Evidence That Reduced Renal Medullary Nitric Oxide
Synthase Activity of Dahl S Rats Enables Small Elevations
of Arginine Vasopressin to Produce Sustained Hypertension
Baozhi Yuan, Allen W. Cowley, Jr
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Abstract—On the basis of observations supporting the functional importance of nitric oxide (NO) in the regulation of renal
medullary function, and a reduced nitric oxide synthase (NOS) enzyme activity in the outer medulla of the Dahl
salt-sensitive (SS/Mcw) rats, we hypothesized that these inbred rats would have reduced capacity to synthesize renal
medullary NO. This reduced capacity would sensitize them to the hypertensive effects of small elevations of circulating
arginine vasopressin (AVP). SS/Mcw and Brown Norway (BN/Mcw) rats with implanted arterial and venous catheters
were fed a 0.4% salt diet and infused intravenously for 14 days with a subpressor dose of AVP (2 ng/kg per min). Mean
arterial pressure (MAP) was measured 2 hours daily in unanesthetized rats maintained in their home cages. MAP in
SS/Mcw rats increased during day 1 of AVP infusion from a control level of 127⫾0.9 mm Hg to an average of
147⫾1.6 mm Hg after 14 days. MAP did not return to control values during the 3 days after the end of AVP infusion.
BN/Mcw rats showed no changes of MAP during 14 days of AVP infusion (90.4⫾0.6 mm Hg and 92.3⫾0.4 mm Hg).
Northern blot analysis of renal tissue from vehicle (saline) -infused rats demonstrated that NOS I and NOS III mRNA
expression was significantly less in SS/Mcw rats in the renal outer medulla compared with BN/Mcw rats. We conclude
that small, normally subpressor elevations of plasma AVP can produce chronic hypertension in SS/Mcw rats and that
this phenomenon is related to the reduced medullary NOS enzyme activity, which in turn reduces the AVP-stimulated
NO synthesis. (Hypertension. 2001;37[part 2]:524-528.)
Key Words: Dahl salt-sensitive rats 䡲 Brown Norway rats 䡲 NOS isoforms 䡲 blood pressure 䡲 vasopressin
I
t is well known that chronic elevation of plasma arginine
vasopressin (AVP) does not produce sustained hypertension in rats, dogs, and in human,1– 4 despite that AVP is one
of the most potent circulating vasoconstrictors and a fluid
retaining hormone. However, previous studies from our
laboratory have found that chronic intravenous infusions of
the AVP V1 receptor agonist [Phe2, Ile3, Orn8]VP resulted in
sustained hypertension.5 It was found that these hypertensive
actions of the V1 agonist were mediated through actions on
the medulla of the kidney because chronic infusion of a
selective V1R antagonist into renal medullary interstitium
prevented the rise of arterial pressure.5 Additionally, hypertension was also achieved when the V1R agonist was infused
directly into the renal medullary interstitium6 at a dose
previously shown to reduce blood flow to the renal
medulla.7–9
The hypertension achieved with V1R stimulation suggested that the failure of AVP to elevate the blood pressure
was related to the stimulation of V2 receptors (V2R), which
activated an opposing renal medullary vasodilator response.
One such mechanism was identified to be the release of NO.
Because AVP increased blood flow within the renal medulla
by V2R-mediated production of NO.7,10 Since the V2R
mRNA could not be detected within the microvasculature of
renal cortex or medulla,10 it was suggested that the elevation
of medullary NO concentrations in response to AVP or V2
agonist stimulation11–13 was the result of V2 receptors stimulation most likely in the medullary collecting ducts. The
concept that NO responses in the medulla served to buffer
AVP-V1 receptor vasoconstrictor actions was validated by
recent studies in which NG-nitro-L-arginine methyl ester
(L-NAME) was infused chronically into the medullary interstitial space of Sprague-Dawley rats to reduce NOS activity
and the NO response to AVP. Even a moderate reduction of
NOS activity in the renal medulla enabled small elevations of
circulating AVP to produce sustained hypertension,14 demonstrating the importance of the medullary NO counterregulatory system. Recently, studies have demonstrated that
SS/Mcw rats exhibit reduced vasodilator responses to compounds that stimulate NO release (eg, acetylcholine)15 and
that renal medullary nitric oxide synthase (NOS) activity is
significant reduced in SS/Mcw rats compared with the Brown
Norway (BN/Mcw) rats.16
Received October 27, 2000; first decision November 27, 2000; revision accepted December 19, 2000.
