(Hypertension. 1998;32:534-540.)
© 1998 American Heart Association, Inc.
Nitric Oxide Synthesis Inhibition Retards Surgical Reversal of One-Kidney Goldblatt Hypertension in Rats
Wann-Chu Huang;
; Ren-Yu Tsai
From the Graduate Institute of Medical Sciences, Tzu Chi College of
Medicine, Hualien, Taiwan, Republic of China.
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Abstract
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Abstract—Surgical correction of
renal artery stenosis in Goldblatt hypertension rapidly
normalizes blood pressure and increases renal function. This study was
conducted in 1-kidney, 1 clip (1K1C) Goldblatt hypertensive rats to
examine whether the unclipping-induced reversal of blood pressure and
renal function is mediated by nitric oxide (NO). The 1K1C rats were
prepared and given tap water with or without supplementation of
NG-nitro-L-arginine methyl ester
(L-NAME). Systolic blood pressure (SBP) before and after renal
artery clipping was measured with the tail-cuff method. Four weeks
later, surgical unclipping was performed while blood pressure and renal
function responses were determined. The results show that clipping the
renal artery for 4 weeks increased SBP from 140±5 to 183±6
mm Hg (P<0.05). Concurrent L-NAME treatment
accelerated and aggravated the clipping-induced increases in SBP from
138±6 to 219±8 mm Hg (P<0.05). Surgical
unclipping reduced blood pressure to normotensive levels within 2 hours
in all hypertensive rats with and without chronic or acute L-NAME
treatment. However, the magnitude of reductions in blood pressure in
the initial 1 hour after unclipping was significantly less in
L-NAME–treated rats than in nontreated rats (9±2% versus 16±1%,
P<0.05). Despite reducing blood pressure, unclipping
significantly increased glomerular filtration rate, urine
flow, and sodium and potassium excretions, but the extent of the
increases in these renal functions was significantly attenuated in
L-NAME–treated rats. These data suggest that NO production
partly contributes to the hypotensive and renal responses to unclipping
but does not mediate the reversal of renovascular hypertension of
this model.
Key Words: hypertension, one-kidney Goldblatt • renal artery obstruction • nitric oxide • diuresis • natriuresis
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Introduction
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Constricting the
renal artery of the remaining kidney in uninephrectomized rats produces
1-kidney, 1 clip (1K1C) Goldblatt hypertension. This hypertensive model
has been generally considered to be volume
dependent.1 2 Surgical removal of the clip from
the renal artery in this model of renovascular hypertensive rats
precipitously decreases arterial blood pressure and
enhances kidney function.3 4 5 6 7 8 9 10 11 The rapid
depressor response to unclipping also occurs in chronic hypertension
(>4 months) and is not a nonspecific effect of
surgery.10 11 The precise mechanism responsible
for such a major fall of blood pressure after renal artery clip removal
is still not completely understood. It has been shown that the pattern
of the depressor response to unclipping is not affected by
indomethacin, aprotinine, platelet-activating
factor receptor antagonist, or changes in the activity of
the renin-angiotensin system.7 8 9 10 11
The salt and volume replacement during natriuresis and diuresis
that accompanies renal artery clip removal attenuates but does not
prevent the depressor response.5 8 Also, surgical
correction of renovascular hypertension is not associated with changes
in the sympathetic nerve activity and plasma noradrenalin
level.12 13 Thus, changes in the most
well-documented factors for blood pressure control and renal function
regulation, such as the renin-angiotensin system, renal
sympathetic nerve activity, prostaglandins, kinins, and
sodium-volume balance, cannot account for the rapid reversal of
hypertension by surgical correction of renal artery stenosis.
