1-74
Membrane Sodium Transport and Salt
Sensitivity of Blood Pressure
Alan B. Weder
R
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esponses of blood pressure to alterations in
the intake of sodium chloride vary widely
between individuals. This variable responsiveness complicates investigations of mechanisms
responsible for salt sensitivity and limits the appeal of
salt restriction as a nonpharmacological antihypertensive therapy. There is therefore considerable interest in the development of markers of salt sensitivity, and several general anthropometric, racial, and
biochemical features of salt-sensitive groups have
been described.1 As yet, however, no single test or
combination of features permits reliable prediction
in individual patients of the responsiveness of blood
pressure to chronic salt loading or depletion. During
the 1980s, burgeoning interest in the role of cellular
Na+ content and transmembrane Na+ fluxes in essential hypertension led to the numerous studies reviewed below that attempted to define the relation of
blood pressure responsiveness to short- and longterm changes in salt balance to membrane markers.
Investigations of a possible role for membrane
transport in the control of blood pressure responses
to salt loading and depletion have addressed two
major issues. The majority of studies have examined
the question of whether acute or chronic changes in
salt balance cause changes in cellular Na+ content or
transport. Less well studied is the issue of whether
baseline cellular cation handling characteristics are
predictive of future blood pressure responses to
dietary salt modification. The few studies that have
examined this latter point are of particular interest in
light of the growing appreciation that some heterogeneities in cellular cation metabolism apparently
reflect genetic lesions that may prove to predispose
to hypertension. In other words, there may be genetically determined cellular phenotypes that predict
salt sensitivity of blood pressure.
Effects of Salt Loading and Depletion on Cellular
Cation Metabolism
The majority of studies of the effects of salt on cells
have involved chronic (days to weeks) changes in
From The University of Michigan Medical Center, Division of
Hypertension, Ann Arbor, Mich.
Address for correspondence: Alan B. Weder, MD, The University of Michigan Medical Center, Division of Hypertension, 3918
Taubman Center, Box 0356, Ann Arbor, MI 48109.
dietary salt intake. As displayed in Table 1, most have
used red blood cells (RBC), the most convenient and
well-characterized model cell system, but there are a
number of studies that used white blood cells (WBC)
as well. In general, these dietary studies are predicated on a hypothesis that grew out of the pioneering
work of Lewis Dahl on his inbred salt-sensitive (DS)
and salt-resistant (DR) rats.2 Based on the demonstration that a DR rat joined parabiotically to a DS
rat becomes hypertensive during high salt intake,
Dahl postulated that a circulating factor produced by
the DS rat diffused through the parabiotic anastomosis and sensitized the DR rat to the high salt diet, in
essence converting it to a DS rat.3 Subsequent transplantation experiments proved that in these rats
hypertension "follows the kidney" (i.e., DR rats
transplanted with kidneys from DS rats develop
salt-sensitive hypertension and DS rats transplanted
with DR kidneys become salt resistant).4-7 Haddy
and Overbeck8 provided experimental support for a
circulating factor in several models of volume-expanded hypertension, and subsequently de Wardener
and MacGregor synthesized these and other observations into a theory of the genesis of essential
hypertension.9 It was postulated that volume expansion provokes the secretion of a circulating inhibitor
of Na+,K+-ATPase, which normally acts in a classical
negative feedback fashion to inhibit basolateral
ATPase in renal tubules, decreasing tubular Na+
reabsorption and facilitating salt and water excretion.
In individuals with defective renal Na+ excretory
capacity, or in those whose Na+ intake exceeds renal
excretory capacity, the concentration of this Na+
transport inhibitor rises to levels at which it can affect
vascular, in addition to renal, Na+,K+-ATPase with
the result that Na+ concentration increases in vascular smooth muscle cells. Blaustein10 had previously
provided a plausible explanation of how increased
cell Na+ in vascular tissues could inhibit transmembrane Na+-Ca2+ exchange, raise cytosolic Ca2+ and
promote vasoconstriction.10 De Wardener and MacGregor hypothesized that the presence of an intrinsic, presumably heritable, defect of renal Na+ handling would predispose affected individuals living in
our current high Na+ milieu to volume overload,
provoking secretion of the circulating factor and
causing the development of a high vascular resistance
hypertensive state. As a corollary, the exposure of
Weder Sodium Transport and Blood Pressure
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circulating blood cells to pathologically high levels of
the Na+,K+-ATPase inhibitor would result in intracellular Na+ accumulation; it was suggested that such
cells, although pathogenetically irrelevant to the
hypertensive process, are markers of the underlying
pathophysiology of hypertension.
