SPECIAL ARTICLE

 

Salt, Volume and the Prevention of Hypertension

Epwarp D. FREIs, M.D.

SUMMARY The evidence supporting the thesis that hypertension
can be prevented by eliminating salt from the diet is based on four
Principal sources: (1) epidemiological studies in unacculturated
peoples showing that the prevalence of hypertension is inversely cor-
related with the degree of salt intake; (2) hemodynamic studies
suggesting that the development of chronic experimental hyperten-
sion is a homeostatic response to a maintained increase in ex-
tracellular fluid volume (ECF); (3) evidence that the ECF of “salt

This special article is designed to correlate data obtained
from various lines of investigation to support a concept
bearing on the pathogenesis and prevention of essential
hypertension. In essence, the concept indicates that essential
hypertension is a disorder of acculturated peoples and is
caused specifically by the acquired habit of eating salt. The
supporting evidence will use data from three principle
sources: 1) epidemiological studies in unacculturated
peoples showing that the prevalence of hypertension is in-
versely correlated with the degree of salt intake; 2) hemo-
dynamic studies suggesting that the development of chronic
experimental hypertension is a homeostatic response to a
maintained increase in extracellular fluid volume (ECF);
and 3) investigations in hypertensive patients receiving either
diets greatly restricted in salt or continuous diuretic therapy
which correlate the fall in blood pressure with a reduction in
ECF.

The importance of salt in the pathogenesis of hyper-
tension was emphasized as early as 1904 by Ambard and
Beaujard’ and later by Allen,” Meneely’ and Dahl.* The
hemodynamic changes relating an increase in ECF as the
initiating factor in a sequence of events leading to chronic
hypertension were shown by Ledingham,° Borst,* Guyton’
and Tobian.* Using a systems analysis approach, Guyton in
particular provided a conceptual framework integrating the
various mechanisms for controlling blood pressure and in-
dicated the overriding importance of the relationship
between arterial blood pressure and renal functional
capacity to handle excess sodium in determining the
presence or absence of hypertension. The crucial role of the
ECF in the reduction of blood pressure with dietotherapy
was emphasized by Murphy® and Watkin,’® and with
diuretics by Dustan” and Wilson and Freis.'? It is not the
purpose of this article to reemphasize such pioneering obser-
vations. Rather it is to combine these and other related
studies in order to present a comprehensive picture of the
tole of salt in the pathogenesis of essential hypertension and

 

From the Departments of Medicine, Veterans Administration Hospital and
Georgetown University School of Medicine, Washington, D.C.

Address for reprints: Edward D. Freis, M.D., Senior Medical Investigator,
Veterans Administration Hospital, 50 Irving Street, N.W., Washington, D.C.
20422.

Received September 29, 1975; revision accepted for publication November
5, 1975.

589

eaters” is expanded in comparison to that of “‘no-salt eaters”; and (4)
investigations in hypertensive patients receiving either diets greatly
restricted in salt or continuous diuretic therapy which correlate the
fall in blood pressure with a reduction in ECF. Although this
mechanism of essential hypertension is still obscure the evidence is
very good if not conclusive that reduction of salt in the diet to below
2 g/day would result in the prevention of essential hypertension
and its disappearance as a major public health problem.

to indicate how these observations point the way toward
prevention.

Salt and Hypertension in Unacculturated Peoples

It is a striking fact that hypertension is not found in unac-
culturated societies nor does the blood pressure rise with age
as occurs in all ‘‘civilized’’ populations. Obviously, there
must be some environmental factor which accounts for the
difference. The hypotheses that have been advanced to ex-
plain the lack of hypertension in unacculturated peoples in-
clude 1) debility produced by parasitic or other diseases, 2) a
simple, slow-paced and noncompetitive way of life, 3) lack
of obesity and 4) a low intake of salt. The evidence suggests
that it is the latter factor which accounts for the virtual
absence of hypertension among primitive peoples.

