Clinical Science (1990)78,533-540
533
Editorial Review
Increased vascular wall sodium in hypertension: where is it,
how does it get there and what does it do there?
GEZA SIMON
Department of Medicine, Veterans Administration Medical Center, and University of Minnesota, Minneapolis, Minnesota, U.S.A.
INTRODUCTION
Thirty-seven years ago Tobian & Binion [l] reported
increased arterial wall Na+ content in human hypertension. This was followed by reports of increased arterial
and myocardial Na+ content in experimental hypertension [2-131, an observation later extended to veins
[ 14-17]. Increased vascular wall Na+ content remains
today the most direct link between Na+ and hypertension,
but its pathophysiological significance is still unknown.
Based on the finding of an increased Na+/Cl- ratio, it was
assumed that the excess Na+ was predominantly intracellular [ l , 31, but little was known about the ion-binding
connective tissue matrix of the arterial wall at that time.
When Losse and co-workers [18] reported in 1960 that
erythrocyte Na+ content was also increased in human
hypertension, attention shifted from the vascular wall
cation content to the membrane events which regulate the
transmembrane Na+ gradient. A report of an early
increase in paracellularly bound Na+ in experimental
hypertension, and the suggestion that it may play a role in
exaggerated vasoconstriction, was largely ignored [ 191.
With recent studies [20, 211 indicating that intracellular
Na+ concentration in the early stages of hypertension
may be reduced, rather than increased, it is time to reexamine the pathogenesis and pathophysiology of
increased vascular wall Na+ content in hypertension.
WHERE IS IT?
The accumulation of excess vascular wall Na' is not a
universal finding in hypertension. It has been reported in
experimental renovascular, renoprival and steroid
[deoxycorticosterone acetate (D0CA)-salt and adrenal
regeneration] hypertension [2- 13, 221. In renovascular
hypertension, the increase in the Na+ content of large and
Correspondence: Dr G. Simon, 1 11 52, Veterans Administration Medical Center, Minneapolis, MN 55417, U.S.A.
small arteries is more pronounced when the intact kidney
has been surgically removed, or when renal blood flow
has been bilaterally reduced [2,3,6,7,9-13,23-251. The
accumulation of excess Na+ appears to be specific to the
cardiovascular system (myocardium, arteries and veins)
because the Na+ content of other organs, such as skeletal
muscle, brain, kidneys and intestines, is not affected unless
there is generalized tissue oedema [2, 3, 12, 16, 24,251. In
steroid hypertension, the magnitude of the change
depends on the stage and severity of hypertension [4,5,8,
261. Increases in the Na+ content of arteries and veins are
readily reversible with the reversal of hypertension [ 17,
231. However, there is no evidence for increased vascular
wall Na+ content in spontaneously or genetically hypertensive rats until late in the course of hypertension [24,
27-30]. Vascular wall Na+ content is also unchanged in
hypertensive Dahl salt-sensitive rats [3 13.
There is little information about vascular wall Na+
content in human hypertension, despite the fact that the
original study reporting increased arterial wall Na+
content in hypertension was performed on post-mortem
specimens obtained from humans [ 11. This report contains little clinical data, and no information regarding the
cause of death, complicating diseases, renal functional
status, or the presence or absence of renal artery stenosis
in the patients studied. Unlike experimental renovascular
hypertension, there were increases in the Na+ content of
not only the arteries but also of the skeletal muscle,
suggesting that in some of the patients the accumulation
of excess Na+ in the wall of arteries may have been due to
generalized oedema or uraemia, or both. Based on this
report, it is not known whether the Na+ content of
arteries is increased only in human renal hypertension or
also in essential hypertension. The composition of the
saphenous vein of patients undergoing coronary artery
bypass surgery has been investigated and increases in the
water and glycosaminoglycan (hexosamine) content, but
not in the Na+ content,'of veins from hypertensive donors
were found [32]. However, 77% of hypertensive donors
534
G. Simon
but only 20% of normotensive donors were receiving
diuretics before surgery. This may have accounted for the
lack of difference in the Na+ content of veins between the
two groups.
The large extracellular space, the heterogeneity of
tissue components and the high connective tissue content
of blood vessels have made the localization of excess
vascular wall Na+ in hypertension difficult [33-391.
Vascular wall Na+ is distributed in at least four phases:
one free in solution and one bound, in both the extracellular and intracellular compartments. Several approaches
have been used in an attempt to quantify the Na+ content
of the various compartments; none have proved satisfactory [36-391. Chemical dissection techniques have
been hampered by the variable penetrability of extracellular fluid markers and underestimation of the extracellular
space. Also, corrections are required to account for Na+
bound to the extracellular connective tissue elements,
mainly glycosaminoglycans [33]. A n alternative way of
estimating extracellularly bound Na+ is the compartmental analysis of 22Na+or 24Na+efflux curves [36-381.
The tissue is loaded with radioactive Na+ and then the
washout is measured in an inactive solution. At best, Na+
efflux curves can be resolved into three compartments,
which makes the precise identification of extracellular and
intracellular free and bound Na+ compartments difficult.
Manipulations of experimental conditions, such as
cooling, incubation in K+-free salt solutions and the
addition of transport inhibitors (such as ouabain), have
been used to identify the membrane-limited (intracellular)
component [37], but even under these circumstances the
transmembrane movement of Na+ may be masked by
extracellular movements from high-affinity, slowly
exchanging sites.
Recognizing the limitations of these techniques,
Friedman and co-workers have used ion-exchange
methods [19, 34, 35, 391. These included direct ionexchange titration to estimate the amount of Na+ bound
to glycosaminoglycans and the exchange of Li' for extracellular Na+ at 2°C. The latter is sufficiently slow in rat
arteries to distinguish the rapid washout of extracellular
Na+ and the much slower washout of intracellular Na+.
Using ion-exchange techniques, the free and bound extracellular and intracellular Na+ compartments in rat
arteries were quantified. According to these
measurements, extracellular and intracellular bound Na +
constitute about 15 and 3% of the total Na+ content,
respectively.
