Hemodynamic, Endocrine, and Electrolyte Changes
During Sodium Restriction in DOC A Hypertensive Pigs
DAVID M. COHEN, PH.D., ROGER J. GREKIN, M.D., JOHN MITCHELL, B.S.,
WILLIAM H. RICE, B.S., AND DAVID F. BOHR, M.D.
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
SUMMARY Effects of a low sodium diet on hemodynamic, endocrine, and electrolyte rariables were studied
in nine DOCA-hypertensive and three control pigs. Sodium intake was reduced from about 200 mEq/24 hr to
20 mEq/24 hr. Low sodium caused the blood pressure (BP) of five pigs to return to within 5% of normal levels
(respondcrs); in four others (nonresponders), BP remained elevated. Cardiac outputs were the same in all
DOCA-treated pigs and not different from pre-low sodium values. Therefore, BP fell in the responders because
of a fall in total peripheral resistance. In nonresponders, total peripheral resistance did not fall. It is suggested
that nonresponders developed irreversible structural or functional vascular changes responsible for maintained
resistance elevation. Urinary sodium excretion fell markedly and sodium balance became less positive in all
pigs. On low sodium, plasma renin activity and aldosterone remained depressed in DOCA-treated pigs, but
rose steadily in control pigs. Serum sodium was unchanged in all pigs, but the bypokalemia seen in DOCAtreated pigs on normal sodium was reversed with low sodium. High water turnover seen in all DOCA-treated
pigs was always reversed by the low-sodium diet. It is concluded that in some animals on a low sodium diet, BP
is lowered to normotensive levels, whereas in others it is not. The failure of a low sodium diet to produce a fall
in arterial pressure in these animals is not related to changes in the renin-angiotensin system, in serum
potassium levels, or water turnover rates. (Hypertension 2: 490-496, 1980)
KEVWORDS
hypokalemia
DOCA hypertension
water turnover
sodium restriction
I
T is well known that the development of mineralocorticoid hypertension is largely sodiumdependent. Although young rats1 and pigs2 on a
standard sodium diet become hypertensive following
large doses of deoxycorticosterone acetate (DOCA),
most animal models require supplemental sodium in
either their food or drinking water to achieve substantial blood pressure (BP) elevation.1' '-•
The ability of sodium restriction to reverse the
hypertensive process is less well established. Although
it is generally assumed that lowering dietary sodium
will reduce BP in most hypertensive subjects,5 reversal
of the hypertensive process does not always occur."-'
Furthermore, in long-standing DOCA hypertension,
the BP does not fall after cessation of DOCA and high
• renin-angiotensin system
sodium administration. This condition of persistent
pressure elevation has been called "metacorticoid
hypertension" and has been reviewed.'
We have studied the effects of dietary sodium
deprivation on DOCA hypertensive pigs to determine
if a low sodium diet always reverses high BP to normotensive levels in this model, and to monitor
hemodynamic, metabolic, and endocrine variables
during sodium depletion so as to characterize
associated factors.
Methods
Animal Care and Instrumentation
Twelve young male feeder pigs (Yorkshire White)
were used for this study. The animals were housed in
4 X 4 ft metabolic cages and given food and water ad
libitum. Each pig ate approximately 1.5 kg Purina Pig
Chow (112 mEq Na+ and 191 mEq K+/kg) per day,
and no salt was added to the food or drinking water.
Each animal was subjected to two major operations.
Thoracic surgery was performed to place an electromagnetic flowprobe (Zepeda Instrument Company) around the ascending aorta for cardiac output
From the Departments of Physiology and Internal Medicine
(Division of Endocrinology and Metabolism), University of
Michigan Medical School, Ann Arbor, Michigan.
Supported by Grant HL-18575 from the National Institutes of
Health, National Heart, Lung and Blood Institute.
Address for reprints: Dr. David M. Cohen, Department of
Physiology, University of Michigan, 7710 Medical Science II, Ann
Arbor, Michigan 48109.
