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Potassium Hypertension
Potassium Hypertension
review article
mechanisms of disease
H
From the Department of Medicine, Baylor ypertension affects approximately 25% of the adult population
College of Medicine; the Department of worldwide, and its prevalence is predicted to increase by 60% by 2025,
Medicine, Methodist Hospital; and the
Renal Section, Veterans Affairs Medical when a total of 1.56 billion people may be affected.1 It is the major risk
Center — all in Houston (H.J.A.); and the factor for cardiovascular disease and is responsible for most deaths worldwide.2
Department of Medicine, Tufts University Primary hypertension, also known as essential or idiopathic hypertension, accounts
School of Medicine, and the Division of
Nephrology, Caritas St. Elizabeth’s Medi- for as many as 95% of all cases of hypertension.3
cal Center — both in Boston (N.E.M.). Primary hypertension results from the interplay of internal derangements (pri-
Address reprint requests to Dr. Madias at marily in the kidney) and the external environment. Sodium, the main extracellular
the Department of Medicine, Caritas St.
Elizabeth’s Medical Center, 736 Cam- cation, has long been considered the pivotal environmental factor in the disorder.
bridge St., Boston, MA 02135, or at Numerous studies show an adverse effect of a surfeit of sodium on arterial pres-
nicolaos.madias@caritaschristi.org. sure.4-7 By contrast, potassium, the main intracellular cation, has usually been
N Engl J Med 2007;356:1966-78. viewed as a minor factor in the pathogenesis of hypertension. However, abundant
Copyright © 2007 Massachusetts Medical Society. evidence indicates that a potassium deficit has a critical role in hypertension and its
cardiovascular sequelae.8-10 In this review, we examine how the interdependency
of sodium and potassium influences blood pressure. Recent evidence as well as
classic studies point to the interaction of sodium and potassium, as compared with
an isolated surfeit of sodium or deficit of potassium, as the dominant environmental
factor in the pathogenesis of primary hypertension and its associated cardiovascu-
lar risk. Our review concludes with recent recommendations from the Institute of
Medicine concerning the dietary intake of sodium and potassium.
Primary hypertension and age-related increases in blood pressure are virtually ab-
sent in populations in which individual consumption of sodium chloride is less
than 50 mmol per day; these conditions are observed mainly in populations in which
people consume more than 100 mmol of sodium chloride per day.3 The Interna-
tional Study of Salt and Blood Pressure (INTERSALT), which included 10,079 sub-
jects from 32 countries, showed a median urinary sodium excretion value of 170
mmol per day (approximately 9.9 g of sodium chloride per day).11 Although indi-
vidual sodium intake in most populations throughout the world exceeds 100 mmol
per day, most people remain normotensive. It appears, then, that sodium intake
that exceeds 50 to 100 mmol per day is necessary but not sufficient for the develop-
ment of primary hypertension.
In an analysis across populations, the INTERSALT researchers estimated an
increase in blood pressure with age over a 30-year period (e.g., from 25 to 55 years
of age); mean systolic blood pressure was 5 mm Hg higher and diastolic blood
pressure was 3 mm Hg higher when sodium intake was increased by 50 mmol per
day. In an analysis within single populations, a positive correlation between sodium
intake and blood pressure was also detected after adjustment for a number of
potentially confounding variables.11
Humans share 98.4% genetic identity with ences in the prevalence of hypertension among
chimpanzees, and a landmark interventional these populations have usually been attributed to
study in chimpanzees showed that adding up to differences in the amounts of dietary sodium
15 g of sodium chloride to the diet per day in- consumed, but they could also reflect differences
creased systolic blood pressure by 33 mm Hg and in potassium intake. The movement of isolated
diastolic blood pressure by 10 mm Hg; the in- populations into more urban areas is consistent
creases were reversed after withdrawal of the ly associated with age-related increases in blood
sodium chloride supplement.12 In the Dietary pressure and a rise in the prevalence of hyper-
Approaches to Stop Hypertension (DASH) sodium tension as the dietary potassium:sodium ratio
study, a reduction in sodium intake caused step- decreases in the new location.15,16
wise decreases in blood pressure. Levels of sodi-
um intake studied in random order were approxi Va s cul a r Effec t s of P o ta s sium
mately 150 mmol per day, 100 mmol per day, and Depl e t ion
50 mmol per day.13 A meta-analysis of random-
ized controlled trials lasting at least 4 weeks con Early reports of the vasodilatory or blood-pres-
cluded that reducing sodium intake by 50 mmol sure–lowering properties of both potassium de-
per day decreases systolic blood pressure by an pletion and potassium supplementation17,18 de-
average of 4.0 mm Hg and diastolic blood pres- layed recognition of the effects of potassium
sure by an average of 2.5 mm Hg in hypertensive depletion that are toxic to the blood vessels.
