(Hypertension. 1999;33:440-445.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Local Renal Medullary L-NAME Infusion Enhances the Effect of Long-Term Angiotensin II Treatment
From the Clinical Research Deptartment, 2nd Institute of Physiology, Semmelweis University of Medicine, Budapest, Hungary (M.S.); Laboratorio de Cardiovascular, Department de Fisiologia, ICBS, UFRGS, Brasil (C.Y.M.); and Department of Physiology, Medical College of Wisconsin, Milwaukee, Wis (A.W.C.).
Correspondence to Mátyás Szentiványi, Jr, MD, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, PO Box 26509, Milwaukee, WI 53226-0509. E-mail szentiva{at}mcw.edu
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Abstract |
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Abstract—We hypothesized that the relatively high doses of angiotensin (Ang) II required to produce hypertension in rats were related to stimulation of renal medullary nitric oxide production, which in turn blunted reductions in medullary blood flow and the development of hypertension. Ang II was infused (5 days at 3 ng · kg-1 · min-1 IV) to uninephrectomized Sprague-Dawley rats in the presence and absence of a continuous medullary interstitial NG-nitro-L-arginine methyl ester (L-NAME) infusion. Renal cortical and medullary blood flows were determined with the use of implanted optical fibers and laser-Doppler flowmetry. Ang II in the absence of medullary nitric oxide synthase inhibition did not change cortical or medullary blood flow or mean arterial pressure. A threshold dose of L-NAME was determined (75 µg · kg-1 · h-1) that did not produce significant short- or long-term changes in medullary blood flow and mean arterial pressure. In rats with blunted medullary nitric oxide synthase activity, Ang II infused intravenously resulted in a 30% reduction in medullary blood flow (from 1.3 to 0.9±0.2V) and
20 mm Hg
increase in mean arterial pressure with Ang II infusion
over 5 days. During 70 minutes after the start of
intravenous Ang II, there was an immediate reduction in
medullary blood flow, with no changes in cortical blood flow or mean
arterial pressure. We conclude that the relative
insensitivity of rats to long-term elevations of circulating Ang II is
due to the potent counterregulatory actions of the nitric oxide system,
specifically within the renal medulla. The results provide novel
insights of how the organism attempts to protect itself from the
hypertensive effects of Ang II.
Key Words: hypertension, renal • kidney • angiotensin II • renal blood flow • nitric oxide • nitric oxide synthase
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Introduction |
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It is well recognized that elevations of circulating angiotensin (Ang) II cause resetting of the pressure-natriuresis relationship to elevated levels of arterial blood pressure through the renal retention of sodium and volume expansion.1 Yet considerable species differences have been found in the concentrations of Ang II required to produce chronic hypertension. We have found that Ang II infused long term at concentrations of 3 to 5 ng · kg-1 · min-1 produce
30 mm Hg increase in mean arterial
pressure (MAP) over a period of 1 week in mongrel dogs maintained on a
normal daily NaCl diet.2 Humans exhibit even greater
pressor sensitivity to prolonged infusions of Ang II.3 In
contrast, prolonged infusion of Ang II at 3 to 5 ng ·
kg-1 · min-1 in
Sprague-Dawley rats does not lead to a significant increase in
MAP,4 and investigators generally administer Ang II at
rates of 30 to 60 ng · kg-1 ·
min-1 to induce prolonged hypertension in
rats.5 A number of studies have demonstrated that the medullary vasculature of Sprague-Dawley rats is relatively refractive to the vasoconstrictor effects of Ang II compared with the cortical circulation.6 7 Subpressor doses of Ang II administered intravenously that can significantly reduce renal cortical blood flow (CBF) fail to change medullary blood flow (MBF).6 7 Yet there appears to be an abundance of Ang II receptors within the renal medulla,8 and Pallone9 has shown that Ang II is a potent constrictor of isolated-perfused rat medullary vasa recta vessels. Recent studies in our laboratory have demonstrated that medullary vascular insensitivity is in large measure a result of Ang II–stimulated medullary nitric oxide (NO) production, which effectively offsets the vasoconstrictor effects of Ang II.10 Because a number of studies in our laboratory have also shown that long-term reductions in renal MBF can result in hypertension,1 we explored in the present study the possibility that the relative insensitivity of rats to elevations of circulating Ang II could be a consequence of the relative insensitivity of the renal medullary circulation. More specifically, we examined the hypothesis that elevations of circulating Ang II stimulate production of NO specifically within the renal medulla, which in turn buffers the medullary actions of this peptide and reduces its hypertensive effects.