On the other hand, medullipin, a polar lipid released from renal
medulla, has been postulated to be one of the candidates for the marked
fall of blood pressure after unclipping.14 15 16
However, the mediator role of renal medullipin in the reversal of
hypertension is not unequivocal.14 15 17
The vascular endothelium is capable of synthesizing
nitric oxide (NO) from L-arginine, a process that can be
competitively inhibited by
NG-nitro-L-arginine methyl
ester (L-NAME) and other substituted L-arginine
compounds that compete for the NO synthase.18 19 20
NO acts on adjacent vascular smooth muscle to produce a cGMP-dependent
relaxation. Acute or chronic inhibition of NO synthesis in experimental
animals results in systemic hypertension and produces substantial
influences on renal function.21 22 23 24 25 26 Because renal
vascular NO synthesis is related to the degree of renal perfusion, and
shear stress is the primary endogenous stimulus for
endothelial NO
production,27 28 it is likely that
increases in renal perfusion pressure resulting from removal of the
renal arterial clip may generate NO or an NO-associated
mechanism for the rapid fall of blood pressure in the Goldblatt
hypertensive model. Thus, we hypothesized that unclipping-induced rises
in renal perfusion increase vascular shear stress and thereby stimulate
the synthesis of NO, which in turn mediates the hypotensive and renal
responses to unclipping, whereas inhibition of NO synthesis blunts the
fall of blood pressure and the enhancement in renal function by
unclipping in this hypertensive model. To test the hypothesis, a 1K1C
model of Goldblatt hypertensive rats was produced, and surgical removal
of the renal arterial clip was performed in the
hypertensive rats with and without inhibition of NO synthesis by
L-NAME. Our results show that sustained L-NAME treatment accelerated
and aggravated the development of 1K1C Goldblatt hypertension in rats.
Also, acute or chronic inhibition of NO synthesis by L-NAME delayed but
did not prevent the normalization of blood pressure after unclipping,
suggesting a modulator but not a mediator role of NO in the surgical
reversal of hypertension in this hypertensive model.
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Methods
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Preparation of 1K1C Goldblatt Hypertensive Rats
Male Sprague-Dawley rats with an initial body weight of 200 to
220 g were used for preparation of 1K1C Goldblatt hypertensive
rats. Rats were anesthetized with ketamine
hydrochloride (60 mg/kg) and xylazine (7.5 mg/kg)
intraperitoneally and underwent right nephrectomy.
All rats were maintained in the animal care facilities of the school.
After a 1-week recovery period, the nephrectomized rats underwent left
renal artery constriction with an internal gap of 0.25 mm, silver
clip. Penicillin G (25 000 U IM) was injected after surgery. Rats were
fed a commercial rat chow (Fu-Sho Co) and allowed free access to
tap water. SBP was measured twice a week with the tail-cuff method
using a programmed electrosphygmomanometer (Ueda, model UR-5000) as
previously described.29 Acute unclipping
experiments were carried out 4 weeks later, when the rats weighted
376±7 g. All procedures were conducted in accordance with the prior
approval of the institutional animal care and use committee of this
school.
Animal Groups
The 1K1C Goldblatt hypertensive rats were randomly divided into
5 groups and treated as follows: group 1 served as time control without
unclipping or L-NAME treatment (n=5); group 2 was subjected to
unclipping alone after 4 weeks of renal artery clipping (n=9); and
group 3 was given chronic oral L-NAME (80 mg/100 mL drinking water,
changed daily, approximately 100 mg/kg per day) immediately after renal
artery clipping. Four weeks later, rats were subjected to acute removal
of the renal arterial clip (n=11). Group 4 received acute
intravenous infusion of L-NAME (10 mg/kg bolus followed by
1.0 mg/kg per minute) 4 weeks after renal artery clipping when the rats
became hypertensive. Surgical unclipping was performed during L-NAME
infusion (n=10). Group 5 received acute intravenous
infusion of L-NAME without unclipping (n=6). The concentrations of
L-NAME were chosen because they have been demonstrated to be effective
in inhibiting endogenous NO synthesis in 1K1C
rats30 and renal cortical and medullary NO
production in normal rats.31
Acute Unclipping Experiments
Rats were anesthetized with 100 mg/kg IP Inactin
(5-ethyl-5-1'-methyl-propyl-2-thiobarbiturate sodium). The rats were
placed on a servocontrolled heated table, and the rectal temperature of
each rat was maintained at 37±0.5°C. The trachea was intubated to
keep the airways patent, and the right jugular vein was catheterized
for the infusion of an isotonic NaCl solution and the drug. The right
femoral artery was cannulated with a PE-50 tube for blood sampling and
for continuous measurement of blood pressure via a Statham P23XL
pressure transducer (Gould-Statham Instruments Inc) and recorded on
an RS-3800 polygraph (Gould Inc). Through a flank incision, the clipped
(left) kidney was exposed and placed in a Lucite cup. The fibrous
tissue surrounding the silver clip on the left renal artery was
carefully dissected free without damaging the renal artery or causing
bleeding. This approach allowed the clip to be removed easily later in
the experiments. Urine samples were sequentially collected by
catheterizing the ureter.