The search for the biochemical basis of the putative
circulating volume-sensitive Na+ transport inhibitors,
the ouabainlike factors, has led investigators on a merry
chase, but despite continued uncertainty as to the
identity of the factors, the de Wardener-MacGregor
formulation has proven very appealing. Today, the
action of a ouabainlike factor on circulating cells remains the dominant theoretical framework for studies
of the effects of dietary salt on cells and is the reason
that most of the studies summarized in Table 1 focus on
the activity of the Na+-K+ pump (usually measured as
the rate constant of ouabain-sensitive 22Na+ efflux, but
also as ouabain-sensitive net Na+ efflux or ouabainsensitive ^Rb* influx) or the consequences of pump
inhibition (increased cell Na+ content).
Studies in Red Blood Cells
The first study to investigate the effect of dietary
salt intake on active RBC Na+ transport was that of
Morgan and coworkers12 who found that in eight
hypertensive patients, 2 weeks of high (more than
200 meq/day) compared with 2 weeks of low (less
than 100 meq/day) Na+ intake resulted in a decrease
in the rate constant of ouabain-sensitive 22Na+ efflux
from RBC. The authors noted that the effect was
present only when RBC were incubated in autologous plasma; efflux into salt solutions was comparable after the two diets. Moreover, there was a suggestion of a relation between the degree of pump
suppression by plasma and the salt sensitivity of
blood pressure. The same investigators subsequently
reported that normotensive individuals have more
heterogeneous responses of 22Na+ efflux to changes
in dietary salt balance, and as a group, normotensive
individuals demonstrate no significant suppression of
a
Na + efflux from RBC.13 They did identify a trend
for those normotensive subjects who demonstrated
Na+-K+ pump suppression during salt loading to
increase their blood pressure, although the correlation between pump activity and salt sensitivity of
blood pressure was not significant.
This study provides strong evidence favoring the de
Wardener-MacGregor hypothesis, and numerous attempts have been made to replicate it. There are
several RBC studies that do show pump suppressjon22,23,25,27,31.33.34
22 26 28 31
or
increased cell Na + con-
tent - " ' during salt loading, but there are also
a number of negative studies.18-20-26-35 In many of
the latter, technical issues may be relevant. Of the
negative studies that examined ouabain-sensitive
RBC 22Na+ efflux, several incubated cells in salt
solutions19-26'35 rather than plasma as suggested by
the original study,12 but one of the positive studies
also used an artificial efflux medium,25 casting some
doubt on the absolute requirement for plasma.
1-75
Alternative measures of pump activity, which measure either RBC 86Rb+ influx27 or net Na+ efflux22
into salt solutions, also have detected pump suppression in salt-loaded patients.
One negative study measured only RBC Na+ content,20 which was not measured in the original
study.12 Although the Na+-K+ pump is clearly the
major regulator of cell Na+ concentration, and therefore cell Na+ would be expected to vary inversely with
pump activity,36 it is possible that changes in cell Na+
could be too small, or the time necessary to produce
them too long, to detect in the reported studies. In
one study, which carefully examined the time course
of changes in RBC Na+ content in response to
dietary salt restriction, RBC Na+ declined significantly within 1 week of imposition of dietary Na+
restriction, presumably as the result of an observed
concomitant rise in Na+-K+ pump activity.27 In addition, experience with cardiac glycosides suggests that
changes in RBC Na+ content provoked by pump
inhibition should be easily measurable: systemic administration of digoxin causes a rise of approximately
60% in cell Na+ content within 5 days.37 It would
appear that if circulating ouabainlike factors have
effects similar to digoxin, in all reports the period of
study has been appropriately long (Table 1) and the
anticipated magnitude of the change in RBC Na+
sufficiently great to be detectable. However, because
changes in RBC transport could require actual replacement of a cell population with new cells, it may
be that the period of dietary salt restriction has, in
fact, been too brief.
Experimental protocols have also deviated from
that of Morgan et al12 in other ways. Although the
nature of the dietary intervention is likely to be
critically important, two of the negative studies examined only salt loading, comparing high salt with
normal salt diets,1920 rather than salt loading with
depletion. Although the original study imposed only
a modest dietary salt restriction (less than 100 meq
Na+/day), it seems arguable that current dietary
habits typically result in a biologically massive salt
overload and that further dietary salt supplementation may not necessarily provoke any greater suppression of active membrane Na+ transport. In addition, dietary Na+ excess itself may not be sufficient to
perturb membrane transport. Zemel et al31 have
shown that RBC Na+ content rises and RBC Na+,K+ATPase falls during high salt (4 g Na+/day) intake
only when Ca2+ intake is concomitantly restricted to
356 mg/day.31 This interaction of dietary Na+ excess
and Ca2+ deficiency has not been specifically addressed by others but may contribute to discrepancies
between the studies summarized in Table 1. Finally,
subject selection must be considered: findings in
hypertensive patients or in normotensive subjects
with a family history of hypertension seem more
consistently positive than those in family historynegative normotensive subjects. Racial differences
may also play a role in determining responses to
dietary salt. Several studies,38-39 but not all,40-42 have
1-76
Supplement I
Hypertension
Vol 17, No 1, January 1991
TABLE 1. Effect of Changing Dietary Na+ Intake on Red Blood CeU and White Blood Cell Na+ Transport
Reference
11
12
13
14
Diet
(mmol/day)
LS10
HS200
LS<100
HS>200
LS58
HS216
LS5O
Duration
6 days
16
17
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18
19
LS 50-85
NS 100-170
LS40
HS250
LS<100
HS>200
LS40
NS110
NS 150
HS330
CeU
(»)
type
Assay
2 weeks
H(8)
N(7)
H(8)
RBC
V ^ Li-Na
countertransport
k os ^ a efflux
2-3 weeks
N(23)
RBC
k ^ a efflux
52 weeks
2 weeks
Borderline
H(41)
Borderline
H(25)
N:FH- (10)
2 weeks
N(10)
3 weeks
N(33)
4 weeks
N:FH+ (17)
and F H - (15)
Na content
(mmol/kg wet wt)
WBC Na content
(mmol/kg wet wt)
WBC k os ^ a efflux
Na content (mmol/kg cells)
RBC k os ^ a efflux
k £s ^ a efflux
Na content (mmol/1 cells)
RBC Na-LJ countertransport
Na content (mmol/1 cells)
RBC *: tot ^ a efflux
NS?