Ang II can stimulate at least several counterregulatory vasodilator systems within the renal medulla. Pretreatment with cyclooxygenase6 or NO synthase (NOS) inhibitors10 greatly enhances the medullary vascular constrictor actions of Ang II in anesthetized Sprague-Dawley rats. NOS protein expression, enzyme activity, and NO concentration have been found to be significantly greater in the renal medulla compared with the cortex of Sprague-Dawley rats.10 11 12 The present study focused on the long-term interactions of Ang II and NO in this region of the kidney because we have recently found that subpressor infusions of Ang II (5.0 ng · kg-1 · min-1 IV) resulted in more than a doubling of medullary NO,10 consistent with observations by others using more indirect indexes of NO production, including measurements of cGMP13 and nitrate and/or nitrite.14
The present study was designed to reduce NOS activity only within the region of the renal medulla. Furthermore, the objective was to only moderately reduce NOS activity in this region by an amount that blunts the counterregulatory actions of NO but not to the extent that would lead to a significant reduction in MBF and hypertension. Rather, the goal was to see whether slight reductions in NO production, specifically within the renal medulla alone, would sensitize the animal to small elevations of circulating Ang II and lead to hypertension. Uninephrectomized Sprague-Dawley rats were instrumented with arterial and venous catheters and a small catheter implanted into the renal medulla for long-term delivery of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Optical fibers implanted in the superficial cortex and inner medulla were used for daily measurements of changes in blood flow to these regions with laser-Doppler flowmetry.15 The effects of long-term intravenous infusion of Ang II (3 ng · kg-1 · min-1) on MAP, CBF, and MBF were then determined. An Ang II dose of 3 ng · kg-1 · min-1 was chosen when it was predetermined that a similar dose did not lower MBF over the short term or result in hypertension during 3 to 5 days of intravenous administration.4 10 Studies were then carried out in which a subpressor dose of L-NAME was infused continuously into the interstitial space of the inner medulla while the effects of the same intravenous dose of Ang II were determined. All experiments were carried out in unanesthetized rats in their home cages, with daily measurements determined at the same time each day.
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Methods |
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Chronic Surgical Preparation and Experimental Procedures
Experiments were performed on Sprague-Dawley rats (250 to 350 g; Harlan Sprague Dawley Inc). All animals were housed individually in the Animal Resource Center at the Medical College of Wisconsin and maintained on normal rat chow and water ad libitum. All procedures were approved by the Institutional Animal Care Committee. To eliminate compensatory responses from the contralateral kidney, all rats were unilaterally nephrectomized with ketamine (30 mg/kg IM) and xylazine (2 mg/kg IM) anesthesia. All surgeries were performed under aseptic conditions, and 7 to 10 days was allowed for recovery.
A second surgery was then carried out for catheter and optical fiber
implantations. The femoral artery and vein were exposed for insertion
of the in-dwelling aortic and vena cava catheters as described
previously.16 The left kidney was then exposed via a flank
incision, and an extruded polyethylene interstitial
catheter (tip size, 100 µm in diameter) was implanted in the
renal medulla to a depth of 5.5 mm as described
previously.16 17 Optical fibers were then implanted in the
renal cortex (2-mm depth) and inner medulla (5.5-mm depth) by use of
techniques developed in our laboratory.15 17 All catheters
and optical fibers were tunneled subcutaneously to the back of the
neck, where they were exteriorized through a midscapular incision and
passed through a spring for protection. Buprenorphine (0.3 mg/kg SC)
was given during the recovery from anesthesia to provide
postoperative analgesia.
Rats were housed individually and received a continuous interstitial infusion of isotonic saline at a rate of 0.5 mL/h for a minimum of 7 days of surgical recovery to ensure patency of the interstitial catheter. At the end of the experimental protocol, the animals were killed, the kidney was evaluated for any gross morphological abnormalities, and the positions of the interstitial catheter and optical fibers were determined after fixation of the kidney in a 10% formalin solution for 24 hours.
