BLOOD PRESSURE 1992; 1: 196-200

 

The Role of Salt in Hypertension

EDWARD D. FREIS

From the Hypertension Research Department of Veterans Affairs, Medical Center, Washington, D.C., U.S.A.

Freis ED. The role of salt in hypertension. Blood Pressure 1992; 1: 196-200.

There is considerable evidence that salt is an important cause of hypertension. Primitive societies who ingest little or no salt
have no hypertension. Also when diets very low in salt such as the rice and fruit diet are given to hypertensive patients, the
blood pressure often falls toward normal. Unfortunately, when diets only moderately low in sodium have been given only
minor reductions in blood pressure occur. Salt-induced hypertension has been produced in both man and experimental
animals. The basic cause of the hypertension is an inability of the kidney to excrete the increased salt. Hemodynamic changes
then occur which raise the blood pressure and so excrete the excess salt by pressure diuresis. The ability to excrete salt at normal
levels of blood pressure varies from one individual to another. Those who require a higher than normal blood pressure are said
to be “‘salt-sensitive”. Those who can excrete excess salt at normal levels of blood pressure are called “‘salt resistant”. The
difference may be due to an inherited defect in the kidney to excrete salt. In any event, salt sensitive hypertension is effectively
controlled with the administration of diuretics. Key words: salt hypertension, hypertension, sodium in hypertension, high blood

pressure and salt.

INTRODUCTION

The importance of salt in hypertension has been
emphasized for many years, first by Ambard & Beau-
jard [1] in 1904 and later by Alten [2], Meneely [3] and
Dahl [4]. There is considerable evidence to support the
hypothesis that essential hypertension frequently is the
result of ingestion of salt. The continual use of salt as a
condiment is not natural to man who in the primitive
state consumed very little of it. The consumption of salt
which modern man regards as normal is a compara-
tively recent development and may, in fact, be far
greater than his biology is adapted to sustain. A
possible mechanism by which salt may exert a hyperten-
sive effect involves the following observations.

EVIDENCE FROM UNACCULTURATED
SOCIETIES

Recent studies of unacculturated societies have dis-
closed that cultures who have practically no contact
with the rest of the world and who live under primitive
conditions have little or no hypertension. Another
characteristic of these peoples, which is opposite to
ourselves, is that the blood pressure does not rise with
age. These characteristics have been noted among
unacculturated peoples in such widely separated parts
of the world as Africa [5] the South Pacific [6] the
highlands of Malaysia [7] and the Amazon Basin of
South America [8].

In searching for differences in habits that might
account for the absence of hypertension among primi-
tive peoples investigators have noted a common thread
which was characteristic of the life style of these peoples
and not of ours. Lowenstein [8] surveyed two neighbor-

ing tribes that lived in the Amazon basin. One of these
tribes, the Manducuras, had been converted by the
missionaries who also introduced them to the use of
table salt. Although still living under relatively primi-
tive conditions these people exhibited a rise of blood
pressure with age and hypertension. The Carajas, on the
other hand, who were not converted and did not use
salt, exhibited no rise of blood pressure with age and no
hypertension.

Additional evidence was provided by Prior et al. [9].
They measured blood pressure and estimated salt
intake (from both dietary histories and 24 h urine
collections) in two ethnically similar but culturally
different tribes of Polynesians, the relatively accultur-
ated Raratongans and the less acculturated Pukapuk-
ans. Among the former, sodium intake averaged 125
mEq per day and hypertension was common. Among
the Pukapukans the sodium intake was much lower and
hypertension was rare.

Page et al. [10] investigated 6 different societies in the
Solomon Island. Some were quite acculturated while
others were not. In agreement with Prior they found the
lowest incidence of hypertension and the smallest intake
of salt in the more unacculturated societies while those
who adapted our ways had a high ingestion of salt, a rise
of blood pressure with age and a high incidence of
hypertension.

The most extensive and most striking observations
were made on the Yanomamo Indians of Brazil [11].
The salt consumption of these people was extremely low
and the average sodium excretion in the urine was only
1 mEq per day. Blood pressure did not rise with age and
hypertension was completely absent. Other interesting
observations were made. Plasma renin activity and
aldosterone excretion rates were markedly elevated by
our standards of normality despite the complete
absence of vascular disease. Undoubtedly these high
values were a reflection of the extremely low salt intake
which, in turn, activated the sodium conserving mech-
anisms. In addition to being essentially sait-free the diet
also was high in potassium. Whether this contributed to
their freedom from hypertension is not known.