15
Patients
6 weeks
RBC
WBC
Na content (mmol/1 cells)
20
21
NS192
HS366
LS18
NS 162
4 weeks
2 weeks
N:FH+ (11)
and F H - (26)
H(12)
N:FH- (12)
RBC
WBC
Na content
(mmol/1 cells)
k ^ a efflux
k os ^ a efflux
22
LS46
NS 98
4 weeks
H(ll)
23
LS30
HS333
1 week
N(22)
24
NS ?
HS NS+240
6 days
N(10)
25
LS100
HS300
1 week
H(25)
N(9)
26
LS20
NS150
4 days
N(14)
H(13)
27
LS35
NS 147
16 weeks
N(9)
28
LS40
NS 135
LS40
HS260
10 days
H(14)
2 weeks
N:FH+ (16)
and F H - (15)
29
RBC
os net Na efflux
fs net Na efflux
li-Na countertransport
Na content (mmol/1 cells)
Results'
LS=HS
LS>HS
(plasma incubations
only)
LS=HS
Yes(?)
LS<NS
Not stated
LS<NS
Not stated
LS<HS
LS=HS
LS=HS
LS=HS
LS=HS
LS=NS
LS=NS
NS<HS
(FH+ only)
NS>HS (FH+
only)
NS>HS
(FH+ only)
LS>NS
(Honry)
LS>NS (/>=0.08)
(Hordy)
LS>NS
LS=NS
LS=NS
LS<NS
Not stated
k os ^ a efflux
LS>HS
Na content
LS=HS
(mmol/kg dry wt)
NS>HSt
RBC Vm, os net Na efflux
NS=HS
koj os net Na efflux
NS>HS
V m bs net Na efflux
V m Li-Na countertransport NS=HS
NS=HS
koj li-Na countertransport
LS>HS (H only)
RBC k tot ^ a efflux
k os ^ a efflux
LS>HS (H only)
LS=HS
Na content (mmol/1 cells)
LS=NS
RBC tot "Rb influx
os MRb influx
LS=NS
LS<NS (N only)
Na content (mmol/1 cells)
LS>NS
RBC os *Rb uptake
LS=NS
is net Na efflux
Vna, Li/Na countertransport
LS=NS
LS<NS
Na content (mmol/1 cells)
LS<NS
RBC Na ion activity (a'n,)
by ion-select electrode
WBC k oi ^ a efflux
LS>HS
k os ^ a efflux
LS=HS
Na content (mmol/kg dry wt) LS=HS
RBC
AFlux/ABPt
Not stated
Yes(?)
Yes(?)
No
No
No
Not stated
Yes-os
net Na efflux
Yes-Na
content
Not stated
Not stated
Yes-* tot ^ a
efflux and k os
^ a efflux
Not stated
No
Not stated
Not stated
Weder Sodium Transport and Blood Pressure
(Continued)
Diet
Reference (mmol/day) Duration
30
LS23
4 weeks
NS137
1-77
TABLE 1.