An absence of hypertension and a failure of the blood
pressure to rise with age has been observed in unacculturated
populations from widely different parts of the world in-
cluding New Guinea," the highlands of Malaysia, the
Easter Islands, the Amazon Basin,"* the San Blas Islands
of Panama,” rural Uganda,"* and the Kalahari Desert of
Africa.” Whereas malaria and other parasitic diseases are
endemic in some of these areas, this is not the case in all.
The desert living Kalahari bushmen were free of these dis-
eases and were in physically excellent condition, being able
to run for long distances in pursuit of game.’* Inhabitants of
some of the more remote South Pacific islands such as
Pukapuka in the Cook Islands” or the Easter Islands'* also
were in excellent health and had little or no hypertension. A
recent survey of six Solomon Island societies indicated that
the lower blood pressure among the less acculturated
peoples could not be ascribed to disease or malnutrition.”

The second possibility, that the absence of hypertension in
unacculturated peoples is due to lack of economic stress,
racial or ethnic tensions, urban way of living, noise, and fast
pace of life is more difficult to examine. However, the life of
primitive man is not always idyllic or free from anxiety. On
the other hand, among the native population of the Virgin
Islands where racial tensions are low, the blacks are in the
majority and the pace of life is relaxed, there is a very high
prevalence of hypertension.” Nor does urban living seem to
be an important factor since the prevalence of hypertension
in the United States is considerably higher among rural
590 CIRCULATION

southern blacks than among blacks living in large cities.”
Therefore, crowding, competition, noise and other forms of
urban socioeconomic stress show no direct correlation with
the presence of hypertension.

Although a relationship between body weight and hyper-
tension is well established in this country” such a correlation
does not seem to hold among less acculturated populations.
Prior” compared the less acculturated Pukapukans who ex-
hibit little hypertension with the more acculturated
Raratongans in whom hypertension is common. He found
that the difference in blood pressure between the two
societies could not be attributed to differences in body
weight. Similarly, Page” in his studies of six Solomon
Island populations could find no correlation between body
weight and systolic blood pressure. Page observed a rise of
blood pressure with age in the relatively acculturated
societies but not in the unacculturated peoples. However, the
rise in the former groups could not be attributed to
differences in body weight. The available evidence,
therefore, does not support the concept that the lack of
hypertension in unacculturated populations is due to their
leaner bodily habitus as compared to acculturated peoples.

On the other hand, a number of studies suggest that it is
the lack of salt in the diet which accounts for the virtual
absence of hypertension in unacculturated peoples. Lowen-
stein surveyed two neighboring tribes living in the Amazon
Basin, the Mundurucus and the Carajos.* The former had
been converted to Christianity by missionaries who also in-
troduced them to the use of table salt. Although still living
under relatively primitive conditions, the members of this
tribe showed a rise of blood pressure with age and some had
hypertension. The Carajos, on the other hand, who spurned
all contact with civilization including the use of table salt,
exhibited no change in blood pressure with increasing age
and hypertension was absent. In their investigation of six
Solomon Island societies, Page and his associates” found a
rise in blood pressure with age in the three most acculturated
societies and no rise in the three most unassimilated peoples.
The differences correlated best with the intake of salt, the in-
gestion of which was substantially greater in the more ac-
culturated populations. In another part of the world, Shaper
carried out investigations of the nomadic peoples of Uganda
over a period of many years.’® He consistently observed that
the tribes without hypertension were those with a low salt in-
take. In tribes with hypertension, the salt intake had in-
creased markedly.

