Relationship of Vascular Sodium-Potassium Pump Activity
to Intracellular Sodium in Hypertensive Rats
TOMMY A. BROCK, P H . D . , JEFFREY B. SMITH, P H . D . , AND HENRY W. OVERBECK, M.D.,
PH.D.
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SUMMARY The activity of the sodium-potassium (Na + -K + ) pump in arterial tissue from rats with chronic
DOCA-salt or one-kidney Grollman renal hypertension was assayed in ritro as the rate of ouabaln-sensltive
M
Rb + uptake. Estimates of total cell Na + and tissue K+ were made by a lithium-substitution method on the
same segment of arterial tissue. In both freshly excised tail arteries and aortas, and in aortas after overnight
cold storage at 4° C and a 3-hour equilibration at 37° C in Krebs-Henseleit, cell Na + content did not differ significantly between control and hypertensive groups. However, ouabain-sensitive "Rb + uptake was increased in
arteries from DOCA-salt and renal hypertensive rats as compared to controls. In overnight-stored and 3-hour
equilibrated aortic tissue, we then used low Na + medium to reduce, or monensin, a Na + ionophore, to increase
total cell Na + , to study the relationship between cell Na + and Na + -K + pump activity. We observed a sigmold
relationship between total cell Na + and ouabain-sensitire M Rb + uptake in tissue from all groups of rats.
However, in tissue from DOCA-salt and renal hypertensive rats, the relationship between cell Na + and pump
activity was shifted, indicating a greater pump activity for each level of total cell Na + and greater maximal
pumping. These data suggest that increases observed in pump activity in in vitro arterial tissue from hypertensive rats may not be solely attributable to elevated cell Na + content and may also involve increases in
number of active sarcolemmal pump molecules per unit tissue weight or in their turnover rate.
(Hypertension 4 (suppl II): II-43-II-48, 1982)
• Na + -K + ATPase • aorta • tail artery
DOCA-salt hypertension • Grollman hypertension
KEY WORDS
T
monensin
elevations in the concentration of intracellular Na + ,
associated with increased passive permeability of the
cell membrane to Na + . M " M Overbeck et al.,18 however, suggested that additional factors may be involved. They found that the lower levels of Na + -K +
pump activity in tissues from normotensive control
animals could not be explained by insufficient
amounts of total cell Na + .
There is little information regarding the dependence
of the Na + -K + pump on internal Na + in vascular
smooth muscle. Therefore, in this study we investigated the relationship between total cell Na + and
pump activity. To alter cell Na + , we used a medium
with low Na + concentration, different excision and incubation techniques, and monensin, a Na + ionophore.
It has been previously shown that monensin increases
the entry of Na + into Swiss 3T3 cells, thereby stimulating Na + -K + pump activity." We studied arterial
tissue from rats in the chronic, uncomplicated stages
of one-kidney DOCA-salt and one-kidney, one figure8 (Grollman) hypertension. We describe procedures
for assaying Na + -K + pump activity and measuring
total cell Na + and tissue K + on the same segment of
arterial tissue.
HE presence of an electrogenic Na + -K + pump
in the sarcolemma of vascular smooth
muscle is well documented.1"8 Stimulation of
+
this Na -K + pump results in hyperpolarization of the
cell membrane, muscle relaxation, and depression of
contractile responses to vasoconstrictor drugs. 410 As
measured by different in vitro techniques, increased
active transport of Na + and K + has been observed in
arterial smooth muscle from spontaneously hypertensive rats,11"1' from Dahl salt-sensitive hypertensive
rats, 17 ' 18 and from DOCA-salt hypertensive rats.11' """
It has been suggested that these increases in vascular
Na + -K + pump activity in hypertension result from
From the Cardiovascular Research and Training Center,
Departments of Medicine, Physiology and Biophysics, and
Biochemistry, the University of Alabama in Birmingham Medical
Center, Birmingham, Alabama.
