967
Bioscience Reports 2, 967-990 (1982)
Printed in Great Britain
Ion transport in hypertension
Review
3. D. SWALES
Department of Medicine, University of Leicester,
Clinical Sciences Building, Leicester Royal Infirmary,
P.O. Box 65, Leicester LE2 7LX, U.K.
A wide range of abnormalities of membrane sodium and
p o t a s s i u m transport can be demonstrated in patients
with essential hypertension~ and in rats with genetic
h y p e r t e n s i o n and with s o m e forms of experimental
hypertension.
In the human red cell increased permea b i l i t y to sodium and potassium~ increased ouabains e n s i t i v e sodium pumping, l i t h i u m - s o d i u m count ert r a n s p o r t , and f r u s e m i d e - s e n s i t i v e co-transport have
been described; by contrast, in the human leucocyte
sodium pumping is r e d u c e d .
In the spontaneously
h y p e r t e n s i v e rat and the rat with mineralocorticoidinduced hypertension, increased permeability to sodium
and potassium, with increased ouabain-sensitive pumping~
is s h a r e d by t he red cell and the arterial smooth
muscle.
This abnormality is associated with decreased
c e l l - m e m b r a n e a f f i n i t y for c a l c i u m and i ncreased
cell-membrane viscosity.
It is p r o p o s e d t h a t in
essential hypertension the decreased membrane affinity
for calcium is a primary pathogenetic change giving
r is e to s e c o n d a r y changes in sodium and potassium
transport.
Introduction
Blood p r e s s u r e in man is an individual c h a r a c t e r i s t i c in which
genetic factors play a major role.
Occasionally high blood pressure
(hypertension) may develop as a consequence of renal, endocrine, or
neurological disease and, unless these diseases are themselves inherited,
no genetic factor is then involved.
The majority of hypertensive
patients however (probably up to 99% in unselected populations) are
c l a s s i f i e d as having ' e s s e n t i a l h y p e r t e n s i o n ' in that no primary
condition
causing
blood-pressure
e l e v a t i o n can be d e t e c t e d .
Classification
is arbitrary: there is no dividing line between normot e n s i v e and h y p e r t e n s i v e patients (Pickering, 1968).
The smooth
uni-modal distribution of blood pressure amongst unselected subjects
has been interpreted as indicating that it is multifactorially determined.
A further confounding f a c tor is that blood pressure is such a
f u n d a m e n t a l p h y s i o l o g i c a l a t t r i b u t e that when it is altered, this
~1982
The Biochemical
Society
968
SWALES
influences almost every tissue in the body, giving rise to secondary
abnormalities. The distinction between primary and secondary changes
becomes an e x t r e m e l y difficult one, particularly as blood pressure rises
over a period of years in patients with essential hypertension so that
few longitudinal studies of the evolution of the disorder have been
carried out.
T h e f u n d a m e n t a l abnormality in most patients with longstanding
hypertension, whether primary or secondary, is an elevated periperal
resistance.
Several hypotheses have been put forward to account for
this.
Most popular among these have been the following:
(a) The
p r e s e n c e of a c i r c u l a t i n g v a s o c o n s t r i c t o r hormone.
The reninangiotensin system is the b e s t - c h a r a c t e r i z e d of these and may play a
partial role in some patients in whom hypertension is due to renovascular disease.
There is no convincing evidence that renin plays a
significant role in maintaining blood pressure in essential hypertension,
however (Swales 1979).
(b) Autoregulatory vasoconstriction produced
by hyperperfusion of tissues
as a result of increased cardiac output
(Guyton et al., 1970).
It is doubtful, however, how far such autoregulatory responses are overridden in vivo and it is equally doubtful
w h e t h e r an i n i t i a l rise in cardiac output is a sine qua non for
hypertension ( F l e t c h e r et al., 1976).
(c) Hyper-responsiveness of
blood vessels to stimuli producing excessive vasoconstriction.
The
blood-pressure response to injection or infusion of a pressor agent such
as angiotensin II or noradrenaline is often increased in hypertensive
patients and animals whether an absolute or a proportionate rise in
blood pressure is studied (Mendlowitz, 1973). Such h y p e r a c t i v i t y need
not be primary however.
Hypertrophy of the arterial and arteriolar
wall with an increased wall-to-lumen ratio changes the c h a r a c t e r i s t i c s
of the response to pressor agents causing apparent hypersensitivity
(Folkow et al., 1973).
In addition, reduction of endogenous angiot e n s i n II l e v e l s which m a y occur as a result of increased renal
perfusion pressure or fluid-volume expansion inhibits renal secretion of
renin, reducing endogenous angiotensin II levels and t h e r e f o r e occupancy of angiotensin receptors: this t oget her with up-regulation of such
r e c e p t o r s causes an apparent hypersensitivity to angiotensin II (Marks
et al., 1982).
In both these situations cause and e f f e c t are easily
confused.
It is possible that abnormalities in tissues not apparently directly
a f f e c t e d by hypertension could provide a clue about the cause of
b l o o d - p r e s s u r e elevation.
The demonstration of altered e l e c t r o l y t e
t r a n s p o r t in blood cel l s of h y p e r t e n s i v e patients and animals is
t h e r e f o r e of g r e a t t h e o r e t i c a l interest: the interpretation of such
changes is, however, fraught with problems no less difficult to resolve
than the problems of resolving changes in the physiology of the blood
vessels in hypertension.
Essential Hypertension (Table l)
Losse et al. (1960) were the first group to report elevation of
i n t r a c e l l u l a r sodium in e r y t h r o c y t e s obtained from subjects with
essential hypertension.
This finding has been confirmed by some
(Fadeke Aderounmu and Salako, 1979; Clegg et al., 1982) but not by
other groups (Burck, 1971; Canessa et al., 1980; Garay et al., 1980;
ION TRANSPORT IN HYPERTENSION
Table i.