During surgery, all rats were infused with an isotonic (154
mmol/L) NaCl solution at a rate of 0.02 mL/min. On completion of
surgery, a priming dose of 0.3 mL 10% Inutest (polyfructosan;
Laevosan-Gesellschaft) in normal saline was administered; this was
followed by infusion of the same solution at a constant rate of 0.01
mL/min throughout the experiment. The saline infusion rate was reduced
to 0.01 mL/min to maintain the total infusion rate constant. One
hour was allowed for the animal to achieve a steady state, and then two
30-minute urine samples for the control period were collected. The rats
were subsequently subjected to unclipping (groups 2 and 3) or infused
with L-NAME (10 mg/kg bolus, 1.0 mg/kg per minute, groups 4 and 5). For
those rats receiving acute L-NAME infusion, unclipping was carried out
after 2 postdrug urine collection periods. For the time control group
(group 1), urine samples were sequentially collected without
intervention. Arterial blood samples of 0.3 mL each were
taken during the control, drug infusion, and postclipping periods. The
plasma was immediately separated by centrifugation. The
blood cells were resuspended in normal saline with a total volume of
0.3 mL and returned to the animal.
Chemical Measurements and Statistical Analysis
The concentration of Inutest in plasma and urine samples was
measured with a semimicroanthrone colorimetric method
as described previously.6 7 Plasma and urine
sodium and potassium concentrations were determined with a flame
photometer (model 943; Instrumentation Laboratory). Plasma osmolality
was measured with an osmometer (model 3D3, Advanced Instrument).
Glomerular filtration rate (GFR) and electrolyte excretion
rates were calculated according to standard clearance formulas. The
data were evaluated statistically by 2-way ANOVA. Bonferroni's test
and Student's t test for paired or unpaired values, when
relevant, were used. A value of P<0.05 was considered
statistically significant. Results are expressed as mean±SEM.
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Results
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Effects of Chronic L-NAME Treatment on Development of 1K1C
Goldblatt Hypertension
As shown in Figure 1
, blood pressure
increased gradually after the renal artery was constricted. Chronic
L-NAME treatment accelerated and aggravated the increase of blood
pressure. Two weeks after renal artery clipping, the SBP of
L-NAME–treated rats significantly increased from 138±6 to 176±6
mm Hg (P<0.05), whereas that of the clipped rats without
L-NAME treatment increased from 139±5 to 156±10 mm Hg
(P<0.05) at the corresponding time points. The SBP of the
L-NAME–treated group further increased to 196±6 mm Hg, which is
significantly greater than that of the nontreated group (184±5
mm Hg, P<0.05) by the end of the 4th postclipping
week.
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Figure 1. Effects of chronic oral administration of L-NAME
on SBP in 1K1C rats in an unanesthetized state.
*P<0.05 vs unclipping alone; +P<0.05 vs
preclipping.
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Blood Pressure and Renal Responses to Unclipping in 1K1C Rats With
Chronic L-NAME Treatment
Acute removal of the renal arterial clip alone
significantly decreased blood pressure from 170±5 to 164±3
mm Hg (P>0.05) within 10 minutes in the hypertensive rats
without L-NAME treatment (Figure 2).