Supported by U.S. Public Health Service Grants HL-25451 and
HL-23312 from the National Heart, Lung, and Blood Institute. Dr.
Brock was supported by Training Grant HL07457 from the
National Heart, Lung, and Blood Institute.
Address for reprints: Henry W. Overbeck, M.D., Ph.D., Cardiovascular Research and Training Center, University of Alabama
in Birmingham, University Station, Birmingham, Alabama 35294.
11-43
11-44
1981 BLOOD PRESSURE COUNCIL
Methods
Animals
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We induced DOCA-salt hypertension in uninephrectomized, male Sprague-Dawley rats (125-175 g) by
implanting strips of silicone rubber impregnated with
deoxycorticosterone acetate (150 mg/kg). Uninephrectomized rats served as normotensive controls.
Both groups were given a standard diet (Na + 0.39%,
K+ 0.96%), and 1% NaCl:0.2% KC1 solution to drink
ad libitum. To prepare one-kidney, one figure-8
(Grollman) renal hypertensive animals we tied a
figure-8 ligature (0 silk) around the left kidney of male
Sprague-Dawley rats (75-100 g) and then 1 week later
removed the contralateral kidney. Sham-constricted
uninephrectomized rats served as normotensive controls. Both groups of rats received the standard diet
and tap water ad libitum. In all rats, systolic blood
pressure (SBP) was monitored weekly by indirect tail
cuff plethysmography (Natsume, Peninsula Laboratories) in conscious restrained animals. Arterial tissue
was excised from these animals approximately 6
weeks after the surgical procedures and approximately 4 weeks after the development of significant
hypertension (SBP > 150 mm Hg).
Tissue "Rb * Uptake, Na+ and K+ Measurements
The activity of the vascular Na + -K + pump was
assayed by measuring ouabain-sensitive M Rb + uptake
in: 1) thoracic aortas that were stored overnight at 4°
C and then allowed to restore ionic gradients; and 2) in
freshly excised tail arteries and aortas. Aortas that
were stored overnight were excised from unanesthetized, decapitated rats, while fresh tail arteries
and aortas to be processed immediately were excised
from rats anesthetized with sodium pentobarbital, 50
mg/kg body weight. In brief, the excised vessels were
rapidly dissected free from loose connective tissue in
4° C Krebs-Henseleit (K-H) solution (mM): NaCl,
118; NaHCO,, 27; KC1, 4.8; KH 2 PO 4 , 1.0; MgSO, •
7H,O, 1.2; CaCI,- 2H 2 O, 1.25; and glucose, 11.1; pH
7.4. Each vessel was opened longitudinally and cut
transversely into segments. Aortic segments to be
stored overnight at 4°C were transferred to cold K-H
solution. The following day, these segments were
allowed to equilibrate for 3 hours at 37° C in continuously aerated (95% O 2 :5% CO2) K-H solution prior
to measuring M Rb + uptake. In the freshly excised
arterial tissue M Rb + uptake was measured immediately (less than 5 minutes) after excision.
For measurements of M Rb + uptake, tissue segments
were preincubated in 2.0 ml of aerated K-H solution
at 37° C for 5 minutes. M RbCl (New England
Nuclear; approximately 150-175 cpm • nmole"1) was
then added, and tissue M Rb + uptake was allowed to
occur for 15 minutes. Immediately following this incubation period each segment was rapidly rinsed (10
seconds) in a 4° C buffered salt solution in which LiCl
was substituted for NaCl (mM): LiCl, 120; CaCl2, 2.0;
MgCl,, 1.0; KC1, 5.0; and HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid)-Tris buffer,
SUPP II, HYPERTENSION, VOL 4, No 3, MAY-JUNE 1982
20; pH 7.6. The segment was then incubated in a
separate tube containing this same buffer for 40
minutes. This procedure allowed the measurement of
cellular Na + by methods developed by Friedman and
coworkers. 28 ' u Tissues were gently blotted, transferred to acid-washed tubes, and weighed. Tissues
were then dried (100° C, 48 hours) and reweighed. To
each sample, 1 ml of 0.75 N HNO, was added, and the
radioactivity present in a 0.9 ml extract was determined by Cerenkov radiation in a liquid scintillation
counter (Packard B-2450). The Na + and K + contents
of this same extract were determined by atomic absorption spectrophotometry (Perkin-Elmer, Model
372). The rate of ouabain-sensitive M Rb + uptake was
calculated as the difference in the rates of M Rb + taken
up by the tissue in the presence and absence of ouabain
(1-2 mM) and was expressed in nmoles Rb • 15
min" • mg dry tissue w f . Cellular Na and tissue K
were expressed as nmoles • kg dry tissue wt".