On the basis of these and other similar observations
there is at least an association between lack of hyperten-
sion in unacculturated peoples and the fact that salt is
not added to their diet. By contrast, it should be noted
that salt ingestion is extremely high in our culture. Not
only is it added in cooking and at the table but it is also
used as a flavoring agent in almost all prepared foods
even including bread. The average salt consumption in
most parts of the world is about 10 g per day and in
some areas such as in northeast Japan, it rises to 20 to 30
g per day. In the primitive societies where hypertension
is completely absent the salt intake is less than 0.1 g per
day, a hundred-fold difference from our average intake.
We have departed a long way from the salt intake of our
primitive forebears and it would not be surprising if this
was a stress that some of us are not able to cope with,
particularly as we grow older.

THE ROLE OF SALT IN EXPERIMENTAL
HYPERTENSION

How could salt exert a hypertensinogenic effect?
Sodium is retained predominately extracellularly in
contrast to potassium which is almost entirely intracel-
lular. Excessive salt ingestion is associated with exces-
sive thirst because of the body’s need to maintain the
isotonicity of extracellular fluid. Cattlemen in the old
days increased the weight of these animals prior to
marketing by feeding them excess salt and then allowing
them free access to water. If expansion of extracellular
fluid goes too far, however, edema will result against
which the body has defenses. It is precisely these defense
reactions which may provide the basis for hypertension.
In order to clarify this concept it is necessary to review
some of the studies on experimental hypertension.
The initial observations were made by Ledingham
{12] who studied Goldblatt hypertension in rats sub-
jected to renal artery constriction. He made the impor-
tant observation that prior to the development of the
elevated blood pressure there was an increase in
extracellular volume. This observation caused Led-
ingham to investigate the cardiac output changes in rats
during the development of renal vascular hypertension
[13]. He found that the early rise in extracellular volume
was associated with an increase in cardiac output and
this, in turn, led to an increase in blood pressure. When

The role of salt in hypertension 197

the blood pressure rose the elevated extracellular
volume was prevented from rising further because of
pressure diuresis. With the further passage of time there
was an increase in total peripheral resistance and a fall
in cardiac output back to preoperative levels.

Ledingham postulated that the chain of events
leading to hypertension originated with the initial
expansion of extracellular volume and then progressed
as follows: (/) extracellular volume is in equilibrium
with plasma volume and expansion of the former leads
to an increase in the latter. (ii) A rise in plasma volume
and of tissue pressure increases venous pressure and
venous return to the heart. (ii) By Starling’s law of the
heart an increase in venous return and right heart filling
pressure causes a rise in cardiac output. (iv) If cardiac
output rises and total peripheral resistance does not fall
proportionately blood pressure will rise. (v) This eleva-
tion of blood pressure raises the glomerular filtration
rate and produces diuresis thereby preventing further
expansion of the extracellular volume. (vi) Because
cardiac output is increased above normal the tissues will
receive more blood supply than they need. The micro-
circulation responds to such an excess blood supply by
vasoconstriction thereby raising total peripheral resis-
tance. (vii) The increased resistance reacts on the left
ventricle to reduce the cardiac output back toward
normal. (viii) The final hemodynamic state, therefore,
resembles that seen in human essential hypertension
which is characterized by an elevated total peripheral
resistance and an essentially normal cardiac output.

Ledingham’s work received little attention at the time
it was first published. However, it has received confir-
mation by other investigators using different methods
for expanding the extracellular volume. Borst [14] was a
clinician in Holland, a country in which the eating of
licorice is popular. Licorice contains a substance which
has an action similar to mineralocorticoid and is known
to cause sodium retention and hypertension when
ingested in large amounts. Borst studied the hemodyna-
mic changes leading to the hypertension in volunteers
fed excess licorice. They exhibited a rise of blood
pressure which was initially associated with an elevation
in cardiac output. Borst postulated an unknown renal
defect requiring a higher than normal blood pressure to
excrete the increased salt and water load.