969
Essential hypertension
Variable
Cell
Change
Reference
Intracellular sodium
Red blood
Increased
Losse et al. (1960)
Clegg et al. (1982)
Increased
Wessels et al. (1967)
Postnov e t al. (1977)
Trans-membrane sodium flux
"
Ouabain-sensitive rubidium uptake
"
Increased
Woods et al. (1981)
Sodium efflux (plasma incubated)
rate constant
"
Increased
Fitzgibbon et al. (1980)
Ouabain-sensitive sodium efflux
rate constant
"
Decreased
Walter & Distler (1982)
Sodium-potassium co-transport
"
Decreased
(Paris)
Garay et al, (1980)
"
Increased
(Boston)
Canessa et al, (1981)
Lithium-sodium counter-transport
"
Increased
Canessa at al. (1980)
Calcium binding
"
Decreased
Postnov et al. (1977)
Cell-membrane fluidity
"
Decreased
Orlov & Postnov (1982)
Decreased
Edmondson at al. (1975)
Increased
Edmondson et al. (1975)
Araoye et al. (1978)
Ouabain-sensitive sodium efflux
rata constant
InI:racellular sodium
White blood
"
Inl~racellular sodium
Lymphocyte
Increased
Ambrosioni et al. (1981)
Intracellular exchangeable calcium
Adipocyte
Increased
Postnov et al. (1980)
Walter & Distler, 1982).
Losse's groups followed up their original
o b s e r v a t i o n by demonstrating increased net sodium flux across the
erythrocyte membrane using a simple technique in which the uptake of
22Na by the red cell was measured (Wessels et al., t967).
Net
transmembrane flux as measured by this technique represents the sum
of carrier-mediated and passive diffusion processes affecting sodium
movement across the cell membrane.
The simplest explanation of
these observations was that cell permeability to sodium was increased
in the h y p e r t e n s i v e p a t i e n t s .
A l t e r n a t i v e l y , a carrier-mediated
e x c h a n g e m e c h a n i s m (such as sodium-to-sodium counter-transport)
could be activated (Canessa et al., 19g0).
Increased cell-membrane permeability to sodium and the consequent
rise in the intracellular sodium concentration would normally stimulate
sodium efflux through stimulation of the energy-dependent ouabainsensitive sodium pump.
This was reported by Postnov et al. (1977).
O u a b a i n - s e n s i t i v e rubidium u p t a k e (which probably reflects such
activity) has also been reported to be increased (Woods et al., i 9 g l ) .
On the other hand ouabain-sensitive sodium efflux in another study was
u n c h a n g e d a l t h o u g h the rate-constant for ouabain-sensitive sodium
efflux (i.e. the fraction of intracellular sodium extruded in unit time)
was slightly diminished (Walter and Distler, 1992).
Another group
reported increased sodium efflux only when cells were incubated in
plasma from hypertensive patients (Fitzgibbon et al., 19g0).
Some of the striking discrepancies in this field could be attributed
to the u n s a t i s f a c t o r y n a t u r e of the red cell and perhaps to its
susceptibility to different influences in different genetic populations.
970
SWALES
Such differences could be genetically but not causally related to blood
pressure.
Thus there may be a marked strain difference in red-cell
pump activity even within a single species (Tosteson and Hoffman,
1960).
A l t h o u g h t h e y are technically more difficult, studies of
white-cell electrolyte handling may more closely reflect the physiology
of other nucleated cells.
The picture with this preparation is more
consistent.
The r a t e c o n s t a n t for isotopic sodium efflux from
pre-loaded cells into an artificial medium is significantly reduced in
essential hypertension (Edmondson et al., 1975; Poston et al., 1981;
Heagerty et al., 1982). This is associated with increased intracellular
sodium (Edmondson et al., 1975).
The wide range for intracellular
sodium c o n c e n t r a t i o n clue probably to the poor sensitivity of the
m e t h o d coupled with c h a n g e s during prelinfinary handling of the
material renders this a less certain observation than studies of sodium
efflux, although it is difficult to see how such technical inadequacies
could introduce a systematic error. Another study of lymphocytes also
showed an increase in intracellular sodium which was directly correlated with blood pressure (Ambrosioni et al., 198f).
The combination of i n c r e a s e d i n t r a c e l l u l a r sodium and reduced pump activity
indicates t h e r e f o r e a primary impairment of active sodium pumping.
Two other carrier-mediated transport pathways have been investig a t e d in t h e h u m a n e r y t h r o c y t e and found to be a b n o r m a l .
Frusernide-sensitive sodium-potassium co-transport is measured as the
r a t i o of sodium extrusion to potassium extrusion in sodium-loaded
ouabain-pretreated erythrocytes. This was found to be decreased in a
group of patients with essential hypertension (Garay et al., 1980).
Even more r e m a r k a b l y t h e r e was no overlap for values between
subjects with essential and secondary hypertension and indeed measurement of co-transport in the red cell was proposed as a diagnostic test
for essential hypertension. Since the diagnosis of hypertension due to
r e n o v a s c u l a r d i s e a s e is difficult and mis-classification of subjects
common, this was wholly unexpected.
Later studies on Dutch and
South African subjects failed to confirm these observations (Swarts et
al., 198i; Davidson et al., 1982) and a further joint study by Garay
and c o - w o r k e r s i n d i c a t e d t h a t sodium-potassium co-transport was
actually increased in American hypertensive subjects (Canessa et al.,
1981).
S o d i u m - l i t h i u m c o u n t e r - t r a n s p o r t is m e a s u r e d by preloading
erythrocytes with lithium and comparing its extrusion into solutions
which c o n t a i n physiological concentration of sodium or no sodium
(Cannessa et al., 1980).
The resulting difference probably represents
activity of a carrier-mediated system which
exchanges intra- and
extra-cellular sodium on a I:i ratio. Lithium-sodium counter-transport
was increased in a group of hypertensive subjects (Canessa et al.,
1980).
Duhm et al. (1982) modified the method by measuring the
u p t a k e of l i t h i u m from sodium-free fluid in the presence of an
inhibitor phloretin: this technique yielded results which correlated well
with the classical method" no abnormality in lithium-sodium countertransport in hypertensive German patients could be detected by this
method.
The striking discrepancies in reported studies of red cells make
convincing conclusions d i f f i c u l t ,
There are two main sources for these
inconsistencies; patient selection and technical shortcomings.
Whilst
ION TRANSPORT IN HYPERTENSION
97i
the latter could easily obscure real differences, syst em at i c errors (i.e.
t h e c r e a t i o n of a p p a r e n t d i f f e r e n c e s or the elimination of real
differences between groups) are likely to be caused by the former.