More recently, electron probe analysis has been used to
measure intracellular Na+ content [40]. Tissue specimens
are frozen instantaneously to stop diffusion of ions and
crystallization of water. Thin frozen sections are placed in
an electron beam. The ions in the field emit X-rays of
characteristic energy that are detected and counted. Using
this method, Junker et al. [40] found a uniform distribution of Na+ in the cytoplasm and intracellular organelles
of .vascular smooth muscle cells but a wide cell-to-cell
variation in Na+ content. They also identified a rapidly
exchanging, temperature-insensitive component of cytoplasmic Na+ efflux in rabbit mesenteric veins. If this rapid
exchange of Na+ is also present in arteries, it may result in
underestimation of intracellular Na' content by the
isotope efflux and the cold-Li+-exchange techniques.
Electron probe analysis, however, does not distinguish
between free and bound intracellular Na+ and can
measure only ionic content and not ionic activity (concentration).
Siege1 et al. [38] combined the use of compartmental
analysis, chemical dissection and quantitative analysis of
the histological tissue sections to quantify the Na+ compartments of the dog carotid artery. They found that
90% of the total Na+ content of the artery was extracellulary located and could be partitioned into at least
three components, one dissolved in extracellular water,
one bound and one contained in a rapidly exchanging
fraction, which they thought might represent Na+ located
in the numerous vesicles of the vascular smooth muscle
cell surface. The latter probably represents the rapidly
exchanging Na+ compartment detected by electron probe
analysis [40]. Due to the close proximity of the surface
vesicles to the cytoplasm, the precise localization of this
Na+ compartment is difficult [38].
Of the available methods for the compartmental
analysis of vascular wall Na*, flux measurements did not
reveal changes in the intracellular Na+ concentration of
arteries from spontaneously or DOCA-salt hypertensive
rats [28, 41, 421. The cold-Li+-exchange method with
arteries from rats with spontaneous, DOCA-salt and
renovascular hypertension [ 19, 39,43-451 gave different
results depending on the preparation of tissue samples
before measurement. T h e intracellular Na+ content of
arteries from spontaneously and DOCA-salt hypertensive
rats was found to be increased when the arteries were
immersed at once in cold-Li+-substituted salt solution for
washout of extracellular Na+ [43, 451. When, after
removal, the arteries were allowed to reach a new steady
state in vitro by prolonged incubation in physiological salt
solution, a reduction in the intracellular Na+ content of
arteries was found [44,45]. The intracellular Na+ content
of arteries removed from rats with two- or one-kidney,
one-clip hypertension and processed fresh was
unchanged.
In contrast to the variable results of intracellular Na+
measurements, the extracellularly bound Na+ fraction of
arteries, measured by ion-exchange o r flux methods, was
found to be consistently elevated in hypertensive rats,
irrespective of aetiology [16, 19, 26, 29, 34, 35, 39, 421.
This is not surprising considering that the accumulation of
cation-binding glycosaminoglycans is in part a pressurerelated phenomenon (see below). What is notable is that
elevations in the paracellularly bound Na+ fraction were
detected as early as 2-4 days after unilateral renal artery
constriction or the administration of DOCA, before the
onset of hypertension [ 193.
Because of the difficulties inherent in the compartmental analysis of blood vessels many investigators have
turned to the study of the cellular elements of blood as
representative of cells in general. Measurements of
erythrocyte Na+ content in human and experimental
hypertension have yielded mixed results, some indicating
Vascular wall Na+ in hypertension
an increase and others no change [46-481. Measurements
of leucocyte Na+ content in hypertension have been more
consistent, the majority of studies showing an increase
[47, 481. We have recently reviewed the evidence for
increased intracellular Na+ content in hypertension and
found several methodological pitfalls, the main one being
the influx of Na+ during the separation of cells from
plasma [49]. The influx of Na+ is also a problem during
the removal of blood vessels because stretch increases
membrane permeability of Na+ [50].
Faced with these methodological pitfalls, how do we
resolve the problem of localizing the excess Na+ that
accumulates in cardiovascular tissue in hypertension?
The solution may lie in the investigation of the earliest
stages of hypertension. The increase in the total Na+
content of arteries in renal and DOCA-salt hypertensive
rats is detectable as early as 24 h to 7 days after the application of the renal artery clip or the administration of
DOCA [16, 261. In DOCA-salt hypertensive rats, during
the same time, the steady-state intracellular Na+ concentration (“a+],) of arteries appears to be at subnormal
levels, so that the transmembrane Na+ gradient, operatively defined as [Na’],/[Na+], (where [Na+I0is extracellular Na+ concentration), is increased. The same changes
have been shown to occur when rat tail arteries are
exposed to aldosterone in vitro [20]. Although
measurements of total vascular wall Na+ content in early
human hypertension are not available, there is evidence
for an early reduction in the Na+ content and concentration of erythrocytes [49]. With evidence for increased
vascular wall Na+ content on the one hand, and reduced
intracellular Na+ concentration on the other, it is reasonable to conclude that in the ‘earlystages of steroid hypertension, if not in other forms of hypertension, the excess
vascular wall Na+ is extracellularly located.
HOW DOES IT GET THERE?
In 1968, Hollander et al. [51] found that the Na+ content
of the ‘hypertensive’ but not of the ‘hypotensive’ portion
of the aorta was increased in dogs with coarctation hypertension. The accumulation of excess Na+ in the ‘hypertensive’ portion of the aorta was in part the result of the
accumulation of Na+-binding glycosaminoglycans. Based
on this report, the consensus opinion has been that the
accumulation of excess Na+ in the wall of arteries in
hypertension is a pressure-related phenomenon. The possibility that the segment of the aorta distal to the coarctation should lose Na+ due to low pressure-related atrophy,
and that an unchanged Na+ content of this portion of the
aorta was inappropriately high, was not considered. In the
coarctation experiments of Villamil et al. [52], the K +
content of the ‘hypotensive’ portion of the aorta was
reduced, providing direct evidence that atrophy may have
occurred.
