(Stroke. 1998;29:1031-1036.)
© 1998 American Heart Association, Inc.
Effect of Chronic Nitric Oxide Deficiency on Angiotensin II–Induced Hypertrophy of Rat Basilar Artery
Pierre Moreau, PhD;
Hiroyuki Takase, MD;
Livius V. d'Uscio, PhD;
Thomas F. Lüscher, MD
From the Division of Cardiology, Cardiovascular Research, University
Hospital, Bern, and Division of Cardiology, University Hospital and Institute
of Physiology, University Zürich (Switzerland) (P.M., H.T.,
L.V.d'U., T.F.L.), and Faculty of Pharmacy, Université de
Montréal (Québec, Canada) (P.M.).
Correspondence to Thomas F. Lüscher, MD, FACC, FESC, Division of Cardiology, University Hospital, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail 100771.1237{at}compuserve.com
 |
Abstract
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Background and Purpose—Although in
vitro studies suggest that nitric oxide has an inhibitory
effect on cellular proliferation and migration, in vivo experiments
failed to support this conclusion. The present study was designed
to determine the effect of endogenous nitric oxide on
angiotensin II–induced hypertrophy of small
arteries in vivo.
Methods—Angiotensin II (200 ng/kg per minute), alone
or in combination with
N
-nitro-L-arginine methyl
ester (L-NAME) (60 mg/kg per day), was administered for 2 weeks in
normotensive rats. Basilar arteries were harvested, and their geometry
was determined in perfused and pressurized conditions.
Results—Angiotensin II increased media thickness,
media-lumen ratio, and cross-sectional area of the arteries, confirming
the presence of hypertrophic remodeling. The concomitant administration
of L-NAME, an inhibitor of nitric oxide synthesis,
prevented vascular hypertrophy. The remodeling of the
basilar artery geometry in the combined treatment was of eutrophic
nature, similar to that observed with the administration of L-NAME
alone.
Conclusions—Our results suggest that endogenous
nitric oxide does not inhibit angiotensin II–induced
vascular hypertrophy in vivo. Nitric oxide may even be a
necessary factor for hypertrophy to develop.
Key Words: angiotensin II • basilar artery • hypertension • nitric oxide • vascular remodeling • rats
|
Introduction
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|---|
In hypertension,
resistance arteries adapt to the increased wall tension by changing
their geometry.1 Accordingly, a reduced lumen
diameter and/or an increased wall thickness can normalize the excessive
tension applied on the vessel wall and may then protect the
microcirculation against the blood pressure rise. However, this
adaptive process may also contribute to the maintenance of
hypertension by elevating total peripheral
resistance2 and, particularly in the cerebral
circulation, to the vascular complications of the disease process.
Alterations of small-artery structure may be mediated by eutrophic (no
increase in CSA) or hypertrophic (CSA increase) remodeling of the
vascular wall or by a combination of both
processes.2 3 The vascular
endothelium, by its anatomic position and by releasing
several factors, may influence the local vascular environment and
modulate the changes of vascular geometry observed in the context of
hypertension.
We have previously shown that chronic NO deficiency with the
administration of L-NAME produces an elevation of blood pressure that
is not associated with hypertrophic remodeling of small arteries of the
cerebral4 and mesenteric
circulations.5 Indeed, in this model eutrophic
remodeling can be observed, and it is believed to develop in close
relation to the elevation of blood pressure.4
These findings, which have also been made by other investigators, also
apply to the heart, which, despite the elevation of blood pressure,
does not become hypertrophied.6 These in vivo results
are at variance with the general belief, from earlier studies in cell
culture systems,7 8 that NO donors and cGMP
analogues are inhibitors of vascular growth. This
hypothesis was reinforced by a recent study showing that local
transfection of the NO synthase gene in balloon-injured carotid
arteries blunts neointimal formation and prevents the
increase in CSA.9 However, this effect may be the
result of inhibition of VSMC migration rather than proliferation by
NO,10 since the former process is necessary for
neointimal formation.9 Furthermore,
Garg and Hassid,7 who reported the
antimitogenic effect of NO donors in passaged cells, more
recently showed that the same agents can actually potentiate fibroblast
growth factor– induced replication of freshly dissociated VSMC in
culture.11 This would suggest that during
passages, cells acquire the ability for their replication to be
inhibited by NO donors, as has been previously
suggested.12 It can also be postulated that NO
may act as a growth promoter or as an enhancer of proliferation in
vivo, thus explaining the lack of vascular and cardiac
hypertrophy during chronic NO deficiency. A recent study of
DOCA-salt hypertension lends support to that postulate, since
hypertrophic remodeling of small arteries and heart
hypertrophy were prevented by chronic L-NAME
treatment.13
To better define the role of endogenous NO in the
modulation of hypertrophic remodeling of small arteries, we studied the
effects of a chronic administration of L-NAME in a model of vascular
hypertrophy induced by the administration of Ang
II.14 15 We hypothesized that if NO indeed has
antiproliferative properties in vivo, we should expect an increased
vascular hypertrophy when animals are treated concomitantly
with Ang II and L-NAME. In opposition, if NO is a growth promoter in
vivo, an inhibition of Ang II–induced hypertrophy should
be observed with L-NAME.