A direct relationship between arterial blood pressure
and urine volume was first shown by Selkurt [15].
Perfusing the isolated kidney at different arterial pres-
sures he demonstrated a direct relationship between
perfusion pressure and urine volume. This is an impor-
tant piece in the puzzle of salt and hypertension because
it provides a positive feedback mechanism for getting
rid of a chronic excess of extracellular volume. Appar-
ently, our regulatory mechanism prefers developing
198 E. D. Freis

hypertension to developing edema. However, nature
did not anticipate that the excess salt and water load
would be continuous as is the case with modern man.
Arthur Guyton used a more direct approach to
induce a continuous expansion of extracellular volume
[16]. In dogs he removed one kidney and half of the
other and then loaded the animals with saline solution.
He noted the same sequence of hemodynamic events,
ic. initial high output hypertension followed by high
resistance hypertension which had been described by
Ledingham. Guyton also constructed computed flow
diagrams to demonstrate the various inter-relationships
of different feedback loops involved in the regulation of
blood pressure. He concluded that the common de-
nominator in the development of any chronic elevation
of blood pressure is the need for the kidney to increase
urine volume and sodium excretion. Guyton postulated
that the intrinsic functional capacity of the kidney to
excrete salt and water varies from one individual to
another. Those with a restricted functional capacity
retain the salt and water, which results in hypertension
(“‘salt-sensitive hypertension’’). The hypertension in
turn permits the kidney with reduced functional capa-
city to excrete the excess salt and water load. Homeosta-
sis between salt ingestion and salt excretion is estab-
lished at the expense of an increased blood pressure.

EVIDENCE FOR A RENAL DEFECT IN
HANDLING SALT

Neither Guyton nor anyone else has as yet been able to
identify a specific renal defect in early essential hyper-
tension. However, there is now evidence indicating that
the kidneys in spontaneously hypertensive rats do have
intrinsic hypertensinogenic properties and fail to
excrete salt and water loads efficiently.

The first piece of evidence comes from cross-trans-
plantation experiments. Bianchi [17] transplanted the
kidneys of a salt sensitive hypertension-prone strain of
rats into normal rats. Hypertension developed in the
normal rats with kidneys taken from the hypertension
prone animals. Then he transplanted the kidneys from
normal rats into hypertensive animals. Blood pressure
normalized in the latter. Working independently pre-
cisely similar observations were made by Dahl [18] thus
confirming the important observation that the kidneys
seem to be the locus of the hypertension in this type of
inherited rat hypertension.

What is the nature of this renal defect? Could it be
associated with the ability of the kidney to excrete salt
and water? Tobian indicated that this ts the case [19]. He
repeated Selkurt’s isolated kidney perfusion experi-
ments, only he compared kidneys from hypertension-
resistant and hypertension-prone strains of rats. He

found that a higher arterial perfusion pressure was
required by the kidneys from hypertension-prone ani-
mals to excrete a given salt load than by the kidneys of
the hypertension-resistant rats.

MECHANISM OF SALT INDUCED
HYPERTENSION

It is tempting to make the jump from inherited hyper-
tension-prone rats to humans with essential hyperten-
sion. We can formulate the following hypothesis: Many
humans are not able to handle large amounts of salt in
their diet. The salt habit is of comparatively recent
origin in our history. The daily ingestion of large
amounts of salt leads to a chronically expanded extra-
cellular volume. The latter acts as a considerable stress
on the functional capacity of the kidney and as the
individual ages renal competency declines and blood
pressure begins to rise. It is the only positive feedback
mechanism available to prevent edema. By contrast, the
renin-angiotensin mechanism is designed mostly to
conserve rather than enhance salt loss. But such a
negative feedback mechanism is severely limited as
opposed to a positive feedback mechanism which has
infinite gain.

An additional facet of this hypothesis is that renal
functional capacity to handle an excess volume is not
uniformly distributed in the population. It varies from
individual to individual as an inherited characteristic.
In fact, it is distributed in the same unimodal way that
blood pressure is distributed in the population. The
individuals who are so unfortunate as to have kidneys
with a poor functional capacity to excrete salt are
destined to develop hypertension if exposed to a daily
intake of salted foods: salt sensitive hypertension.
Those with a high functional capacity to excrete salt and
water loads will maintain normal diastolic blood pres-
sure throughout their lifetimes: salt resistant hyperten-
sion.