subjects and decreases systolic blood pressure by These studies of the effects of a low intake of
an average of 2.0 mm Hg and diastolic blood potassium on blood pressure, performed mostly
pressure by an average of 1.0 mm Hg in normo- in young rats, also involved a low intake of sodi-
tensive subjects.14 um and chloride. Potassium restriction causes a
deficit in cellular potassium that triggers cells to
gain sodium in order to maintain their tonicity
P o ta s sium C on ten t
of S odium-R ich Die t s and volume.19 The deficits of potassium, sodium,
and chloride in the body imposed by those early
As compared with diets based on natural foods, studies contracted both the intracellular and ex-
diets based on processed foods are high in sodium tracellular compartments, thereby engendering a
and low in potassium.3,10 For example, two slices decrease in blood pressure.18,20 Subsequent stud-
of ham (57 g) contain 32.0 mmol of sodium and ies in rats showed that the pressor effect of potas-
4.0 mmol of potassium, and a cup of canned sium depletion requires abundant consumption
chicken noodle soup contains 48.0 mmol of so- of sodium chloride (e.g., 4.5 g of sodium chloride
dium and 1.4 mmol of potassium. Conversely, per 100.0 g of dietary intake).21
diets containing abundant fruits and vegetables Population studies have shown an inverse
are sodium-poor and potassium-rich.3,10 For exam relation of potassium intake to blood pressure,
ple, an orange (131 g) contains no sodium and the prevalence of hypertension, or the risk of
6.0 mmol of potassium, and a cup of boiled peas stroke.8,22‑25 After adjusting for potentially con-
contains 0.3 mmol of sodium and 9.8 mmol of founding variables, the INTERSALT researchers
potassium. Isolated populations that eat natural estimated that a decrease in potassium excretion
foods have an individual potassium intake that by 50 mmol per day was associated with an in-
exceeds 150 mmol per day and a sodium intake crease in systolic pressure of 3.4 mm Hg and an
of only 20 to 40 mmol per day (the ratio of dietary increase in diastolic pressure of 1.9 mm Hg. The
potassium to sodium is >3 and usually closer to urinary potassium:sodium ratio in the INTERSALT
10).6,8,10 By contrast, people in industrialized na- study had a significant, inverse relation with
tions eat many processed foods and thereby ingest blood pressure. This ratio bore a stronger statis-
30 to 70 mmol of potassium per day and as much tical relationship to blood pressure than did ei-
as 100 to 400 mmol of sodium per day (the usual ther sodium or potassium excretion alone.11 As
dietary potassium:sodium ratio is <0.4).3,10 compared with whites, blacks have a higher prev
Hypertension affects less than 1% of people alence of hypertension and lower potassium in-
in isolated societies but approximately one third take; sodium intake among whites and blacks is
of adults in industrialized countries.3,10 Differ- similar.10,23 For example, in the Evans County
Study, 23% of whites and 38% of blacks had a cation and 38% required no antihypertensive
diastolic pressure of 90 mm Hg or higher. The medication for blood-pressure control, as com-
24-hour urinary potassium excretion averaged pared with 29% and 9%, respectively, in the con
40 mmol per day for whites and 24 mmol per day trol group at 1 year of follow-up.32
for blacks.26 In the DASH trial, a diet rich in fruits and
In clinical studies, a diet low in potassium vegetables, as compared with the typical Ameri-
(10 to 16 mmol per day) coupled with the partici- can diet, reduced systolic pressure in the 133 hy-
pants’ usual sodium intake (120 to 200 mmol pertensive subjects by 7.2 mm Hg and diastolic
per day) caused sodium retention and an elevation pressure by 2.8 mm Hg, at a constant level of
of blood pressure; on average, systolic pressure sodium intake.33 The potassium content of the
increased by 6 mm Hg and diastolic pressure by diet of fruits and vegetables was more than twice
4 mm Hg in normotensive subjects, and systolic as high as that of the typical American diet;
pressure increased by 7 mm Hg and diastolic pres therefore, its higher potassium:sodium ratio prob
sure by 6 mm Hg in hypertensive subjects.24,25 ably accounted for most of the observed reduction
in blood pressure.