490
SODIUM RESTRICTION AND DOCA HYPERTENSION/CoAen et al.
measurements and to implant a Tygon catheter in the
aortic arch just distal to the flowprobe for arterial
pressure recording. Following recovery from this surgery, a laparotomy was performed to implant a Tygon
catheter in the inferior vena cava with its tip in the
central venous pool. Catheters and flowprobe leads
were exteriorized on the left side near the eighth rib
and tied to a wire that was looped under the skin. This
instrumentation was protected by a heavy canvas
jacket. Operative details are presented elsewhere.1
Hemodynamic Measurements
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Aortic and venous pressures and cardiac outputs
were monitored daily in each pig. Because of
difficulties in terminal flowprobe calibrations, cardiac
outputs are expressed as percent change in millimeter
of pen deflection instead of absolute flow values.2
Total peripheral resistance was calculated as the
quotient of mean arterial pressure (MAP) divided by
cardiac output.
Metabolic Measurements
Water intake, urine output, and food intake were measured daily. Dietary sodium and potassium (mEq/24 hr)
values were calculated and urinary electrolyte concentrations were measured on a National Instrument
Laboratories flame photometer with an internal standard of lithium. Water and electrolyte balances
(dietary intake-urinary output) were calculated.
Blood Sampling
Blood for endocrine determinations was collected
on ice. The plasma was Separated by centrifugation
and frozen until assayed. Plasma renin activity (PRA)
was measured by radioimmunoassay of angiotensin I
generated during a 30-minute incubation." Serum
aldosterone was also determined by radioimmunoassay using antiserum directed against aldosterone7-lactone.10
Blood for determination of sodium and potassium
concentrations was collected in plastic tubes and centrifuged immediately at room temperature. Plasma
was refrigerated until assayed.
DOCA Implantation
Following a stabilization period post surgery, nine
pigs received subcutaneous implantations of DOCA
(Sigma Chemical), 100 mg/kg body wt, impregnated
in a Silastic (Dow Corning) matrix, 1:2 by weight.
Three control pigs received Silastic implants without
DOCA. These implantations were made on the left
flank with the pig under light thiamylal sodium
(Surital, Parke-Davis) anesthesia.
Low Sodium Intervention
Following DOCA implantation, MAP steadily rose
in all pigs.2 This pressure rise was complete by 2-3
weeks. At that time, the animals were placed on a
"normal sodium" powdered diet for 4-12 days. The
491
concentration of sodium in this diet was 121 mEq/kg;
that of potassium was 253 mEq/kg. This change in
diet was given to prepare the animals for the altered
consistency of a powdered "low sodium" diet (10.1
mEq Na/kg). The "low sodium" diet was usually
given for 22 days. However, since one animal received
the diet for only 17 days and because major changes in
metabolic, endocrine, and hemodynamic variables
were complete within this period of time, the data are
presented for just the first 17 days. The time from implant to the beginning of sodium restriction ranged
from 15 to 21 days for Silastic control pigs and from
29 to 54 days for DOCA-treated pigs.
Analysis of Data
The data are expressed as means ± SEM. Comparisons of hemodynamic, metabolic, and endocrine
variables were made between control and DOCA
hypertensive pigs on given days. Variables were also
compared for each group before the low sodium intervention (Days —4 to —1) and afterward (Days +11
to +17). Statistical significance of difference between
and within groups was determined by Student's t test.
Results
Effects of DOCA and Silastic implantation on
hemodynamic, metabolic, and endocrine variables in
our pigs are presented in table 1. The MAP rose in all
DOCA-treated pigs, initiated by increases in cardiac
output alone, total peripheral resistance alone, or a
mixture of the two.3 Central venous pressures were
slightly elevated in all DOCA-treated pigs, and heart
rates were unchanged. Control pigs showed no
changes in arterial BP, central venous pressure, or
heart rate following implantation.
Following DOCA implantation, serum DOC rose
20-fold within the first 24 hours and remained elevated
for at least 2 months thereafter.11 By Day 10 following
implant, plasma renin had fallen to levels that could
not be measured. Serum aldosterone (not shown) was
suppressed, but to a lesser degree. Water turnover increased dramatically in these animals, with no significant change in water balance. Serum sodium remained constant following implantation; however,
serum potassium fell. Since hypokalemia occurred at
a time when potassium balance remained unchanged
(there was no kaluresis in these animals), it was inferred that there war a shift of potassium intracellularly.11 No important changes in these variables
occurred in control pigs.