The view that the accumulation of vascular wall Na+ in
hypertension was pressure-related prevailed until
Parnnani & Overbeck [14] repeated in rats the experiments of Hollander et al. [511and found an accumulation
of excess Na+ and water not only in the ‘hypertensive’
535
portion but also in the ‘normotensive’portion of the aorta
and in veins [14]. Accumulation of excess Na+ was also
demonstrated in the femoral veins of dogs with onekidney, one-wrapped hypertension and in the vena cava
and portal vein of rats with two- or one-kidney, one-clip
hypertension [15-17,531. The portal vein changes of rats
with one-kidney, one-clip hypertension were detectable as
early as 24 h after constriction of one renal artery and
removal of the contralateral kidney [16]. Although a
subtle elevation of venous pressure during the development of hypertension cannot be ruled out, alterations in
vein wall composition are more likely to be the result of
neural or humoral influences than of increased intraluminal pressure.
It thus appears that there are two types of vascular wall
Na+ accumulation in hypertension, one pressure-related
and one pressure-independent. With chronic hypertension, there is accumulation of Na+-binding glycosaminoglycans in the wall of arteries [51]. This is a
non-specific, time-dependent process that can be
detected in all forms of hypertension, including the
genetic forms which initially do not show an increase in
arterial wall Na+ content [24, 27-30]. The pressureindependent accumulation of vascular wall Na+ is
detected in the pre-hypertensive stage or on the lowpressure side of the circulation, in veins [14-17,261. The
latter is the key to our understanding of the pathophysiology of excess vascular wall Na+ in hypertension.
We have investigated the possible role of humoral
factors in the pathogenesis of increased vascular wall Na+
content in experimental renovascular hypertension in
several ways [53-561. In parabiotic rats, one with twokidney, one-clip hypertension and one unoperated and
normotensive, we found increased Na+ content of the
vena cava in both [53].Passive transfer of serum from rats
with one-kidney, one-clip hypertension to syngeneic
normotensive rats for 3 weeks resulted in exaggerated
pressor responses and the accumulation of excess Na+ in
the myocardium and excess water in the aorta of the
recipient rats [MI. These two experiments have shown
that circulating factor(s) do play a role in the pathogenesis
of increased Na+ content of cardiovascular tissue in renovascular hypertension. Direct evidence for the role of
humoral factors was provided by tissue culture experiments [54, 551. Rabbit aorta explants cultured in the
serum of dogs with two- or one-kidney, one-wrapped
hypertension accumulated more Na+ than explants
cultured in the serum obtained from the same dogs before
the induction of hypertension. In an attempt to localize
the excess Na+, the experiments were repeated using
monolayers of fibroblasts instead of intact aorta [57]. To
our surprise, the Na+ content and concentration of fibroblasts cultured in the serum from dogs with one-kidney
one-wrapped hypertension for 5-7 days was reduced, not
increased. A similar reduction in intracellular Na+
content was found when vascular smooth muscle cells
were cultured in the serum from rats with one-kidney,
one-clip hypertension [58]. These tissue culture experiments mimic the results of vascular tissue analysis in the
early stages of experimental steroid hypertension, where
536
G. Simon
Vascular reactivity is increased in the established phase of
both human and experimental hypertension [63,64]. This
is true of renovascular and steroid hypertension where
vascular wall Na+ content is increased, and of other forms
of hypertension where the vascular wall Na+ content
unchanged. In the established phase of hypertension,
structural redesign of small resistance vessels appears to
be the primary mechanism responsible for hyper-reactivity to agonists [63-651. These observations do not
preclude a potential role for Na+ in the developmental
stage of some forms of hypertension.
There are several ways in which the accumulation of
excess extracellular Na+ in the wall of arteries and veins
may lead to vasoconstriction or to exaggerated vasoconstrictor responses to agonists. In each case, it is
assumed that some of the excess Na+ is freely diffusible.
by Tobian & Binion [l, 31. Friedman and co-workers
elaborated on this theme by attributing a specific role to
the thermoelastic properties, state of hydration and
physical dimensions of the paracellular matrix in the
regulation of vascular resistance [19, 661. In their view
[66], ‘the smooth muscle cells of blood vessels are laced
together by a network of collagen fibers floating in a gellike polysaccharide sea’.
Polysaccharides occur as single helices that may take
up several different symmetries depending on the ion
attracted to the negatively charged carboxyl and sulphoester groups [67].The selectivity of these sites for H + ,K+
and Na+ are similar, whereas bivalent cations have
greater affinity [67]. Because Na+ is the most abundant
extracellular cation, polysaccharides exist predominantly
as Na+ salts. In this form polysaccharides are highly
soluble in water, forming a viscoelastic gel. The polysaccharide gel maintains a stable concentration of diffusible Na+ adjacent to the cell membrane in two ways. It
functions as a cation-exchange resin, and by creating a
highly charged microvolume, it attracts cations without
binding them to any particular charged site on the polyanions [33-35,38,39,67].
The ionic strength of the polysaccharide gel determines
the stiffness, hydration volume and physical dimensions
of vascular muscle at rest and during contraction [66,67].
During contraction, vascular smooth muscle cells change
from an elongated to a rounded configuration. In a
confined environment, such a change in the geometry of
circumferentially distributed vascular muscle is expected
to cause an intraluminal bulge. The more confined the
paracellular space is, the more pronounced the intraluminal bulge may be.
The Na+-binding capacity of the paracellular matrix of
arteries is increased within days after the induction of
renovascular or steroid hypertension in rats [19]. Such a
change is expected to cause swelling of tissue, thus
exaggerating the intraluminal bulge during contraction. If
a similar change also occurs in the small resistance
vessels, it would be detected as increased reactivity to
agonists. It is not known whether this early increase in
Na+ binding of arteries is due to qualitative changes in the
physicochemical properties of the matrix or to increased
production of polysaccharides by vascular smooth muscle
cells. Crane [68] found increased glycosaminoglycan
synthesis in mesenteric arteries excised from rats with
chronic DOCA-salt hypertension, but no such change
was detectable after only 1 day of treatment. That the
viscoelastic properties of arteries are altered in the
established phase of hypertension is well known [69].
These changes have been previously related to ‘waterlogging’ and increased glycosaminoglycan content of
arteries [69].Whether there are changes in the viscoelastic
properties of arteries in the pre-hypertensive state has not
been established.