EXTRACELLULAR VOLUME. WHAT IS
NORMAL?

What ts a normal extracellular volume? In the days
when the rice and fruit diet (which contains less than 8
mEq of sodium per day) was popular, blood pressure
could be reduced in many hypertensive patients for as
long as the patients could tolerate the diet. Investigators
at that time found that the reduction of blood pressure
was associated with a 15% fall in extracellular volume
and a 10% decrease in plasma volume [20, 21].
Wilson & Freis [22] found that during treatment with
chlorothiazide the fall in blood pressure was associated
with a 15% reduction in extracellular volume and a 10%
reduction in plasma volume. The agreement with the
rice, no-salt diet was identical. At that time we postu-
lated that there was a readily mobilizable pool of
extracellular volume the removal of which led toward
normalization of blood pressure. Following thiazides
bodily defenses such as the renin-angiotensin system
and reduction of blood pressure itself (causing a fall in
glomerular filtration rate and possibly other renal
changes) prevented a further depletion of extracellular
volume with continued treatment with thiazide diure-
tics.

What is the significance of this mobilizable pool of
extracellular volume that is removed by diets very low in
sodium or by diuretics and which results in a fall to or
toward normal in blood pressure? Probably man in the
primitive state did not have such a mobilizable excess of
extracellular fluid that we have today because of their
very low sodium intakes. If we can judge from the high
renin and aldosterone levels of the unacculturated
Yanomamo Indians and by their very low salt diets it is
likely that they do not have this labile pool of extracellu-
lar fluid either. If so, the extracellular and plasma
volumes of modern man are chronically expanded 10 to
15% above what nature intended for us to have. This
abnormal expansion of extracellular volume provides
the stimulus to hypertension in susceptible (salt-sensi-
tive) individuals. The response to this volume expansion
is the same that Ledingham, Borst & Guyton observed
in their experimental forms of hypertension.

ANCILLARY MECHANISMS

The mechanistic theory of Ledingham is not the only
way in which excess volume can induce hypertension.
There are, in fact, several other possible mechanisms.
The hypertensive response to norepinephrine is
enhanced when volume is expanded and is decreased
when volume is contracted [23]. Similarly, the response
to antihypertensive agents is increased by volume
depletion [24]. Therefore, an expanded extracellular
and plasma volume tends to raise blood pressure by
enhancing the effects of pressor stimuli and diminishing
the activity of depressor stimuli.

Another possible enhancing mechanism is resetting
of the baroreceptors. If an expansion of volume acts as a
pressor stimulus the hypertension will be combatted by
the baroreceptors only if the volume stimulus is of
relatively short duration. However, if the elevation of
blood pressure continues for several days the barore-
ceptors tend to reset to the higher level of blood pressure
[25].

CONCLUSION

There is a close relationship in many individuals
between salt-induced volume changes and blood pres-

The role of salt in hypertension 199

sure. Firstly, an increase in volume induces a series of
hemodynamic changes often leading to hypertension.
Secondly, reduction of blood pressure with many
antihypertensive drugs, other than diuretics, often lead
to salt and water retention. Thirdly, cross-transplant-
ation of the kidneys of a salt sensitive rat into a salt
resistant animal results in the development of hyperten-
sion in the salt resistant rat. When the kidneys from a
salt resistant rat are transplanted into a salt-sensitive
animal, the latter becomes normotensive. These experi-
ments indicate that there is an inherited defect which is
related to the kidney’s intrinsic ability to excrete salt.
This defect is present in some individuals (salt sensitive)
and not in others. Diuretics act by enhancing the ability
of the kidney to excrete excess salt and, thereby, lower
blood pressure.

REFERENCES

1. Ambard L, Beaujard E. Causes de ’hypertension arter-
ielle. Arch Gen Med 1904;1:520.

2. Allen FM. Treatment of kidney diseases and high blood
pressure. Morristown, The Psychiatric Institute, 1925.

3. Meneely GR, Dahl LK. Electrolytes in hypertension: the
effect of sodium chloride. The evidence from animal and
human studies. Hypertension and its treatment. Med Clin
North Am 1961;45:271.