Patients
CeU
(«)
type
N:FH- (9)
31
LS17
HS68
2 weeks
32
LS76
HS198
NS 147
HS254
4-6 weeks H(12)
33
H:all black
(11)
5 days
N(19)
34
LS50
HS340
1 week
H(19)
35
LS10
HS200
~1 week
N(14)
H(26)
Assay
WBC k tot ^ a efflux
it os ^ a efflux
Na content (mmol/kg dry wt)
RBC Na,K-ATPase
(membrane fragment)
Na content (mg/ml cells)
k os ^Na efflux
Na content (mmol/1 cells)
RBC Na,K-ATPase
(membrane fragment)
Na content (mmol/1 cells)
RBC, os net RBC Na efflux
WBC RBC Na content (mmol/1 cells)
WBC Na content (mmol/kg wet
RBC
Results'
LS<NS
LS<NS
LS>NS
LS>HS (low
Ca2+ diet only)
LS<HS (low Ca2+
diet only)
LS=HS
LS=HS
NS>HS
NS=HS
LS>HS
LS<HS
LS<HS
AFlux/ABPt
Not stated
Not stated
No
Not stated
Not stated
wt)
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RBC
Vjn, os net Na efflux
Vnaa Na-K-2C1 cotransport
Jfca5 Na-K-2Q cotransport
Vnn Li-Na countertransport
Na content (mmol/1 cells)
LS=HS
LS<HS (H only)
LS<HS (H only)
LS=HS
LS=HS
Not stated
Dietary salt is either stated goal or measured 24-hour urine excretion; ?, dietary salt is unknown or not stated; BP, blood pressure; LS,
low salt; NS, normal salt; HS, high salt; H, hypertensive; N, nonnotensive; FH—, negative family history of hypertension; FH+, positive
family history of hypertension in first degree relatives; RBC, red blood cells; WBC, white blood cells; k, rate constant; /fcoj, concentration
required for half-maximal stimulation; V,,,^ maximal rate; tot, total; os, ouabain-sensitive; oi, ouabain-insensitive; fs, furosemide-sensitive;
bs, bumetanide-sensitive; units are given for Na+ content.
•Statistically significant differences in each transport function related to dietary intervention indicated by < or >; nonsignificant
differences by =.
fRelation for change influxparameter to change in blood pressure: for many studies in which a relation is not stated, it may be assumed
that no relation existed. Yes (?), indicates a possible relation.
^Significance is calculated from data presented in reference.
suggested that blacks have a lower level of ouabainsensitive cation transport in RBC than whites, and it
is possible that low basal Na+,K+-ATPase activity or
pump expression40 may predispose blacks to salt
sensitivity of blood pressure.
Studies in White Blood Cells
RBC may not be the best cell model. WBC are
potentially superior for studies of maneuvers expected to change membrane transport because they
are nucleated and therefore capable of more rapid
and flexible responses to perturbations. In addition,
small effects may be more easily detectable in WBC,
which exhibit at least 10-fold higher rates of ^Na*
efflux than RBC. For whatever reason, in all studies
of essential hypertensive patients, WBC responded
to salt depletion as predicted by the theory (i.e.,
comparing low salt with high salt diets, either WBC
Na+ content was lower14-15-34 or the rate constant for
Na+ efflux was higher21). It appears that nonnotensive subjects are less likely than hypertensive subjects
to show significant depression of active Na+ transport
in WBC in response to changing from a low salt to a
high salt intake,16-19-29 although acute intravenous
Na+ loading in nonnotensive subjects does result in
the appearance of a plasma factor capable of suppressing leukocyte ^ a * efflux.43
Problems With Studies of Responses of
Circulating Cells
To summarize the findings of these studies, it
seems prudent to conclude that the evidence is
suggestive, although by no means conclusive, that
active membrane Na+ transport is suppressed by a
high salt intake. Whether pump suppression results
from the action of a circulating ouabainlike factor is
certainly not yet proven. Although reports of decreased 22Na+ efflux in RBC of salt-fed patients are
compatible with the action of such a factor, one study
that reported a significant suppression of ouabainsensitive 22Na+ efflux during a high salt diet searched
for and failed to find a circulating inhibitor.23 Even in
those studies that demonstrate pump suppression by
plasma obtained during high salt intake, the data
permit interpretations other than the effect of a
ouabainlike inhibitor; 22Na+ efflux is only one limb of
Na+ transport, and changes in unidirectional ouabain-sensitive Na+ efflux would best be interpreted in
relation to rates of Na+ influx and concentrations of
Na+ and K+ in the cytoplasm and extracellular me-
1-78
Supplement I Hypertension Vol 17, No 1, January 1991
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dium. Unfortunately, a complete description of all
parameters is rarely reported. Only two studies measured unidirectional Na+ influx,19-26 and neither demonstrated altered influx, although both were also
among those reports that failed to provide support
for Na+-K+ pump inhibition by salt loading. Even
more disturbing are recent observations summarized
by Simon,44 which call into question the validity of
cellular Na+ measurements performed by standard
methods relying on extensive washing of cells to
separate them from extracellular Na+. If reported
measurements of RBC Na+ are unreliable, then
conclusions regarding the basis of changes in the
activity of the Na+-K+ pump, which is usually reported as the rate constant for efflux (Na+ efflux/
[Na+],), must be regarded as suspect. Indeed, since
one critical link in the hypothetical chain joining
pump inhibition to hypertension is increased cell Na+
concentration,9-10 observations of low RBC Na+ content in essential hypertension seriously challenge the
validity of the hypothesis.