From these steady-state levels, a lowered sodium
diet produced the hemodynamic, endocrine, and
metabolic changes in DOCA hypertensive and control
pigs described below.
Hemodynamics
Based on the changes in arterial pressure resulting
from the low sodium diet, two clearly different groups
of pigs could be distinguished. In five pigs, BP fell to
within 5% of normotensive levels (responders); in four
others (nonresponders), BP remained at least 30%
492
HYPERTENSION
higher than normal (fig. 1). Prc-low sodium mean
arterial pressures of the responders fell from 134 ft 2
to 101 ± 2 rtlm Hg on Days 11-17 of low sodium
(135% ± 1% to 103% ± 1% of pre-DOCA implant
pressure). Nonresponder pressures fell from 145 ± 8
to 136 ± 3 mm Hg (from 150% ± 2% to 140% ± 2%
of pre-DOCA implant pressure). Pre-low sodium
pressures were significantly higher in nonresponders
TABLE 1. Effects of DOCA and SHastic Implantation on
Hemodynamic, Metabolic; and Endocrine Variables
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Variable
Control
(n = 3)
DOCA
(n = 9)
Days from implant to low
sodium
17 = 2
38 =*• 4
Body weight (kg)
Pre-implant
Pre-low Na+
30 = 3
38 = 4
35 ± 2
55 ± 2
Serum Naf (mEq/liter)
Pre-implant
Pre-low Na+
142
140*
142
145
1
2
Serum Kt (mEq/liter)
Pre-implant
Pre-loW Na+
4.8 =< 0.8
5.1 ± 0.8
4.6
3.4
MAP (mm Hg)
Pre-implant
Pre-low Na+
93 = 4
95 • 4
98 ± 3
139 ± 4
Cardiac output
(% of pre-impiant)
Pre-implant
Pre-low Na +
100
111 =- 11
100
152
Total perepheral resistance
(% of pre-implant)
Pre-implant
Pre-low Na+
100
88 ±
100
94
Central venous pressure
(mm Hg)
Pre-implant
Pre-low Na+
3.5
3.0J
4.8
5.4
Heart rate
Pre-implant
Pre-low Na+
Plasma renin activity
(ng/AI/ml/hr)
Pre-implant
Pre-low Na+
Water intake (llters/24 hr)
Pre-implant
Pre-low Na +
*n = 2.
tn - 8.
tn - 1.
0.3
0.2
VOL 2, No
4, JULY-AUGUST
1980
than in responders (p < 0.01). Aortic pressure of control pigs did not change from preimplant Values at any
time during the postimplant or low sodium periods.
Neither responders nor nonresponders showed a
change in cardiac output while on the low sodium diet
(table 2). Since cardiac output was the same in all
DOCA hypertensive pigs and not different from prelow sodium values, BP fell in responders because of a
fall in total peripheral resistance. In nonresponders,
the total peripheral resistance did not fall (table 2).
The time from DOCA implant to the onset of low
sodium intervention ranged from 27 to 54 days (mean
= 38 days) in the responders and from 29 to 48 days
(mean = 39 days) in the nonresponders.
Central venous pressures in the DOCA-treated pigs
did not fall significantly when the animals were placed
on a low sodium diet. There was no difference in the
degree of change between responders and nonresponders. Central venous pressure in the control
animals did not change significantly throughout the
low sodium study. Heart rates of all animals on a low
sodium diet were unchanged from pre-low sodium
values.
Endocrines
Plasma renin activities of control pigs climbed
steadily from 2.6 ± 0.6 to 12.9 ± 2:0 ng Al/ml/hr,
whereas plasma renin activities of all DOCA-treated
pigs remained depressed for the duration of the low
sodium intervention. Plasma renin activities of
DOCA-treated responders, however, became measurable by Days 11-17 whereas those of the nonresponders did not (table 3). Plasma aldosterone levels
paralleled those of plasma renin for each group of
animals (table 3).