|
Materials and Methods
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Wistar-Kyoto rats were purchased from IFFA CREDO (L'Arbesle,
France) and treated for 2 weeks from 9 weeks of age. Seven untreated
rats served as controls. One group of 7 rats was treated with Ang II
that was administered from subcutaneously implanted osmotic pumps
(model 2002, Alzet Corp) at a rate of 200 ng/kg per minute. Other
groups were treated with L-NAME alone or in combination with Ang II.
The dose of L-NAME, calculated from the water intake, was 58±5 mg/kg
per day in the L-NAME group and 61±4 mg/kg per day in the Ang II plus
L-NAME group (P=NS). Before and at the end of the treatment,
the rats were weighed and their systolic blood pressure and
heart rate were determined by the tail cuff method with the use of a
pulse transducer (model LE 5000, Letica). These procedures were
approved by the Commission for Animal Research of the Canton of Bern,
Switzerland.
Basilar arteries were harvested from the animals that had been
previously anesthetized (thiopental 50 mg/kg IP) and prepared
under a dissecting microscope in cold Krebs' solution of the following
composition (in mmol/L; control solution): NaCl 118.6, KCl 4.7,
CaCl2 2.5,
KH2PO4 1.2,
MgSO4 1.2, NaHCO3 25.1,
edetate calcium disodium 0.026, glucose 10.1. The arteries were then
pulled and sutured on two small glass cannulas positioned in a vessel
chamber (Living Systems Instrumentation) and superfused with control
solution maintained at 37°C and oxygenated (95%
O2/5% CO2). The vessel
perfusion chamber was positioned on the stage of an inverted microscope
(Nikon, TSM-F), and the amplified image was transmitted to a monitor
and a video dimension analyzer (V91, Living Systems
Instrumentation), allowing for the measurements of lumen diameter and
media thickness. The basilar arteries were equilibrated for 60 minutes
in a calcium-free control solution to prevent myogenic tone. The
longitudinal stretch was controlled by adjusting the length of the
vessel to a value slightly superior to the one required to produce a
small bending of the vessel. The perfusion pressure was then increased
from 25 to 55 mm Hg in 10-mm Hg steps, and the efferent pressure
was adjusted to maintain a constant flow. Lumen diameter and media
thickness were determined at each pressure step.
Values are expressed as mean±SEM. The CSA, the growth index, and the
remodeling index were calculated for the different treatment groups
(TRx) from the lumen diameter (LD) and the external diameter (ED)
according to the formulas previously
described.2 4
 |
 |
 |
where
 |
Since CSA does not change with pressure, it was calculated at 25, 35,
45, and 55 mm Hg, and the mean of these four values was used to
calculate the growth index. Other parameters were
calculated at 35 mm Hg as previously described. The
distensibility of the basilar artery is expressed as
micrometer changes per millimeters of mercury of pressure
increase and represents the slope of the pressure–lumen
diameter curve. Statistical evaluation was done by a one-way ANOVA with
Bonferroni's correction for multiple
comparisons16 or by one-sample analysis
(growth index). The contrasts selected a priori for the ANOVA were
(1) Ang II and L-NAME compared with the control group and (2) Ang II
plus L-NAME compared with Ang II alone. Pearson's correlation
coefficients were calculated by linear regression. P<0.05
was considered significant.
|
Results
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During the treatment period, control rats gained 42.3±3.1 g
(initial value, 276.6±8.7 g), while those treated with Ang II and Ang
II plus L-NAME gained 21.3±2.6 and 3.7±7.9 g, respectively
(P<0.05). Weight gain was normal in the L-NAME group
(40.6±2.8 g). Chronic administration of Ang II, L-NAME, or the
combination of both vasopressors induced a similar and significant
increase in systolic blood pressure (Figure 1
). Final blood pressure values were
136±4, 167±6, 180±6, and 189±7 mm Hg in control, Ang II,
L-NAME, and Ang II plus L-NAME groups, respectively. Heart rate was not
significantly modified by any chronic treatment (control value, 323±11
beats per minute).