4. Dahl LK. Salt and hypertension. Am J Clin Nutr
1972;25:231.

5. Kaminer B, Lutz WPW. Blood pressure in bushmen of
the Kalahari desert. Circulation 1960;22:289.

6. Cruz-Coke R, Etcheverry R, Nagel R. Influence of
migration on blood pressure of Easter Islanders. Lancet
1964;7:697.

7. Burns-Cox CJ, Maclean JD. Splenomegaly and blood
pressure in an Orang Asli community in West Malaysia.
Am Heart J 1970;80:718.

8. Lowenstein FW. Blood pressure in relation to age and sex
in the tropics and subtropics. A review of the literature
and an investigation in two tribes of Brazil Indians.
Lancet 1961;2:389.

9. Prior AM, Evans JG, Harvey HPB, Davison F, Lindsey
M. Sodium intake and blood pressure in two Polynesian
populations. N Engl J Med 1968;279:515.

10. Page LB, Danion A, Moellering RD Jr. Antecedents of
cardiovascular diseases in six Solomon Islands societies.
Circulation 1974;49:1132.

11. Oliver WJ, Cohen EL, Neel JV. Blood pressure, sodium
intake and sodium related hormones in the Yanomamo
indians, a “no-salt” culture. Circulation 1975;52:146.

12. Ledingham JM. Distribution of water, sodium and
potassium in heart and skeletal muscle in experimental
renal hypertension in rats. Clin Sci 1953;12:337.

13. Ledingham JM, Cohen RD. The role of the heart in the
pathogenesis of renal hypertension. Lancet 1963;i:979,

14. Borst JGG, Borst DeGA. Hypertension explained by
Starling’s theory of circulation homeostasis. Lancet
1963;i:677.

15. Selkurt EE. Effects of pulse pressure and mean arterial
pressure modifications on renal hemodynamics and elec-
trolyte and water excretion. Circulation 1951;4:541.
200

16.

19.

20.

21.

E. D,. Freis

Guyton AC, Coleman TG, Cawley AW, Manning RD Jr,
Norman RA, Ferguson JD. A systems analysis approach
to understanding long-range arterial blood pressure
control and hypertension. Cir Res 1974;35:159.

. Bianchi G, Fox V, DiFrancesco GF, Giovannetti AM.

Pagetti D. Blood pressure changes produced by kidney
cross-transplantation between spontaneously hyperten-
sive rats (SHR) and normotensive rats (NR). Clin Sci Mol
Med 1974;47:435.

. Dah! LK, Heine M, Thompson K. Genetic influence of

the kidneys on blood pressure. Evidence from chronic
renal homografts in rats with opposite predispositions to
hypertension. Cire Res 1974;40:94.

Tobian L, Lange J, Azar S, Iwai J, Koop D, Coffee K.
Reduction of intrinsic natriuretic capacity in kidneys of
Dahl hypertension-prone rats. Annual Fall Conference,
The Council for High Blood Pressure Research, Cleve-
land, Ohio. October 27 and 28, 1977.

Murphy RJF. The effect of “rice diet” on plasma volume
and extracellular fluid space in hypertensive subjects. J
Clin Invest 1950;29:912.

Watkin DM, Fraeb HF, Hatch FT, Gutman AB. Effects

22,

23.

24.

25.

of diet in essential hypertension. IT. Results with unmodi-
fied Kempner rice diet in fifty hospitalized patients. Am J
Med 1950;9:441.

Wilson IM, Freis ED. Relationship between plasma and
extracellular fluid volume deletion and the antihyperten-
sive effect of chlorothiazide. Circulation 1959;20:1028.
Freis ED, Wanko A, Schnaper HW, Frohlich ED.
Mechanism of the altered blood pressure responsiveness
produced by chlorothiazide. J Clin Invest 1960;39:1277.
Freis ED. Treatment of hypertension with chlorothia-
zide. JAMA 1959;169:89.

McCubbin JW, Green JH, Page IH. Baroreceptor func-
tion in chronic renal hypertension. Cir Res 1956;4:205.

Submitted July 8, 1992; accepted July 17, 1992

Address for correspondence:

Edward D. Freis, M.D.
VA Medical Center

50 Irving Street, N.W.
Washington, D.C. 20422
U.S.A.