5f
5f
0.6
Electrolytes and Water
Urinary sodium excretion (fig. 2) fell precipitously
and equivalently in all three groups of pigs within the
first 24 hours on the low sodium diet, confirming the
equivalent diminution in sodium intake in the three
groups. Sodium balances, which were highly positive
in these growing pigs on the standard sodium diet,
0.2
TABLE 2. Hemodynamic Changes in DOCA Hypertensive
and Control Pigs on a Low Sodium Diet
132
152 ±10132=*
10
147 ±1 10
130
4
5
Pig type
2.7
2.1*
3.5 ±1 1.6
3.4 ±1 1.2
2.4 ± 0.3
<0.05
3.5 ± 1.4
21.0 ± 3.0
Control
(n = 3)
Responders
(n = 4)*
Non-responders
(n = 4)
Total peripheral
Cardiac output
resistance
(% pre-low sodium) (% pre-low sodium)
Days 11-17
Days 11-17
110 ± 6
92 ± 4
103 ± 5
77 * 3f
98 ± 5
98 ± 6
*Aortic flow probe was nonfunctional in one of the responder pigs.
tSignificantly less than 100% of pre-low sodium value
(p < 0.05).
SODIUM RESTRICTION AND DOCA HYPERTENSION/Co/wi et al.
§1
en 5?
IS ?
IS?t
493
Non- Responders (N =4)
140
c
£H i
120
Responders(N=5)
100
Controls (N=3)
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3
5
7
9 11
DAYS ON LOW No+
-4
1
1
17
FIGURE 1. Mean arterial pressure changes in DOCA-hypertensive and control pigs on a low sodium diet.
Data are expressed as % of pre-implant mean arterial pressure. Circles represent mean values obtained on a
single day and bars are one standard error of the mean. Closed circles are control pigs; open circles + solid
lines are responder pigs; and open circles + dashed lines are nonresponder pigs.
(140)
Urinary No + in DOCA-Hypertensive
(112 5)
and Control Pigs
FIGURE 2. Urinary sodium excretion
in
DOCAhypertensive and control pigs on a low sodium diet. Data are
expressed as mEq urinary sodium/24 hr. Circles represent
mean values obtained on a single day. Closed circles are control pigs; open circles + solid lines are responder pigs; and
open circles + dashed lines are nonresponder pigs.
Respon<J ers(N'5)
Noo-Responders (N»4)
rols(N.3)
-4
-2
1
3
5
7
9
11
DAYS ON LOW No+
1
5
17
TABLE 3. Endocrine Changes in DOCA-Hypertensive and Control Pigs on a Low Sodium Diet
Pig type
Control
(n ~ 3)
Respondere
(n = 5)
Nonresponders
(n = 4)
Plasma renin activity (ng Al/ml/hr)
Pre-low sodium
Days 11-17
Aldosterone (ng/dl)
Pre-low sodium
Days 11-17
2.6 ± 0.6
12.9 ± 2.0*
6.5 =t= 0.5
53.5 =±• 18.7*
<0.02
0.9 ± 0.4f
4.4 •*• 1 . 1
7.5 =• 2.4f
<0.02
<0.02
3.4 =t= 1.0
2.3 =: 0.2
'Significantly greater than control values, pre-low sodium (p < 0.001).
fSignificantly greater than non-responder values, days 11-17 (p < 0.01).
494
HYPERTENSION
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became less positive in all three groups so that little, if
any, sodium was retained. Serum sodium levels did
not change measurably throughout the study in any of
the three groups (table 4).
Serum potassium in control pigs remained unchanged throughout the study. All DOCA-treated pigs
were hypokalemic on the standard sodium diet (table
1). The hypokalemia of both responders and nonresponders returned toward normal values within the
first few days on the low sodium diet and remained
normal for the duration of the study (table 4).
Potassium balances were equally positive in all three
groups of pigs and not measurably changed by the low
sodium diet.
The water turnover, which was very high in all
DOCA-treated pigs before they were placed on the
low sodium diet (table 1), was reversed by this
procedure in both responders and nonresponders (fig.
3). Water intake of DOCA-treated responders fell
from 19.1 ± 0.8 liter/24 hr to 5.7 ± 0.6 liter/24 hr on
Days 11-17. Nonresponder intakes fell from
21.0 ± 0.5 to 5.2 ± 0.4 liter/24 hr. Water turnover
values of the control pigs were unchanged during the
low sodium diet (3.4 ± 0.2 to 3.3 ± 0.1 liter/24 hr).