Obviously, elucidation of the biochemical basis of
circulating ouabainlike factors and the development
of standardized techniques for their quantitation
would greatly facilitate studies of the mechanisms
mediating changes in pump activity during dietary
Na+ manipulations, but alternative approaches may
be found. For instance, the tools of molecular genetics may provide novel insights into how dietary Na+
interacts with membrane transport. As noted above,
stimulation by dietary salt restriction of pump activity
in WBC of hypertensive patients seems to be a
consistent cellular effect. Because they are nucleated,
WBC are capable of regulating Na+-K+ pump expression, apparently coordinately with expression in
RBC.45 If WBC pump activity is modulated by a
circulating factor that is responsive to changes in
dietary Na+ intake, even if the identity of the factor
remains obscure, it may reveal its effect by altering
messenger RNA (mRNA) levels encoding the subunits of Na+,K+-ATPase.46 If changes in nuclear
transcription cause upregulation of mRNA encoding
the pump, then regulatory proteins capable of binding to the genes could be involved, and regulatory
sequences in the genes encoding the pump subunits
may be identified. Alternatively, if changes in mRNA
degradation prove to be the cause of increased
mRNA abundance, regulatory mechanisms must exist within the mature mRNA molecule itself. In
either case, investigations of the nuclear and cytoplasmic events regulating Na+,K+-ATPase gene
expression may circumvent many of the difficulties
yet to be overcome in the isolation of the ouabainlike
factors and the delineation of their impact on membrane transport.
Cellular Transport Characteristics as Predictors of
Salt Sensitivity
Although the studies above have examined the
effects of dietary Na+ on cell cation transport or
content, an equally appealing feature of some RBC
cellular transport systems is their resistance to changes
in dietary salt intake. This stability suggests that they
could be useful as markers of a hereditary predisposition to salt sensitivity. The best-studied systems are
those mediating RBC Li+-Na+ countertransport and
Na+-K+-2C1~ loop-diuretic-sensitive cotransport, but
although both have received considerable attention as
markers for essential hypertension, they have featured
less prominently in studies of salt sensitivity. In 1980,
Canessa et al11 reported that changing salt balance did
not alter RBC Li+-Na+ countertransport activity, and
several other investigators have confirmed that observation. 18 ^ 27 ^ The usefulness of RBC Li+-Na+ countertransport as a predictor of blood pressure responsiveness to changes in dietary Na+ intake has not been
reported, although Redgrave et al47 have described an
increased prevalence of high RBC Li+-Na+ countertransport levels in the non-modulating subset of normal and high renin hypertensive patients,47 who have
been suggested to be salt-sensitive in other studies.48
Is Increased Red Blood Cell Li+-Na+
Countertransport a Marker of Salt Sensitivity?
Dr. Brent Egan and I have recently directly tested
the relation of RBC Li+-Na+ countertransport to salt
sensitivity of blood pressure in a small group of
essential hypertensive patients. We found that patients who demonstrate the greatest degree of elevation of blood pressure in response to a change from
a low salt to a high salt diet have, as a group, a
significant elevation in the V,^ of RBC Li+-Na+
countertransport.
Eighteen borderline and mild hypertensive patients
were studied in a randomized, placebo-controlled
blinded trial of low (20 meq/day) versus high (200
meq/day) salt intake. Diets were maintained for 1
week each with a 2-week period of ad libitum salt
intake interposed. Blood pressures were measured
directly in the brachial artery in the supine position
and salt sensitivity determined from the difference
between calculated mean arterial pressure (MAP)
during low and high salt intakes. Salt sensitivity was
defined by a rise in MAP on the high salt intake of at
least 5 mm Hg and salt resistance as either no change
or a fall in MAP on the high salt diet. Patients in
whom the high salt diet caused a rise in MAP of less
than 5 mm Hg were classified as indeterminant.
Salt-sensitive patients {n=l) demonstrated a rise in
MAP of 9.3 ±2.4 mm Hg, whereas salt-resistant patients (n=7) lowered their MAP by 4.7 ±4.6 mm Hg,
and the indeterminant group (n=4) raised their
MAP 1.2±0.5 mm Hg (/><0.0001 by analysis of variance). There were no significant differences between
the dietary regimens for RBC Na+ or H2O content,
bumetanide-sensitive Na+ or K+ cotransports, or
Na+-Li+ countertransport. When the relation between salt sensitivity and RBC transport characteristics was examined, RBC Li+-Na+ countertransport
was found to vary significantly (p<0.05 by analysis of
variance) between the groups (Figure 1). Although
there was overlap between the classes, no salt-resis-
Weder
700 -^
1-
600 —
SS
1
a
o
SR
D
500 —
o
f 5 « 400 —
UIU,
u
200 —
100 —
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FIGURE 1. Graph showing values for Vmax of red blood cell
(RBC) U+-Na* countertransport in hypertensive patients classified as sab-sensitive (SS), salt-resistant (SR), or indeterminant (I). SS patients demonstrated higher mean arterial blood
pressure (MAP) of more than 5 mm Hg on 200 meq Na+/day
versus 20 meq Na+/day. SR patients had MAP on 200 meq
Na +/day equal to or less than MAP on 20 meq Na +/day. Blood
pressure in I patients on the high salt diet increased less than
5 mm Hg. Differences between the groups are significant
(p<0.05 by analysis of variance). Shaded area represents
normal range for RBC countertransport in normotensive
subjects.
tant subject had an elevated (more than 0.32 mmol
Li+/1 cells/hr) V ^ for RBC Li+-Na+ countertransport. This small study provides support for the contention that an elevated V ^ for RBC Li+-Na+
countertransport may be a marker for a hereditary
predisposition to salt sensitivity of blood pressure,
and recommends measurement of RBC Li+-Na+
countertransport in future studies of salt sensitivity.