Sodium sensitivity, defined as an increase in
C a r diova s cul a r Effec t s
of P o ta s sium Suppl e men tat ion blood pressure in response to a higher sodium
chloride intake than that in the baseline diet,
Studies have shown that increasing the potassium occurs in many normotensive and hypertensive
intake of hypertensive rats that were fed high- subjects34; in normotensive subjects, sodium sensi
sodium diets lowered blood pressure, reduced tivity appears to be a precursor of hypertension.
the incidence of stroke and stroke-related death, Dietary potassium has been shown to exert a pow-
and prevented cardiac hypertrophy, mesenteric erful, dose-dependent inhibitory effect on sodium
vascular damage, and renal injury.27,28 In one of sensitivity. With a diet that was low in potassium
the studies, these benefits were independent of (30 mmol per day), 79% of normotensive blacks
the blood pressure–lowering effect of the diet.27 and 36% of normotensive whites had sodium
Kempner’s rice–fruit diet, which was intro- sensitivity. Supplementation with 90 mmol of po
duced in the 1940s, was rich in potassium and tassium bicarbonate per day resulted in sodium
extremely low in sodium. This diet was widely sensitivity in only 20% of blacks; this proportion
used in treating hypertension and congestive matched that of whites when they received supple-
heart failure.29 Subsequently, many studies exam- mentation with only 40 mmol of potassium bi-
ined the effect of potassium on blood pressure carbonate per day. An increase in dietary potas-
and most of them identified a salutary effect.8,30 sium can even abolish sodium sensitivity in both
A meta-analysis of 33 randomized trials that eval normotensive and hypertensive subjects.10,34
uated the effects of an increased potassium in-
take on blood pressure concluded that potassium L ack of A da p tat ion of the
supplementation (≥60 mmol per day in all but K idne ys t o the Moder n Die t
2 trials) lowered systolic pressure by an average
of 4.4 mm Hg and diastolic pressure by an aver- Human kidneys are poised to conserve sodium
age of 2.5 mm Hg in hypertensive subjects and and excrete potassium. Prehistoric humans, who
lowered systolic pressure by an average of 1.8 consumed a sodium-poor and potassium-rich diet,
mm Hg and diastolic pressure by an average of were well served by this mechanism.5 With such
1.0 mm Hg in normotensive subjects.31 This effect a diet, sodium excretion is negligible and potas-
was independent of a baseline potassium deficien sium excretion is high, matching potassium in-
cy, and it was greater at higher levels of sodium take. The kidneys account for 90% or more of po-
excretion (≥160 mmol per day) and in trials in tassium loss, with the remainder exiting through
which at least 80% of the subjects were black. the fecal route. This mechanism, however, is un-
Potassium supplementation can reduce the fit for the sodium-rich and potassium-poor mod-
need for antihypertensive medication. One study ern diet. The end result of the failure of the kid-
showed that with an increased dietary potassium neys to adapt to this diet is an excess of sodium
intake in hypertensive subjects, 81% of the sub- and a deficit of potassium in hypertensive patients
jects needed less than half of the baseline medi- (Fig. 1).