In some aortic segments, total cell Na + content was
altered during the MRb+ uptake period. A higher level
of total cell Na + was achieved by incubating tissue in
K-H with monensin (Calbiochem), 10 Mg/m'- A
reduced level of intracellular Na + was achieved by
substituting the following low Na + media for K-H
(mM): NaCl, 20; sucrose, 200; KC1, 5; CaCI,, 2;
MgClj, 1.0; glucose, 10; and HEPES-Tris, 20; pH 7.6.
Statistical Analysis
All data are expressed as the mean ± standard error
of the mean (SEM). Data were analyzed by unpaired
Student's / test where appropriate. A p value <. 0.05
was considered to be significant.
12
(20)
(18) i
o
e
(12)
Control
DOCA-solt
Control
One-Kidney
Grollman
FIGURE 1. Mean ± SEM of in vitro "Rb+ uptake by aortic
tissue from DOCA-salt, one-kidney Grollman and control
rats. Aortas were stored overnight at 4° C and allowed to
equilibrate the following day for 3 hours prior to "Rb+ uptake studies. Open bars = ouabain-insensitive "Rb+ uptake;
shaded bars = ouabain-sensitive **Rb+ uptake. Numbers in
parentheses indicate the number of animals in each group.
•p <, 0.05.
U-45
SODIUM PUMP IN DOCA AND RENAL HYPERTENSION/flroc/t et al.
Results
Systolic blood pressures were significantly elevated
(p < 0.05) in both groups of hypertensive animals at 2
weeks following surgery, and at 6 weeks the values
were (mm Hg, mean ± SEM): control, 135 ± 5, vs
DOCA-salt, 190 ± 4; control, 131 ± 4 , vs one-kidney
Grollman, 203 ± 6. Serum creatinine in the same rats
remained within the normal range in all groups of
animals (mg%): control, 0.7 ± 0 . 1 ; DOCA, 0.8 ± 0.2;
one-kidney Grollman, 0.6 ± 0 . 1 . Serum K + also did
not differ between groups (mEq/liter): control, 3.6 ±
0.3; DOCA, 3.8 ± 0 . 1 ; one-kidney Grollman, 3.4 ±
0.2. All animals were apparently in good general
health 6 weeks after the surgical procedures when
arterial tissue was excised.
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50-
1
40
^ M Incubated Tissue
+ Monensin
1 Fresh Tissue
V//A Incubated Tissue
Q+
f
* .\
T
a,
30
20-
-
(14)
-
10-
60-
z _
§.§20
#
(14)
H
O
•o
*
(7)
(10)
(f)
CD
<
Figure 1 illustrates M Rb + uptake by aortic tissue
that had been stored overnight at 4° C and allowed to
equilibrate for 3 hours the next day. As indicated, both
the ouabain-insensitive and the ouabain-sensitive components of M Rb + uptake were increased in aortic
tissue from DOCA-salt and one-kidney Grollman
hypertensive rats, as compared to their respective controls (p < 0.05). The results in figures 2 and 3 demonstrate that cell Na + was not different in the hypertensive and control groups. Tissue K + also was not
significantly different in any of the groups (control vs
DOCA-salt, 82 ± 7, vs 80 ± 6 mmoles • kg dry wf1;
control vs one-kidney Grollman, 82 ± 6 vs 87 ± 6
mmoles • kg dry wr 1 ).