Daily Measurement of MAP, CBF, and MBF
During the 1 week after surgery, the rats were trained to rest
in a tubular Plexiglas restrainer within their home cages for 2 hours
each day. Daily measurements of MAP, CBF, and MBF were then begun by
use of an on-line data collection (rate, 100 Hz) and analysis
system as previously described.15 The flow signals from
the renal cortex and medulla were measured and processed by a 2-channel
laser-Doppler flowmeter (Transonics, Inc). Continuously
recorded signals were transformed to minute averages for
analysis.
Experimental Protocols
Protocol 1: Effect of L-NAME Infusion Into the Renal
Medulla
After 1 week of recovery from surgery, MAP was measured in a
group of Sprague-Dawley rats (n=4) at the same time each morning to
obtain values from 3 stable control days. A medullary
interstitial infusion of L-NAME (75 µg ·
kg-1 · h-1) was
then started, and MAP was measured daily for 10 days.
Protocol 2: Long-Term Effects of Subpressor Infusion of Ang II (3.0
ng · kg-1 · min-1 IV) on MAP,
CBF, and MBF in the Absence of Medullary L-NAME Infusion
After 1 week of recovery from surgery and after 3 days of stable
control MAP, CBF, and MBF measurements, an infusion of Ang II was begun
at a dose of 3 ng · kg-1 ·
min-1 IV (n=7). The infusion of Ang II
(Ile5-angiotensin II, Sigma Chemical
Co) was continued for 5 days while daily measurements of MAP, CBF, and
MBF were obtained. A similar dose has been shown previously to be
nonhypertensive over a period of 1 week of continuous infusion in
Sprague-Dawley rats fed normal rat chow.4 10 On the
morning that the Ang II infusion was begun, control measurements were
obtained during the first hour of recording and throughout the
first 70 minutes after the start of Ang II infusion. After 5 days, the
Ang II infusion was ended, and daily measurements were obtained each
morning for the following 2 days. Isotonic saline was infused at a rate
of 0.5 mL/h throughout the experiment as a vehicle control for protocol
3 in which L-NAME diluted in isotonic saline was infused at the same
rate.
Protocol 3: Effect of Subpressor Dose of Intravenous
Ang II Infusion on MAP, CBF, and MBF in Rats Receiving a Continuous
Infusion of L-NAME Into the Renal Medulla
After recovery from surgery and 3 days of stable control MAP,
CBF, and MBF measurements, L-NAME (Sigma Chemical; 75 µg ·
kg-1 · h-1) was
added to the medullary interstitial infusate. It was
determined in a previous study using anaesthetized Sprague-Dawley rats
that a renal medullary interstitial infusion of L-NAME at a
dose of 75 µg · kg-1 ·
h-1 was the average threshold dose to reduce
MBF.10 This infusion was adjusted in the present
study if necessary to be "subpressor" and continued for a period of
3 days with daily measurements of MAP, CBF, and MBF. The infusion of
Ang II (3.0 ng · kg-1 ·
min-1 IV) was then begun after 1 hour of control
measurements. Measurements continued throughout the first 70 minutes
after the start of Ang II infusion. The Ang II infusion was continued
for 5 days with daily recording of hemodynamic
variables. After cessation of the Ang II infusion, daily
measurements of blood pressure and renal blood flows were obtained for
2 additional days while medullary L-NAME infusion was continued.
Statistical Analysis
Data are presented as mean±SEM. For statistical
comparisons, 1-way ANOVA with repeated measures was used, and Duncan's
multiple range test as a post hoc test was carried out. All statistical
analyses were performed on the raw data. We considered
P<0.05 to be statistically significant.