Excess of sodium
in the body
Extracellular- Release
fluid volume of digitalis-
expansion like factor
Na+/K+–ATPase
Hypertension
Figure 1. Interaction of the Modern Western Diet and the Kidneys in the Pathogenesis of Primary Hypertension.
The modern Western diet interacts with the kidneys
AUTHOR: to generate
Adrogué excess sodium
(Madias) RETAKE and1stcause a deficit of potassium
ICM
in the body; these changes increase peripheral vascular
FIGURE: 1 of 5 resistance and establish hypertension.
2nd An initial increase in
REG F
the volume of extracellular fluid is countered by pressure natriuresis. 3rd
CASE Revised
EMail Line 4-C SIZE
ARTIST: ts H/T H/T 33p9
Aldosterone contributes to the retention of
Enon
A
low-potassium diet leads to a potassium
Combo
sodium by the kidneys. Evidence from theAUTHOR, Fram- PLEASE
deficit
NOTE:in the body as a result of inadequate con-
Figure has been redrawn and type has been reset.
ingham Offspring Study suggests that relative
Please check carefully. of potassium by the kidneys and the
servation
aldosterone excess, as defined by the higher aldo- alimentary tract; with such a diet, fecal potassi-
sterone values within the physiologic
JOB: 35619 range, pre- um lossesISSUE: exceed even urinary losses.37 Fur-
can 05-10-07
disposes normotensive subjects to hypertension. 35 thermore, a high-sodium intake increases kali-
In animals and humans, a low-potassium diet it- uresis, especially when sodium reabsorption by
self causes renal sodium retention by means of the renal cortical collecting tubule (where sodium
several mechanisms.10,24,25,36 reabsorption and potassium secretion are func-
Figure 2. Molecular Mechanisms Implicated in the Retention of Sodium and Loss of Potassium by the Kidneys in Primary Hypertension.
Solid arrows indicate an increase or stimulation, and the broken arrow indicates inhibition. Numbers on the left denote the approxi-
mate percentage of reabsorption of filtered sodium in each nephronal segment during normal conditions. Several influences acting
on the luminal sodium transporters and the basolateral sodium pump stimulate sodium retention and potassium loss. Promotion of
sodium reabsorption by the activated epithelial sodium channel (ENaC) generates a more negative luminal membrane voltage (Vm)
in the collecting duct that enhances potassium secretion through the luminal potassium channel and promotes kaliuresis. NHE-3 de-
notes sodium–hydrogen exchanger type 3, ACE angiotensin-converting enzyme, NKCC2 sodium–potassium2 chloride cotransporter,
and NCC sodium–chloride cotransporter. PST 2238 (rostafuroxin) antagonizes the effect of digitalis-like factor on the sodium pump.
behavioral interactions that differ within a pop- coids56,57 (Table 1). In both settings, the conse-
ulation and across populations.55 quences of an excess of sodium and a potassium
In rats, coadministration of sodium and min- deficit in the body could be largely responsible for
eralocorticoids results in sodium retention, potas the hypertension and associated tissue injury.58
sium depletion, hypertension, and extensive tis- Furthermore, in primary aldosteronism, potassium
sue damage. These changes bear a remarkable administration augments aldosterone levels and
similarity to the changes in rats with hypertension yet reduces blood pressure, normalizes the circu-
induced by a high-sodium and low-potassium latory reflexes of increased sympathetic activity,
diet, which suppresses endogenous mineralocorti and corrects baroreceptor hyporesponsiveness.59‑61
Figure 3. Molecular Pathways Implicated in the Generation of Increased Arterial and Arteriolar Smooth-Muscle Tone by an Excess of Sodium
and a Deficit of Potassium in Primary Hypertension.