Figure 2 shows the rate of ouabain-sensitive " R b +
uptakes in aortic tissue from DOCA-salt and control
-
T
T
•
CONTROL
Im
DOCA-SALT
FIGURE 2. Top: Mean ± SEM of in vitro ouabain-sensitive
**Rb+ uptake by freshly excised or stored aortas from control and DOCA-salt rats. Tissue was stored overnight at 4°
C and allowed to equilibrate the following day for 3 hours
prior to "Rb+ uptake studies. The concentration ofmonensin was 10 ng/ml. Bottom: Mean ± SEM of total cell Na+
in the same tissue. Cellular Na+ was measured using a
lithium-substitution method. The numbers in parentheses
represent the number of animals in each group. *p <; 0.05.
CONTROL
ONE-KIDNEY
GROLLMAN
FIGURE 3. Top: Mean ± SEM of in vitro ouabain-sensitive
"Rb+ uptake by aortic tissue from one-kidney Grollman
hypertensive rats under different incubation conditions.
Tissue was stored overnight at 4° C and allowed to
equilibrate the following day for 3 hours prior to "Rb+ uptake studies. The tissue was then placed in buffer containing
either 150 mM Na+ or 20 mM M?+. The concentration of
monensin was 10 fig/ml. Bottom: Mean ± SEM of total cell
Na+ in the same tissues. Data are expressed as previously
described. *p
1981 BLOOD PRESSURE COUNCIL
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Discussion
The functional status of the Na + -K + pump in
vascular smooth muscle in hypertension is not well understood, in part because the relationship between
pump activity and intracellular Na + is not clear. We
designed the present study to examine the effect of induced changes in total cell Na + on pump activity in
50
A,a
No Additions
•,0
P1u> Monensin
l , D No Additions
INCUBATED TISSUE
FRESH TISSUE
y. M 40
+ '»
IS
8
(IO)
-
SENSIT IVE
moles • 15 min'
rats under incubation conditions that produced
different levels of total cell Na + . In freshly excised
tissue, Na + -K + pump activity was highest. Equilibrating stored tissues for 3 hours in K-H markedly
reduced pump activity. Monensin stimulated ouabainsensitive M Rb + uptake in equilibrated tissues, but not
to the level found in fresh tissue. These changes in
ouabain-sensitive " R b + uptake reflected changes in
total cell Na + (fig. 2, p < 0.05). It should be noted,
however, that ouabain-sensitive M Rb + uptake was
always higher in hypertensive tissue for any given condition, although total cell Na + did not differ between
groups. In freshly excised tissue, aortic K + content
was significantly lower in the DOCA-salt group
(DOCA vs control: 83 ± 10 vs 120 ± 5 mmoles • kg
dry w f , p < 0.05). Unchanged cell Na and
decreased K+ content of tail arteries from DOCAhypertensive rats have previously been found.2*
We also assayed pump activity in freshly excised
tail arteries from DOCA-salt and control rats. As in
aortic tissue, ouabain-sensitive M Rb + uptake was
higher in tail arteries from DOCA-salt hypertensive
rats (control, n = 7 vs DOCA-salt, n = 7: 18.8 ± 2.6
vs 27.3 ± 3.0 nmoles • 15 min"1 • mg dry wf1, p <
0.05). Again, total cell Na + did not differ between
groups (control vs DOCA-salt: 61.6 ± 3.2 vs 60.2 ±
3.7 mmoles • kg dry wt"1). No differences were
detected in ouabain-insensitive " R b + uptake.