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Results |
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Protocol 1: Effect of L-NAME Infusion Into the Renal Medulla
Infusion of L-NAME into the renal medulla (n=4) had no significant effect on MAP measured for 10 days. MAP averaged 107±4 mm Hg during saline control and never rose >4 mm Hg over the 10 days of L-NAME infusion. On day 10 of L-NAME infusion, MAP averaged 110+1 mm Hg. These results indicate that the dose of L-NAME used in these studies did not reduce medullary NO production or MBF sufficiently to cause hypertension but rather merely blunted the Ang II–induced increase in NO production as we have measured directly and previously reported.10
Protocol 2: Immediate- and Long-Term Effects of Subpressor
Infusion of Ang II (3.0 ng · kg-1 ·
min-1 IV) on MAP, CBF, and MBF in the Absence of
Medullary L-NAME Infusion
The effects of long-term administration of Ang II (3.0 ng
· kg-1 · min-1
IV; n=7 rats) in the absence of medullary administration of L-NAME are
summarized in Figure 1
. MBF, CBF, and MAP
were not significantly changed during the 5-day period of Ang II
infusion, although there was a tendency for MAP to rise above the
control value of 114±2 mm Hg to an average of 121±2 mm Hg
during days 4 and 5. MBF averaged 1.3±0.2 V and CBF averaged 3.6±0.8
V over the 3 days of unanesthetized control measurements.
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The immediate responses during the first hour after the start of the
intravenous Ang II are summarized in Figure 2. In the absence of medullary L-NAME,
when only saline was infused into the renal medulla, Ang II resulted in
no significant changes in MBF, CBF, or MAP. Resting control values of
MAP averaged 113±2 mm Hg, CBF averaged 3.0±0.7 V, and MBF
averaged 1.2±0.4 V in these unanesthetized rats (n=6).
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Protocol 3: Immediate- and Long-Term Effects of Subpressor Dose of
Ang II (3.0 ng · kg-1 · min-1
IV) on MAP, CBF, and MBF in Rats Receiving a Continuous Infusion of
L-NAME Into the Renal Medulla
Figure 3 summarizes the effects of
long-term intravenous Ang II infusion on MBF, CBF, and MAP
of rats (n=10) receiving an infusion of medullary L-NAME. The results
in this figure indicate that the amount of L-NAME administered to these
rats was very near the threshold dose required to lower MBF and elevate
MAP. That is, the average MBF control value of 1.5±0.15 V was reduced
slightly but not significantly to 1.3±0.10 V, and the MAP of
116±2 mm Hg rose to 119±3.5 mm Hg during the 3 days of
medullary L-NAME infusion before intravenous Ang II
infusion. Greater changes than this were prevented if necessary
by slight adjustments of the L-NAME infusion rate during this period
because the goal of this study was to only moderately blunt the ability
of Ang II to stimulate NO production, as would be more likely
in naturally occurring pathological states.
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The most important observation summarized in Figure 3
is that
the 3.0-ng · kg-1 ·
min-1 IV dose of Ang II, which was subpressor in
the absence of medullary L-NAME administration (Figures 1 and 2), resulted in significant elevations of MAP, which rose to
levels averaging 137±4 mm Hg on days 4 and 5 of Ang II infusion.
MBF continued to decrease, reaching its lowest value on day 5,
averaging 0.9±0.1 V (P<0.05), which was a 30% reduction
in flow compared with the final day of the L-NAME control period. CBF
remained unchanged throughout the entire study, indicating that a
reduction in NOS activity and enhancement of the Ang II vasoconstrictor
actions were most likely localized to the renal vasculature of only the
medullary circulation. Curiously, after cessation of Ang II infusion,
neither MBF nor MAP fully returned to control levels during the 2 days
in which these variables were recorded while the medullary
L-NAME infusion was continued.
After the studies were completed on the first 3 rats in this group, it
was decided that the immediate response to the Ang II should be
followed. Figure 4 illustrates the
immediate responses to Ang II infusion in those rats (n=6) receiving
the long-term medullary infusion of L-NAME. It can be seen that MBF was
reduced by 30%, from 1.7±0.2 to 1.2±0.2 V (P<0.05),
during the 70 minutes after initiation of the Ang II infusion (3.0
ng · kg-1 ·
min-1 IV). No significant changes, however, were
observed in either CBF (from 2.1±0.3 to 1.7±0.4 V) or MAP (from
121±3 to 121±4 mm Hg) during this same period. Measurements in
these same 6 rats 22 hours later showed that MBF remained 20% less
than on the previous day, although this was not statistically
significant. The response of these 6 rats was the same as the response
of the 9 rats shown in Figure 3. Meanwhile, MAP had risen from
119±3.5 to 131±4 mm Hg (P<0.05).