Further evidence is provided by Prior and his associates”
who measured blood pressure and estimated salt intake from
both dietary samples and urine collections in two ethnically
similar groups of Polynesians in the Cook Islands. There
were no significant differences in height, weight or general
health among the two populations. In the more acculturated
Rarotongans, sodium intake averaged about 125 mEq per
day and hypertension was common. Among the Puka-
pukans, however, sodium intake averaged 60 mEq per day
and hypertension was rare. A blood pressure of 160/95 mm
Hg or higher was observed in 28% of Rarotongan males and
in only 3% of Pukapukan males. While the Pukapukans used
no salt in cooking, they sometimes ate canned beef which
may account for the occasional cases of hypertension
observed among them.

Further evidence for a relationship between salt ingestion

Voi. 53, No. 4, Aprit 1976

and the presence of hypertension is provided by two ad-
ditional studies, one of the Yanomamo Indians of Brazil*®
and another of a native population in the highlands of New
Guinea.”* In the former, the urinary excretion of sodium was
only 1.0 mEq per 24 hours while in the latter it was ap-
proximately 15 mEq. Hypertension was absent among the
Yanamamo Indians and was present in only 3% of the New
Guinea adult population. When it was found, the hyper-
tension was practically limited to the 20 to 40 year age group
in contrast to acculturated populations where the prev-
alence of hypertension increases with age.

When unacculturated peoples who are free of hyper-
tension adapt modern ways of life, blood pressure rises and
hypertension appears. At the same time, their salt intake in-
creases dramatically. Maddox investigated five populations
in New Guinea." In the highland regions where salt or salty
foods were not used, no hypertension was found and blood
pressure did not rise with age. However, in a coastal fishing
population, blood pressure rose with age and hypertension
was present. The coastal peoples ate salted canned foods in
contrast to the highlanders who did not, a fact confirmed by
the finding of a considerably higher sodium-potassium ratio
in the urine of the coastal population. The urban Zulu ex-
hibits hypertension while the nonsalt eating rural Zulu does
not.27 Semiacculturated Cook Islanders have more hyper-
tension than their more primitive neighbors.” In every
epidemiological study of this type, when salt is not added to
the diet hypertension is low or absent, and when salt is used
the prevalence of hypertension is high. In almost every re-
cent epidemiological survey of unacculturated peoples, the
importance of salt has been emphasized as the leading
possibility for determining the presence or absence of hyper-
tension.?* 20, 21, 25, 28

The evidence for the role of salt in the development of
hypertension is admittedly circumstantial. Obviously, many
social, economic and dietary factors change with accultura-
tion. Yet the evidence points away from other factors such
as pace of life, crowding and improved general health as be-
ing important factors. The observation of Lowenstein of the
two tribes in the Amazon basin indicates that urbanization is
not the important factor since both groups lived in essen-
tially the same environment except for their diet. The con-
siderably higher prevalence of hypertension in rural
southern blacks as compared to those who migrated to the
large cities of the north indicates that urbanization, per se, is
not an important influence. Of the various changes that are
brought about with acculturation by far and away the most
important seems to be an increase in the intake of dietary
salt.

Role of the ECF in Blood Pressure Regulation

Salt ingested in the diet is distributed predominantly to
the extracellular space. Excess amounts of salt or water are
eliminated primarily through the kidneys. Over the past 20
years, there has been a growing realization of the impor-
tance of the relationship between extracellular fluid volume
(ECF) and arterial blood pressure.*’° Ledingham in 1953
called attention to the fact that prior to the development of
hypertension, the ECF increased in rats subjected to renal
arterial constriction.’ Floyer and Richardson concluded that
the relationship between the blood volume and capacitance
vessels was important in the blood pressure control of
PREVENTION OF HYPERTENSION/Freis 591

parabiotic rats with experimental hypertension.*® These ob-
servations caused Ledingham to investigate the cardiac
output changes in rats during the development of experimen-
tal renovascular hypertension.” The rise in extracellular
volume in the early period following renal arterial constric-
tion was accompanied by an increase in cardiac output anda
rise in blood pressure. The elevated extracellular volume
then receded due to diuresis and cardiac output fell while
total peripheral resistance increased to maintain the hyper-
tension. Ledingham postulated that the increased cardiac
output led to autoregulation of the resistance vessels so that
the peripheral resistance increased. The resulting further rise
in blood pressure increased left ventricular afterload and,
thereby, returned cardiac output to normal. Thus, the
chronic stage of the hypertension was represented by a nor-
mal cardiac output and an increased peripheral resistance.