Red Blood Cell Na+-K+-2Cl' Cotransport and
Salt Sensitivity
Although we did not observe any significant effects
of changing dietary salt on RBC Na+ or K+ cotransport, and others have also failed to find changes in
furosemide-sensitive isotopic17 or net Na+ efflux,22^27
Canessa et al35 carefully characterized the kinetics of
RBC Na+-K+-2C1~ cotransport and observed a lower
Vm,, and Km for Na+-K+-2CT cotransport in hypertensive patients on a low (10 meq/day) versus a high
(200 meq/day) salt diet.35 In this study, normotensive
subjects on similar diets did not show changes in VmMI
or Km, although Dagher et al24 did report suppression
of V ^ for outward bumetanide-sensitive Na+-K+2C1~ cotransport in salt-loaded normotensive subjects.24 In a study of the predictive value of cotransport, Canessa et al49 observed that the Km for Na+ at
the inner face of the Na+-K+-2C1~ cotransporter is
significantly lower in salt-sensitive than in salt-resistant black adolescents.49 These very interesting observations suggest that dysregulation of Na+-K+-2C1~
cotransport, a system known to mediate Na+ transport in vascular smooth muscle50 and endothelial51
cells, may predispose to hypertension during high salt
intake.
Sodium Transport and Blood Pressure
1-79
In conclusion, dietary salt may affect blood pressure in part through its impact on membrane transport systems. The hypothesis that plasma volume
expansion resulting from excessive dietary salt intake
or insufficient renal Na+ excretory capacity leads to
elaboration of a circulating ouabainlike substance
that suppresses active membrane Na+ transport has
been tested indirectly in studies of the effects of
modifying dietary salt intake on membrane transport
functions. The studies are in considerable, although
not perfect, agreement that a decreased dietary salt
load stimulates the Na+-K+ pump; the contribution
of putative ouabainlike factors to this effect is still not
clear. The role of membrane transport functions as
markers of individual susceptibility to the pressor
effect of dietary salt is less well studied, although
there is suggestive evidence for both RBC Li+-Na+
countertransport and Na+-K+-2CT cotransport as
markers for salt sensitivity. These membrane transport characteristics may prove to be related to a
genetic predisposition to salt sensitivity.
References
1. Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg
NS: Definitions and characteristics of sodium sensitivity and
blood pressure resistance. Hypertension 1986;8(suppl II):
II-127-II-134
2. Dahl LK, Heine M, Tassinari L: Effects of chronic salt
ingestion: Evidence that genetic factors play an important role
in susceptibility to experimental hypertension. / Exp Med
1962;115:1173-1190
3. Dahl LK, Knudsen KD, Iwai J: Humoral transmission of
hypertension: Evidence from parabiosis. Circ Res 1969;
24(suppl I):I-21-I-33
4. Tobian L, Coffee K, McCrea P, Dahl LK; A comparison of the
antihypertensive potency of kidneys from one strain of rats
susceptible to salt hypertension and kidneys from another
strain resistant to it (abstract). / Clin Invest 1966;45:1080
5. Dahl LK, Heine M, Thompson K: Genetic influence of renal
homografts on the blood pressure of rats from different
strains. Proc Soc Exp BM 1972;140:852-856
6. Dahl LK, Heine M, Thompson K: Genetic influence of the
kidneys on blood pressure: Evidence from chronic renal
homografts in rats with opposite predispositions to hypertension. Circ Res 1974^34:94-101
7. Dahl LK, Heine M: Primary role of renal homografts in setting
chronic blood pressure levels in rats. Circ Res 1975;36:692-696
8. Haddy FJ, Overbeck HW: The role of humoral agents in
volume expanded hypertension. Life Sci 1976;19:935-948
9. De Wardener HE, MacGregor GAJ Dahl's hypothesis that a
saluretic substance may be responsible for a sustained rise in
arterial pressure: Its possible role in essential hypertension.