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Discussion |
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The results of this study provide evidence that the relative insensitivity of rats to long-term elevations of circulating Ang II is due to the potent counterregulatory actions of the NO system, specifically within the renal medulla. Little has been known about the long-term actions of Ang II on the renal medullary circulation, and the present study provides some novel insights into how the organism attempts to protect itself from the hypertensive effects of this potent pressor peptide.
Although the role of Ang II in the regulation of whole-kidney hemodynamics and glomerular-tubular functions has been studied extensively,18 19 far less is known about the role of Ang II in deep nephrons and the renal medullary microcirculation, which have been technically more difficult to study. MBF has been reported to increase,20 decrease,21 or remain unchanged22 during Ang II infusion to the anesthetized rat. More recently, by using laser-Doppler flowmetry techniques enabling the direct and continuous recording of changes in MBF, Mattson et al6 7 found that the medullary circulation of anesthetized Sprague-Dawley rats was very refractory to Ang II vasoconstrictor actions. Specifically, infusions of Ang II at concentrations of 20 ng · kg-1 · min-1 IV produced significant reductions in CBF, whereas papillary blood flow was not significantly altered. Indeed, Nobes et al20 reported increases in papillary blood flow when even higher concentrations of Ang II (300 ng · kg-1 · min-1) were infused.
The relative insensitivity of the medullary circulation to Ang II may be explained in part by the stimulation of medullary prostaglandin6 or kinin production,20 although the long-term effects of these pathways on MBF remain to be explored. The present study, however, demonstrates that Ang II–induced NO production contributes importantly to the long-term ability of the organism to buffer against the hypertensive actions of circulating Ang II. These results are consistent with recent studies by Zou et al,10 who found that subpressor doses of Ang II (5.0 ng · kg-1 · min-1 IV) stimulated renal medullary NO production and that acute medullary interstitial administration of L-NAME in amounts similar to those used in the present study greatly enhanced the ability of Ang II to reduce MBF, independent of changes in CBF.
The renal hemodynamic responses recorded during the
initial 70 minutes after the initiation of the intravenous
Ang II infusion (Figures 2 and 4) generally confirmed the
previous results of both Mattson et al6 7 and Zou et
al,10 which were obtained in anesthetized rats.
That is, only rats receiving the medullary infusion of L-NAME responded
to the intravenous suppressor dose of Ang II with
significant reductions in MBF. It is apparent from the immediate
reduction in MBF at the start of the Ang II infusion that these changes
preceded the increase in MAP, indicating that the reduction in blood
flow to the renal medulla initiated the hypertension. These initial
responses were not determined in the first 3 rats used for the
long-term studies, which accounts for the smaller number
analyzed to determine the immediate changes. The rats were
examined on the first day with the recognition that the within-day
variation in flow measurement is less than the between-day variation.
We believe that this accounts for the statistically significant
reduction in MBF seen during the first 70 minutes of infusion that was
not fully apparent in the long-term study until greater reductions of
flow had occurred by day 3 of Ang II infusion.
Initial Responses to Intravenous Ang II
Infusion
An important implication of this study is that very small
elevations of circulating Ang II can stimulate the production
of medullary NO, which serves to buffer the vasoconstrictor actions of
Ang II in the medullary circulation for the long term and protect
against hypertension. We have found that the renal medulla is
particularly rich in NOS enzyme activity, protein expression, and NO
concentration, which are much higher compared with the
cortex.10 11 12 Small suppressor doses of Ang II were
found to result in significant elevations of medullary [NO] as
determined by microdialysis oxyhemoglobin-NO trapping
techniques.10
Short-term studies by others also support the conclusions that Ang II releases NO and that inhibition of NOS activity enhances the renal vasoconstrictor actions of Ang II in rat kidneys.23 Ang II infusion has been reported to elevate renal excretion of nitrate and/or nitrite14 and increase cGMP concentration in renal cortical interstitial fluid.13 Madrid et al24 have shown that renal NO production buffers Ang II effects on pressure-natriuresis and on the CBF and papillary blood flow.25 Taken together with the initial hemodynamic responses to Ang II seen in the present study, these results indicate that when medullary NOS activity is only moderately reduced, vasoconstrictor actions of Ang II within the renal medulla of rats are greatly enhanced.