Solid arrows indicate an increase or stimulation, and broken arrows indicate a decrease or inhibition. The inhibition of the sodium pump
and the resulting stimulation of the sodium–calcium exchanger type 1 (NCX1) increase the intracellular concentration of calcium that in
turn triggers actin–myosin interaction and stimulation of vascular contraction. Na+i denotes intracellular sodium concentration, K+i intracel-
lular potassium concentration, Ca2+i intracellular calcium concentration, Vm membrane potential, and RyR ryanodine-receptor calcium
channel. PST 2238 (rostafuroxin) antagonizes the effect of digitalis-like factor on the sodium pump. SEA-0400 is a specific inhibitor of
the bidirectional NCX1 preferentially blocking the calcium influx pathway.
probably caused by changes in the ionic compo- spinal fluid by the intraventricular administration
sition of the vascular wall.7,75 Natriuresis triggers of hypertonic saline raises blood pressure, where-
cellular sodium loss and the redistribution of as increasing the concentration of potassium in
potassium into cells.76 The activation of potas- the cerebrospinal fluid by administering potas-
sium channels contributes to thiazide-induced sium chloride has the opposite effect.45,78 Increas-
vasodilatation.77 ing dietary sodium chloride in animals and hu-
mans elicits small but significant increases in
Effects on the Brain serum sodium83,84; limited data suggest that the
Changes in the concentrations of sodium and resulting increases in the concentration of so-
potassium in the cerebrospinal fluid, acting on a dium in the cerebrospinal fluid contribute to an
sensing region of the brain probably located near elevation in blood pressure.45,84
the third ventricle, have substantial but obverse The intraventricular infusion of aldosterone at
effects on blood pressure (Fig. 5).45,78-82 Increas- a dose that is too small to raise blood pressure
ing the concentration of sodium in the cerebro- when infused systemically decreases potassium
in the cerebrospinal fluid and causes hyperten- tracellular potassium in the brain, thereby moder
sion. The administration of either potassium or ating sympathetic discharge.85
prorenone, a mineralocorticoid antagonist, through The central actions of changes in the concen-
the same route prevents the decrease in potas- trations of sodium and potassium in the cerebro-
sium in the cerebrospinal fluid and the pressor spinal fluid and of an excess of sodium and a
effect of aldosterone (Fig. 5).80,81 The salutary ac- deficit of potassium in the body are probably
tion of small doses of spironolactone or eplere- mediated by changes in the activity of the neu-
none in hypertension and heart failure may large ronal sodium pump and the renin–angiotensin
ly depend on the central effects of the drugs in system in the brain.45,78,82 These changes alter
preventing or minimizing a reduction in the ex- sympathetic outflow, which then causes direc-
A B
Central infusion of Potassium Potassium Excess of sodium Central infusion Central infusion
potassium chloride feeding depletion in the body of hypertonic of aldosterone
sodium chloride
Neuronal Neuronal
sodium pump sodium pump
Sympathetic- Sympathetic-
nerve activity nerve activity
Figure 5. Molecular Pathways Implicated in the Central Effects of Sodium and Potassium on Blood Pressure.
Solid arrows indicate an increase or stimulation, and broken arrows indicate a decrease or inhibition. Panel A depicts the central effects
of intracerebroventricular infusion of potassium chloride
AUTHOR:or of potassium
Androgué feeding on
(Madias) the blood
RETAKE 1st pressure of normotensive rats. Long-term
ICM
intracerebroventricular infusion of potassium chloride prevents the development of deoxycorticosterone–salt
2nd hypertension. Panel B depicts
REG F FIGURE: 5 of 5
3rd
the central effects of potassium depletion and sodium excess in the body, or of the intracerebroventricular infusion of hypertonic sodium
CASE Revised
chloride or aldosterone on the blood pressure of normotensive rats.Line K+CSF denotes
4-C potassium concentration in the cerebrospinal fluid
+ EMail SIZE
and Na CSF sodium concentration in the cerebrospinal fluid.tsProrenone
ARTIST: H/Tis an H/T
aldosterone antagonist.