From the Department of Physiology, Medical College of Wisconsin, Milwaukee.
Correspondence to Allen W. Cowley Jr, PhD, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI
53226. E-mail [email protected]
© 2001 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
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Yuan and Cowley
AVP Produced Hypertension in SS/Mcw Rats
525
Taken together, these findings provided the rationale for
the present study. Specifically, studies were carried out to
determine whether small elevations of circulating AVP that
failed to produce hypertension in normotensive BN/Mcw rats
(as shown in Sprague-Dawley rats14) would lead to chronic
hypertension in SS/Mcw rats even when maintained on a low
salt diet (0.4%). Northern blot analyses were performed to
determine whether NOS mRNA of the three NOS isoforms
were reduced in the medulla of SS/Mcw rats.
Methods
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Twelve-week-old male inbred Dahl S (SS/JrHsdMcw) and Brown
Norway (BN/SsNMcw) rats from colonies maintained at the Medical
College of Wisconsin were used in the experiments. These rats will
be referred to as SS/Mcw and BN/Mcw throughout this manuscript.
The Brown Norway rat was chosen as the normotensive saltinsensitive control strain because we carried out a genetic linkage
analysis using the inbred BN/Mcw and SS/Mcw strains and found
differences between these 2 strains that can be combined with the
genetic mapping studies to link genes to function.17 All rats received
free access to tap water and were maintained throughout the study on
low salt (0.4% NaCl) rat chow (Dyets).
Renal Regional NOS mRNA Expression Studies in
Dahl S and BN/Mcw Rats
Male adult SS/Mcw and BN/Mcw rats maintained throughout life on
low 0.4% salt intake were killed with an overdose of sodium
pentobarbital; the kidneys were quickly removed, dissected, and
rinsed free of blood with ice cold normal saline. The renal cortex,
outer medulla, and inner medulla were separated, and the tissues
were frozen quickly on dry ice and transferred to ⫺80°C freezer until
use. Total RNA was extracted using TRIzol Reagent (Life Technologies) according to the manufacturer’s protocol. A total of 20 ␮g of
total RNA from cortex, outer medulla, and 10 ␮g of total RNA from
inner medulla were separated on 5% formaldehyde-MOPS denaturing agarose (1%) gel by electrophoresis. The RNA was then
transferred onto a positively charged nylon membrane (Amersham
Pharmacia) by overnight capillary transfer action that was then UV
cross-linked (Stratagene). The specific probes for neuronal NOS
(NOS I), inducible NOS (NOS II), and endothelial NOS (NOS III)
used in subsequent Northern blot analysis were generated by reverse
transcriptase-polymerase chain reaction (RT-PCR) using specific
primers described previously.18 PCR products were purified (PCR
purification kit, QIAGEN, Germany), and the probes were labeled
with 32P (RepPrime II DNA Labeling Kit, Amersham). The membrane was prehybridized (Rapid-Hyb buffer, Amersham Pharmacia)
for 1 hour, and then 25 ng of labeled probe was added to the
hybridization solution (Rapid-Hyb buffer, Amersham Pharmacia)
and hybridized for 2.5 hours. The membrane was washed with 2⫻
SSC (3.0 mol/L sodium chloride and 0.3 mol/L sodium citrate) and
0.1% SDS (sodium dodecyl sulfate solution) for 20 minutes, then
washed twice for 30 minutes with 1⫻ SSC and 0.1% SDS, and 0.1⫻
SSC and 0.1% SDS, respectively. The membrane was then exposed
to the x-ray film with intensifying screen, 48 hours for eNOS, nNOS,
and 72 hours for iNOS at ⫺80°C, respectively. The signals were
analyzed by densitometry scanner and ImagQuant software (Molecular Dynamics).
Surgical Preparation and Chronic MAP
Measurement in Dahl S, Dahl R, and
BN/Mcw Rats
Rats were surgically prepared with the femoral arterial and femoral
vein catheters for the measurement of arterial pressure and intravenous infusion as described previously.17 Rats were allowed to
recover for 5 to 7 days while saline was infused intravenously at a
rate of 0.25 mL/h throughout the recovery and experimental control
period.
Figure 1. Northern blot analysis showing NOS III mRNA expression in tissue of the renal cortex, outer medulla, and inner
medulla in SS/Mcw and BN/Mcw rats. A total of 20 ␮g of total
RNA from cortex and outer medulla and 10 ␮g of total RNA
from inner medulla were tested in this study. n⫽5 for each
group. *Significant difference when compared with BN/Mcw rats
(P⬍0.05).