During the corresponding time period, unclipping in the L-NAME–treated
rats did not cause a significant change in blood pressure (from 178±3
to 176±3 mm Hg, P>0.1). Blood pressure was then
further reduced toward the preunclipping levels in both groups (to
119±5 mm Hg in L-NAME–treated rats versus 113±6 mm Hg in
nontreated group at 2 hours after unclipping). The magnitude of
decreases in blood pressure in response to unclipping was significantly
less in L-NAME–treated rats than in the nontreated rats at the first
(9±2% versus 16±1%, P<0.05) but not the second
postunclipping hour (32±2% versus 33±2%, P>0.1), as
shown in Figure 6.
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Figure 2. Effects of unclipping (UC) on mean blood pressure
(MBP) of 1K1C Goldblatt hypertensive rats with and without chronic
administration of L-NAME. Time control group of 1K1C Goldblatt
hypertensive rats did not receive unclipping or L-NAME.
*P<0.05 vs UC alone; +P<0.05 vs
preclipping.
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Removal of the renal arterial clip caused marked increases
in GFR, urine flow, and sodium and potassium excretion rates
(UNaV and UKV) in both
L-NAME–treated and nontreated groups (Figure 3). However, the extent of increase in
renal function after unclipping was significantly less in
L-NAME–treated rats than in the nontreated rats at both the first
postunclipping hour (13±1% versus 18±1% for GFR, 90±4% versus
174±5% for urine flow, and 26±3% versus 64±3% for
UNaV; all P<0.05) and the second hour
(12±1% versus 16±1% for GFR, 75±2% versus 130±3% for urine
flow, and 35±3% versus 60±3% for UNaV; all
P<0.05), as illustrated in Figure 6
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Figure 3. Effects of unclipping (UC) on renal function in
1K1C Goldblatt hypertensive rats with and without chronic
administration of L-NAME. Time control rats did not receive unclipping
or L-NAME. *P<0.05 vs UC alone; +P<0.05
vs preclipping. V indicates urine flow; UNaV, urinary
sodium excretion; UKV, urinary potassium excretion; and
FENa, fractional excretion of sodium.
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Effects of Acute Infusion of L-NAME and Subsequent Unclipping on
Blood Pressure and Renal Function
Acute administration of L-NAME for 40 minutes increased the mean
blood pressure of 1K1C hypertensive rats by 12±3 mm Hg
(P<0.05), as depicted in Figure 4. In the absence of unclipping (L-NAME
treatment alone), the elevated blood pressure was maintained throughout
the experiments. After the renal arterial clip had been
removed in the presence of continuous infusion of L-NAME, blood
pressure fell significantly from 189±3 to 178±2 mm Hg
(P<0.05) over 40 minutes of unclipping and then further
declined to 128±4 mm Hg by the end of the experiments. Acute
administration of L-NAME did not significantly alter renal function.
Subsequent unclipping induced dramatic increases in GFR, urine flow,
and electrolyte excretion (Figure 5). The
magnitudes of decrease in blood pressure and increase in renal function
of the acute L-NAME–treated group were comparable to those of the
chronic L-NAME–treated group but were significantly less than those of
the nontreated group (Figure 6).
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Figure 4. Effects of acute intravenous infusion
of L-NAME and subsequent unclipping (UC) on mean blood pressure (MBP)
in 1K1C Goldblatt hypertensive rats. *P<0.05 vs L-NAME
treatment alone; +P<0.05 vs preclipping.
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Figure 5. Renal response to acute infusion of L-NAME and
subsequent unclipping in 1K1C Goldblatt hypertensive rats.
*P<0.05 vs L-NAME alone; +P<0.05 vs
preclipping. V indicates urine flow; UNaV, urinary sodium
excretion; UKV, urinary potassium excretion; and
FENa, fractional excretion of sodium.
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Comparison of Body Weight, Kidney Weight, and Plasma Electrolytes
and Osmolality Between Groups
As summarized in the Table, there
were no significant differences in body weight, kidney weight, plasma
osmolality, and plasma concentrations of sodium and potassium among
groups of 1K1C hypertensive rats. Neither drug treatment nor unclipping
altered plasma concentrations of electrolytes and osmolality.