The majority of studies present few clinical details of their hypertensive and control groups. Even age-matching hag not been achieved
in several of the quoted studies: none report details of body weight,
although hypertensive patients are usually significantly heavier than
their normotensive controls.
Obesity is associated with reduced
numbers of erthrocyte-sodium pump units, decreased pump activity, and
increased intracellular sodium (De Luise et al., 1980). In most studies
( t h e r e p o r t by E d m o n d s o n et al. (1975) on previously untreated
p a t i e n t s is a n o t a b l e e x c e p t i o n ) , t r e a t m e n t was discontinued for
variable periods before blood samples were take.
Some forms of
anti-hypertensive therapy increase the reduced l e u c o c y t e sodium efflux
r a t e of hypertension (Thomas et at., 1975) and lower intracellular
sodium (Araoye et al., 1978)).
The assumption that discontinuation
for a short period of time reverses the e f f e c t s of t r e a t m e n t which
may have been administered for many years is without experimental
proof and this could t h e r e f o r e be an important unrecognized source of
s y s t e m a t i c error.
Racial factors are clearly important determinants of e r y t h r o c y t e
e l e c t r o l y t e transport by more than one system (Canessa et al., 1981;
Woods et al., 1981), but they are usually ignored in descriptions of
patient groups.
The role of technical factors is more difficult to
assess, since such a wide variety of methods has been applied in the
analysis of different transport systems.
In some studies, however,
pre-incubation procedures have been carried out at 2~
(Postnov et
al., 1977), in some cases at room t e m p e r a t u r e (Poston et al., 1981),
and in some cases at 37~
(Walter & Distler, 1982). Concentrations
of e l e c t r o l y t e s utilized vary widely, so that in some cases transport
processes can be assumed to be saturated whilst in other cases failure
to saturate transport processes results in values which r e f l e c t affinity
of transport systems as well as their rate (Tosteson et al., 1981).
T a k e n in isolation these clinical studies can only yield limited
conclusions.
It is clear that changes in membrane transport can be
d e m o n s t r a t e d in both e r y t h r o c y t e s and leucocytes of hypertensive
patients: these defects are heterogeneous and not necessarily related
to hypertension as such.
The presence of similar abnormalities in
n c m - h y p e r t e n s i v e r e l a t i v e s of h y p e r t e n s i v e s (Meyer et al., 1981;
C a n e s s a et al., 1981; H e a g e r t y et al., 1981) suggest that these
changes are genetically determined, related to hypertension, but that
they do not r e f l e c t direct causal processes. To carry the i nt erpret ation of the published l i t er a t ur e further it is necessary to turn to the
m o r e c a r e f u l l y c o n t r o l l e d l a b o r a t o r y c o n d i t i o n s of experimental
hypertension.
Genetic Hypertension
(Table 2)
Almost all studies of membrane electrolyte transport have been
carried out in the rat, and the majority have utilized genetic hypertension in an inbred strain on the grounds that this may provide a
better model for essential hypertension in man than models which
r e q u i r e a d m i n i s t r a t i o n of mineralocorticoids or renal manipulations,
972
SWALES
Table 2.
Variable
Model
Sodium and potassium
permeability
SHR
Genetic hypertension in the rat
Tissue
Change
Reference
Red blood
Increased
Postnov et el. (1976)
Yamori et al. (1977)
Friedman et el. (1976)
"
Increased
Friedman et el. (1977)
Net sodium efflux
"
SHR
"
Sabra
"
hypertensive
Decreased
"
De Mendonca et al. (1980)
De Mendonca et al. (1980)
Net potassium influx
Lyon
"
hypertensive
Increased
de Mendonca et al. (1980)
Calcium binding
SHR
I!
Decreased
Postnov et al. (1979)
DevTnck et al. (1981)
Ouabain-resistant net
SHR
potassium and sodium flux
II
Cell-membrane
fluidity
Sodium content and
ouabain-sensitive
sodium efflux
t!
Adipocyte
Decreased
Postnov and Orlov (1980)
SHR
I!
Decreased
Orlov et al. (1982)
SHR
Thymocyte
Decreased
Jones et el. (1981)
Net sodium efflux
SHR
Tall artery
Increased
Friedman (1979)
Sodium and potassium
turnover
SIIR
Arterial wall
Increased
Jones (1974)
Ouabain-insensitive
sodium efflux
SHR
Arterial
smooth muscle
Increased
Friedman et el. (1982)
Calcium binding
SHR
Arterial wall
(sub-cellular
fraction)
Decreased
Wei et al. (1976)
11
Aortic
smooth muscle
Decreased
Zsoter et al. (1977)
I!
Sodium-potassium ATPase
SIIR
Arterial
smooth muscle
Increased
Webb and Bohr (1979)
Intracellular calcium
pool
SHR
Adipocyte
Increased
Postnov et al. (1981)
SHR
=
spontaneously hypertensive r a t .
Great caution has to be applied in the extrapolation of animal models
to man.
For instance the Dahl and Milan strains of hypertensive rat
develop hypertension when salt intake is increased whilst a common
l a b o r a t o r y strain~ the Sprague-Dawley rat, shows a rise in blood
pressure with salt restriction (Seymour et a l , 1980).
A t the same
t i m e the d e m o n s t r a t i o n of similar changes in diflerent tissues of
genetically hypertensive rats and in patients with essential hypertension
might throw light upon the mechanisms responsible for blood-pressure
elevation in both species.
In addition it is possible to have direct
access to blood vessels in animal models.
Most studies of the e r y t h r o c y t e and arterial wall maintained in
artificial media have shown increased sodium-potassium permeability
a s s o c i a t e d with i n c r e a s e d t u r n o v e r of t h e s e cations (Table 2).
Exceptionally, de Mendonca et al. (19g0) reported decreased sodium
efflux in the Okamoto spontaneously hypertensive rat (SHR).
