkalemia has the opposite effects. A deficit of body Kþ or hypokalemia inhibits Kþ channels causing membrane depolarization and vasoconstriction. Downregulation of large conductance Kþ channels in VSM contributes to the increased vascular tone in primary hypertension.
Perspective Current evidence indicates that the pathogenesis of hypertension is critically dependent on brain responses to Naþ surfeit and Kþ deficit. Changes in plasma/CSF [Naþ] and [Kþ], complemented by the circulating levels of angiotensin II, aldosterone, and EO (that are conditioned by the altered cationic homeostasis), are detected by circumventricular sensors that relay input to hypothalamic nuclei. The latter evoke responses to the NTS in the brain stem culminating in increased sympathetic activity and
hypertension. Peripheral effects on the vascular wall of the Naþ surfeit and Kþ deficit themselves as well as the circulating RAS, aldosterone, and EO contribute to the hypertension phenotype. These fresh insights point to new avenues for targeted pharmacotherapy of hypertension.1,60 The body’s dominant cations, Naþ and Kþ, are intertwined regarding dietary intake, body stores, physiological roles, and vascular effects. This interdependency points to natural means for preventing and treating hypertension and its cardiovascular sequelae. Age-related increases in blood pressure and primary hypertension are largely observed in societies consuming >100 mmol of Naþ per day. Efforts at decreasing daily consumption of Naþ is an important strategy toward this goal.1,22 The totality of the experimental and clinical evidence indicates that Kþ is a powerful, natural antidote for the pernicious effects of Naþ excess and its accomplices, namely angiotensin II, aldosterone, and EO, on blood pressure and cardiovascular risk. Table 2 juxtaposes the adverse effects of Kþ depletion with the salutary effects of Kþ administration on blood pressure and cardiovascular events.1,87,93 Therefore, a second strategy for the primary prevention and treatment of hypertension is to increase Kþ intake.22 This strategy is equally important as Naþ restriction and trumps it in terms of ease of implementation. Acknowledgments The authors wish to acknowledge Geri Tasby for her skillful assistance in the preparation of the manuscript.
References 1. Adrogue HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007;356: 1966–78. 2. Langford HG, Watson RL. Electrolytes and hypertension. In: Paul O, editor. Epidemiology and control of hypertension. New York: Stratton; 1975. P. 119–30. 3. Luft FC, Weinberger MH. Sodium intake and essential hypertension. Hypertension 1982;4(sup III):III-14–9. 4. Kirkendall AM, Connor WE, Abboud F, Rastogi SP, Anderson TA, Fry M. The effect of dietary sodium chloride on blood pressure, body fluids, electrolytes, renal function, and serum lipids of normotensive man. J Lab Clin Med 1976;87:411–34. 5. Whelton PK. Potassium and blood pressure. In: Izzo JL Jr, Black HR, editors. Hypertension primer. 3rd ed. Dallas: American Heart Association/Council on High Blood Pressure Research; 2003. P. 280–2. 6. He FJ, MacGregor GA. Beneficial effects of potassium. BMJ 2001;323:497–501. 7. Intersalt Cooperative Research Group. Intersalt: an international study of electrolyte excretion and blood
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