One week after surgery, daily 2-hour measurements of MAP were
begun and continued for 3 to 4 days for the control period and 14
days for the experiment period using an on-line data collection and
analysis system described previously.17 Intravenous infusion of AVP
diluted in isotonic saline was then began at a rate of 2 ng/kg per
minute and infused continuously (0.25 mL/h) for 14 days. The
infusion solution was changed back to saline after 14 days of AVP
and blood pressure was measured for another 3 days. A control group
of SS/Mcw rats received a 14-day intravenous chronic infusion of
saline (0.25 mL/h). The AVP dose used in these studies was found
in previous studies to increase plasma AVP levels to 10 to 12 pg/mL,
but did not cause sustained hypertension when infused intravenously
for 14 days to normal Sprague-Dawley rats.19
Statistical Analysis
Data are expressed as means⫾standard error. Within-group changes
in MAP were evaluated with a 1-way ANOVA for repeated measures
and Duncan’s post hoc test. Northern Blots were analyzed using
ImagQuant software from Molecular Dynamics. The t test was used
to examine the differences in mRNA expression between strains. The
level of significance was P⬍0.05.
Results
NOS 3 Isoform mRNA Expression in SS/Mcw and
BN/Mcw Rats
Figure 1 shows NOS III mRNA was present in the outer and
inner medulla of both SS/Mcw and BN/Mcw rats receiving a
low salt diet. The outer medulla of SS/Mcw rats contained
significantly less NOS III mRNA when compared with
BN/Mcw rats. However, there was no significant difference
for NOS III expression between SS/Mcw and BN/Mcw rats in
the inner medulla.
Similar results were obtained for NOS I mRNA (Figure 2)
with the outer medulla of SS/Mcw showing significantly less
mRNA expression than BN/Mcw rats, whereas no significant
differences were found in the inner medulla.
Northern blot analysis was also performed for NOS II
mRNA in SS/Mcw and BN/Mcw rats, but this isoform could
not be detected in any renal regions from either strain. The
mRNA levels for the three NOS isoforms were also very low
and undetectable in renal cortex from both strains, as indicated in Figures 1 and 2. These observations do not suggest
an absence of these isoforms but do indicate a significantly
reduced total tissue expression of the mRNA because the
Northern blot membranes were exposed for similar times.
526
Hypertension
February 2001 Part II
Figure 2. Northern blot analysis showing NOS I mRNA expression in renal cortex, outer medulla, and inner medulla in
SS/Mcw and BN/Mcw rats. n⫽5 for each group. *Significant
difference when compared with BN/Mcw rats (P⬍0.05).
Effects of Long-Term Intravenous Infusion of
AVP on MAP in SS/Mcw and BN/Mcw Rats
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Figure 3 summarizes the effects of intravenous infusion of
subpressor dose of AVP (2 ng/kg per min) on MAP in SS/Mcw
and BN/Mcw rats. The SS/Mcw rats showed a significant higher
MAP during the control period (averaged 125.0⫾3.9 mm Hg
(n⫽7), P⬍0.0001) when compared with the control levels of
MAP in BN/Mcw rats (90.0⫾2.7 mm Hg). Moreover, MAP in
SS/Mcw rats was increased significantly to an average of
143.6⫾5.7 mm Hg after 14 days of administration of AVP when
compared with the control levels. The blood pressure was
increased significantly even after 1 day of AVP infusion. MAP
did not return back to the control level for 3 days after ending the
AVP infusion, averaging 149.1⫾7.4 mm Hg during this postAVP infusion period. BN/Mcw exhibited no significant changes
of MAP during the 14 days of AVP infusion. The control MAP
averaged 90.0⫾2.7 mm Hg in BN/Mcw rats (n⫽6), and
92.3⫾2.3 mm Hg during the intravenous AVP infusion. These
results clearly indicate different sensitivity to AVP for these two
strains of rat.
Figure 4 summarizes the time control studies and shows that
SS/Mcw rats, even when maintained on a low (0.4%) salt diet,
exhibited a gradual increase of MAP from 126.5⫾1.9 mm Hg to
a level of 135.0⫾1.8 mm Hg by day 12 of intravenous infusion
Figure 3. Measurement of MAP in SS/Mcw and BN/Mcw
infused with 2 ng/kg per minute of AVP intravenously for 14
days. All animals were infused with normal saline and had blood
pressure measured for 3 stable control days; then the infusion
solution was changed to AVP on day 1 and continuously infused
for 14 days. Blood pressure was measured for another 3 days
after infusion solution was changed back to normal saline.