This
group utilized a method in which e r y t h r o c y t e s were first loaded with
sodium and depleted of potassium by t r e a t m e n t with p-chloromercurobenzenesulphate, a technique similar to that employed tn measurmg
frusemide-sensitive sodium-potassium co-transport: the authors did not
ION TRANSPORT IN HYPERTENSION
973
d e f i n e the a b n o r m a l i t y any further and the relationship of these
a b e r r a t i o n s to o t h e r studies oi the red cell, measuring isotope
movements or utilizing ion-selective electrodes, remains obscure.
Increased c e l l - m e m b r a n e permeability to sodium and potassium
would normally be associated with increased a c t i v i t y of (Na+/K+) ATPase-mediated sodium pumping in SHR. There is some evidence for
this.
Thus, when a c t i v i t y of sodium pumping was reduced by cooling
tc 15~
the trans-membrane potential of vascular smooth muscle of
SHR was less than that of normotensive controls although there was
no difference at 37~
(Hermsmeyer, 1976).
Webb & Bohr (1979)
i n v e s t i g a t e d the relaxation of vascular smooth muscle produced by
depolarizing the cell membrane with increased potassium concentration
in the surrounding medium. Such relaxation was greater in SHR than in
n o r m o t e n s i v e c o n t r o l s although the duration of relaxation was no
different.
The difference in response between SHR and normotensive
controls could be eliminated by ouabain.
This was interpreted as
indicating increased a c t i v i t y of the ouabain-sensitive sodium pump in
SI-IR and is consistent with other studies indicating increased sodium
and potassium p e r m e a b i l i t y and the resulting stimulation of the
electrogenic sodium pump (Table 2).
One series of observations on the thymocyte is out of line with
this conclusion. 3ones et al. (1991) observed a significantly negative
correlation between blood pressure and the rate constant for ouabainsensitive sodium efflux in this preparation.
Both the technique and
the results are similar to observations on white cells of patients with
essential hypertension (Edmondson et al., 1975; Heagerty et a]., 1992).
However, blood pressure rises with age in SHR. A correlation between
sodium e f i l u x and blood pressure was no longer significant when
corrected for age, so that it seems at least possible that age was
responsible for the reduced sodium efflux.
Neither of the discordant
studies listed in Table 2 therefore necessarily negates the concluMon
that in the most widely studied genetic model of hypertension, the
Okamoto SHR, cell-membrane permeability to sodium is increased and
t h i s is associated w i t h increased active sodium pumping through
(Na+/K +) ATPase activity.
E x p e r i m e n t a l H y p e r t e n s i o n ( T a b l e 3)
A l t h o u g h t h e r e have been fewer investigations of experimental
hypertension, a similar pattern of change has been demonstrated in
Mood vessels maintained in artifical media and obtained from rats with
mineralocorticoid-induced hypertension, i.e. permeability to sodium and
potassium is enhanced and pump activity is increased (Table 3). Only
when plasma is included in the medium in which isolated arterial wall
is incubated can a reduction in pump activity (measured by ouabainsensitive rubidium uptake) be demonstrated (Pamnani et al., 1981). It
is suggested that when extracellular fluid volume is expanded as part
of the procedure for inducing hypertension, a circulating ouabain-like
s,ubstance is produced.
Whether such a substance is an essential
component of the processes which cause hypertension or is incidental
~.~; not certain.
Curiously, in arterial tissue from the salt-sensitive
97zt
SWALES
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ION TRANSPORT IN HYPERTENSION
975
strain of Dahl rat, ouabain-sensitive pump activity measured in this
way was increased (Pamnani et al., 1980; Overbeck et al., 1981).
This is ironic as the de Wardener-MacGregor hypothesis of a circulating inhibitor of sodium transport (see below) is based upon an original
suggestion ol Dahl put forward to explain the salt-sensitive nature of
blood pressure in this strain of rat (de Wardener & MacGregor, 1980).
It seems likely in summary that SHR and rats with mineralocorticold hypertension share an in vitro d e f e c t in arterial smooth-muscle
m e m b r a n e s which c a u s e s i n c r e a s e d p e r m e a b i l i t y to sodium and
p o t a s s i u m , and stimulation of pump activity.
In vivo, circulating
f acto r s may modify these changes.
C e l l - M e m b r a n e D i s t u r b a n c e and t h e P a t h o g e n e s i s of H y p e r t e n s i o n
It is reasonable to conclude that at least some of the observed
changes in c e l l - m e m b r a n e e l e c t r o l y t e transport which have been
observed are related to hypertension and are not the result of errors
in laboratory method or matching of controls.
The observed associal:ion could occur in one of three ways:
a, The electrolyte abnormality could be the result of hypertension.
b. It could represent a characteristic genetically linked with hypertension but not responsible for it.
c. The m e m b r a n e abnormality could participate in the mechanism
responsible for blood-pressure elevation or could be associated with it.
It seems unlikely that the changes are a consequence of hypertension.
Thus some of the described abnormalities are present in
Mood cells not obviously involved in the hypertensive process.
More
i m p o r t a n t , perhaps, s i m i l a r abnormalities can be demonstrated in
normotensive relatives of hypertensive subjects (Meyer et al., 1981;
Heagerty et al., 1982) but cannot be demonstrated in patients with
renovascular hypertension (Garay et al., 19g0).
The p o s s i b l i t y that ion-transport abnormalities simply act as a
genetic marker for hypertension cannot be excluded, particularly as
t h e y can occur i n d e p e n d e n t l y of h y p e r t e n s i o n in such families.
However, the fact that membrane ion transport is such a fundamental
p a r t i c i p a n t in smooth muscle excitation-contraction makes it more
likely that these abnormalities are in some way related to the process
which elevates blood pressure. At the same time any hypothesis has
to account for the fact that hypertension is not a necessary consequence of these abnormalities.
Vascular smooth-muscle contraction is mediated by an increase in
ionized calcium in the cytoplasm in the region of the contractile
protein (Bolton, 1979).
This change is produced by the entry of
calcium ions into the cell, the eflect of which is amplified by the
release of calcium bound by the cell membrane and by intracellular
stores. The increase in cell-membrane permeability to calcium is due
to the opening of two types of ion channel. One opens in response to
depolarization produced by a change in sodium or potassium gradient
across the membrane. Receptor-operated channels, on the other hand,
respond to specific agonists by increasing cell-membrane pereability to
calcium and (probably to a greater extent) to other ions. A degree
of d e p o l a r i z a t i o n may t h e r e f o r e r e s u l t from agonist binding to
receptors with the resultant opening of potential-mediated as well as
976
SWALES
r e c e p t o r - m e d i a t e d channels.