pressure: results for 24-hour urinary sodium and potassium excretion. BMJ 1988;297:319–28. 8. Meneely GR, Ball COT, Youmans JB. Chronic sodium chloride toxity: the protective effect of added potassium chloride. Ann Intern Med 1957;47:263–73. 9. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approches to Stop Hypertension (DASH) diet. N Engl J Med 2001;344:3–10. 10. Tobian L, Lange J, Ulm K, Wold L, Iwai J. Potassium reduces cerebral hemorrhage and death rate in hypertensive rats, even when blood pressure is not lowered. Hypertension 1985;7:1110–4. 11. Simpson FO. Blood pressure and sodium intake. Handbook of Hypertension, Vol 20: Epidemiology of Hypertension. C.J. Bulpitt, ed. Amsterdam: Elsevier Science B.V., 2000; 274–295. 12. Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension 1996;27:481–90. 13. Richardson SI, Freedman BI, Ellison DH, Rodriguez CJ. Salt sensitivity: a review with focus on non-Hispanic blacks and Hispanics. J Am Soc Hypertens 2013;7:170–9. 14. Morris RC Jr, Sebastian A, Forman A, Tanaka M, Schmidlin O. Normotensive salt sensitivity: effects of race and dietary potassium. Hypertension 1999;33:18–23. 15. Bulpitt CJ. Blood pressure and potassium consumption. Handbook of Hypertension, Vol. 20: Epidemiology of Hypertension. C.J. Bulpitt, ed. Amsterdam: Elsevier Science B.V., 2000;296–312. 16. Hansen J. Blood volume and exchangeable sodium in essential hypertension. Acta Med Scand 1968;184: 517–23. 17. Lever AF, Beretta-Piccoli C, Brown JJ, Davies DL, Fraser R, Robertson JIS. Sodium and potassium in essential hypertension. Br Med J (Clin Res Ed) 1981; 283:463–8. 18. Kopp C, Linz P, Wachsmuth L, Dahlmann A, Horbach T, Sch€ ofl C, et al. Na magnetic resonance imaging of tissue sodium. Hypertension 2012;59:167–72. 19. Millis RM. Epigenetics and hypertension. Curr Hyperten Rep 2011;13:21–8. 20. Bhave G, Neilson EG. Body fluid dynamics: Back to the future. J Am Soc Nephrol 2011;22:2166–81. 21. Cook NR, Obarzanek E, Cutler JA, Buring JE, Rexrode KM, Kumanyika SK, et al. Joint effects of sodium and potassium intake on subsequent cardiovascular disease. The Trials of Hypertension Prevention Follow-up Study. Arch Intern Med 2009;169:32–40. 22. Adrogue HJ, Madias NE. Shared primacy of sodium and potassium on cardiovascular risk. Am J Kidney Dis 2009;54:598–601. 23. O’Donnell MJ, Salim Y, Mente A, Gao P, Mann JF, Teo K, et al. Urinary sodium and potassium excretion and risk of cardiovascular events. JAMA 2011;306:2229–38.
211
24. Yang Q, Liu T, Kuklina EV, Flanders WD, Hong Y, Gillespie C, et al. Sodium and potassium intake and mortality among US adults. Prospective data from the third National Health and Nutrition Examination Survey. Arch Intern Med 2011;171:1183–91. 25. Liu J, Yan Y, Liu L, Xie Z, Malhotra D, Joe B, et al. Impairment of Na/K-ATPase signaling in renal proximal tubule contributes to Dahl salt-sensitive hypertension. J Biol Chem 2011;286:22806–13. 26. Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N, et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med 2004;351:33–41. 27. Amin MS, Reza E, El-Shahat E, Wang HW, Tesson F, Leenen FH. Enhanced expression of epithelial sodium channels in the renal medulla of Dahl S rats. Can J Physiol Pharmacol 2011;89:159–68. 28. Kaplan NM, Carnegie A, Raskin P, Heller JA, Simmons M. Potassium supplementation in hypertensive patients with diuretic-induced hypokalemia. N Engl J Med 1985;312:746–9. 29. Pratt JH. Central role for ENaC in development of hypertension. J Am Soc Nephrol 2005;16:3154–9. 30. Ellison DH, Hoorn EJ, Schrier RW. Mechanisms of diuretic action. In: Coffman TM, Molitoris BA, Falk RJ, Neilson EG, Schrier RW, editors. Schrier’s Diseases of the Kidney. 9th Ed. Philadelphia: Lippincott Williams & Wilkins; 2013. P. 1906–37. 31. Hoorn EJ, Nelson JH, McCormick JA, Ellison DH. The WNK kinase network regulating sodium, potassium, and blood pressure. J Am Soc Nephrol 2011;22:605–14. 