Renal Structural Properties in Prehypertensive
Dahl Salt-Sensitive Rats
Fumihiro Tomoda, Masanobu Takata, Hiroyuki Kinuno, Shin Tomita, Kotaro Yasumoto, Hiroshi Inoue
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Abstract—In 10- to 12-week-old Dahl salt-sensitive (DS) and salt-resistant (DR) rats fed a 0.3% salt diet (n⫽10 in each
group), flow-pressure and pressure– glomerular filtration rate (F-P and P-GFR, respectively) relationships were
established for maximally vasodilated perfused kidneys. From these relationships, 3 indices of vascular structural
properties were estimated: slope of F-P (minimal renal vascular resistance reflecting overall luminal dimensions of
preglomerular and postglomerular vasculature), slope of P-GFR (glomerular filtration capability against pressure), and
threshold pressure for beginning filtration at P-GFR (preglomerular-to-postglomerular vascular resistance ratio).
Thereafter, maximal renal vascular resistance was determined to assess wall-to-lumen ratios of the resistance vessels in
half of each group. In the remainder, the kidneys were perfusion-fixed for histological analysis. Mean arterial pressure
did not differ between the DS and DR rats. There were no significant differences in the slopes of F-P between the 2
groups. In contrast, the slope of P-GFR was significantly lower (33%) in DS rats than in DR rats, although the DS
kidneys began filtering at a threshold pressure similar to that of the DR kidneys. Thus, in DS rats, there were no
abnormalities in luminal dimensions at preglomerular and postglomerular vascular segments, but the kidney filtration
capacity decreased at any given increase in pressure. Maximal vascular resistance was greater in DS than in DR rats,
a finding compatible with the histological appearance, which showed vascular hypertrophy with little, if any, vascular
narrowing in the interlobular arteries of DS rats. In conclusion, hypertrophic remodeling without vascular narrowing at
preglomerular resistance vessels and structural defects in filtering at the glomeruli could occur in prehypertensive
DS rats. (Hypertension. 2000;36:68-72.)
Key Words: renal artery 䡲 rats, Dahl 䡲 kidney 䡲 remodeling 䡲 hypertension, sodium-dependent
O
any given level of vasoconstrictor stimuli.14 –16 Therefore, the
vascular structural property is considered to be one of the
important factors determining the intrarenal hemodynamics in
hypertension. Actually, vascular remodeling, vascular hypertrophy, or both occur mainly in the preglomerular resistance
vessels, leading to vascular luminal narrowing in the prehypertensive or early hypertensive stage seen in SHR.17–23 Thus, in the
spontaneous form of hypertension, such as that seen in SHR, it
is assumed that these structural changes would promote an
increase in renal vascular resistance, especially in the preglomerular vasculature, and thereby serve to maintain normal
glomerular pressure in the face of systemic hypertension.24 The
intrarenal hemodynamics characterized by these structural properties is consistent with the hemodynamics obtained in SHR in
vivo.3,25,26 Similarly, there are previous reports examining the
renal vascular structural designs in salt-induced hypertensive
models.27–30 However, these results of these reports were obtained mainly at the stage of established hypertension, which
could be confounded by the nonspecific pressure-mediated
structural effects, and did not represent the real structural
properties specific for salt-induced hypertension.
n the basis of intrarenal hemodynamic data in various
hypertensive animal models, it is recognized that in
models of salt-induced hypertension, including Dahl saltsensitive (DS) rats and deoxycorticosterone-salt rats, intraglomerular pressure is elevated compared with models of spontaneous (ie, non–salt-induced) hypertension, such as the
spontaneously hypertensive rat(s) (SHR).1– 6 Because intraglomerular hypertension plays an important role in the
genesis of glomerular injuries,7 it might be responsible for the
early onset and rapid progression of hypertensive renal
damages that are found in association with salt-induced
hypertension in animals and humans.8 –13 Accordingly, from
the viewpoint of cardiovascular protection, it is clinically
important to elucidate the precise mechanisms causing intraglomerular hypertension in salt-induced hypertension.