The ability of the tissues to autoregulate blood flow by
local changes in resistance is clearly demonstrated in pa-
tients with coarctation of the aorta.*° Despite widely differ-
ing blood pressures above and below the coarctation, blood
flows in the arm and leg are similar. This nice regulation of
blood flow must be accomplished by appropriate and strictly
local changes in peripheral vascular resistance.

Borst, in studies on licorice-induced hypertension in man,
postulated that the elevated blood pressure results from cir-
culatory adjustments that occur in response to an increase in
extracellular volume.* He found that venous filling pressure
rises and is followed by an increase in cardiac output and a
rise of blood pressure. As a result of the increased blood
pressure, the kidney is able to excrete the increased volume
(see below). To explain the occurrence of hypertension in
some individuals and not in others, Borst postulated an un-
known renal defect requiring a higher than normal blood
pressure to excrete the increased salt and water load, a
remarkably prophetic insight in view of later developments.

A direct relationship between arterial blood pressure and
urine volume was first clearly demonstrated by Selkurt™ and
has since been confirmed by many different investigators.
The important relationship between ECF and arterial blood
pressure has been elegantly presented by Guyton and his
associates’ and by Tobian.* Guyton produced a continued
expansion of ECF by salt and water loading animals with
reduced renal mass. He observed the same sequence of
hemodynamic events leading to hypertension which included
a temporary rise in cardiac output followed by an elevated
total peripheral resistance. An increase in urinary output
and reduction in ECF accompanied the rise in blood pres-
sure. As a result of these and other experiments involving
additional blood pressure control mechanisms, Guyton
constructed systems-analysis type of flow diagrams to dem-
onstrate the interrelationships of the various feedback
loops involved in the regulation of blood pressure. He con-
cluded that the common denominator in the development of
any chronic elevation of blood pressure is the need for the
kidney to increase urine volume and sodium excretion, that
is, to prevent a chronically expanded ECF. The level of
blood pressure required to produce the diuresis will depend
upon the ability of a particular kidney to excrete an excess of
sodium which varies from one individual to another. The
gradient of the curve which relates urinary output to arterial
blood pressure will depend on the intrinsic functional
capacity of the kidney; the more impaired the function, the

steeper the slope of the curve modified by other influences as
described below including the renin-angiotensin-aldosterone
mechanism, the sympathetic nervous system, ADH secre-
tion and probably other factors.

It is frequently noted in hypertensive patients that con-
tinuous reduction of blood pressure with antihypertensive
agents other than diuretics will result in an accumulation of
extracellular fluid.*?** In this case, the arterial blood
pressure apparently has been forced below a level at which
the hypertensive kidney can maintain homeostasis of the
ECF,

Of great interest has been the demonstration in rats that
the predisposition to hypertension is inherited and at least in
some strains, seems to reside in the kidneys. Dahl selectively
inbred hypertension-prone strains and hypertension-resistant
strains of rats.‘ The hypertension-prone strain regularly
developed hypertension with any of the usual experi-
mental maneuvers including renal arterial constriction and
high salt feeding, while the hypertension-resistant strain
seldom exhibited hypertension following these maneuvers.
Bianchi also produced a hypertensive strain of rats by selec-
tive inbreeding.“ In a brilliant surgical tour-de-force he
succeeded in transplanting the kidneys of the hypertensive
rats into normotensive rats. The normotensive rat with hy-
pertensive kidneys then becaine hypertensive. Transplanta-
tion of the kidneys of normotensive rats into hypertensive
rats led to a reduction of blood pressure in the latter. Similar
observations have been made by Dahl.*