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Table 1. Comparisons of Body Weight, Kidney Weight, Plasma Osmolality,
and Concentrations of Sodium and Potassium Among Various Groups of 1K1C
Goldblatt Hypertensive Rats
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Discussion
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The present study demonstrates that chronic oral
administration of L-NAME to inhibit NO synthesis accelerated and
aggravated the pressure increase in 1K1C Goldblatt hypertensive rats.
Surgical correction of renal artery stenosis by unclipping
caused a prompt decrease in blood pressure and a concurrent increase in
renal function. Chronic or acute L-NAME treatment attenuated but did
not prevent the unclipping-induced hypotensive and renal responses in
the first 1 hour after unclipping. Blood pressure further declined to
prehypertensive levels in the second hour after unclipping. The
elevated renal function after unclipping was maintained until the end
of the experiments, but the plateau was significantly lower in rats
with L-NAME treatment than in rats without L-NAME administration. These
results suggest that NO production contributes to the early
reduction of blood pressure and the partial restoration of renal
function due to renal artery clip removal but does not mediate the
reversal of this renovascular hypertension after unclipping.
The unclipping-induced hypotensive response noted in the present
study is in accordance with the observations of previous studies from
this and other laboratories.3 4 5 6 7 8 9 10 11 The precise
mechanism for the prompt and marked fall of blood pressure after
surgical unclipping is still not fully understood. Earlier studies
suggested that unclipping-induced depressor response occurred in the
denervated kidney and was not attributable to prostanoids, kinins,
platelet-activating factor, suppression of the
renin-angiotensin system, or urinary loss of sodium and
water.3 4 5 6 7 8 9 10 11 12 13 Observations on the role of NO in
mediating the hypotensive response to unclipping and increased renal
perfusion are inconsistent.17 32 33
Thomas et al17 demonstrated that NO synthesis
inhibition did not prevent the hypotensive response to increased renal
perfusion in rabbits. In contrast, Beierwaltes et
al32 reported that acute blockade of NO synthesis
by L-NAME abolished the reduction of blood pressure for 1 hour after
unclipping in 2-kidney, 1 clip (2K1C) Goldblatt hypertensive rats.
Also, Bergstrom et al33 showed that NO synthesis
inhibition reduced the hypotensive response of an assay rat to
high-pressure perfusion to an isolated kidney. Our present results
show that both chronic and acute administration of L-NAME attenuated
but did not prevent the unclipping-induced hypotensive response in the
first hour after unclipping, and blood pressure progressively declined
to prehypertensive levels within 2 hours after unclipping. The
inability of L-NAME treatment to completely prevent unclipping-induced
normalization of blood pressure is not related to the effectiveness of
the drug. On one hand, both the chronic and acute doses of L-NAME used
in the present study have previously been shown to effectively
inhibit endogenous NO production in 1K1C rats as
well as renal cortical and medullary NO synthesis in normal
rats as determined by plasma nitrite/nitrate and intrarenal NO
levels.30 31 On the other hand, short-term and
long-term treatment with these doses of L-NAME in 1K1C rats similarly
caused an additional increase in blood pressure compared with the
nontreated 1K1C rats (Figures 1 and 4), suggesting the effective
inhibition of NO synthesis by L-NAME in the present study. Thus,
the reason for the aforementioned disparities in observations on the
mediating role of NO in the hypotensive response to unclipping and
increased renal perfusion is unclear, but differences in animal models
used and the duration of experimental observations after unclipping
probably all contributed. In the studies by Thomas et
al17 and Bergstrom et al,33
an extracorporeal circuit rather than unclipping was used to increase
renal perfusion in anesthetized normal rabbits or of the
isolated kidney, whereas Beierwaltes et al32 used
2K1C Goldblatt hypertensive rats and did not continue to follow the
blood pressure response to unclipping beyond 1 hour after unclipping,
as we did in the present study. Nevertheless, the partial
dependency on NO of the early but not late hypotensive response to
unclipping as seen in the present study suggests that in addition
to NO, other factors or mechanisms initiated by unclipping may also
participate in the surgical reversal of hypertension of this model.