Na+ binding in the paracellular matrix
Transmembrane Na+ gradient
The idea that peripheral vascular resistance may not be
determined solely by the state of tension of vascular
muscle, but also by its water content, was first advanced
Due to its transmembrane gradient, Na+ is an important component of inward current during agonistmediated vasoconstriction. The best example is ANG 11.
there is also an accumulation of excess Na+ extracellularly and a reduction of intracellular Na+ concentration [19-2 11. Interestingly, the passive transfer of serum
from hypertensive salt-sensitive Dahl rats into normotensive salt-sensitive rats for 2 weeks also resulted in
increased Na+ content of the aorta in the recipient rats,
although this type of hypertension is not characterized by
accumulation of excess Na+ in cardiovascular tissue [59].
Recently, we obtained evidence which suggests that
angiotensin I1 (ANG 11) may cause the accumulation of
excess vascular wall Na+ [60]. ANG I1 administered to
rats in subpressor doses for 24 h or 7-10 days increased
the total Na+ content of the aorta without a change in
intracellular Na+. The precise mode of action of ANG I1
and of serum factors that increase the Na+ content of
arteries and veins is not known.
In steroid hypertension, the cellular events leading to
the accumulation of excess vascular wall Na+ are better
understood than in renovascular hypertension [20,21,28,
41, 42, 44, 45, 61, 621. The cellular effects of mineralocorticoids that were found in vivo can be also demonstrated in vitro in the presence of phenoxybenzamine
blockade, indicating that their action on the target organ
is a , direct one [61]. The primary effect of mineralocorticoids appears to be an increase in membrane
permeability to Na+ and other ions [20, 21, 28, 41, 451.
The inward leak of Na+ stimulates Na+-K+-pump
activity [20, 21, 611. In the pre-hypertensive stage and in
the earliest stage of hypertension, a situation may ensue
whereby enhanced active Na+ extrusion dominates the
transmembrane Na+ balance resulting in a reduction of
intracellular Na+ concentration [20,21,61]. These events
are associated with a general increase in protein synthesis
[45, 611, including Na+-binding glycosaminoglycans
which are deposited extracellularly in the paracellular
matrix.
WHAT DOES IT DO THERE?
Vascular wall Na+ in hypertension
Several groups of investigators found that the action of
ANG I1 on effector tissue was influenced by alterations in
the external Na+ concentration as long as the changes
were kept in the physiological range [70-751. The findings
were attributed to interaction at the receptor sites. A
small rise in the Na+ concentration (8 mmol/l) of the
perfusate potentiated the constrictor responses of the
isolated rabbit ear artery to ANG I1 [74]. The increased
reactivity to A N G I1 was accompanied by an increase in
the rapidly exchangeable and, presumably, extracellular
Na+ content of arteries. The authors suggested that the
excess intracellular Na+ may have increased Na+ flux
along its concentration gradient. Heistad et al. [73] found
a direct correlation between serum Na+ concentration
and vasoconstrictor responses to A N G I1 in the human
forearm circulation. They raised serum Na+ concentration (by 7 mmol/l) by the infusion of disodium sulphate
and lowered it (by about 27 mmol/l) by infusing sucrose
or mannitol. The fact that A N G I1 stimulates Na+ influx is
the most likely explanation for the dependence of A N G
11-mediated vasoconstriction on the external Na+ concentration. A N G 11-mediated Na+ influx has been investigated in detail in vascular smooth muscle cells in tissue
culture [75] but can also be demonstrated 6 1 vivo [76,77].
During intravenous infusion of A N G 11 in rats and dogs,
Jamieson & Friedman [78] detected a shift of Na+ from
the extracellular to the intracellular space. In the pumpperfused dog forelimb vascular bed, vasconstrictor concentrations of ANG I1 reduced the Na+ concentration of
the perfusate. Besides A N G 11, vasopressin also
stimulates Na+ influx [79].
When viewed in light of the cellular mode of action of
agonists, it is theoretically possible that an early increase
in the transmembrane Na+ gradient in hypertension may
potentiate vasoconstrictor responses to some, although
not all, agonists. Friedman et al. [80] found that the
response of the rat tail artery to agonists was reduced with
abolition of the transmembrane Na+ and K + gradients by
cooling, and progressively restored as the transmembrane
gradients were re-established during rewarming. They
suggested that the Na+ gradient plays a role in the
‘priming’ of vascular smooth muscle cells. Harris &
Palmer [8 11 altered the transmembrane Na+ gradient by
treating arterial segments with hyaluronidase which
reduced both the Na+ binding of paracellular matrix and
the vasoconstrictor responses to agonists. However, due
to the harsh treatment in these experiments, other
unrelated changes in the composition of arteries may have
also contributed to the reduced responsiveness.
In our laboratory, we have made some observations
which bear indirectly on the relationship between the
transmembrane Na+ gradient and agonist-mediated
tension development. In chronically catheterized conscious normotensive rats, we found a direct correlation
between pressor responses to intravenously administered
ANG I1 and the total Na+ content of the aorta ([56];
G. Simon, unpublished work). In mongrel dogs, we found
a wide spontaneous, presumably, genetically determined,
variation in the total Na+ content of the saphenous veins
[82]. A similar degree of spontaneous variation also exists
537
in the total Na+ content of arteries among dogs [ l l , 831.
Dogs with a spontaneously high Na+ content of the
saphenous vein were more prone to development of the
malignant form of one-kidney, one-wrapped hypertension
than were dogs with a spontaneously low Na+ content of
the saphenous veins [82]. These findings suggested to us
that the Na+ content of blood vessels may be a determinant of the magnitude of response to vasoconstrictor
stimuli. We investigated this possibility by measuring the
reactivity of the saphenous vein of dogs to acetylcholine
(ACh) [84]. We tested ACh instead of A N G I1 because of
tachyphylaxis of dog veins to the latter [85]. In the dog,
ACh is a venoconstrictor. Like A N G 11-mediated
responses of smooth muscle, the contractile responses to
ACh are also directly related to the external Na+ concentration [86]. Like A N G 11, ACh and carbachol, a
stable analogue of ACh, stimulate Na+ influx [87, 881. In
the dog saphenous vein, we found a direct correlation
between Na+ content and the magnitude of AChmediated venoconstriction. Variations in the extracellular,
but not the intracellular, Na+ content accounted for this
relationship. ACh-mediated venoconstriction was inhibited by a relatively low concentration (1x
mmol/l)
of amiloride, a Na+-channel-blocking agent.