In the light of the various experimental and clinical ob-
servations cited above, it is possible to reemphasize the fol-
lowing hypothesis of the pathogenesis of hypertension.’ * Ho-
meostasis of the ECF is maintained by a balance between
salt and water intake and urinary output. The latter depends
in part on the level of arterial blood pressure and this rela-
tion will differ from individual to individual depending on
the intrinsic renal functional capacity to handle salt and
water loads. If the ECF expands as in primary aldoster-
onism or excessive licorice ingestion, venous filling pressure
will increase and a series of hemodynamic events will occur
resulting in a rise of blood pressure sufficient to increase
urine volume and sodium excretion by the amount neces-
sary to prevent edema. In experimental renovascular hyper-
tension, a similar sequence of events has been shown to
occur possibly through activation of the renin-angiotensin-
aldosterone system. In essential hypertension, it is suggested
that there is an inherited defect in the handling of sodium
such that the kidney requires a higher than normal perfusion
pressure to maintain ECF homeostasis in the presence of a
high sodium intake.’

While the renal functional ability to handle an increased
ECF load appears by this theory to be the crucial patho-
genetic determinant of hypertension, it is also probable that
the expanded ECF of acculturated peoples increases the
pressor responses to other, more short-term pressor stimuli.
For example, the pressor response to infusion of norepine-
phrine in man is greater when the ECF is “norma!” than
when it is reduced by the administration of a diuretic.** Also,
salt loaded rats exhibit an enhanced pressor response to
angiotensin whereas ECF depletion has the opposite effect.”

There also is evidence that frequently repeated elevations
of blood pressure will eventually lead to structural changes
in the resistance vessels so that the wall is thickened and the
592 CIRCULATION

lumen is correspondingly narrowed. Folkow demonstrated
structural changes in the resistance vessels of spontaneously
hypertensive rats during the period in which they developed
hypertension.“ He postulated that the hypertension seen in
these rats is the result of a vicious circle in which frequent,
probably neurogenically mediated, pressor reactions lead to
structural alterations of the resistance vessels and a rise in
basal blood pressure. Further pressor stimuli will then result
in even higher blood pressures and greater thickening of the
arterial walls, a vicious circle resulting in progressive struc-
tural changes and elevations of blood pressure. If essential
hypertension is of similar origin, it would follow that the
pressor influences, neurogenic or otherwise, would be
amplified in the presence of an expanded ECF such as is
present in acculturated peoples but not in unacculturated
populations.

The ECF is “normal” in patients with essential hyper-
tension.** “© This finding, however, is not inconsistent with
the volume-load hypothesis because the kidney maintains
ECF homeostasis by reason of the fact that the blood
pressure is elevated. Nevertheless, the ECF probably is ex-
panded by the standards of unacculturated peoples and also
by that of our primitive forebears. The evidence for this
statement, which is presented more fully below, includes the
following: 1) nonedematous hypertensive patients con-
suming diets containing less than 10 mEq sodium per day
maintain a reduction of approximately 15% of their ECF.
While ECF has not been measured directly in unac-
culturated peoples, there is no reason to believe they would
behave any differently from hypertensive patients. 2) Unac-
culturated peoples exhibit characteristics usually associated
with ECF ‘‘depletion”’ including elevated plasma renin ac-
tivity and urinary aldosterone excretion despite low normal
levels of blood pressure. Therefore, in addition to the con-
stant stress placed on the sodium excretory mechanisms, the
relatively expanded ECF would also enhance the effects of
all pressor stimuli as compared to primitive man.