Kidney Int 198O;18:l-9
10. Blaustein MP: Sodium ions, calcium ions, blood pressure
regulation, and hypertension: A reassessment and a hypothesis. Am J Physiol 1977;232:C165-C173
11. Canessa M, Adragna N, Bize I, Connolly T, Solomon H,
Williams G, Slater E, Tosteson DC: Ouabain-insensitive cation transport in red cells of normotensive and hypertensive
subjects, in Zumkley H, Losse H (eds): Intracellular Electrolytes
and Arterial Hypertension New York, Georg Thieme Verlag,
1980, pp 239-250
12. Morgan T, Myers J, Fitzgibbon W: Sodium intake, blood
pressure and red cell sodium efflux. Clin Exp Hypertens 1981;
A3:641-653
13. Fitzgibbon WR, Morgan TO, Myers JB: Salt sensitivity of
normotensives: Interactions between changes in red blood cell
^ a efflux rate constant, dietary sodium intake and changes in
blood pressure. Clin Exp Pharmacol Physiol 1982;9:291-295
1-80
Supplement I
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14. Costa FV, Ambrosioni E, Montebugnoli L, Paccaloni L,
Vasconi L, Magnani B: Effects of a low-salt diet and of acute
salt loading on blood pressure and intralymphocytic sodium
concentration in young subjects with borderline hypertension.
Clin Sci 1981;61:21s-23s
15. Ambrosioni E, Costa FV, Borghi C, Montebugnoli L, Giordani
MF, Magnani B: Effects of moderate salt restriction on
intrah/mphocyte sodium and pressor response to stress in
borderline hypertension. Hypertension 1982;4:789-794
16. Swales ID, Bing RF, Bradlaugh R, El-Ashry A, Godfrey N,
Heagerty AM, Thurston H: Cell membrane handling of
sodium, sodium balance, and blood pressure. / Cardiovasc
Pharmacol 1984;6:S42-S48
17. Morgan TO, Myers JB, Edwards K, Adam W, Wellard M:
Effect of changes in sodium intake on cell transport parameters. Clin Exp Hypertens 1984;A6:455-467
18. Cooper R, Trevisan M, Van Horn L, Larbi E, Liu K, Nanas S,
Ueshima H, Sempos C, Ostrow D, Stamler J: Effect of dietary
sodium reduction on red blood cell sodium concentration and
sodium-lithium countertransport. Hypertension 1984;6:731-735
19. Gudmundsson O, Andersson O, Herlitz H, Jonsson O, Naucler J, Wikstrand J, Berglund G: Blood pressure, intraerythrocyte content, and transmembrane fluxes of sodium during
normal and high salt intake in subjects with and without a
family history of hypertension: Evidence against a sodium
transport inhibitor. / Cardiovasc Pharmacol 1984;6:S35-S41
20. Gudraundsson O, Herlitz H, Jonsson O, Hedner T, Andersson
O, Berglund G: Blood pressure and intra-erythrocyte sodium
during normal and high salt intake in middle-aged men:
Relationship to family history of hypertension, and neurogenic
and hormonal variables. Clin Sci 1984;66:427-433
21. Poston L, Johnson VE, Gray HH, Hilton PJ, Markandu ND,
MacGregor GA: The effect of dietary sodium restriction on
leucocyte sodium transport in normotensive subjects and in
patients with essential hypertension. Klin Wochenschr 1985;
63(suppl III):136-138
22. Krzesinskj JM, Rorive GL: Effect of salt depletion on sodium
ion transport from human erythrocytes. Klin Wochenschr 1985;
63(suppl ni):45-48
23. Weissberg PL, West MJ, Kendall MJ, Ingram M, Woods KL:
Effect of changes in dietary sodium and potassium on blood
pressure and cellular electrolyte handling in young normotensive subjects. / Hypertens 1985^:475-480
24. Dagher G, Brossard M, Feray JC, Garay RP: Modulation of
erythrocyte Na transport pathways by excess sodium intake.
Life Sci 1985;37:243-253
25. Saito K, Furuta Y, Sano H, Okishio T, Fukuzaki H: Abnormal
relationship between dietary sodium intake and red cell
sodium transport in salt-sensitive patients with essential
hypertension. Clin Exp Hypertens 1985;A7:1217-1232
26. Stokes GS, Monaghan JC, Middleton AT, Shirlow M, Marwood JF: Effects of dietary sodium deprivation on erythrocyte
sodium concentration and cation transport in normotensive
and untreated hypertensive subjects. / Hypertens 1986;4:35-38
27. Lijnen P, M'Buyamba-Kabangu JR, Fiocchi R, Hespel P,
Fagard R, Staessen J, Goossens W, DeWreede K, Lissens W,
Amery A: Sodium and potassium fluxes and concentrations in
erythrocytes of normal subjects during prolonged sodium
depletion and repletion. Postgrad Med] 198<5;62(suppl 1):3-12
28. Zidek W, Karoff C, Losse H, Vetter H: Weight reduction and
salt restriction in hypertension: Effects on blood pressure and
intracellular electrolytes. Klin Wochenschr 1986;64:1183-1185
29. Heagerty AM, Alton SM, El-Ashry A, Bing RF, Thurston H,
Swales JP: Effects of changes in sodium balance on leucocyte
sodium transport: Qualitative differences in normotensive
offspring of hypertensives and matched controls. / Hypertens
1986;4:333-337
30. Jest P, Pedersen KE, Klitgaard NA, Arentoft A, Nielsen JR:
Cell membrane handling of sodium in lymphocytes during salt
restriction in normotensives. Scand J Clin Lab Invest 1987;47:
813-818
31. Zemel MB, Kraniak J, Standley PR, Sowers JR: Erythrocyte
cation metabolism in salt-sensitive hypertensive blacks as
affected by dietary sodium and calcium. Am J Hypertens
1988;l:386-392
32. Herlitz H, Fagerberg B, Jonsson O, Hedner T, Andersson OK,
Aurell M: Effects of sodium restriction and energy reduction
on erythrocyte sodium transport in obese hypertensive men.