Taken together, these experiments suggest that variations in the extracellular Na+ content of blood vessels
may exist under physiological circumstances, and that
extracellular Na+ content is a determinant of the transmembrane Na+ gradient and, consequently, of the
magnitude of the vasoconstrictor response to agonists
whose mode of action includes the stimulation of Na+
influx. Whether spontaneous (possibly, genetically
determined) and hypertension-related variations in transmembrane Na+ gradient have a bearing on graded depolarization and myogenic tone in non-spike-generating
vascular muscle remains to be tested.
Na+-linked noradrenaline transport
T h e uptake and release of noradrenaline (NA) from
nerve endings is only one example of active transport
driven by the electrochemical energy of the transmembrane Na+ gradient [89, 901. The rate of uptake of
the transported molecule varies directly with the external
Na+ concentration, whereas the efflux is enhanced by an
increase in internal Na+ concentration. Transport is
abolished in the absence of a Na+ gradient.
In the early, pre-hypertensive stage of DOCA-salt
hypertension, De Champlain et al. [89] found an
unchanged endogenous N A content but a reduced NA
uptake by sympathetic nerves in the myocardium. A lowNa+ diet reversed this change. T h e authors suggested that
some as yet unspecified intracellular ion disturbance may
be the cause of the reduced uptake of NA. According to
the Na+-linked transport theory, the intracellular ion disturbance that reduces N A uptake would be an increase in
intracellular Na+ concentration [go]. Experimental
evidence, on the other hand, favours the view that in early
DOCA-salt hypertension the intracellular Na+ concentration of vascular muscle and myocardium is
538
G. Simon
reduced, not increased (see above) [21, 911. The findings
of De Champlain et al. [89] cannot be explained on the
basis of Na+-linked transport unless changes in the transmembrane Na+ gradient of nerve endings are opposite to
those found in cardiovascular tissue. This is possible
because the ionic changes discussed so far are specific to
cardiovascular tissue (see above).
Na+-dependent amino acid transport
Like NA uptake, amino acid transport for the type A
(alanine-preferring) carrier is linked to the electrochemical energy gradient generated by the transmembrane Na+ gradient [92, 931. Other amino acids are
transported intracellularly through the Na+-independent
type L (leucine-preferring) amino acid membrane carrier.
The enhanced transmembrane Na+ gradient in early
DOCA-salt hypertension may stimulate the uptake of
some amino acids, but we do not know of measurements
of this kind in experimental hypertension. If there is
stimulation of amino acid transport by vascular muscle in
early hypertension, such a finding would help to explain
the structural changes which accompany the rise in
peripheral vascular resistance.
Finally, there are several other Na+-linked transport
systems in vascular muscle whose operation may be
altered by changes in the transmembrane Na+ gradient,
including Na+-Ca2+ countertransport [94] and Na+-H+
exchange. Because intracellular Na+ concentration of
vascular muscle in early hypertension appears to be
reduced, not increased (see above), Na+-Ca2+ countertransport is not likely to play major role in vasoconstriction at this stage of the hypertensive process.
The prime regulator of Na+-H+ exchange is intracellular pH and not the transmembrane Na+ gradient
[95]. Because intracellular pH is regulated within a
narrow range, it is unlikely that the operation of this
exchange system would result in major translocations of
Na+. This does not mean, however, that Na+-H+
exchange is unaffected by the transmembrane Na+
gradient. It has been shown in tissue culture experiments
that growth-factor-stimulated intracellular alkalinization
is dependent on external Na+, and Na+-H+ exchange
can be increased by a reduction in the intracellular Na+
concentration [95, 961. These observations raise the interesting possibility that trophic stimulation of vascular
muscle in early hypertension is triggered by an enhanced
transmembrane Na+ gradient. Experimental evidence to
either support or reject this possibility is'lacking.
CONCLUSIONS
For any change in the Na+ distribution of cardiovascular
tissue to have a causal role in hypertension, it must begin
early in the course of hypertension or precede its onset.
The accumulation of excess Na+ in the vascular wall
occurs early in the course of experimental renovascular
and steroid hypertension and is extracellularly located
[16, 19, 26, 601. In early steroid hypertension, the
increased vascular wall Na+ content is accompanied by
increased transmembrane Na+ gradient because steady-
state intracellular Na+ concentration is at a subnormal
level [20,21].
In renin-dependent renovascular hypertension, A N G
I1 may cause the accumulation of excess vascular wall
Na+ [60]. In chronic, renin-independent renovascular
hypertension, a serum factor of unknown source appears
to be responsible 153-561. The serum factor also reduces
the intracellular Na+ content and concentration of fibroblasts and vascular smooth muscle cells in tissue culture
[57,58].
The accumulation of excess extracellular Na+ in the
wall of arteries in the early stages of renovascular and
steroid hypertension may result in tissue swelling and
exaggerated vasoconstriction. Alternatively, some of the
excess extracellular Na+ may be freely diffusible and contribute to the transmembrane Na+ gradient. The increase
in transmembrane Na+ gradient may potentiate vasoconstrictor and trophic responses to agonists whose mode
of action includes the stimulation of Na+ influx [66, 74,
81, 841. A genetically determined high Na+ content of
blood vessels may be a predisposing factor to hypertension [82].
To better understand the role of vascular wall Na+ in
hypertension, we need measurements of freely diffusible
extracellular Na+ and of Na+ influx during agonistmediated vasoconstriction.
ACKNOWLEDGMENT
Research in my own laboratory summarized here was
supported by Merit Review Research funds (1976-1987)
from the Veterans Administration.
REFERENCES
1. Tobian, L. & Binion, J.T. Tissue cations and water in arterial
hypertension. Circulation 1952; 5,754-8.
2. Ledingham, J.M. The distribution of water, sodium and
potassium in heart and skeletal muscle in experimental renal
hypertension. Clin. Sci. 1953; 12, 337-49.