In aortic tissue from the rats with one-kidney
Grollman hypertension, total cell Na + was lowered by
incubation of the segments in the low Na + medium
(fig. 3). Again a decrease in total cell Na + was accompanied by a reduction in ouabain-sensitive M Rb + uptake. However, M Rb + uptake remained greater in the
renal hypertensive group. In the presence of monensin,
ouabain-sensitive M Rb + uptake remained greater in
tissue from the renal hypertensive group. The
observed differences in M Rb + uptake could not be attributed to differences in total cell Na + .
Figure 4 represents a plot of ouabain-sensitive
M
Rb + uptake as a function of total cell Na + in aortic
tissue from DOCA-salt and control rats. Control data
from rats drinking water or saline were pooled
because no differences in the relationship were
observed. There appears to be a sigmoid relationship
between total cell Na + and pump activity in aortic
tissue from both groups of rats. Especially noteworthy
is the finding that, for any level of total cell Na + ,
ouabain-sensitive " R b + uptake was increased in
vascular tissue from the DOCA hypertensive group. A
similar relationship occurred in aortic tissue from rats
with one-kidney Grollman hypertension.
SUPP II, HYPERTENSION, V O L 4, No 3, MAY-JUNE 1982
30
CONTROL
20
10
20
40
+
60
H
TOTAL CELL Na (mmoles-Kg )
FIGURE 4. Mean ± SEM ofouabain sensitive "Rb+ uptake
as a function of total cell Na+ content in aortic tissue from
control and DOCA-salt rats. This figure represents a composite of all data collected in freshly excised aortas and in
aortas stored overnight at 4° C and allowed to equilibrate
for 3 hours. Data from control normotensive animals drinking water or saline were pooled. Number of animals is indicated in the parentheses.
arterial tissue from rats with chronic DOCA-salt and
one-kidney, one figure-8 (Grollman) hypertension.
The most significant finding of this study is that Na + K+ pump activity, as assessed by ouabain-sensitive
M
Rb + uptake, is always increased in arterial tissue
from hypertensive as compared to normotensive rats
under conditions that altered cell N a + . These
differences in pump activity cannot be attributed to
differences in total cell Na + .
Our results in freshly excised arterial tissue from
rats with chronic DOCA-salt hypertension differ from
the decreases in in vitro vascular pump activity
previously reported in fresh tissue.™ These observed
decreases in pump activity in DOCA-salt (presumably volume-expanded) hypertension have been
attributed to the effects of a circulating digitalis-like
substance.*0'S1 Technical differences related to assay
conditions, to duration or severity of the hypertension, or to tissue K+ levels may explain the discrepancies.
Under the usual in vitro conditions of excess K + and
ATP, the activity of the Na + -K + pump in cells is
limited by the relatively low concentration of intracellular N a + . " In the present study, we observed a
similar dependence of the pump on total cell Na + in
aortic tissue from both control and hypertensive rats.
In freshly excised aortas with high levels of intracellular Na + , M ouabain-sensitive M Rb + uptake was
extremely high, while in tissue allowed to equilibrate
SODIUM PUMP IN DOCA AND RENAL HYPERTENSION/5rocA: et al.
with K-H solution in order to lower total cell N a + ,
R b + uptake was much less (fig. 2). Incubation of aortic tissue in low N a + medium reduced total cell N a +
and M R b + uptake to their lowest levels, whereas addition of monensin, a N a + ionophore, increased both
total cell N a + and M R b + uptake in equilibrated tissues
(figs. 2 and 3), as has previously been found in Swiss
3T3 cells." These observations suggest that normally
the low level of N a + inside the vascular smooth muscle
cell limits the activity of the N a + K + pump, and that
elevating total cell N a + increases pump activity.
A sigmoid relationship between cell N a + and pump
activity is seen in erythrocytes." 1 u There appears to
be a similar sigmoid relationship between total cell
N a + and pump activity in aortic tissue from control,
DOCA-salt, and Grollman hypertensive rats (fig. 4).
This type of relationship between pump activity and
internal N a + in vascular smooth muscle was also seen
by Jones. 21 As compared to the controls, the curve for
tissue from the DOCA-salt hypertensive rats was
shifted, as was also observed by Jones. These data
suggest that, for any level of total cell N a + , N a + - K +
pump activity is higher in arterial tissue from the
DOCA-salt hypertensive rats.