32. Wang W, Shen J, Cui Y, Jiang J, Chen S, Peng J, et al. Impaired sodium excretion and salt-sensitive hypertension in corin-deficient mice. Kidney Int 2012;82:26–33. 33. Bouley R. Corin: a key protein of an adaptive renal mechanism to respond to salt variation? Kidney Int 2012;82:7–8. 34. Vehaskari VM. Heritable forms of hypertension. Pediatr Nephrol 2009;24:1929–37. 35. Choi M, Scholl UI, Yue P, Bj€orklund P, Zhao B, Nelson-Williams C, et al. Kþ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011;331:768–72. 36. Meneton P, Oh YS, Warnock DG. Genetic disorders of renal apical Naþ transporters. In: Dubose TD Jr, Hamm LL, editors. Acid-base and electrolyte disorders: a companion to Brenner & Rector’s The Kidney. Philadelphia: Elsevier Science (Saunders); 2002. P. 335–46. 37. Ji W, Foo JN, O’Roak BJ, Zhao H, Larson MG, Simon DB, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nature Genetics 2008;40:592–9. 38. Fang L, Li D, Welling PA. Hypertension resistance polymorphisms in ROMK (Kir1.1) alter channel
212
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
function by different mechanisms. Am J Physiol Renal Physiol 2010;299:F1359–64. Monette MY, Rinehart J, Lifton RP, Forbush B. Rare mutations in the human Na-K-Cl cotransporter (NKCC2) associated with lower blood pressure exhibit impaired processing and transport function. Am J Physiol Renal Physiol 2011;300:F840–7. Subramanya AR, Welling PA. Toward an understanding of hypertension resistance. Am J Physiol Renal Physiol 2011;300:F838–9. Acu~ na R, Martinez-de-la-Maza L, Ponce-Coria J, Vazquez N, Ortal-Vite P, Pacheco-Alvarez D, et al. Rare mutations in SLC12A1 and SLC12A3 protect against hypertension by reducing the activity of renal salt cotransporters. J Hypertens 2011;29:475–83. Vlahakos D, Gavras H. Central sympathetic stimulation produced by sline application into the nucleus tractus solitarii area of conscious rats. Neurosci Lett 1988; 92:335–40. de Leeuw PW, Birkenh€ager WH. Sodium and adrenergic mechanisms. Handbook of Hypertension, Vol 8: Pathophysiology of Hypertension - Regulatory Mechanisms. A. Zanchetti, R.C. Tarazi, eds. Amsterdam: Elsevier Science B.V., 1986;203–215. Schlaich MP, Lambert E, Kaye DM. Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine uptake, and angiotensin neuromodulation. Hypertension 2004;43:169–75. Sato Y, Fujita T. Suppression of renal sympathetic activity with potassium supplement in DOCA-salt rats. Jpn Heart J 1984;25:253–61. Crowley SD, Gurley SB, Oliverio MI, Pazmino AK, Griffiths R, Flannery PJ, et al. Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. J Clin Invest 2005;115:1092–9. Ferrario CM, Ueno Y, Diz DI, Barnes KL. The reninangiotensin system: physiological actions on the central nervous system. Handbook of Hypertension, Vol 8: Pathophysiology of Hypertension - Regulatory Mechanisms. A. Zanchetti, R.C. Tarazi, eds. Amsterdam: Elsevier Science B.V., 1986;431–454. Huang BS, Zheng H, Tan J, Patel KP, Leenen FHH. Regulation of hypothalamic renin-angiotensin system and oxidative stress by aldosterone. Exp Physiol 2011;96:1028–38. Huang BS, Cheung WJ, Wang H, Tan J, White RA, Leenen FHH. Activation of brain renin-angiotensinaldosterone system by central sodium in Wistar rats. Am J Physiol Heart Circ Physiol 2006;291: H1109–17. Wang Q, Clement S, Gabbiana G, Horisberger JD, Burnier M, Rossier BC, et al. Chronic hyperaldosteronism in a transgenic mouse model fails to induce cardiac remodeling and fibrosis under a normal-salt diet. Am J Physiol Renal Physiol 2004;286:F1178–84.