3. Tobian, L. & Binion, J. Artery wall electrolytes in renal and
DCA hypertension. J. Clin. Invest. 1954; 33, 1407-14.
4. Tobian, L. & Redleaf, P.D. Effect of hypertension on arterial
wall electrolytes during deoxycorticosterone administration.
Am. J. Physiol. 1957; 189,451-4.
5. Daniel, E.E. & Dawkins, 0. Aorta and smooth muscle
electrolytes during early and late hypertension. Am. J.
Physiol. 1957; 190,71-6.
6. Tobian, L. & Redleaf, P.D. Ionic composition of the aorta in
renal and adrenal hypertension. Am. J. Physiol. 1958; 192,
325-30.
7. Redleaf, P.D. & Tobian, L. Sodium restriction and reserpine
administration in experimental renal hypertension. Circ.
Res. 1958; 6,343-51.
8. Gross, F. & Schmidt, H. Natrium- und Kaliumgehalt von
Plasma und Geweben beim Cortexon-Hochbruck. Arch.
Exp. Pathol. Pharmakol. 1958; 233,311-22.
9. Koletsky, S., Resnick, H. & Behrin, D. Mesenteric a r t e j
electrolytes in experimental hypertension. Proc. Exp. Biol.
Med. 1959; 102,12-15.
10. Tobian, L. Interrelationship of electrolytes, juxtaglomerular
cells and hypertension. Physiol. Rev. 1960; 40,280-3 12.
11. Jones, A.W., Feigl, E.D. & Peterson, L.H. Water and electrolyte content of normal and hypertensive arteries in dogs.
Circ. Res. 1964; 15,386-92.
Vascular wall Na+ in hypertension
12. Swales, J.D. Sodium metabolism in disease. London: LloydLukeLtd, 1975: 196-9.
13. Page, I.H. Hypertension mechanisms. Orlando, FL: Grune
and Stratton Inc., 1987: 482-5.
14. Pamnani, M.B. & Overbeck, H.W. Abnormal ion and water
composition of veins and normotensive arteries in coarctation hypertension in rats. Circ. Res. 1976; 38, 375-8.
15. Simon, G., Pamnani, M.B. & Overbeck, H.W. Decreased
venous compliance in dogs with chronic renal hypertension.
Proc. Exp. Biol. Med. 1976; 152,122-5.
16. Rorive, G. & Bovy, P. Ionic composition of the arterial wall
and experimental hypertension. In: Rorive, G. & van
Cauwenberge, H., eds. The arterial hypertensive disease.
Paris: Masson, 1976: 109-25.
17. Simon, G. Reversibility of arterial and venous changes in
renal hypertensive rats. Hypertension 1980; 2, 192-7.
18. Losse, H., Weymeyer, H. & Wessels, F. Der Wasser- und
Elektrolyt-gehalt von Erythrocyten bei arterieller Hypertonie. Klin. Wochenschr. 1960; 38,393-5.
19. Friedman, S.M. & Friedman, C.L. The ionic matrix of vasoconstriction. Circ. Res. 1967; 20-21,11-147-55.
20. Friedman, S.M. Evidence for an enhanced transmembrane
sodium (Na+) gradient induced by aldosterone in the
incubated rat tail artery. Hypertension 1982; 4,230-7.
21. Friedman, S.M., McIndoe, R.A. & Tanaka, M. Prehypertensive changes in sodium transport induced by deoxycorticosterone acetate in incubated rat tail artery.
Hypertension 1986; 8,592-9.
22. Houck, C.R. Sodium, potassium and water content of aortas
in hypertensive nephrectomized dogs. Fed. Proc. Fed. Am.
Soc.Exp. Biol. 1955; 14,76.
23. Tobian, L., Janacek, J., Tombulian, A. & Ferreira, D.
Sodium and potassium in the walls of arteries in experimental renal hypertension. J. Clin. Invest. 1961; 40,
1922-5.
24. Phelan, E.L. & Wong, L.C.K. Sodium, potassium and water
in the tissues of rats with genetic hypertension and constricted renal artery hypertension. Clin. Sci. 1968; 35,
487-94.
25. DeLaRiva, I., Blaquier, P. & Basso, N. Water and electrolytes during experimental renal and DCA hypertension.
Am. J. Physiol. 1970; 219,1559-63.
26. Villamil, M.F., Amorena, C., Ponce, J., Muller, A. &
Tacquini, A.C. Changes in vascular ionic composition at different stages of DOC-salt hypertension in the rat. Clin. Sci.
1981;61,115-18.
27. Nagaoka, A., Kikuch, K. & Aramaki, Y. Participation of
tissue electrolytes and water in the spontaneous hypertension in rats. Jpn. Circ. J. 1970; 34,489-97.
28. Jones, A.W. Altered ion transport in vascular smooth
muscle from spontaneously hypertensive rats and influences
of aldosterone, norepinephrine, and angiotensin. Circ. Res.
1973; 33,563-72.
29. Jonsson, O., Lundgren, Y. & Wennergen, G. The distribution of sodium in aortic walls from spontaneously hypertensive and normotensive rats. Acta Physiol. Scand. i975;
93,548-52.
30., Simon, G., Altman, S. & Conklin, DJ. Venous wall electrolytes and hexosamines in hypertensive rats. Proc. Exp. Biol.
Med. 1980; 165,13-16.
31 Brown, T.W., Worth, J.M., Webb, K.B., Virmani, A., Hulse,
M.C. & Manger, W.M. Effect of excess dietary NaCl on BP
and tissue concentrations of Na+, K+ and catecholamines in
Dahl S-S (S)and resistant (R) rats. Fed. Proc. Fed. Am. SOC.
Exp. Biol. 1984; 43,505.
32. Simon, G., Conklin, D.J. & Altman, S. Abnormal saphenous
vein composition in human hypertension. Ctin. Exp. Hypertens. 1981; 3,69-83.
33. Headings, V.E., Rondell, P.A. & Bohr, D.F. Bound sodium
in artery wall. Am. J. Physiol. 1960; 199,783-7.
34. Friedman, S.M., Gustafson, B., Hamilton, D. & Friedman,
C.L. Compartments of sodium in a small artery. Can. J.