Friedman et al. 1 1 ' i e have demonstrated that there is
a slightly increased exchange of L i + for cell N a + and
K + in tail artery from DOCA-salt hypertensive rats.
Since we used a Li + substitution method to estimate
cell N a + , increased N a + - L i + exchange might account
for a portion of the shift of the DOCA-curve. Jones 2 1
did not use the Li + substitution method to estimate
cellular N a + , but found a similar shift in the curve
relating K + -stimulated N a + efflux and cell N a + in aortic tissue from DOCA-salt hypertensive rats.
There is strong evidence that the vascular smooth
muscle membrane is more permeable to N a + in
animals with certain forms of hypertension. 11 - "• M~"
This increased "leakiness" of the plasma membrane
would be expected to supply the pump with more of its
rate-limiting substrate, N a + . The net result would be
an increase in the active transport of N a + out of the
cell, thus preventing N a + accumulation. Therefore,
the increased pump activity seen in hypertensive
arteries may be the major factor in maintaining cell
N a + at normal levels in our preparations.
In contrast, under in vitro conditions where total
cell N a + is not rate-limiting for maximal pump activity, e.g., freshly dissected tissue with excess intracellular N a + , increased entry of N a + into the cell
would not be expected to increase pump activity
because the N a + sites on the pump molecule would be
saturated. Thus, our data, and those of others, 1 1 ' a i
suggest that factors additional to the level of intracellular sodium may be involved in elevating pump activity in arteries from hypertensive rats. Jones 1 1 found
that maximal K + -stimulated N a + efflux is increased in
aortic tissue from DOCA-salt hypertensive rats. In the
present study, freshly excised, Na + -loaded aortic
tissue from DOCA-hypertensive rats exhibited a
similar increase in maximal pump activity. The
amount of total cell N a + in freshly -excised aortic
tissue from normal animals has been shown by
M
11-47
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Overbeck et al.1*'** to be sufficient to maximally
stimulate the N a + - K + pump; however, maximal
pumping by Na + -loaded normotensive control arteries
remains lower than that of hypertensive (Dahl saltsensitive 18 and Goldblatt") arteries.
Monensin increased membrane permeability to
N a + in aortic tissue from both normotensive and
hypertensive rats. Yet, even in the presence of monensin, sodium pump activity for a given level of total cell
N a + in normotensive tissues remained lower than that
in corresponding tissue from DOCA-salt or Grollman
hypertensive rats (fig. 2 and 3), suggesting that
differences in pump activity may not simply reflect
differences in membrane permeability.
Thus, we and others have interpreted the elevated
pump activity in arteries from hypertensive rats
studied in vitro as evidence for an increase in the
number of active pump molecules per unit tissue
weight 11 ' "• M or in their turnover rate. 11 ' "• "• 19 ' "• M
Overbeck et al.** have suggested that a circulating,
digitalis-like pump i n h i b i t o r * ' " may induce new
pump molecules in vivo. Observations of increased
pump activity in hypertensive vascular tissue studied
in vitro remains compatible with this hypothesis,
because there is in vivo evidence in renal hypertensive
rats for decreased pump activity suggesting inhibition." In this regard, when vascular tissue is removed
and studied in vitro, the inhibitor may rapidly dissociate from rat tissue and the effects of the added active pump molecules are then seen as increased pump
activity. Involvement of endogenous substances that
stimulate the pump, such as prostaglandins," or induced synthesis of pump molecules by mineralocorticoids, 11 ' " merit consideration as additional factors
that may increase vascular pump activity in hypertension. Further studies are needed to clarify these
possibilities.
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1981 BLOOD PRESSURE COUNCIL
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Hypertension. 1982;4:43-48
doi: 10.1161/01.HYP.4.3_Pt_2.43
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