Indeed, some studies have demonstrated that unclipping induces release
of renal medullipin, a vasodepressor lipid, which may be partially
responsible for the depressor response after unclipping, although the
chemical nature of medullipin remains
obscure.14 15 16 34
It has been documented that acute or chronic inhibition of NO synthesis
by L-NAME and other substituted L-arginine compounds that
compete for the NO synthase in normal rats produces
peripheral vasoconstriction, elevation of blood pressure,
and decreases in renal blood flow, GFR, and sodium
excretion.20 21 22 23 24 25 26 27 In the present study,
chronic administration of L-NAME caused a faster and greater increase
in blood pressure after clipping the renal artery in rats. Acute
infusion of L-NAME increased the blood pressure further in 1K1C
hypertensive rats. These observations are consistent with
previous studies21 25 34 and support the notion
that NO is intimately involved in the regulation of blood pressure in
normal and hypertensive conditions.18 Dubey et
al30 recently demonstrated that NO synthesis was
increased 2 weeks after renal artery clipping and the elevated NO
production then gradually declined to prehypertensive levels 5
weeks after renal artery clipping in 1K1C hypertensive rats. It is
likely that the early increase in NO production is a
compensatory mechanism that slows the initial rise in
arterial pressure. Thus, blockade of NO synthesis by L-NAME
accelerates the pressure increase after renal artery constriction, as
observed in the present study (Figure 1). The later decrease in NO
production could be the result of either an adaptation to the
high blood pressure or endothelium damage caused by
hypertension.30
Despite the profound reductions of blood pressure, surgical removal of
the renal arterial clip sharply increased GFR and renal
excretions of water, sodium, and potassium. We have previously
demonstrated that the function of the clipped kidney of 1K1C
hypertensive rats is pressure dependent.6 It is
likely that surgical correction of the renal artery stenosis
after removal of the clip restored or increased the
arterial perfusion to the ipsilateral kidney and hence
caused it to increase filtration load and to diminish tubular
reabsorption, as reflected by the increased fractional excretion of
sodium seen in the present study (Figures 3 and 5). In addition,
the relief of renal arterial stenosis by unclipping
restored or increased renal perfusion and thereby stimulated NO
production, which in turn enhanced GFR and urinary excretions
of sodium, potassium, and water. Thus, the smaller increases in GFR and
renal excretory function after unclipping in the L-NAME–treated group
compared with the rats with unclipping alone may be attributed to the
absence of NO-mediated renal response under these experimental
conditions.
In summary, chronic administration of L-NAME enhanced the development
of 1K1C Goldblatt hypertension in rats. Surgical correction of the
renal artery stenosis rapidly normalized blood pressure within
2 hours. Marked increases in GFR and renal excretory function
accompanied unclipping were also observed. Acute or chronic L-NAME
treatment attenuated the hypotensive response to unclipping in the
initial 1-hour period but did not prevent the subsequent decline of
blood pressure toward prehypertensive levels. The unclipping-induced
increase in renal function was also attenuated in L-NAME–treated rats.
These results suggest that release of NO in response to an increased
vascular shear stress due to removal of the renal arterial
clip partially contributes to the early phase of reduction of blood
pressure but is not responsible for the mediation of blood pressure
normalization after unclipping in 1K1C Goldblatt hypertensive rats.
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Acknowledgments
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This study was partly supported by grant NSC 86-2314-B-320-010
from the National Science Council, Taiwan, Republic of China. The
authors wish to thank Hui-Min Chang for her technical and
secretarial assistance.
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Footnotes
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Reprint requests to Wann-Chu Huang, PhD, Graduate Institute of Medical Sciences, Tzu Chi College of Medicine, 701 Chung-Yang Rd, Section 3, Hualien, Taiwan, Republic of China.
Received January 5, 1998;
first decision March 3, 1998;
accepted April 15, 1998.
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Abstract
Introduction
MBP indicates changes in mean blood pressure;