Physiol. Pharmacol. 1968; 46,673-9.
.
539
35. Palaty, V., Gustafson, B. & Friedman, S.M. Sodium binding
in the arterial wall. Can. J. Physiol. Pharmacol. 1969; 47;
763-70.
36. Garay, R.P., Moura, A.M., Osborne-Pellegrin, MJ., Papadimitriou, A. & Worcel, M. Identification of different sodium
compartments from smooth muscle cells, fibroblasts and
endothelial cells, in arteries and tissue culture. J. Physiol.
(London) 1979; 287,213-29.
37. Jones, A.W. Content and fluxes of electrolytes. In: Bohr,
D.F., Somlyo, A.P. & Sparks, H.V., eds. Handbook of
physiology, vol. 11, section 2, The cardiovascular system.
Bethesda, MD: American Physiological Society, 1980:
253-9.
38. Siegel, G., Walter, A., Rettig, W., Kampa, C.H., Ebeling, B.J.
& Bertsche, 0. Sodium compartments in the arterial wall.
In: Zumkley, H. & Losse, H., eds. Intracellular electrolytes
and arterial hypertension. New York: Thieme-Stratton,
1980: 30-50.
39. Friedman, S.M. Sodium ions and regulation of vascular tone.
Adv. Microcirc. 1982; 2,20-42.
40. Junker, J.L., Wasserman, A.J., Berner, P.F. & Somlyo, A.P.
Electron probe analysis of sodium and other elements in
hypertrophied and sodium-loaded smooth muscle. Circ.
Res. 1984; 54,254-66.
41. Jones, A.W. Kinetics of active sodium transport in aorta
from control and deoxycorticosterone hypertensive rats.
Hypertension 1981; 3,631-40.
42. Jones, A.W. Ionic dysfunction and hypertension. Adv.
Microcirc. 1982; 2,134-59.
43. Friedman, S.M. An ion exchange method approach to the
problem of intracellular sodium in the rat tail artery. Circ.
Res. 1974; 34-35,I-123-30.
44. Friedman, S.M., Nakashima, M. & Friedman, C.L. Cell Na
and K in the rat tail artery during the development of hypertension induced by deoxycorticosterone acetate. Proc. SOC.
Exp. Biol. Med. 1975; 150,171-6.
45. Friedman, S.M. & Friedman, C.L. Cell permeability, sodium
transport, and the hypertensive process in the rat. Circ. Res.
1976; 39,433-41.
46. Parker, J.C. & Berkowitz, L.R. Physiologically instructive
genetic variants involving the human red cell membrane.
Physiol. Rev. 1983; 63,261-313.
47. DeWardener, H.E. & MacGregor, G.A. The relation of a
circulating sodium transport inhibitor (the natriuretic
hormone?) to hypertension. Medicine 1983; 62,310-26.
48. Hilton, P.J. Cellular sodium transport in essential hypertension. N. Engl. J. Med. 1986; 314,222-9.
49. Simon, G. Is intracellular sodium increased in hypertension? Clin. Sci. 1989; 76,455-61.
50. Dawkins, D. & Bohr, D.F. Sodium and potassium movement
in the excised rat aorta. Am. J. Physiol. 1960; 199,28-30.
51. Hollander, W., Kramsch, D.M., Farmelant, M. & Madoff,
1.M. Arterial wall metabolism in experimental hypertension
of coarctation of the aorta of short duration. J. Clin. Invest.
1968; 47,1221-9.
52. Villamil, M.F. & Mathoff, J. Changes in vascular ionic content and distribution across aortic coarctation in the dog.
Am. J. Physiol. 1975; 228,1087-93.
53. Simon, G. Venous changes in renal hypertensive rats: role of
humoral factors. Blood Vessels 1978; 15,311-21.
54. Simon, G. Angiopathic serum factor in perinephritic hypertensive dogs. Hypertension 1979; 1, 197-201.
55. Simon, G., Conklin, D.J. & Song, L.B. Further studies of
angiopathic serum factor in perinephritic hypertensive dogs.
Clin. Exp. Hypertens. 1981; 3,1183-94.
56. Simon, G. Passive transfer of pressor hyperresponsiveness
from renal-hypertensive to normotensive rats. Proc. SOC.
Exp. Biol. Med. 1983; 174,356-62.
57. Simon, G., Conklin, D.J. & Altman, S. Cell growth and
sodium content in the serum of uninephrectomized and
renal-hypertensive dogs, J. Lab. Clin. Med. 1986; 107,
439-46.
540
G. Simon
58. Simon, G., Altman, S. & Conklin, DJ. Humorally-mediated
reduction of intracellular sodium content in experimental
renal hypertension. IRCS Med. Sci. 1985; 13,320-1.
59. Hirata, Y., Tobian, L., Simon, G. & Iwai, J. Hypertensionproducing factor in serum of hypertensive Dahl saltsensitive rats. Hypertension 1984; 6,709-16.
60. Simon, G. Stimulation of vascular Na-K pump with subpressor angiotensin I1 in rats. Clin. Res. 1989; 37,904A.
61. Magliola, L., Garwitz-McMahon, E. & Jones, A.W.
Alterations
in
active Na-K
transport
during
mineralocorticoid-salt hypertension in the rat. Am. J.
Physiol. 1986; 250, C540-6.
62. Friedman, J.M. & Tanaka, M. Increased sodium permeability and transport as primary events in the hypertensive
resuonse to deoxvcorticosterone acetate (DOCA) in the rat.
J. Hypertens. 19g7; 5,341-5.
63. Sivertsson, R. Hemodynamic importance of structural
vascular changes in essential hypertension. Acta Physiol.
Scand. 1970; Suppl. 343,6-56.
64. Folkow, B., Grimby, G. & Thulesius, 0. Adaptive structural
changes in the vascular walls in hypertension and the relation to the control of peripheral resistance. Acta Physiol.
Scand. 1985; 44,255-72.
65. Folkow, B., Hallback, M., Lundgren, Y. & Weiss, L. Backaround of increased flow resistance and vascular reactivity
Fn spontaneously hypertensive rats. Acta Physiol. Scand.