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Figure 1. Net increase in systolic blood pressure
(SBP) between values obtained before and after 2 weeks of the
respective treatments (n=7 per group). SBP was measured with the tail
cuff method in conscious rats. *P<0.05 compared with
control (Ctl) (ANOVA+Bonferroni). The Ang II+NAME group was not
significantly different from the Ang II group.
|
|
Ang II administration increased media thickness and media-lumen ratio
of basilar arteries without modifying the lumen diameter
(Table, Figure 2). The CSA and growth index were also
significantly increased by Ang II (Table, Figure 2). The administration
of L-NAME, alone or in combination with Ang II, produced an increase in
media thickness and media-lumen ratio comparable to that in the Ang
II–treated animals. However, these changes were accompanied by a
reduction of lumen diameter, without modification of CSA or growth
index (Table, Figure 2). A significant statistical interaction was
observed among the groups for the growth index (two-way ANOVA).
There was a strong positive correlation between systolic blood
pressure and media-lumen ratio in basilar arteries (Figure 3). In contrast, no correlation was
observed between systolic blood pressure and CSA. The
distensibility of the basilar artery, as determined by the
pressure–lumen diameter curves, was similar in all groups (slope
2 µm/mm Hg; data not shown), implying that the modifications
of vascular structure could not be accounted for by increased stiffness
of the vessel wall.
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Figure 3. Correlation analysis between
systolic blood pressure and media-lumen ratio (A) or CSA (B) in
the four treatment groups. These results demonstrate a relationship
between media-lumen ratio and arterial pressure but not
between CSA, an index of vascular hypertrophy, and
arterial pressure. Therefore, the pressure-dependent change
in media-lumen ratio does not necessarily involve vascular
hypertrophy. Indeed, the relationship between media-lumen
ratio and CSA was not significant (r=.342; data not
shown).
|
|
|
Discussion
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|---|
In the present study we investigated the in vivo modulation of
Ang II–induced vascular hypertrophy by
endogenous NO by chronically blocking its synthesis with
L-NAME. Our results not only suggest that endogenous NO
does not exert a marked antiproliferative effect, but they rather
demonstrate that NO seems necessary for hypertrophy to
develop in this model of Ang II–induced hypertension.
The chronic administration of an initially subpressor dose of Ang II
induced an increased media thickness and media-lumen ratio of basilar
arteries. This alteration of the vascular geometry followed what has
been described as hypertrophic remodeling, as shown by the significant
increase in CSA and growth index. Furthermore, the calculated
remodeling index (8%) does not support eutrophic remodeling
(rearrangement of the vascular tissue around a smaller lumen) as an
important contributor to the remodeling
process.2 17 Our results therefore confirm those
previously reported in this model,14 which also
emphasized that hypertrophy, and not hyperplasia, explains
the increased CSA, at least in mesenteric
arteries.2 However, we did not measure VSMC
number and size in basilar arteries in this study, and it remains
possible that the increased CSA was due to an increased cell number or
to an enhanced production of extracellular matrix in these
small arteries, although there was no noticeable change in vascular
stiffness.
The chronic administration of L-NAME induced an increase in
systolic blood pressure and media-lumen ratio comparable to
that in Ang II–treated animals. The strong correlation between blood
pressure and media-lumen ratio supports the notion that this
parameter of vascular morphology is adaptive to the
increase in pressure. However, the process involved with L-NAME is
eutrophic remodeling (reduced lumen diameter without increase in the
CSA; calculated remodeling index for the basilar artery: 97%) instead
of hypertrophic remodeling. This confirms our previous reports in
L-NAME–induced hypertension.4 5 The new finding
of this study is that the chronic inhibition of endogenous
NO production did not enhance the proliferative efficacy of Ang
II, in contrast to what has been suggested from some studies in
cultured VSMC.7 8 18 Since we have previously
shown that the same chronic dose of L-NAME inhibits as much as 50% of
NO synthase activity,19 we would therefore expect
at least part of the antiproliferative properties of NO to be
eliminated by L-NAME. In contrast, our results obtained in the basilar
artery support the notion that NO may be important to facilitate VSMC
proliferation in vivo, as suggested by a recent study with fibroblast
growth factor in freshly dissociated VSMC.11 The
significant statistical interaction of the growth index confirms that
blockade of NO synthesis inhibits Ang II–induced increase in CSA.