In hypertension, it is well known that resistance vessels
become thicker or encroach into the lumen (ie, vascular hypertrophy or vascular remodeling) in the kidneys as well as in other
vascular beds.14,15 In such hypertrophic or remodeled resistance
vessels, vasoconstriction could be potentiated by increased
constrictive force or greater vascular narrowing in response to
Received October 4, 1999; first decision November 1, 1999; revision accepted February 4, 2000.
From the Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan.
Presented in part at the 17th Scientific Meeting of the International Society of Hypertension, Amsterdam, Netherlands, June 7–11, 1998.
Reprint requests to Masanobu Takata, MD, Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani,
Toyama, 930-0194, Japan. E-mail [email protected]
© 2000 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
68
Tomoda et al
Therefore, the purpose of the present study was to investigate the structural properties of renal resistance vessels at
the prehypertensive stage of DS rats, one of the salt-induced
hypertensive models, with Dahl-salt resistant (DR) rats used
as controls. The renal structural properties were estimated by
measuring their hemodynamic behavior and histological appearance in in vitro, maximally vasodilated, perfused kidneys.31–34 To the best of our knowledge, the present study was
the first to demonstrate the renal structural characteristics that
might be involved in the genesis of glomerular hypertension
in DS rats.
Methods
Animals and Procedures
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Five-week-old male DS and DR rats that were obtained from the
Mollegaard Breeding Center (Ejby, Denmark) were bred and supplied by Seiwa Experimental Animals Ltd (Fukuoka, Japan) (n⫽10
in each group). Standard laboratory rat chow containing 0.3% NaCl
and tap water were supplied ad libitum. The rats were housed in a
room maintained at constant temperature (23°C to 25°C) with a
12-hour light/dark cycle until the initiation of the experiments. When
they were 10 to 12 weeks old, each rat was subjected to the
experiments described below. The study design and experimental
protocols were in accordance with our institutional guidelines for
animal research.
The rats were anesthetized with pentobarbital sodium (60 mg/kg
IP) and placed on a warm operating table. Once a surgical level of
anesthesia had been established, tracheotomy and cannulation of the
left jugular vein by a polyethylene catheter (PE-50) were performed,
and then a continuous infusion of pentobarbital sodium in saline (5
mg/h) was begun via the left jugular vein. After blood pressure was
measured via a catheter (PE-50) inserted into the tail artery, a
midline abdominal incision was performed. The urine was obtained
from the bladder for measurement of urinary protein and creatinine
levels with the use of 2 commercial kits (Bio-Rad protein assay;
creatinine assay kit, Boehringer-Mannheim). Thereafter, the intestines were removed, and the abdominal aorta was isolated 1 cm
proximally and distally to the left renal artery. The left ureter was
cannulated (PE-10, 6 cm) for collection of urine, and the mesenteric
artery was cannulated (PE-50) for measurement of aortic pressure
close to the left renal artery. This pressure was considered to be the
renal arterial inflow pressure. All visible branches of the isolated
aorta were ligated except for the left renal artery and mesenteric
artery. After heparinization (3000 U/kg IV) and ligation of the
abdominal aorta at the bifurcation of the iliac arteries, a PE-90
catheter connected to the perfusion setup was inserted retrogradely
through the abdominal aorta to a position distal to the left kidney.
The aorta was tied off just above the mesenteric artery to make a
closed arterial circuit, including the left kidney, and the renal vein
was cut. Then perfusion of the left kidney was begun with oxygenated (95% O2 and 5% CO2) artificial perfusate by use of a peristaltic
pump (Advantec Tokyo Kaisha Ltd), and the flow rate was initially
maintained at 3.0 mL/min. The rats were killed by an overdose of
pentobarbital, and the renal capsule was removed to minimize
increments in tissue pressure during the kidney perfusion. The
adrenal glands were also removed to eliminate the confounding
effects of glucocorticoids or mineralocorticoids on the hemodynamic
analysis. A needle (25 gauge, inner diameter 0.3 mm) was inserted
into the midcortex for measurement of intrarenal tissue pressure.