1970: 80.93-106.
66. Friedman', S.M. Sodium in blood vessels. A brief review.
Blood Vessels 1979; 16,2- 16.
67. Comper, W.D. & Laurent, T.C. Physiological function of
connective tissue polysaccharides. Physiol. Rev. 1978; 58,
255-315.
68. Crane, R.K. Na+-dependent transport in the intestine and
other animal tissue. Fed. Proc. Fed. Am. SOC.Exp. Biol.
1965; 24,1000-6.
69. Feigl, E.O., Petersen, L.H. & Jones, A.W. Mechanical and
chemical properties of arteries in experimental hypertension. J. Clin. Invest. 1963; 42, 1640-7.
70. Napodano, R.J., Caliva, FJ., Lyons, C., Desimore, J. &
Lyons, R. The reactivity to angiotensin of rabbit aorta strips
after either alterations of external sodium or direct addition
of benzhydroflumethiazide. Am. Heart J. 1962; 64,
498-502.
71. Blair-West, J.R., Harding, R. & McKenzie, J.S. The action of
angiotensin I1 on guinea pig ileum and its modification by
changes of sodium concentration. Br. J. Pharmacol. 1967;
31,229-43.
72. Blair-West, J.R., Harding, R. & McKenzie, J.S. Effect of
sodium concentration on the vasoconstrictor action of
angiotensin in the rabbit ear. Eur. J. Pharmacol. 1968; 4,
77-82.
73. Heistad, D.D., Abboud, EM. & Ballard, D.R. Relationship
between plasma sodium concentration and vascular reactivity in man. J. Clin. Invest. 1977; 50,2022-32.
74. Harris, G.S. & Palmer, W.A. Effect of increased sodium ion
on arterial sodium and reactivity. Clin. Sci. 1972; 42,
300-9.
75. Smith, J.B. & Brock, T.A. Analysis of angiotensinstimulated sodium transport in cultured smooth muscle cells
from rat aorta. J. Cell. Physiol. 1983; 114,284-90.
76. Friedman, S.M., Friedman, C.L. & Nakashima, M. Effect of
angiotensin on the distribution of sodium, potassium and
water in the rat. Nature (London) 1957; 180, 194-5.
77. Friedman, S.M., Butt, R.M. & Friedman, C.L. Cation shifts
and blood pressure regulation in the dog. Am. J. Physiol.
1957; 190,507-12.
78. Jamizson, J.D. & Friedman, J.M. Sodium and potassium
shifts associated with peripheral resistance changes in the
dog. Circ. Res. 1961; 9,996-1004.
79. Mendoza, S.A., Wigglesworth, N.M. & Rozengurt, E. Vasopressin rapidly stimulates Na entry and Na-K pump activity
in quiescent cultures of mouse 3T3 cells. J. Cell. Physiol.
1980; 105,153-62.
80. Friedman, S.M., Nakashima, M. & Friedman, C.L. Effect of
cooling and rewarming on sodium, potassium, and tension
changes in rat tail artery. J. Physiol. Pharmacol. 1968; 46,
25-34.
81. Harris, G.S. & Palmer, W.A. The effect of enzymatic
depolymerization of arterial mucopolysaccharides on
sodium ion content and vessel reactivity. Clin. Sci. 1971; 40,
293-303.
82. Simon, G. & Conklin, D.J. Abnormalities of vascular wall
sodium content in dogs with benign and malignant hypertension. Clin. Exp. Hypertens. 1984; 6,647-58.
83. Tobian, L. & Fox, A. The effect of norepinephrine on the
electrolyte composition of arterial smooth muscle. J. Clin.
Invest. 1956; 35,297-301.
84. Berczi, V. &Simon, G. Relationship between dog saphenous
vein reactivity and Na content. Am. J. Physiol. 1988; 255,
H860-5.
85. Shepherd, J.T. & Vanhoutte, P.M. Veins and their control.
London, Philadelphia, Toronto: W.B. Saunders Co., Ltd,
1975: 38-40.
86. Bullring, E. & Szurszenski, J.H. The stimulant action of
noradrenaline (a-action) on guinea pig myometrium compared with that of acetylcholine. Proc. R. SOC.London
Ser. B. 1974; 185,225-62.
87. Durbin, R.P. & Jenkinson, D.H. The effect of carbachol on
the permeability of depolarized smooth muscle to inorganic
ions. J. Physiol.(London) 1961; 157,74-89.
88. Goodfraind, T. Angiotensin auto-potentiation. Br. J.
Pharmacol. 1970; 40,542P-3P.
89. De Champlain, J., Krakoff, L.R. & Axelrod, J. Relationship
between sodium intake and norepinephrine storage during
the development of experimental hypertension. Circ. Res.
1968; 23,479-91.
90. Bogdanski, D.F. & Brodie, B.B. The effects of inorganic ions
on the storage and uptake of 3H-norepinephrine by rat heart
slices. J. Pharmacol. Exp. Ther. 1969; 165, 181-9.
91. Ledinnham, J.M. Disturbances in water and electrolyte
m e t a b h m in experimental hypertension. Br. Med. Bull.
1957:. 13.33-8.
.
92. Heinz, E., Geck, P. & Pietrzyk, C. Driving forces of amino
acid transport in animal cells. Ann. N.Y. Acad. Sci. 1975;
264,428-41.
93. Heinz, E., Geck, P., Pietrzyk, C., Burkhardt, G. & Pfeiffer,
B. Energy sources for amino acid transport in animal cells.
J. Supramol. Struct. 1977; 6,125-35.
94. Blaustein, M.P. Sodium ions, calcium ions, blood pressure
regulation and hypertension: a reassessment and a
hypothesis. Am. J. Physiol. 1977; 232, (2165-73.
95. Mahnensmith, R.L. & Aronson, P.S. The plasma membrane
sodium-hydrogen exchanger and its role in physiological
and pathophysiological processes. Circ. Res. 1985; 56,
773-88.
96. Wall, S.M., Kraut, J.A. & Muallem, S. Modulation of
Na+-H+ exchange activity by intracellular Na+, H + , and
Li+ in IMCD cells. Am. J. Physiol. 1988; 255, F331-9.