Ann Clin Res 1988;20(suppl 48):61-65
33. Quintanilla AP, Weffer MI, Koh H, Rahman M, Molteni A,
Del Greco F: Effect of high salt intake on sodium, potassiumdependent adenosine triphosphatase activity in the erythrocytes of normotensive men. Clin Sci 1988;75:167-170
34. Kido K, Matsuura H, Otsuki T, Matsumoto K, Shingu T,
Oshima T, Inoue I, Kajiyama G: Sodium chloride sensitivity,
intracellular sodium concentration in erythrocytes and lymphocytes, and renin profile in essential hypertension. Jpn Ore
J 1989^3:101-107
35. Canessa M, Redgrave J, Laski C, Williams G: Does sodium
intake modify red cell Na+ transporters in normal and hypertensive subjects? Am J Hypertens 1989;2:515-523
36. Smith EKM: Observations on the measurement and regulation of the sodium content of human erythrocytes. Clin Sci
1972;42:447-453
37. Astrup J: The effect of hypokalemia and of digoxin therapy on
red cell sodium and potassium content: Some clinical aspects.
Scand J Clin Lab Invest 1974^3:11-16
38. Beutler E, Kuhl W, Sacks P: Sodium-potassium-ATPase activity is influenced by ethnic origin and not by obesity. N Engl J
Med 1983;309:756-760
39. Lasker N, Hopp L, Grossman S, Bamforth R, Aviv A: Race
and sex differences in erythrocyte Na+, K+, and Na+-K+adenosine triphosphatase. / Clin Invest 1985;75:1813-1820
40. Henncssy JF, Ober KP: Racial differences in intact erythrocyte ion transport. Ann Clin Lab Sci 1982;12:35-41
41. Tuck ML, Gross C, Maxwell MH, Brickman AS, Krasnoshtein
G, Mayes D: Erythrocyte Na+,K+ cotransport and Na+,K+
pump in black and Caucasian hypertensive patients. Hypertension 1984;6:536-544
42. Smith JB, Wade MB, Fineberg NS, Weinberger MH: Influence of race, sex, and blood pressure on erythrocyte sodium
transport in humans. Hypertension 1988;12:251-258
43. Poston L, Wilkinson S, Sewell RB, Williams R: Sodium
transport during the natriuresis of volume expansion: A study
using peripheral blood leucocytes. Clin Sci 1982;63:243-249
44. Simon G: Is intracellular sodium increased in hypertension?
Clin Sci 1989;76:455-461
45. DeLuise M, Flier JS: Evidence for coordinate genetic control
of Na, K pump density in erythrocytes and lymphocytes.
Metabolism 1985^4:771-776
46. Shull MM, Lingrel JB: Multiple genes encode the human
Na\K+-ATPase catalytic subunit. Proc Nad Acad Sci USA
1987;84:4039-4O43
47. Redgrave J, Canessa M, Gleason R, Hollenberg NK, Williams
GH: Red blood cell lithium-sodium countertransport in nonmodulating essential hypertension. Hypertension 1989;13:
721-726
48. Hollenberg NK, Moore T, Shoback D, Redgrave J, Rabinowe
S, Williams GH: Abnormal renal sodium handling in essential
hypertension. Am J Med 1986;81:412-418
49. Canessa M, Bize I, Spahins A, Falkner B, Katz S: Na-K-Cl
cotransport and Na pump in red cells of young blacks and
blood pressure response to salt loading. / Clin Hypertens
1986;2:101-108
50. Owen NE: Regulation of Na/K/Q cotransport in vascular
smooth muscle cells. Biochem Biophys Res Common 1984;125:
500-508
51. Brock TA, Burgnara L, Canessa M, Gimbrone MA: Bradykinin and vasopressin stimulate Na+-K+-Q~ cotransport in
cultured endothelial cells. Am J Physiol 1986;250:C888-C895
KEY WORDS • sodium transport • blood pressure • sodiumsensitive hypertension • red blood cells
Membrane sodium transport and salt sensitivity of blood pressure.
A B Weder
Hypertension. 1991;17:I74
doi: 10.1161/01.HYP.17.1_Suppl.I74
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