The perfusate consisted of a modified Tyrode’s solution containing 148 mmol/L Na⫹, 4.3 mmol/L K⫹, 133 mmol/L Cl⫺, 2.5 mmol/L
Ca2⫹, 0.8 mmol/L Mg2⫹, 25 mmol/L HCO3⫺, 0.5 mmol/L H2PO4⫺,
5.6 mmol/L D-glucose, and 20 g/L dextran (Sigma Chemical Co),
with a pH of 7.4 and a partial O2 pressure of 903 mm Hg when
bubbled with 95% O2 and 5% CO2. The perfusate also included
0.9 mmol/L sodium nitroprusside (Sigma), 10 mg/L furosemide
(Hoechst Marion Roussel Ltd), and 10 mg/L inulin (Inutest, Laevosan). The amounts of nitroprusside and furosemide used in the
Renovascular Structure in Dahl Salt-Sensitive Rats
69
present study were believed to be sufficient to make the kidneys
maximally vasodilated and inhibit tubuloglomerular feedback, because the perfused kidneys almost lost their autoregulatory capabilities (see Results). This was also tested in additional experiments in
which an additional infusion of 0.07 mg/min acetylcholine did not
further reduce renal perfusion pressure.
Thirty minutes after initiating the renal perfusion, collections of
urine and measurements of arterial inflow pressure and intrarenal
tissue pressure were repeated during 7 or 8 stepwise increments of
perfusion flow from 3.0 to 19.0 mL/min. The urinary volume was
determined gravimetrically. Inulin concentrations in the perfusate
and urine were measured by the anthrone method,35 and the
glomerular filtration rate (GFR) was calculated as inulin clearance.
After the final measurement, the perfusion was continued at 3.0
mL/min. Twenty minutes later, 100 ␮mol/L phenylephrine (Sigma),
1.25 ␮mol/L [Arg8]vasopressin (Wako Pure Chemical Industries
Ltd), and 1.0 ␮mol/L angiotensin II (Bachem AG) dissolved in
Tyrode’s solution were added to the perfusate for another 5 minutes
to assess the maximal renal vasoconstrictor response in a half of each
group. In the remaining half of each group, the perfusate was
changed to a fixative containing 2% formaldehyde and 0.5% glutaraldehyde in 0.075 mol/L phosphate buffer (pH 7.2), and the kidneys
were perfused at 3.0 mL/min for 50 to 60 minutes. In this preparation, perfusion of the fixative did not alter the perfusion pressure,
suggesting that there was no effect on the relaxed status of the
vasculature. Then the left kidney was removed and placed in 7.4%
formaldehyde. The kidneys were embedded in paraffin, sectioned at
3- to 4-␮m thickness, and stained with hematoxylin and eosin. At the
end of the experiment, the heart was dissected into left and right
ventricles and weighed separately.
Estimations of Renal Hemodynamics in
Perfused Kidneys
In the maximally vasodilated perfused kidneys, neurohumoral and
active autoregulatory control systems are assumed to be inoperative;
therefore, the analysis of hemodynamic behavior enables us to
perform functional assessments of structural properties in the renal
resistance vessels.17,20,31–33 In the flow-pressure relationship, the
slope is the renal vascular resistance at maximal dilatation (ie,
minimal renal vascular resistance), which is an accurate index of
averaged overall luminal dimensions of the preglomerular and
postglomerular vasculature. In the pressure-GFR relationship, the
intercept of the line with the pressure axis (ie, the threshold pressure
for the initiation of filtration) and the slope of the line reflect the
preglomerular-to-postglomerular vascular resistance ratio and filtration capability against pressure, respectively.
In the present study, the flow-pressure and pressure-GFR relationships were established by the use of perfusion flow, arterial distending pressure, and GFR at each flow rate to estimate the abovementioned 3 functional parameters. In these relationships, arterial
distending pressure (ie, transmural pressure), calculated as arterial
inflow pressure minus renal tissue pressure, was adopted as pressure,
because tissue pressure was built up during the perfusion, thereby
inhibiting the distension of the vasculature.32–34 Maximal renal
vascular resistance was also calculated from the data during the renal
vasoconstrictor response to vasoactive substances.
Renal Morphological Measurements
Cross-sectional areas of the wall and lumen in the proximal interlobular arteries and glomerular tuft areas were measured with a
digitizing tablet (SD-510C, Wacom Co) under a light microscope.
The proximal interlobular arteries were defined as being within the
inner cortex, branching for 500 ␮m from the arcuate arteries at the
corticomedullary junction.19 The wall-to-lumen ratio was calculated
by dividing the cross-sectional area of the wall by that of the lumen.