Enhanced vascular smooth-muscle
contraction could therefore result from"
(a)
increased local agonist
concentration producing opening of receptor-mediated calcium channels
and perhaps also membrane depolarization; (b) membrane depolarization produced independently of the above; (c) increased intracellular
concentration of calcium produced by changes either in transmembrane
calcium pumping or release from intracellular stores; or (d) changes in
calcium binding by the intracellular receptor protein and the intracellular mechanisms which link this to contraction.
Two groups of
hypothesis have been put forward to link cation transport with the
processes mediating smooth-muscle contraction.
One postulates
physiological inhibition of transmembrane calcium movements, whilst
the other postulates an intrinsic membrane abnormality.
Calcium-Sodium Hypotheses
Blaustein (1977) summarized the evidence for a sodium-calcium
transport mechanism exchanging three sodium ions for one calcium ion
across the vascular smooth-muscle membrane. Inhibition of this pump
by a r e d u c t i o n in external or an increase in internal sodium would
p r o d u c e an i n c r e a s e in intracellular calcium.
When intracellular
i o n i z e d c a l c i u m c o n c e n t r a t i o n s lie within a critical range on the
d o s e - r e s p o n s e c o n t r a c t i o n curve, Blaustein calculated that smoothmuscle tension would be critically dependent upon intracellular sodium.
Thus, using representative values for electrolyte concentrations he
calculates that an increase of 5% in intracellular sodium concentration
will increase smooth-muscle tension by about 50%.
A circulating
ouabain-like inhibitor of sodium pumping such as that postulated by
H a d d y et al. (1978) could therefore increase peripheral resistance
through an elevation of intracellular sodium inhibiting sodium-calcium
exchange and thereby raising intracellular calcium concentrations (Fig.
1).
De Wardener and MacGregor (1980) emphasized experiments by
Dahl's group which suggested that hypertension in the 'salt-sensitive'
s t r a i n of rats was due to a humoral factor (DaM et al., 1969).
E s s e n t i a l hypertension, they went on to postulate, was due to an
i n h e r i t e d difficulty in eliminating dietary sodium with consequently
increased levels of 'natriuetic hormone' which inhibits the vascular
smooth-muscle sodium pump as well as that of the renal tuble. Later
they were able to demonstrate increased levels of a substance in
plasma from hypertensive subjects which stimulated glucose-6-phosphate
dehydrogenase activity in renal slices. This preparation responded to
ouabain in a similar way and it was therefore concluded that such
patients indeed had elevated levels of (Na+/K+)ATPase inhibitor: in
support of that hypothesis, salt loading also increases inhibitor activity
measured in this way (MacGregor et al., 1981). In further studies it
was shown that the defect in ouabain-sensitive sodium efflux present
in the leucocytes of hypertensive patients could be induced in normal
leucocytes by pre-incubation with serum from hypertensive patients
(Poston et al., 1981), although the nature of the inhibition produced in
these experiments was not characterized further.
The de Wardener-MacGregor hypothesis can be regarded as a more
specific form of the Blaustein hypothesis, upon the validity of which it
depends. The Blaustein hypothesis could thus still be valid even if the
ION TRANSPORT IN HYPERTENSION
977
'Clrculmi~
I
Inhibitor I
Raised
Introcelluiar Sodium
Na Ca Exchange
Raised
Intmcellular Calcium
Fig. I.
Sequence of changes according to the
Blaustein-de Wardener hypothesis.
A circulating
inhibitor of sodium transport perhaps stimulated by
volume retention inhibits ouabain-sensitive sodium
pumping causing an elevation of intracellularsodium-inhibited sodium-calcium exchange and thereby
raising intracellular calcium.
de Wardener-MacGregor hypothesis were not.
Thus, calcium-sodium
exchange could be inhibited by elevation of intracellular sodium by a
m e c h a n i s m o t h e r than h u m o r a l i n h i b i t i o n of t h e sodium pump.
However, in view of the overlapping nature o5 these two hypotheses
they will be considered together under their relevant components.
The
e x i s t e n c e of this mechanism is of course central to both
hypotheses.
It is further assumed that the exchange mechanism is a
d e t e r m i n a n t of i n t r a c e l l u t a r ionized calcium and that changes in
calcium induced by physiological alterations in sodium gradient across
tlhe ceil membrane lie within the sensitive dose-response range for
excitation-contraction
c o u p l i n g under p h y s i o l o g i c a l c o n d i t i o n s .
U n f o r t u n a t e l y , at present there is no agreement over either the
relevance of sodium-calcium exchange carrier system to c o n t r a c t i l i t y
or indeed over the existence of such a system (Van B r e e m e n et al.,
1979).
Thus a reciprocal relationship between calcium and sodium
would be observed in both extraceilular and intracellular spaces if
t h e r e were competition by sodium and calcium for the same binding
sJLtes. Alternatively, sodium could compet e with calcium 5or the same
t r a n s m e m b r a n e channels; thus there is evidence that sodium-Sree
solutions enhance the passive inS]ux o5 calcium into smooth-muscle
cells (Droogmans & Casteels, 1979). The e55ects of a carrier system
might be overridden by energy-dependent (Ca2+)ATPase pump a c t i v i t y
if, for instance, the two transport processes operated in parallel (Van
B r e e m e n et a]., 1979). Alternatively, the relationship between calcium
and sodium would be observed i5 the (CaZ+)ATPase pump were
978
SWALES
dependent upon sodium concentration (Duggan 1977).
In a recent
study by Aaronson and Van Breemen (1981) of guinea-pig taenia coil)
replacement of external sodium with sucrose or choline chloride caused
a decrease in calcium ef[lux rate.
On the other hand, inhibition of
the sodium pump by ouabain, whilst producing the anticipated rise in
intracellular sodium, had no effect on cell calcium.
Whilst extreme
changes in e x t e r n a l sodium concentration affect both intracellular
c a l c i u m and s m o o t h - m u s c l e c o n t r a c t i l i t y ,
the relevance of such
phenomena to p h y s i o l o g i c a l a l t e r a t i o n s in sodium and peripheral
r e s i s t a n c e is more doubtful.