*Significant difference when compared with respective controls
(P⬍0.05). Plus signs indicate significant difference between
SS/Mcw and BN/Mcw rats (P⬍0.0001).
Figure 4. Measurement of MAP in SS/Mcw rats with intravenous infusion of normal saline. All animals were fed 0.4% low
salt diet during the entire experimental period. Blood pressure
was measured daily for 2 hours. n⫽6. *Significant difference
when compared with the average of the first 3 MAP measurement (P⬍0.05).
of saline. However, the increases of MAP reached a level of
statistical significant only on days 11 and 12 of isotonic saline
infusion, whereas significant changes in MAP with AVP occurred in the first day.
Discussion
Our previous studies have shown that NO in the renal
medulla protects from vasopressin-induced hypertension and
that there is a reduced capacity of SS/Mcw rats to produce
NO in response to stimuli such as angiotensin II.13,16 The
present study was designed to determine whether AVP could
produce hypertension in rats that exhibited reduced endogenous medullary NOS and NO production.
Evidence of Reduced Medullary NOS Gene
Expression in Dahl S Rats
Northern Blot analysis indicated that NOS III mRNA and
NOS I mRNA isoforms were abundantly expressed in both
the outer and inner medulla of SS/Mcw and BN/Mcw rats.
However, it was found that SS/Mcw rats contained significantly less mRNA for these 2 NOS isoforms in the outer
medulla. These observations conform with other preliminary
studies from our laboratory, which indicate that NOS III and
NOS I enzyme activity and protein expression are also
reduced significantly in the outer medulla of SS/Mcw rats
compared with BN/Mcw rats.16 Despite the lower NOS
enzyme activity and protein expression in SS/Mcw rats, there
was no significant difference in NO concentration under basal
conditions between SS/Mcw and BN/Mcw rats as measured
by microdialysis Hb trapping techniques.16 It therefore appears that there exists sufficient NOS enzyme and substrate,
L-arginine (L-Arg), in the medulla to maintain the basal NO
concentrations in the renal medulla in SS/Mcw rats. Because
the microdialysis technique for the measurement of NO
concentration determines NO in the whole medulla, it is also
possible that the inner medullary NOS could contribute a
disproportionate amount of NO to the assay, which masks the
decreased enzyme activity in the outer medulla. We and
others have observed that, in Sprague-Dawley rats, both NOS
enzyme activity and protein expression were substantially
higher in the inner medulla than in the outer medulla.20,21 The
decreased NOS expression in the outer medulla of SS/Mcw
Yuan and Cowley
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rats may be responsible for the reduction of NO production
induced by different stimuli such as AVP. Previous studies in
our laboratory have shown that AVP stimulates NO production in normal Sprague-Dawley rats and that NO counteracts
the vasoconstrictor effects of AVP.13,16 The present study
further defined the significance of this AVP-stimulated NO
production in the long-term control of arterial pressure. The
results also demonstrated a deficit in the NOS RNA levels in
the SS/Mcw rats. Taken together, we conclude that decreased
outer medullary NOS expression primarily contributes to a
reduction of NO production in response to AVP, which
abolishes the counteracting effect of NO on medullary vasoconstriction resulting in AVP-induced hypertension.
Although we and others have reported previously that NOS
II mRNA and proteins are present in rat renal medulla,20,22 the
inducible NOS isoform was not detectable by Northern blot
analysis in the present study in either SS/Mcw or BN/Mcw
kidneys. The failure to demonstrate the NOS II mRNA in the
renal outer and inner medulla in the present study could
simply be due to the limitation of tissue mRNA amount (20
␮g for outer medulla and 10 ␮g for inner medulla) in the
Northern blot study. The present data indicate only that
SS/Mcw and BN/Mcw rats express much less NOS II mRNA
than NOS III and NOS I under normal physiological
conditions.
In light of other recent data from our laboratory, the present
study provides the basis for a more integrated understanding
of the overall impairment of the renal NO system in Dahl S
rats. Because the concentration of NO does not appear to
differ in the medulla of SS/Mcw and BN/Mcw rats16 under
basal conditions, the deficits in NOS enzyme expression of
the medulla seem to attenuate the AVP-stimulated increases
of tissue NO concentration. We have also recently found in
preliminary studies an inability of angiotensin II to increase
medullary NO concentration in SS/Mcw rats, despite significant increases in BN/Mcw rats.16 It is this reduced ability of
AVP to stimulate medullary NO production in SS/Mcw rats
and the lack of this counterregulatory system that we believe
enables small elevations of AVP to produce hypertension in
this strain of rats.