Data Analysis and Statistics
All data are expressed as mean⫾SEM. In renal hemodynamic
measurements, inflow volume and GFR were expressed as values
divided by the wet weight of the right kidneys. The assumption that
70
Hypertension
July 2000
TABLE 1. Hemodynamics, Organ Weights, and Urinary
Protein Excretion
DS Rats
(n⫽10)
Variables
DR Rats
(n⫽10)
P
Body weight, g
393⫾6
332⫾5
0.01
Mean arterial pressure, mm Hg
126⫾7
122⫾3
0.57
Heart rate, bpm
436⫾23
404⫾12
0.24
Left ventricle, g/100 g of BW
0.223⫾0.004
0.209⫾0.003
0.02
Right ventricle, g/100 g of BW
0.062⫾0.002
0.060⫾0.002
0.49
Right kidney wet weight, g/100 g
of BW
0.453⫾0.016
0.404⫾0.004
0.01
9.02⫾1.63
2.05⫾0.27
0.01
Urinary protein/creatinine ratio
Values are mean⫾SEM. BW indicates body weight.
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flow-pressure and pressure-GFR relationships were linear in all
individual experiments was tested by using the Pearson correlation
coefficient in simple regression analysis. The slope and x-intercept
of these relationships were derived from the individual regression
lines. The intergroup comparisons of all data were performed by the
Student unpaired t test. A value of P⬍0.05 was considered statistically significant.
Results
Body weight, left ventricle, and right kidney wet weight were
greater in DS rats than in DR rats (Table 1). However, there
were no differences in mean arterial pressure and pulse rate
between the 2 groups. The urinary protein-to-creatinine ratio
in DS rats was 4 times that in DR rats.
The relationships between perfusion flow and arterial
distending pressure in the maximally vasodilated perfused
kidneys are shown in Figure 1. Regression analysis showed a
significant linear relationship within each individual experiment, with Pearson correlation coefficients (r 2) ranging from
0.96 to 1.00. There was no significant difference in the slope
(3.48⫾0.27 versus 3.77⫾0.27 mm Hg 䡠 mL⫺1 䡠 min⫺1 䡠 g
kidney wet wt⫺1 in DS versus DR rats, respectively; P⫽NS),
indicating that minimal vascular resistance was similar for
both groups.
Arterial distending pressure and GFR also showed a
significant linear relationship within each individual experiment, with Pearson correlation coefficients (r2) ranging from
0.74 to 0.99 (Figure 2). The slope was lower (33%) in DS rats
(3.53⫾0.24 ␮L 䡠 min⫺1 䡠 g wet kidney wt⫺1 䡠 mm Hg⫺1) than
in DR rats (5.28⫾0.30 ␮L 䡠 min⫺1 䡠 g wet kidney
Figure 2. Relationship between arterial distending pressure and
GFR in DS and DR rats. Left and middle panels show results
from each individual experiment in DS and DR rats, respectively.
Right panel shows averaged lines of relationship in DS rats (solid lines) and DR rats (broken lines).
wt⫺1 䡠 mm Hg⫺1) (P⬍0.01). In contrast, there was no significant difference in the extrapolated intercept of the line with
the abscissa (ie, the threshold pressure for initiation of
filtration) between the 2 groups (28.5⫾1.8 mm Hg in DS rats
versus 24.6⫾2.6 mm Hg in DR rats, P⫽NS). Thus, at any
given increase of pressure, glomerular filtration was less in
DS rats than in DR rats, although glomerular filtering began
at a similar distending pressure in the 2 groups. Maximal
renal vascular resistance measured under the dosing of
vasoconstrictors was greater in DS rats (109⫾8 mm Hg 䡠
mL⫺1 䡠 min⫺1 䡠 g kidney wet wt⫺1) than in DR rats
(66⫾9 mm Hg 䡠 mL⫺1 䡠 min⫺1 䡠 g kidney wet wt⫺1) (P⬍0.01).
Table 2 depicts the histological analysis of the renal
resistance vessels and glomeruli at maximal vasodilatation.