For instance, Ma and Bose (1977)
s t i m u l a t e d t a e n i a coli smooth muscle with high potassium in the
incubation medium in the absence of sodium. Relaxation was produced
when external sodium, at a concentration of more than 7 mmol/l, was
r e i n t r o d u c e d and the effect appeared to be produced by calcium
extrusion. Such changes are of course outside the physiological range.
Brading et al. (19g0) studied the effect o[ the removal of sodium
f r o m the i n c u b a t i o n f l u i d upon the c o n t r a c t i l e response of this
preparation to carbachol and explained the inhibition produced in terms
both of an effect upon trans-membrane calcium movement and of an
effect of intracellular sodium depletion upon refilling of the internal
store of bound calcium. Such conditions do not however occur in vivo
and the changes produced by Aaronson and Van Breemen ( 1 9 g l ) with
ouabain seem more likely to reproduce physiological effects of the
postulated circulating inhibitor.
The major unresolved problem in this
area is the determination of free cytosolic calcium concentration in
the region of the contractile protein. The proposed role for sodium in
the regulation of intracellular calcium and smooth=muscle c o n t r a c t i l i t y
cannot be regarded as proved at the moment (Van Breemen et al.,
1979).
The e f f e c t upon vascular smooth muscle of inhibiting the sodium
pump either by ouabain or by a reduction in the external potassium is
more complex.
A l t h o u g h a t r a n s i e n t c o n t r a c t i o n is i n d u c e d
(Bonaccorsi et al., 1977; Palaty, I980), this is attributable mainly if
not e x c l u s i v e l y to enhanced release of endogenous catecholamines
resulting from pump inhibition of the nerve terminals. The subsequent
relaxation is associated with a decrease in responsiveness to noradrenaline (Palaty, 1980).
Chronic inhibition with ouabain sufficient to
produce chemically detectable 'waterlogging' of the arterial wall in
dogs was not associated
with hypertension in another study, although
the authors speculate that drug toxicity may have prevented hypertension (Overbeck et al., 19g0).
A reduction in external sodium concentration would be expected
n o r m a l l y to inhibit calcium-sodium exchange and enhance vasoconstriction.
Clinically, however, changes in serum sodium concentration
are not associated with consistent changes in blood pressure (Berl et
al., 1976), whilst in large populations systolic blood pressure is
postively rather than negatively correlated with plasma sodium (Bulpitt
et al.~ 1981).
The reactivity of peripheral human arteries is reduced
by a fall in the sodium concentration of the perfusate (Heistad et al.,
1971).
At present it has to be concluded that the existence of a
carrier-mediated calcium-sodium exchange mechanism in physiological
conditions and its relevance to smooth-muscle contractility and blood
pressure are unproven.
ION TRANSPORT IN HYPERTENSION
Ouabain.like
979
ihhibitor and blood pressure
Previously described work from de Wardener's group on patients
with essential hypertension and from Haddy, Overbeck, and Pamnani in
w)lume-expanded experimental hypertension suggests the presence of a
humoral inhibitor of (Na+/K+)ATPase.
The de Wardener-MacGregor hypothesis requires the validity of two
testable postulates.
Firstly the humoral ouabain-like ATPase inhibitor
must be responsible for sufficient peripheral vasoconstriction to cause
hypertension, and secondly patients with essential hypertension should,
in the initial phase at least, exhibit impairment in sodium excretion
sufficient to stimulate the secretion of the natriuretic ouabain-like
factor.
Three major difficulties arise in associating humoral inhibition of
the sodium pump and hypertension.
a.
I n h i b i t i o n of the r e d - c e l l ouabain-sensitive pump can be
d e m o n s t r a t e d in a wide variety of conditions without hypertension
( S w a l e s , 1975).
For instance such inhibition occurs in Bartter's
syndrome, hypothyroidism, uraemia, and obesity. In particular, uraemic
plasma contains a factor which can inhibit (Na+/K+)ATPase, but such
inhibition is not specifically associated with hypertension (Cole et al.,
1968).
The reduction in red-cell sodium pumping in obese subjects
(De Luise et al., 1980) may reflect an intrinsic membrane defect but
it is also not consistently associated with hypertension.
b.
Inhibition of the sodium pump has only consistently been
observed in the white cell.
A variety of abnormalities has been
reported in the red-cell membrane in essential hypertension, and indeed
in the SHR an increased rate of sodium pumping has been fairly
consistently demonstrated (Table 2). Even the depression in white-cell
sodium efflux can be dissociated from hypertension in the relatives of
hypertensive subjects (Heagerty et al., 1982).
c.
The i m p a i r m e n t of sodium-excreting capacity in essential
hypertension is debatable.
Plasma volume is reduced in proportion to
the degree of blood-pressure elevation, whilst the majority of studies
of exchangeable sodium in essential hypertension have failed to show
any abnormality as long as the patients were not in renal failure or
cardiac failure (Swales, 1975). Indeed, in one recent study, exchangeable sodium was significantly subnormal in hypertensive subjects below
the age of 35 years (Beretta-Piccoli et al., 1982), suggesting that the
e a r l y s t a g e of hypertension is associated with a negative sodium
bMance produced by perfusion-pressure natriuresis through the normal
kidney, a phenomenon which has been demonstrated in renovascular
h y p e r t e n s i o n produced by unilateral renal-artery stenosis.
Another
approach is the study of the excretion of a sodium load in the early
sl~ages of hypertension before secondary changes which may confuse
the physiological response have had time to develop.
Since genetic
f a c t o r s are so important in hypertension, first-degree relatives of
hypertensive patients are at high risk of developing hypertension later
in life: they can therefore be regarded as pre-hypertensive. Grim et
al. (1979) o b s e r v e d t h a t urinary sodium excretion after a saline
infusion was less in such individuals, although a later report indicated
that plasma renin was slightly higher, suggesting that they did not
have significant sodium retention before infusion (Luft et al., 1982).
980
SWALES
I n d e e d t h e s e observations are more consistent with a mild sodium
deficit in this group.
Another study using a shorter saline infusion
period showed a greater immediate natriuretic response in relatives of
hypertensive patients (Wiggins et al., 1968).