Urine volumes paralleled water intake so that water
balance was unchanged and not different among any
of the three groups.
Discussion
Effects of Low Sodium Treatment in Hypertension
Although patients with mild hypertension have been
successfully treated with low dietary sodium,*-13' 1S the
effects of dietary sodium restriction on DOCA-salt
hypertension have not been clearly defined. It has been
shown that "metacorticoid" hypertension — a selfsustaining arterial pressure elevation that is no longer
dependent upon a continuing administration of
DOCA — is resistant to sodium restriction.' Musilova
et al. u studied rats given 1% NaCl to drink and made
hypertensive by injections of microcrystalline suspensions of DOCA. When the salt water was replaced
with tap water 10 weeks following the termination of
DOCA administration, the hypertension was reversed.
De Champlain et al.16 have observed that rats made
hypertensive with weekly subcutaneous injections of
VOL 2, No
4, JULY-AUGUST
DOCA and 1% NaCl in their drinking water exhibit a
BP fall following the cessation of DOCA and salt administration. Furthermore, when other DOCA
hypertensive rats were placed on a sodium deficient
diet, their hypertensions were reversed despite continued DOCA administration. Our present study is the
first to characterize hemodynamic, electrolyte, and endocrine changes that occur in DOCA-dcpendent hypertension in response to low sodium treatment.
Hemodynamic Changes
Results of this study show that some DOCA
hypertensive animals maintain an elevated arterial BP
in the presence of reduced dietary sodium, whereas
others do not. The observation that hypertension is
reversible in some subjects but not in others on a low
sodium diet is not a novel one. Dole et al." reported
that treatment of "benign and uncomplicated" hypertension by lowering dietary sodium from 180 to 7
mEq/24 hr resulted in the return to normotensive BP
levels in just 60% of their patients. Experimentally,
Swales and Tange7 reported evidence for two types of
renal hypertensive rats. They showed that one-kidney
Goldblatt hypertensive rats responded to acute
sodium depletion by becoming normotensive, whereas
two-kidney Goldblatt hypertensive rats did not.
Since nonresponders did not decrease total
peripheral resistance on the low sodium diet (table 2),
it is possible that these animals have developed
irreversible changes in the walls of their resistance
vessels. Support for this possibility comes from the
fact that the pre-low sodium mean arterial pressures
of nonresponders were significantly higher than those
of responders (fig. 1). Such a situation would be compatible with adaptive structural changes in the
vascular wall due to an increased pressure load.16 It
has been observed that vascular changes exist in pigs
with hypertension resulting from DOCA treatment
identical to that of the current study. Such changes include increases in vascular smooth muscle sensitivity
and increases in structural resistance.17 The maintained vascular resistance in the nonresponders of this
study may have been due to a persistence of either or
both of these changes. Since the time from implant to
low sodium treatment was not different between
responders and nonresponders, it is possible that certain animals are intrinsically more predisposed to
these "vascular changes." Three of four animals that
TABLE 4. Serum Electrolyte Changes in DOCA-Hypertensive and Control Pigs on a Low Sodium Diet
Pig type
Control
(n = 3)
Responder
(n = 5)
Nonresponder
(n = 4)
1980
Serum Na+ (mEq/1)
Pre-low Na +
Days 11-17
Serum K+ (mEq/1)
Days 11-17
Pre-low Na
142 * 1.0
142 =* 1.1
5.1 ± 0.9
5.6 *: 0.8
147 ± 2.4
144 =t 3.0
3.7 ± 0.2
5.1 =*: 0.3*
144 ± 2.2
144 =" 1.2
3.3 =fa 0 . 3
4.3 * 0.4*
•Significantly greater than pre-low sodium values (p < 0.05).
SODIUM RESTRICTION AND DOCA HYPERTENSION/Co/ien et al.
495
H 2 0 Intoke in DOCA-Hypertensive
°nd Control Pigs
No+
+^,-_J1-f-k*3
Responds* (N» 5)
Non-Responders (N«4)
I I I 1 i I I ]Controls (N.3)
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-4
-2
1
3
5
7 9 11
DAYS ON LOW No+
13 15
subsequently became responders (one of the five
responders had a nonfunctional flow probe) developed
their hypertension by an increase in cardiac output,
whereas all four pigs that were to become nonresponders had initial BP elevations that were dependent upon increases in total peripheral resistance.