At the interlobular arteries, medial cross-sectional area was
significantly greater in DS rats than in DR rats. The internal
luminal area was 6% less in DS rats than in DR rats, although
the difference was not significant. Consequently, the mediato-lumen ratio was elevated in DS rats compared with DR
rats. There were no increases in mesangial matrix and no
glomerular sclerosis revealed by microscopy for either group.
However, the glomerular area was significantly greater in DS
rats than in DR rats, especially at the superficial glomeruli.
Discussion
In the perfused kidneys, the slope of the flow-pressure
relationship did not differ between DS rats and DR rats.
Therefore, the averaged overall luminal dimensions of the
TABLE 2. Morphological Characteristics of Preglomerular
Vessels and Glomeruli in Maximally Vasodilated Kidneys
DS Rats
(n⫽5)
DR Rats
(n⫽5)
P
Luminal cross-sectional
area, ␮m2⫻1000
10.49⫾0.26
11.12⫾0.36
0.20
Medial cross-sectional
area, ␮m2⫻1000
3.99⫾0.15
3.50⫾0.17
0.05
Media/lumen ratio
0.39⫾0.01
0.32⫾0.01
0.01
Superficial glomeruli
13.54⫾0.53
11.56⫾0.24
0.01
Juxtamedullary glomeruli
16.90⫾0.96
14.85⫾0.31
0.08
Morphological Variables
Interlobular artery
Figure 1. Relationship between perfusate flow and arterial distending pressure in DS and DR rats. Left and middle panels
show results from each individual experiment in DS and DR
rats, respectively. Right panel shows averaged lines of relationship in DS rats (solid lines) and DR rats (broken lines).
Glomerular area, ␮m2⫻1000
Values are mean⫾SEM.
Tomoda et al
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
preglomerular and postglomerular vasculature did not differ
between the 2 groups. In contrast, the pressure-GFR relationship was less steep in DS rats than in DR rats, although the
x-intercept of the line was similar between the 2 groups.
Thus, glomerular filtration was initiated at a similar pressure
in the 2 groups, but it was lower at any given increase of
pressure in DS rats compared with DR rats. These findings
suggest that there is no abnormality in the luminal dimensions
of the resistance vessels in either the preglomerular and
postglomerular segments but that the whole-kidney filtration
capability decreases in the maximally vasodilated kidneys of
DS rats.
The maximum contractile response in vascular beds is
affected mainly by the averaged maximal contractile strength
of the renal vascular wall in relation to its luminal size (ie,
wall-to-lumen ratio) if the contractile property is similar in
both groups.14,17 In the present study, the maximal renal
vascular resistance was greater in DS rats than in DR rats.
Combined with the hemodynamic data obtained for the
vasodilated kidneys, these findings suggest that the wall-tolumen ratio is greater in the renal vasculature of DS rats
probably because of increased wall thickness but not because
of alterations in luminal dimension. This notion was also
supported by the histological appearance of the proximal
interlobular arteries of DS rats, which showed an increase in
the wall-to-lumen ratio that was mainly due to the increased
wall cross-sectional area. Therefore, expressed in terms of
vascular remodeling,36,37 the observed vascular structural
changes can be described as hypertrophic remodeling with
little, if any, luminal narrowing.
In the renal tissues fixed under vasodilated conditions, the
glomeruli in DS rats exhibited no abnormalities indicative of
glomerular damages on light microscopy. However, the marked
proteinuria implies the existence of some undetectable structural
defects leading to a disturbance in glomerular permeability in the
prehypertensive stage of DS rats. This possibility is supported by the
observation of Sterzel et al8 showing that electron microscopy
detected segmental losses of epithelial foot processes despite no
apparent abnormalities detected by light microscopy in the glomeruli of very young (ie, 4-week-old) DS rats. Thus, in DS rats, it is
presumed that the structural defects already exist in the glomeruli
before the development of hypertension. Possibly, the above glomerular structural defect may provide a basis for the reduction in
glomerular permeability and low GFR in the pressure-GFR relationship. The observed glomerular hypertrophy also appears to be a
compensatory adjustment to offset the loss of glomerular permeability by increasing the glomerular surface area.