This discrepancy could
r e f l e c t differences either in the protocol used or in the populations
studied, since 'normality' of blood pressure is difficult to define in the
absence of 24-hour blood-pressure records.
Another argument in favour of abnormal renal handling of sodium
in hypertension relies upon more generally agreed data.
Elevation of
renal perfusion pressure to the levels observed in essential hypertension
causes a major increase in sodium and water excretion: this is not
observed of course in patients with essential hypertension.
It has
accordingly been concluded that there is a primary abnormality in the
r e l a t i o n s h i p between renal perfusion pressure and the excretion of
sodium, i.e. a shift in the pressure-natriuresis curve (Guyton et al.,
197t~).
Such a view, however~ overlooks the fact that a natriuresis
p r o d u c e d by hypertension would induce a negative sodium balance
which would tend to oppose further natriuresis until a steady s t a t e was
achieved in which output was normalized although at the expense of
slightly reduced plasma and extraceliular fluid volume (Swales, 1977;
Omvik et al., 19g0).
In summary, there is no currently agreed body of data to support
t h e view t h a t e s s e n t i a l h y p e r t e n s i o n is a s s o c i a t e d with sodium
r e t e n t i o n c a u s i n g i n h i b i t i o n of s m o o t h - m u s c l e - m e m b r a n e sodium
pumping
and increased intracellular calcium through inhibition of a
sodium-calcium exchange mechanism.
On the other hand, there is
eviderice for inhibition of the ouabain-sensitive sodium pump in the
leucocytes of patients with essential hypertension, although in the red
c e l l s of such patients and in the blood-vessel wall of genetically
hypertensive rats sodium pumping appears to be enhanced rather than
the reverse. There is some direct evidence for a circulating inhibitor
of sodium pumping but these data require confirmation and further
c h a r a c t e r i z a t i o n of the nature of the material.
Intrinsic-Membrane-Abnormality Hypothesis
Other workers rather than incriminating a specific abnormality of
one pathway have postulated a genetic membrane d e f e c t in essential
hypertension (Canessa et al., 198t; Orlov et al., 1982).
Thus in
addition to abnormalities of sodium and potassium handling, red-cell
m e m b r a n e v i s c o s i t y is i n c r e a s e d and calcium binding by red-ceil
m e m b r a n e s r e d u c e d in e s s e n t i a l hypertension (Table i ) .
Similar
abnormalities have been described in the red ceils of SHR (Table 2):
in addition, calcium binding by the arterial smooth muscle is reduced
in this strain (Table 2). If this is associated with an increase in free
i n t r a c e l l u l a r c a l c i u m e i t h e r directly or as a result of decreased
a f f i n i t y for the ATP-dependent calcium extrusion pump, this would
provide a basis for enhanced smooth-muscle tone.
There is little
direct evidence on this in man~ although an increase in intracellular
f r e e c a l c i u m has been described in adipocytes from patients with
e s s e n t i a l h y p e r t e n s i o n ; h o w e v e r , insufficient clinical details were
p u b l i s h e d to d e t e r m i n e whether this could solely be attributed to
ION TRANSPORT IN HYPERTENSION
9gl
hypertension or not (Postnov et al., 1980).
On the other hand, a
similar change was described in the adipocytes of SHR (Postnov and
Orlov, 1980).
If increased intracellular calcium as a result of a
de.creased c e l l - m e m b r a n e affinity for calcium were responsible for
enhanced smooth-muscle contractility, the previously described changes
in potassium and sodium handling could merely represent a marker for
the primary abnormality.
It is also possible, however, that they are
more directly linked to calcium handling. Two properties of calcium
may be relevant.
Firstly, increasing intracellular calcium enhances
red-cell sodium and potassium permeability (Romero & Whittam, 1977)
and there is a close relationship between potassium loss from red-cell
g h o s t s and i n t r a c e l l u l a r calcium (Whittam, 1968; Romero, 1976).
Secondly, high external calcium concentrations stabilize smooth-muscle
cell membranes, reducing potassium efflux and inhibiting excitation
(Rothstein, 1968; Holloway & Bohr, 1973).
3ones has suggested that
the increased turnover of potassium in arterial smooth muscle in SHR
(3ones, 197/~) and deoxycorticosterone (DOC) salt hypertension (3ones
& Hart, 1975) is due to a decreased ability of cell membranes in
these models to bind calcium.
Thus removal of calcium from the
p e r f u s i n g fluid acclerated #2K efflux from the arterial wall more
rapidly in these models than in controls, and for any given external
ca!lcium level ~2K efflux was greater in DOC hypertension than in
control animals. Aortae from such animals had significantly increased
total concentrations of potassium, magnesium, and calcium (3ones &
Hart, 1973).
Holloway and Bohr (1973) examined the response of
helical strips of femoral artery to potassium chloride, which depolarize:5 the smooth-muscle membrane and provokes a constrictor response.
Strips from rats with DOC and Goldblatt 2-kidney hypertension had a
lower t h r e s h o l d for constriction.
The response was depressed by
increased external concentrations of calcium, perhaps as a result of
the aforementioned membrane stabilization: greater concentrations of
calicium were required to inhibit the potassium response in rats with
DOC s a l t , s p o n t a n e o u s , and Goldblatt 2-kidney l-clip hypertension.
The p r e s e n c e oi an a b n o r m a l i t y in renovascular hypertension is
sulrprising and raises the possiblity that this functional change is
secondary to hypertension rather than being a primary determinant of
enhanced vasoconstriction.
In summary, there is good evidence for decreased calcium binding
by the cell membranes in spontaneously hypertensive rats and perhaps
also in essential hypertension. There are theoretically two mechanisms
by which this would induce changes in membrane handling of sodium
and p o t a s s i u m : e i t h e r increased intracellular calcium concentration
weuld increase permeability to these ions, or decreased binding of
c a l c i u m would destabilize the membrane, producing the same end
results.
In either case a link would be forged between the welldocumented increase in cell permeability to sodium and potassium and
vasoconstriction which would result from an increase in free intracellular calcium.
The physiological response to increased membrane
permeability to sodium and potassium would be elevation of intraceilular sodium concentration and decrease in intracellular potassium,
as these two ions diffuse down their concentration gradients.