Relationships Between Dietary Sodium,
ECF and Blood Pressure

The importance of dietary sodium in the maintenance of
the ECF has been known for many years.“’ Murphy in 1950
measured the changes in plasma volume and ECF in hyper-
tensive patients treated with the Kempner rice diet.* This
diet is very low in sodium containing less than 8 mEq per
day. While there was no change in serum sodium concentra-
tion, plasma volume decreased 10% and ECF fell 12% over a
three-week period. This was accompanied by a reduction in
arterial blood pressure. Watkin and his associates found
similar changes in patients treated with the rice diet.'°
Plasma volume was reduced 9% and ECF 15%. A fall in
blood pressure accompanied the reductions in volume. The
volume changes correlated significantly with changes in
body weight suggesting that the weight loss was due
primarily to the reduction in ECF. The addition of 3.0 gm of
salt daily restored the plasma volume and this was accom-
panied by a partial rise of the blood pressure toward control
levels. Addition of 1.0 g of salt only slightly raised plasma
volume and did not increase blood pressure. Thus, the
critical level of salt ingestion for re-expansion of the ECF
was between | and 3 g per day. In discussing the degree of

Vor. 53, No. 4, Aprit 1976

sodium restriction required for effective treatment, Watkin
commented, ‘The critical level of sodium intake with
respect to hypertension appears to be extremely low, at least
in many patients with advanced stages of hypertension a
sodium intake above the critical level causes a more or less
prompt return of hypertensive manifestations.”

Similar changes have been observed following the con-
tinuous administration of thiazide diuretics. Plasma volume
and ECF fall by nearly identical percentages as with the rice
diet. ? Right heart filling pressures and cardiac output
decrease." *? Responses to depressor agents such as
adrenergic blocking drugs or vasodilator agents are
enhanced while the effects of pressor stimuli are depressed.**
Although it is generally taught that ECF returns to normal
after several weeks of diuretic treatment, the burden of
evidence strongly indicates the contrary. All studies except
one* indicate that plasma volume and ECF remain reduced
after long periods of treatment.’* ** “* Furthermore, discon-
tinuation of the diuretic after prolonged treatment results in
a prompt rebound of these volumes indicating that they had
remained depressed during the treatment period.’ “ These
observations are important because they indicate that a con-
tinued reduction in volume is required to maintain the anti-
hypertensive effect of the diuretic agents. Further evidence
against a vasodilator action of the thiazides is indicated by
the fact that the drug exerts no antihypertensive effect in
nephrectomized animals.“

Only one well controlled trial has claimed an anti-
hypertensive effect from moderate as opposed to severe
sodium restriction.” In this trial in patients with mild hyper-
tension, a degree of sodium restriction was imposed suf-
ficient to decrease the 24 hour excretion of sodium from 191
to 93 mEq per day. The blood pressure fell minimally, the
reduction being only 7.7/4.4 mm Hg as compared to a fall of
16.1/8.1 mm Hg in the same patients given thiazide
diuretics. Plasma or ECF volumes were not measured.

It is suggested on the basis of the various lines of evidence
presented that the antihypertensive effect of either sodium
restriction or diuretic therapy depends upon the main-
tenance of a reduced ECF. The decreased volume load per-
mits the hypertensive kidney to operate at a lower level of
arterial blood pressure and still maintain homeostasis of the
ECF. The studies that have been done indicate that a reduc-
tion of salt intake to about 1 gm or 17 mEq per day is re-
quired to produce more than a minimal reduction of blood
pressure.’* #

The above considerations explain much of the discrepancy
that exists in the literature concerning the relationship
between dietary sodium and hypertension. The evidence
from unacculturated peoples which was reviewed above in-
dicated an absence of hypertension when no salt was added
to the diet. The level of dietary intake of sodium was such
that a contraction of the ECF would be expected as com-
pared to salt eating populations. On the other hand, signifi-
cant differences in ECF in peoples who ingest canned goods
and other salted foods would not be expected regardless of
different degrees of additional salting of food. Salt is added
to almost all processed foods, even to bread, so that ECF is
expanded in all “civilized” peoples compared to man living
under primitive conditions. Therefore, the hypertensive
stimulus of a relatively expanded ECF will be present regard-
less of use of a salt shaker. It is not surprising, therefore,
PREVENTION OF HYPERTENSION /Freis 593

that neither Dawber and associates** nor Miall** found any
correlation between sodium intake and blood pressure in ac-
culturated Western populations. They evaluated salt intake
primarily on the basis of whether a salt shaker was used in
cooking and/or at the table. Even their low-salt group,
however, must have been ingesting enough salt to expand the
ECF. On the other hand, severe salt restriction results in a
significant fall in blood pressure.® 1° 5°»