Long-Term Elevation of Plasma AVP on Blood
Pressure Regulation in SS/Mcw Rats
The present study demonstrates that small elevations of
plasma AVP are capable of producing sustained hypertension
in animals that are genetically deficient in NO. Numerous
studies in rats, dogs, and human have observed that chronic
administration of AVP resulted in either no significant
elevation of blood pressure, or elevations that lasted only
days despite the elevated plasma AVP.1– 4 This was also
clearly demonstrated in the present study in that BN/Mcw rats
were unable to develop hypertension with chronic administration of AVP. Sustained hypertension has been produced
with AVP only under special circumstances when the water
intake was fixed23 or when renal mass was substantially
reduced.24,25
Recently, studies by Szentivanyi et al14 demonstrated that
when medullary NOS activity was selectively blunted by
chronic infusion of L-NAME into the renal medulla, intrave-
AVP Produced Hypertension in SS/Mcw Rats
527
nous infusion of AVP produced sustained hypertension in
Sprague-Dawley rats. Because Park et al13 demonstrated that
acute administration of AVP directly into the renal medulla
resulted in significant elevation of medullary NO concentrations and Szentivanyi et al14 found that [NO] levels were
sustained elevated throughout a 10-day intravenous infusion
of AVP, there is clear evidence that small elevations of
plasma AVP normally increase the production of NO in the renal
medulla. Taken together, these data indicate that this increased
NO production serves as a counterregulatory mechanism to
offset the medullary vasoconstrictor and hypertension effects of
AVP, because chronic reduction of medullary blood flow results
in hypertension.26 Because the SS/Mcw rats cannot increase the
production of medullary NO with AVP stimulation and are
enable to overcome the medullary vasoconstrictor effects of
AVP, SS/Mcw rats are susceptible to the hypertensive actions of
small elevations of circulating AVP.
The saline infusion study summarized in Figure 4 served as
a vehicle control experiment, because we added AVP in
saline for the intravenous infusion. With a very low infusion
rate (0.25 mL/h), the rats received 54 mg NaCl/24 hours,
which amounts to approximately a 0.1% salt diet. Because the
diet of these rats was 0.4%, the total daily intake was
equivalent to a 0.5% salt diet. It seems that this small amount
of intravenous NaCl may contribute to the slight elevation of
MAP in these SS/Mcw rats on the last 2 days of the infusion
period, but this contribution of the saline (vehicle) to the rapid
and sustained increase of MAP in the AVP-infused SS/Mcw
rats seems to be minimal in this study.
It is not clear what causes the NO deficiency in SS/Mcw
rats. Chen et al27 identified a single nucleotide mutation in the
NOS II gene in SS/Mcw rats. However, because most
investigators find the level of NOS II in the outer and inner
medulla is quite low, the functional significance of this
variation remains to be determined. Deng and Rapp28 reported that NOS III does not segregate with the trait of blood
pressure in a genetic linkage study. An alternative hypothesis
to explain reduced NO production with AVP stimulation
could be a reduced expression of AVP V229 –31 or V2-like
receptors,32 because they modulate vasodilatory effects in the
renal medulla by increased production of NO. However, this
would not explain why SS/Mcw rats are also hyperresponsive to angiotensin II16 and norepinephrine. These
observations would suggest a generally reduced capacity to
produce NO for reasons that remain to be determined.
In conclusion, we have shown that SS/Mcw rats, like the
medullary L-NAME infused rats, exhibit an abnormal NO
system in the renal medulla. This defect in the NO system
makes them more vulnerable to vasoconstrictor effect of
AVP, such that long-term elevation of plasma AVP causes
sustained hypertension.
Acknowledgments
This work was supported by the National Institute of Health grant
HL49219 and by American Heart Association Fellowship Award
0020517Z. Baozhi Yuan is the recipient of AHA postdoctoral
fellowship award. The authors thank Meredith M. Skelton for careful
review of the manuscript.
528
Hypertension
February 2001 Part II
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Evidence That Reduced Renal Medullary Nitric Oxide Synthase Activity of Dahl S Rats
Enables Small Elevations of Arginine Vasopressin to Produce Sustained Hypertension
Baozhi Yuan and Allen W. Cowley, Jr
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Hypertension. 2001;37:524-528
doi: 10.1161/01.HYP.37.2.524
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