Enon 39p6
Combo
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
tional changes in blood pressure.86,87 Barorecep- onset type 2 diabetes.93 Treatment of thiazide-
Please check carefully.
tor sensitivity is depressed by potassium depletion induced hypokalemia with potassium augments
JOB: 35619 59
and restored by potassium supplementation. the antihypertensive effect
ISSUE: of the diuretic.94
05-19-07
Effects on Metabolism
Impl ic at ions for Pr e v en t ion
Potassium depletion inhibits insulin secretion and a nd T r e atmen t
is associated with glucose intolerance, whereas
potassium infusion and hyperkalemia increase A modified diet that approaches the high potas-
the secretory rate of insulin by changing the mem- sium:sodium ratio of the diets of human ances-
brane potential of pancreatic beta cells.88,89 Insu- tors is a critical strategy for the primary preven-
lin triggers endothelium-dependent vasodilatation tion and treatment of hypertension. Weight loss
in skeletal muscle by causing the release of nitric with diets rich in fruits and vegetables has been
oxide90; this response is impaired in primary hy- attributed both to the low caloric density and to
pertension.91 the high potassium content of these diets, which
Thiazide-induced hypokalemia worsens glu- tend to increase the metabolic rate.95
cose intolerance in type 2 diabetes mellitus and In its 2002 advisory, the coordinating com-
increases the risk of the disorder; correction of mittee of the National High Blood Pressure Edu-
hypokalemia ameliorates the glucose intoler- cation Program identified both a reduction in
ance.92 As compared with diuretics, angiotensin- dietary sodium and potassium supplementation
converting–enzyme inhibitors and angiotensin II as proven approaches for preventing and treating
receptor blockers, which promote potassium re- hypertension.96 The Institute of Medicine recom-
tention, are associated with a lower risk of new- mends an intake of sodium of 65 mmol per day
(approximately 3.8 g of sodium chloride per day) sitivity appears to be groundless for the recom-
for adults 50 years of age or younger, 55 mmol per mended sodium intake.10 Forms of potassium
day (approximately 3.2 g of sodium chloride per that do not contain chloride, such as those found
day) for adults 51 to 70 years of age, and 50 mmol naturally in fruits, vegetables, and other foods,
per day (approximately 2.9 g of sodium chloride offer larger cellular entry in exchange for sodium
per day) for those 71 years of age or older. The and greater antihypertensive effects.10,97
institute also advises adults to consume at least Following these recommendations would re-
120 mmol of potassium per day (approximately quire a comprehensive, culture-sensitive campaign
4.7 g of potassium per day, which is about twice targeting both the general public and health care
the current U.S. average).10 These targets would professionals. Food processing drastically chang-
require modifications for special groups, includ- es the cationic content of natural foods, increas-
ing competitive athletes, persons working in hot ing sodium and decreasing potassium. Only ap-
environments, patients with chronic kidney dis- proximately 12% of dietary sodium chloride
ease or diabetes, and persons taking medications originates naturally in foods, whereas approxi-
that affect potassium balance. Adoption of the mately 80% is the result of food processing, the
institute’s recommendations would increase the remainder being discretionary (added during cook
dietary potassium:sodium ratio by a factor of 10, ing or at the table).98 Apart from educating the
from approximately 0.2 to approximately 2.0, public, an agreement by the food industry to
which is much closer to our ancestral standard. limit the deviation of the cationic content of pro-
The concern that sodium restriction might in cessed foods from their natural counterparts is
crease cardiovascular risk by activating the sym- essential.
pathetic and renin–angiotensin system and by No potential conflict of interest relevant to this article was
adversely affecting blood lipids and insulin sen- reported.
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