The surveys of Dawber and Miall indicate that within the
range of intake encompassed by the ordinary Western diet
which is about 5 to 15 grams of salt per day there is little in-
fluence on blood pressure. Beyond this range of salt intake,
however, there is some evidence to suggest that an excess of
hypertension may appear. For example, in the northeastern
district of Japan, the daily intake of salt averages about 25
grams per day.’* The prevalence of hypertension in the fifth
decade was found to be 30 to 40%, significantly higher than
in most parts of the world. Such high levels of sodium
ingestion must greatly stress the homeostatic control mech-
anisms and a high level of arterial blood pressure could well
be required by the kidney to handle the ECF load. Possibly,
there are critical levels of sodium ingestion which cause the
blood pressure to rise with age and for some to develop
hypertension. With sodium intakes below 10 mEq per day,
ECF is contracted (by our standards) and hypertension is
absent. In the range of 10 to 70 mEq per day, a few cases of
hypertension will appear as in the Pukapukans,” while in the
range of 70 to 350 mEq per day, about 15% of adults will ex-
hibit hypertension, the percentage rising with age. When salt
intake rises above 350 mEq per day, hypertension may be
found in about 30% of the population.”

The inference from these considerations with respect to
the prevention of hypertension would now be fairly obvious.
The level of ECF which we call normal probably is an ex-
panded one compared to our primitive forebears. This con-
dition has arisen because acculturated man has developed a
taste for salt. Its elimination from the diet and a return to
natural, unsalted foods will, by contracting ECF, reduce the
stimulus to develop hypertension that presently exists in our
society.

Other ECF Control Mechanisms

This discussion would not be complete without con-
sidering the role of the renin-angiotensin-aldosterone system
in the pathogenesis of hypertension. Certainly, it is a subject
of great current interest.** However, with respect to the pres-
ent discussion, the role of this system seems to be of sec-
ondary importance. While the renin-angiotensin-aldosterone
system is involved in the homeostatic control of the ECF,
the ability of this mechanism to cope with a continued in-
crease in ECF appears to be rather limited.’ As Guyton has
pointed out, the renin feedback loop does not have the in-
finite gain provided by the arterial blood pressure-urine
volume relationship. Although it aids and abets the kidney
in control of volume, the renin-angiotensin-aldosterone
system is incapable of maintaining for long periods
homeostasis of the ECF in the presence of a high salt intake
and a reduced intrinsic functional capacity of the kidney to
excrete salt and water loads at normal levels of blood
pressure.

There is no increase in renin, angiotensin nor aldosterone
levels in mild or moderate essential hypertension.*? In fact,

many hypertensive patients exhibit reduced plasma renin ac-
tivity (PRA)."* While this observation appears at first glance
to be paradoxical, it is, in fact, consistent with the renal-
body fluid pressure control theory of hypertension. A reduc-
tion in the activity of renin feedback system would be ex-
pected as an additional compensatory reaction in individuals
who have a reduced renal functional capacity for handling
excess salt and water loads.