51. Conway J. Hemodynamics in mineralocorticoid hypertension. Handbook of Hypertension, Vol 7: Pathophysiology of Hypertension-Cardiovascular Aspects. A. Zanchetti, R.C. Tarazi, eds. Amsterdam: Elsevier Science B.V., 1986;217–224. 52. Gomez-Sanchez EP. Central mineralocorticoid receptors and cardiovascular disease. In: Koch CA, Chrousos GP, editors. Endocrine Hypertension: Underlying Mechanisms and Therapy. Contemporary Endocrinology. New York: Springer New York; 2013. P. 289–309. 53. Funder JW. Minireview: aldosterone and mineralocorticoid receptors: past, present, and future. Endocrinology 2010;151:5098–102. 54. Kusche-Vihrog K, Callis C, Fels J, Oberleithner H. The epithelial sodium channel (ENaC): Mediator of the aldosterone response in the vascular endothelium? Steroids 2010;75:544–9. 55. Nguyen Dinh Cat A, Griol-Charhbili V, Loufrani L, Labat C, Benjamin L, Farman N, et al. The endothelial mineralocorticoid receptor regulates vasoconstrictor tone and blood pressure. FASEB J 2010;24:2454–63. 56. Gros R, Ding Q, Armstrong S, O’Neil C, Pickering JG, Feldman RD. Rapid effects of aldosterone on clonal human vascular smooth muscle cells. Am J Physiol Cell Physiol 2007;292:C788–94. 57. Adler GK, Williams GH. Aldosterone – villain or protector? Hypertension 2007;50:31–2. 58. Ritz E, Tomaschitz A. Aldosterone, a vasculotoxic agent – novel functions for an old hormone. Nephrol Dial Transplant 2009;24:2302–5. 59. Manunta P, Messaggio E, Casamassima N, Gatti G, Carpini SD, Zagato L, et al. Endogenous ouabain in renal Naþ handling and related diseases. Biochimica et Biophysica Acta 2010;1802:1214–8. 60. Manunta P, Hamlyn JM, Simonini M, Messaggio E, Lanzani C, Bracale M, et al. Endogenous ouabain and the renin-angiotensin-aldosterone system: distinct effects on Na handling and blood pressure in human hypertension. J Hypertens 2011;29:349–56. 61. Hamlyn JM, Manunta P. Endogenous Ouabain: A link between sodium intake and hypertension. Curr Hypertens Rep 2011;13:14–20. 62. Blaustein MP, Leenen FHH, Chen L, Golovina VA, Hamlyn JM, Pallone TL, et al. How NaCl raises blood pressure: a new paradigm for the pathogenesis of saltdependent hypertension. Am J Physiol Heart Circ Physiol 2012;302:H1031–49. 63. Iwamoto T. Vascular Naþ/Ca2þ exchanger: implications for the pathogenesis and therapy of saltdependent hypertension. Am J Physiol Regul Integr Comp Physiol 2006;290:R536–45. 64. Guyton AC. Blood pressure control - special role of the kidneys and body fluids. Science 1991;252:1813–6. 65. Gavras I, Gavras H. ‘‘Volume-expanded’’ hypertension: the effect of fluid overload and the role of the
H.J. Adrogue and N.E. Madias / Journal of the American Society of Hypertension 8(3) (2014) 203–213
66.
67.
68.
69.
70.
71.
72.
73. 74.
75.
76.
77.
78.
79.
sympathetic nervous system in salt-dependent hypertension. J Hypertens 2012;30:655–9. Villamil MF, Amorena C, Ponce-Hornos J, M€ uller A, Taquini AC. Role of extracellular volume expansion in the development of DOC-salt hypertension in the rat. Hypertension 1982;4:620–4. Huang BS, Amin S, Leenen FHH. The central role of the brain in salt-sensitive hypertension. Curr Opin Cardiol 2006;21:295–304. Shah J, Jandhyala BS. Studies on the role(s) of cerebrospinal fluid osmolality and chloride ion in the centrally mediated pressor responses of sodium chloride. Clin Exp Hypertens A 1991;13:297–312. Shah J, Jandhyala BS. Role of Naþ, Kþ-ATPase in the centrally mediated hypotensive effects of potassium in anaesthetized rats. J Hypertens 1991;9: 167–70. Sun Y, Zhang J, Zhao D, Wang QS, Gu YC, Ma HP, et al. Role of the epithelial sodium channel in saltsensitive hypertension. Acta Pharmacologica Sinica 2011;32:789–97. He FJ, Markandu ND, Sagnella GA, de Wardener HE, MacGregor GA. Plasma sodium, ignored and underestimated. Hypertension 2005;45:98–102. Suckling RJ, He FJ, Markandu ND, MacGregor GA. Dietary salt influences postprandial plasma sodium concentration and systolic blood pressure. Kidney Int 2012;81:407–11. Oberleithner H, de Wardener HE. Sodium: a wolf in sheep’s clothing. Blood Purif 2011;31:82–5. Klarr SA, Keep RF, Betz AL. Chronic central potassium infusion prevents deoxycorticosterone-salt hypertension in rats. Am J Physiol 1995;268: H646–52. Atarashi K, Matsuoka H, Takagi M, Yamada K, Hirata Y, Hayakawa H, et al. Effects of intracerebroventricular infusion of aldosterone on blood pressure and sodium and potassium concentrations in cerebral spinal fluid in rats. Clin Exp Hypertens A 1988;10: 317–22. Gomez-Sanchez EP, Gomez-Sanchez CE. Effect of central amiloride infusion on mineralocorticoid hypertension. Am J Physiol 1994;267:E754–8. Vigh-Teichmann I, Vigh B. The system of cerebrospinal fluid-contacting neurons. Arch Histol Jpn 1983; 46:427–68. Korf HW, Viglietti-Panzica C, Panzica GC. A golgi study on the cerebrospinal fluid (CSF)-contacting neurons in the paraventricular nucleus of the Pekin duck. Cell Tissue Res 1983;288:149–63. Blaustein MP, Hamlyn JM. Signaling mechanisms that link salt retention to hypertension: Endogenous ouabain, the Naþ pump, the Naþ/Ca2þ exchanger and TRPC proteins. Biochimica et Biophysica Acta 2010; 1802:1219–29.