Long-Term Effects of Ang II on MBF and the Role of Medullary NO in
Buffering These Actions
The major contribution of the present study was the
demonstration that long-term reduction in NOS activity, specifically in
the renal medulla, renders the animal vulnerable to very small
elevations of plasma Ang II, resulting in sustained reductions in MBF
and hypertension. Given the variance of laser-Doppler measurements
between days and the relatively small number of rats used in these
studies, this reduction in MBF was not statistically significant until
the third day of Ang II infusion. However, 6 of the 9 rats showed a
clear reduction in MBF >25% on the morning after the start of Ang II
infusion (eg, 22 hours). The sequence of events leading to the slow
increase in arterial pressure was not determined in the
present study, although it is presumed that the reduction of MBF
leads to enhanced tubular reabsorption of sodium, leading to volume
expansion and hypertension. Direct tubular actions of deep nephron
segments and the collecting duct cannot be excluded. Long-term infusion
of Ang II at 5.0 ng · kg-1 ·
min-1 IV has been shown to increase plasma Ang
II concentrations of Sprague-Dawley rats from 11.3 to 19.7
pg/mL,4 whereas plasma Ang II concentrations increased
from 3.9 to 18.8 pg/mL when rats were switched from a 4.0% to 0.4%
salt diet. This indicates that changes in plasma Ang II within the
physiological range can have important consequences
on MBF and MAP in situations in which medullary NO
production is blunted. The reason for the slow return of MBF
and MAP toward control levels after the cessation of Ang II infusion is
unclear. CBF remained unchanged, and morphological examination of the
kidneys at the end of the study did not reveal sufficient fibrosis
surrounding the infusion catheter or optical fibers to explain these
events. It is possible that the continued medullary infusion of L-NAME
after cessation of the Ang II infusion retarded the loss of sodium and
water.
As seen in the present study, moderate reductions in medullary NOS
enzyme activity alone may be insufficient to produce hypertension but
can make the organism vulnerable to the hypertensive actions of Ang II.
As shown clearly in this study, Ang II infused long term at these low
concentrations did not normally produce hypertension (Figure 1).
It is also important to recognize that the results of our studies
indicate that L-NAME infused long term into the renal medulla did not
escape in sufficient amounts to exert vasoconstrictor actions on the
systemic vasculature. Neither short- nor long-term reductions in CBF
nor significant elevations of MAP were observed with medullary infusion
of L-NAME. If recirculation of L-NAME had occurred, one would have
expected reductions in CBF during the first 4 hours of the medullary
L-NAME infusion, changes that were not observed. The renal cortical
vasculature is more sensitive than the medullary vessels to Ang
II,6 7 15 so blunting of NOS activity in the renal cortex
should have amplified these differences. The enhanced vasoconstrictor
effects of Ang II were confined strictly to the renal medulla. By the
same reasoning, if L-NAME escaped from the kidney in sufficient amounts
to influence the systemic circulation, one would have anticipated an
increase in MAP during the first several hours of medullary
infusion.
Changes in the endogenous renin-angiotensin system are not likely to be a reason for the different sensitivity to Ang II in L-NAME–pretreated and nontreated rats. L-NAME has been shown to increase plasma Ang II concentrations,26 which in itself would be expected to reduce the pressor actions of infused Ang II. Exogenous Ang II even at this low dose (3 ng · kg-1 · min-1) has been shown to suppress plasma renin activity so that plasma Ang II levels are only slightly increased.4 The same would be expected to occur in the L-NAME–treated rats. Thus, the hypertension in the present study appears to have been caused by the inability of medullary NO to buffer the vasoconstrictor actions of Ang II and not by other mechanisms.
In summary, the present study indicates that the renal medullary production of NO serves as an important counterregulatory mechanism to buffer the hypertensive effects of elevations in circulating Ang II. The great responsiveness of the medullary NO system to Ang II in rats appears to account in large measure for the relative insensitivity of this species to the hypertensive effects of Ang II.
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Acknowledgments |
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This work was supported by National Institute of Health grant HL-29587. We thank Meredith M. Skelton for the careful review of the manuscript. Dr Szentiványi was a visiting postdoctoral fellow from Semmelweis University of Medicine, Budapest, Hungary. Dr Maeda was a visiting fellow from the Department de Fisiologia, ICBS, UFRGS, Brasil.
Received September 16, 1998; first decision October 20, 1998; accepted November 1, 1998.
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