This
would normally lead to increased active sodium pumping.
There is
evidence for all these changes in several models (Tables 1-3).
982
SWALES
S u c h a h y p o t h e s i s does not, h o w e v e r , explain the r e d u c e d
o u a b a i n - s e n s i t i v e sodium pump and f r u s e m i d e - s e n s i t i v e s o d i u m p o t a s s i u m c o - t r a n S p o r t a c t i v i t y d e s c r i b e d in the leucocytes and
e r y t h r o c y t e s r e s p e c t i v e l y of p a t i e n t s with essential hypertension.
However, since neither the controlling factors nor the carrier mechanism of co-transport has been defined, it is not possible to speculate on
the nature of the disturbance, although co-transport is sensitive to
changes in membrane lipids.
More information is available, however,
about the ouabain-sensitive sodium pump. It is possible that inhibition
of the sodium pump (where it can be demonstrated) is secondary to a
primary disturbance of membrane structure. Thus decreased membrane
fluidity induced by cooling produces a reduction in sodium pumping
(Skou, 1975), and changes in erythrocyte membrane viscosity have
been observed in genetic hypertension (Tables 1-2). The cause of this
d i s t u r b a n c e or the n a t u r e of its e f f e c t upon sodium pumping is
obscure. However, it seems probable that it could result in changes in
access of substrate ion to the pump.
Thus pump activity can be
increased by exposure of membranes to limited amounts of detergent
(Jorgensen, I975).
There is further, more direct evidence for an
e f f e c t of membrane fluidity on sodium pumping.
(Na+/K+)ATPase
a c t i v i t y is c o m p l e t e l y i n h i b i t e d b y r e m o v a l of the phospholipid
c o m p o n e n t and a c t i v i t y can be restored by reintroducing certain
p h o s p h o l i p i d s of which p h o s p h a t i d y l serine is the most e f f e c t i v e
(Wheeler & Whittam, 1970; Roelofson & van Deenen, 1973).
The
fluidity of the phospholipid component is criticah maximal reactivation
of (Na+/K+)ATPase only occurs when the fatty acyl chains are such
t h a t the r e s u l t i n g phospholipid is fluid.
Arrhenius plots of the
influence of temperature upon (Na+/K+)ATPase activity show a break
corresponding to transition from the gel to the liquid crystalline form
of the phospholipid (Kimelberg & Papahadjopoulos, 1972).
M e m b r a n e phopholipids also account for about 20% of calcium
binding b y the red-cell membrane (Forstner & Manery, 1971; Duffy &
S c h w a r z , 1 9 7 3 ) : a physiological role has been attributed to both
phosphatidyl serine (Long & Mouat, 1971) and phosphatidyl inositol in
this c o n t e x t ( B u c k l e y & Hawthorne, 1972; Michell, I975).
It is
noteworthy that the decrease in cell-membrane affinity for calcium on
the the inner side of the cell membrane has been demonstrated and
t h e p r e s e n c e of n e g a t i v e l y c h a r g e d phospholipids is an essential
r e q u i r e m e n t for h y d r o l y s i s of ATP by ( N a + / K + ) A T P a s e on the
cytoplasmi c side of the cell membrane where the negatively charged
phospholipids predominantly lie (de Caldentey & Wheeler, 1979).
A
p r i m a r y a b n o r m a l i t y of the phospholipid component of the cell
m e m b r a n e could t h e r e f o r e underlie both the decreased membrane
calcium affinity and its consequences, together with the reduction is
sodium pumping observed in some tissues (Fig. 2).
Alternatively,
membrane viscosity could be increased by a disturbance of g!ycoprotein
structure, since fluidity is influenced by the carbohydrate side-chain of
glycoproteins (Skou, 1975).
As the sialic acid component of sialog l y c o p r o t e i n s is important in membrane calcium binding (Long &
Mouat, 1971; Forstner & Manery, 1971), there is another potential link
between calcium binding and sodium pumping.
The hypothesis that there is a primary abnormality in the physicoc h e m i c a l s t r u c t u r e of the cell membrane underlying both calcium
ION TRANSPORT IN HYPERTENSION
983
/Decreos~l Ca
r IncreasedIMrocellular
Affinity ~.~L
Caliklm
Membrane
Abnormality
? Glycoprotein
? Phospholipld
Increasld K, Na
Perrneab411fy
~'~
Na Pump ,,
Depolarization
flalsed Intracellular
Sodium
Fig. 2.
Sequence of events according to the
membrane-abnormality hypothesis.
A global disturbance of membrane function causes decreased calcium
affinity as well as inhibiting the sodium pump.
Elevation of intracellular calcium causes secondary
increase in sodium and potassium permeability with
increased intracellular sodium tending to oppose
primary reduction in sodium pumping.
According to
this hypothesis, therefore, sodium pumping might be
either elevated or reduced although turnover of
sodium and potassium is increased.
binding and the sodium pump independently cannot be regarded as
other than speculative at the moment.
However, apart from explaining several puzzling observations it does resolve a major enigma in the
published l i t er a t ur e, i.e. the presence of enhanced sodium pumping in
some tissues from hypertensive patients and reduced sodium pumping in
others, since the sodium pump would be under two opposing influences
(Fig. 2).
On t he one hand increased membrane permeability to
sodium and potassium would stimulate pumping, whilst on the other
hand the membrane abnormality would impede it: the net results would
be a c h a n g e in e i t h e r direction depending upon the preponderant
influence.
W h a t e v e r t he f i nal c o n c l u s i o n , the s t r i k i n g n a t u r e of these
abnormalities in hypertensive individuals and animals suggests that they
a r e m a n i f e s t a t i o n s of a fundamental disturbance of cell function,
p r o b a b l y g e n e t i c in o r i g i n , which plays an essential role in the
development of high blood pressure.
The final resolution of these
p r o b l e m s a w a i t s m o r e p r e c i s e c h a r a c t e r i z a t i o n of the underlying
processes and the manner in which they are disturbed.
Acknowledgement
My thanks are due to Professor R. Whittam for helpful discussions
throughout the preparation of this review.
98/4
SWALES
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ION T R A N S P O R T IN HYPERTENSION
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