There are also other inconsistencies in relating the renin-
angiotensin-aldosterone system to the pathogenesis of essen-
tial hypertension. Normalization of blood pressure with cer-
tain antihypertensive agents such as diuretics®® or
vasodilator drugs®* leads to a rise in PRA, that is, blood
pressure falls despite an increase in PRA. Furthermore, in
no-salt cultures, a chronic elevation of PRA is associated
with an absence of hypertension. In Oliver’s studies** on the
blood pressure, sodium excretion, PRA and urinary
aldosterone excretion of the unacculturated Yanomamo In-
dians of Brazil, the urinary excretion of sodium was extra-
ordinarily low averaging 1 + 1.5 mEq per 24 hours. Blood
pressure, which averaged below 110/70 mm Hg, did not rise
with age and hypertension was completely absent. On the
other hand, PRA and urinary aldosterone excretion were ab-
normally elevated according to our standards of normalcy.
Although ECF was not measured, it undoubtedly was
reduced because of the extremely low intake of salt in the
diet.* '° Needless to say, such findings are hardly consistent
with the hypothesis that elevated renin or aldosterone secre-
tion rates are important factors in the pathogenesis of
hypertension.

Unlike no-salt cultures, the blood pressures of all pop-
ulations which use salt as a condiment rise with age. Perhaps
the ability of the human organism to handle a chronically in-
creased ECF load diminishes with age and a rise of blood
pressure occurs as a compensatory reaction for maintaining
homeostasis of the ECF. A decreased ability to maintain
ECF homeostasis in the face of a high salt intake could oc-
cur via several mechanisms. First, the intrinsic functional
capacity of the kidney to handle excess salt and water may
deteriorate gradually with age. Second, the various other
supportive processes could begin to fail. An increased salt
intake leads to inhibition of renal sympathetic nerve
stimulation, ADH secretion, and the renin-angiotensin-aldo-
sterone activity.’ These homeostatic mechanisms for the
control of the ECF support the renal-body fluid system in
the control of the ECF and ultimately in the control of the
blood pressure. However, if they should fail, the kidney must
rely more on the blood pressure-urine volume relationship
and hypertension could result. The curve relating renal
arterial perfusion pressure and urine volume is much steeper
in the isolated kidney than in the intact organism where all
of the other homeostatic mechanisms can exert their effects.’

Role of Inheritance

That there may be inherited differences in the intrinsic
renal functional capability for handling a salt load is sug-
gested by the already alluded to transplantation experi-
ments of Bianchi and Dahl.* At least in the rat a higher
blood pressure seems to be required by some kidneys than by
others and this function is inherited. This hypothesis would
explain the mechanism for the inherited tendency toward es-
594 CIRCULATION

sential hypertension in man. Also, an inherited defect in one
or more of the ancillary feedback mechanisms for main-
taining homeostasis of the ECF would equally explain the
familial trend in essential hypertension. However, there is as
yet little more than suggestive evidence to support any of
these hypotheses.

Whether due entirely to an inherited renal functional
deficiency in handling an excessive ECF load or to a volume-
induced increased responsiveness to other pressor influences,
the difference in the prevalence of essential hypertension
between acculturated and unacculturated societies appears
to be due to the amount of dietary salt. Nature did not in-
tend for us to handle a chronically expanded ECF. In con-
genitally predisposed individuals, the mechanisms for han-
dling the increased load may deteriorate with aging so that a
higher than normal blood pressure is required to maintain
homeostasis of the ECF. If so, essential hypertension is a
comparatively new disease in the history of man.

Unacculturated peoples have demonstrated that even with
severe physical exertion in tropical climates, the addition of
salt to our food is not essential for good health and physical
performance. Salt is an acquired taste inculcated at a very
early age by flavoring infant foods. The infant who is not ex-
posed will not develop this habit. On the basis of present
knowledge, it would seem wise for individuals with a family
history of essential hypertension to accustom themselves to
a truly salt free diet (less than 1 gm of salt or 15 mEq of
sodium per day) and to prevent their children from acquiring
the habit of eating salted foods. While this is difficult at
present, an increased variety of unsalted foods would be
made available if there were sufficient public demand. It is
quite possible, if not probable, that we already have the
knowledge to prevent essential hypertension and its various
complications.

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