213
80. Ciura S, Liedtke W, Bourque CW. Hypertonicity sensing in organum vasculosum lamina terminalis neurons: a mechanical process involving TRPV1 but not TRPV4. J Neurosci 2011;31:14669–76. 81. Gabor A, Leenen FHH. Mechanisms in the PVN mediating local and central sodium-induced hypertension in Wistar rats. Am J Physiol Regul Integr Comp Physiol 2009;296:R618–30. 82. Takahashi H, Yoshika M, Komiyama Y, Nishimura M. The central mechanism underlying hypertension: a review of the roles of sodium ions, epithelial sodium channels, the renin-angiotensin-aldosterone system, oxidative stress and endogenous digitalis in the brain. Hypertens Res 2011;34:1147–60. 83. Leenen FH. The central role of the brain aldosterone‘‘ouabain’’ pathway in salt-sensitive hypertension. Biochimica et Biophysica Acta 2010;1802:1132–9. 84. Dolson GM, Ellis KJ, Bernardo MV, Prakash R, Adrogue HJ. Acute decreases in serum potassium augment blood pressure. Am J Kidney Dis 1995;26:321–6. 85. Dolson GM, Adrogue HJ. Low dialysate [Kþ] decreases efficiency of hemodialysis and increases urea rebound. J Am Soc Nephrol 1998;9:2124–8. 86. Dolson GM, Wesson DE, Adrogue HJ. Vascular relaxation probably mediates the antihypertensive effect of a high potassium diet. A role for enhanced vascular Na-K ATPase activity. J Hypertens 1995;13(12 Pt 1):1433–9. 87. McCabe RD, Young DB. Potassium inhibits cultured vascular smooth muscle cell proliferation. Am J Hypertens 1994;7(4 Pt 1):346–50. 88. Oberleithner H, Callies C, Kusche-Vihrog K, Schillers H, Shahin V, Riethm€uller C, et al. Potassium softens vascular endothelium and increases nitric oxide release. Proc Nat Acad Sci USA 2009;106:2829–34. 89. Panza JA, Quyyumi AA, Brush JB Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990;323:22–7. 90. Fujiwara N, Osanai T, Kamada T, Katoh T, Takahashi K, Okumura K. Study on the relationship between plasma nitrite and nitrate level and salt sensitivity in human hypertension: modulation of nitrite oxide synthesis by salt intake. Circulation 2000;101:856–61. 91. Haddy FJ, Vanhoutte PM, Feletou M. Role of potassium in regulating blood flow and blood pressure. Am J Physiol Regul Integr Comp Physiol 2006;290:R546–52. 92. Amberg GC, Bonev AD, Rossow CF, Nelson MT, Santana LF. Modulation of the molecular composition of large conductance, Caþþ activated Kþ channels in vascular smooth muscle during hypertension. J Clin Invest 2003;112:717–24. 93. Wang W, Soltero L, Zhang P, Huang XR, Lan HY, Adrogue HJ. Renal inflammation is modulated by potassium in chronic kidney disease: possible role of Smad7. Am J Physiol Renal Physiol 2007;293:F1123–30.