There are several aspects of the design of the present study
that require comment. In the present study, the lumen of the
renal vasculature was hemodynamically assessed by using the
in vitro maximally dilated whole-kidney perfusion technique.17,20,31–33 This methodology has already been applied
for measurements of the vascular structure in SHR by
Göthberg and colleagues,17,20,31 and their results in the vasodilated perfused kidney model are in good agreement with
those obtained by other techniques.21–23 In contrast to histological analysis, this technique is accurate and sensitive
enough to detect the alterations of lumen in small resistant
vessels, because vascular resistance varies inversely with the
Renovascular Structure in Dahl Salt-Sensitive Rats
71
fourth power of the radius, according to the Poiseuille’s law.
It can also determine whether the changes of the lumen are
confined to the preglomerular or postglomerular circulation.
However, our technique does not allow us to conclude
whether the luminal changes are in the afferent arteriole,
larger upstream vessels, or both or whether the changes are in
the cortical or medullary vessels. In addition, renal denervation or adding of spironolactone to the perfusate might have
been required to exclude completely the possible residual
influences of renal nerves or aldosterone on the measurements. In the histological analysis, renal tissues were
perfusion-fixed under maximally vasodilated conditions to
minimize the artificial vasoconstriction induced by fixative
during the perfusion-fixation process.
Our data of the renal vascular structure in DS rats are
clearly different from those reported in the prehypertensive or
early hypertensive SHR. In the vasodilated perfused kidneys
of SHR compared with those of age-matched normotensive
controls, the pressure-GFR relationship shows a slightly
greater x-intercept without changes in the slope of the
line.17,20 This hemodynamic observation in the vasodilated
kidneys indicates that the glomerular filtration capability
against pressure is maintained normally in SHR, although the
preglomerular-to-postglomerular vascular resistance ratio is
elevated.17,20,31 Therefore, it seems likely that renal structural
alterations precede frank hypertension in both DS rats and
SHR, but the most affected sites are different between them.
In particular, a structural defect in filtering is present in the
glomeruli of DS rats but not SHR. On the other hand, vascular
narrowing occurs in the preglomerular resistance vessels of
SHR but not DS rats.
Accordingly, on the basis of the structural properties, we
hypothesize the following sequence of events with age in the
kidneys of DS rats: (1) The reduced glomerular filtration
capacity and the elevation of the wall-to-lumen ratio in the
renal vasculature occur as early events before the development of hypertension. The former could reduce renal excretory function, which leads to volume expansion. The latter
will tend to enhance vascular contractile response if the
neurohumoral influences to the kidneys remain unchanged.
This enhanced renal vasoconstriction could lower glomerular
pressure and aggravate the reduction in renal excretory
capability further. (2) As a result, systemic pressure will
increase to offset the reduced renal excretory functions. The
glomerular area might also increase to compensate for the
decreased glomerular filtration and thereby increase the
filtration fraction. (3) Thereafter, vascular hypertrophy could
progress with age by pressure loading, thus encroaching into
the lumen, as reported for the hindquarter vasculature.38
Furthermore, this vascular narrowing will accentuate the
development of hypertension if DS rats are maintained on a
low salt diet39,40 or will lead to a malignant-type hypertension
on a high salt diet. In addition, it could be also hypothesized
that in DS rats, intraglomerular pressure might increase
concomitantly during the development of hypertension because of the less pronounced vascular narrowing at the
preglomerular vasculature than is found in SHR. However, to
confirm the above hypothesis, further studies are needed
concerning the effects of salt loading or aging on the renal
72
Hypertension
July 2000
vasculature. It must be also emphasized that such intrarenal
hemodynamics is confounded or modified by the alterations
of other factors, including intrarenal autoregulation mechanism, vascular reactivity, and endothelial function.41– 44
In conclusion, our data reveal that hypertrophic remodeling
without a luminal narrowing at the preglomerular resistance
vessels and a permeability defect in filtering at the glomeruli
exist in the prehypertensive stage of DS rats. The observed
renal structural characteristics may be involved in the genesis
of glomerular hypertension in DS rats.
21.
22.
23.
24.
25.
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Renal Structural Properties in Prehypertensive Dahl Salt-Sensitive Rats
Fumihiro Tomoda, Masanobu Takata, Hiroyuki Kinuno, Shin Tomita, Kotaro Yasumoto and
Hiroshi Inoue
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Hypertension. 2000;36:68-72
doi: 10.1161/01.HYP.36.1.68
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