Endocrine Changes
Whereas control pigs showed a steady rise in
plasma renin activity while on low sodium, plasma
renin levels remained markedly depressed in all
DOCA-treated pigs throughout most of the post implant and all of the low sodium period. This observation argues against a role for the renin-angiotensinaldosterone system in the maintenance or regression
of hypertension in this model.
Water and Electrolyte Changes
The high water turnover in mineralocorticoid hypertension18' " was reversed in all DOCA-treated pigs
in this study. Since nonresponders showed an
equivalent fall in water turnover with no change in BP,
it is evident that the polydipsia-polyuria that accompanies DOCA hypertension in this model is merely
coincident with and not necessary for the maintenance
of sustained BP elevation. DOCA hypertension can
develop in the absence of increased water turnover.20' " However, the persistence of hypertension
after the termination of an elevated turnover has not
been previously reported.
The hypokalemia observed in all pigs was reversed
in DOCA-treated pigs on a low sodium diet (table 4).
Since it has been suggested that the original
hypokalemia was the result of a shift of potassium into
cells,11 it appears that this intracellular movement of
potassium was at least partially sodium-dependent.
Additionally, since hypokalemia was reversed in all
FIGURE 3. Water intake in DOCA-hypertensive
and control pigs on a low sodium diet. Data are expressed as liters of water drunk in 24 hr. Circles
represent the mean values obtained on a single day
and bars are 1 standard error of the mean. Closed
circles are control pigs; open circles + solid lines
are responder pigs; and open circles + dashed lines
are nonresponder pigs.
DOCA pigs, the maintenance of high BP seen in some
pigs was not dependent upon low levels of potassium
in the blood.
Serum sodium levels were not significantly changed
throughout the study (table 4). Since there were no
differences between values obtained from responders
and nonresponders, it seems likely that major changes
in serum sodium are not necessary for the regression
of hypertension seen in this study.
Urinary sodium excretion fell and sodium balance
became less positive when the pigs were subjected to
the low sodium diet. The fact that sodium excretion
was decreased in these animals was not surprising and
has been reported previously.'•' However, the time
course of the fall was quite abrupt (fig. 3). In each
group of animals, sodium excretion fell dramatically
within the first 24 hours of dietary sodium restriction.
This happened without an apparent change in serum
sodium. An obvious explanation for changes seen in
control pigs is that an increase in activity of the reninangiotensin-aldosterone system contributes to the fall
of urinary sodium." However, this cannot explain the
phenomenon seen in DOCA-treated animals, where
the renin-angiotensin system has been rendered inoperative and changes in aldosterone concentration
would have been masked by high concentrations of
DOCA.
The changes observed in the measured variables of
this study permit some insight into the mechanisms
that may be responsible for the reversal of the pressure
elevation with lowered dietary sodium. We considered
that either or both of the following processes may play
a role in this phenomenon: 1) The reduction in the
positive sodium balance in our growing pigs, which occurs in the absence of measurable changes in serum
sodium or in water balance, is compatible with the
possibility that intracellular sodium concentration had
fallen. Such transmembrane distribution changes of
496
HYPERTENSION
sodium have been implicated in the etiology of hypertension" and may play a role in the hemodynamic
changes observed in our study. 2) Alternatively, since
water turnover rates were so high just prior to low
sodium treatment, a slight, but important decline in
water balance during low sodium may have gone unnoticed. If water balance fell along with sodium
balance, this would argue that extracellular fluid
volume had fallen. This volume change might also be
responsible for the observed changes in a number of
variables that occur during low sodium.
It is concluded that some animals are unable to
achieve a lowered BP while on a low sodium diet. The
failure of a low sodium diet to produce a fall in arterial
pressure in these animals is not related to changes in
the renin-angiotensin system, in serum potassium
levels, or in water turnover rate.
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D M Cohen, R J Grekin, J Mitchell, W H Rice and D F Bohr
Hypertension. 1980;2:490-496
doi: 10.1161/01.HYP.2.4.490
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