Similar findings have also been reported in the DOCA-salt model of
hypertension.13 However, in this model the RAS is
blunted, and Ang II is an unlikely candidate to explain the vascular
hypertrophy. Indeed, vascular hypertrophy is
not influenced by angiotensin-converting enzyme
inhibitors.13 Nonetheless, chronic
L-NAME treatment inhibited hypertrophy of the heart and of
the small arteries.13 In the aorta, however,
L-NAME potentiated the hypertrophy. This observation was
also recently reported for Ang II, as a chronic L-NAME treatment
enhanced Ang II–induced hypertrophy of the
aorta.20 Thus, the role of NO on vascular growth
seems to differ between large conduit and small resistance arteries, an
observation that was already emphasized for other vascular
functions.21 It is therefore interesting to note
that VSMC used in culture systems are normally derived from the aorta.
But even with aortic VSMC, culture conditions seem to determine the
effect of NO on cellular growth.7 11 12 In vivo,
however, NO appears to be necessary for small arteries to proliferate,
the stimulus being Ang II or DOCA-salt treatment.
From the present experiments, it is not possible to determine the
mechanism by which NO can enhance vascular hypertrophy.
However, from the results reported by Hassid et
al11 in freshly dissociated VSMC, it is
reasonable to speculate that an increased production of cGMP
mediates the effect. Furthermore, cGMP levels have been shown to be
reduced in the L-NAME model of hypertension.22
This reduction could explain the blunted hypertrophy, but
this hypothesis needs to be addressed further. There are concerns that
L-NAME may actually prevent hypertrophy by an action that
is unrelated to NO synthase blockade. One attempt to test this
hypothesis was recently presented, and although 1 mmol/L
of L-NAME blunted mitogen-induced cellular replication, the same dose
was ineffective in inhibiting stimulated protein synthesis in
VSMC.23 Thus, it seems unlikely that L-NAME
exerted a direct inhibition of Ang II–induced vascular
hypertrophy in the present study, if indeed
hypertrophy is the mechanism involved in the increased CSA
(see above). High doses of L-NAME have also been shown to antagonize
muscarinic receptors in vitro,24 and although
stimulation of these receptors enhances proliferation of
glial25 and prostate cancer
cells,26 the relevance of this antagonism to the
modulation of vascular hypertrophy is
undetermined.
Although the present study was not designed to determine the
involvement of the RAS in L-NAME–induced hypertension, the use of Ang
II warrants discussion of this aspect. Measurement of PRA yielded
conflicting results regarding the implication of the RAS in this model
of hypertension. Indeed, some reports show increased
PRA,27 28 whereas others do not show any
alteration or even show a decrease,6 29 and one
study shows a different effect depending on the salt
diet.30 To our knowledge, only one study measured
plasma Ang II levels directly, and the authors reported a reduced
concentration of the peptide.31 The conflicting
data do not seem to be related to the dose of L-NAME or to the duration
of treatment. Some have suggested that hypertrophy in this
model is proportional to the activity of the
RAS.6 The lack of hypertrophy in our
study suggests that RAS activity was not enhanced, although we did not
measure PRA to confirm this. In most studies,
angiotensin-converting enzyme inhibitors and
AT1-receptor antagonists are
effective to lower pressure, especially if given chronically. However,
it is not known whether this is due to interruption of a hyperactive
RAS or to enhancement of endothelium-dependent
vasodilation, as suggested by several groups, including
ours.19 32 33
In conclusion, the inhibition of NO synthesis did not enhance Ang
II–stimulated vascular growth, arguing against an important
antiproliferative action of NO in small arteries in vivo. In contrast,
the change in vascular geometry resulting from the combination of
L-NAME and Ang II appeared similar to that observed with L-NAME alone
and consisted of pressure-dependent eutrophic remodeling. Therefore, in
the basilar artery, NO seems to be necessary for Ang II to augment
vascular CSA.
|
Selected Abbreviations and Acronyms
|
|---|
| Ang II |
= |
angiotensin II |
| CSA |
= |
cross-sectional area |
| DOCA |
= |
deoxycorticosterone acetate |
| L-NAME |
= |
N-nitro-L-arginine methyl
ester |
| NO |
= |
nitric oxide |
| PRA |
= |
plasma renin activity |
| RAS |
= |
renin-angiotensin system |
| VSMC |
= |
vascular smooth muscle cells |
|
|
Acknowledgments
|
|---|
This study was supported by a grant from the Swiss National
Research Foundation (grant No. 3200–051069.97/1). Dr Moreau holds a
fellowship from the Medical Research Council of Canada, and Dr d'Uscio
is a recipient of a stipend from the Intermedia Foundation, Bern,
Switzerland.
Received July 10, 1997;
revision received January 16, 1998;
accepted February 10, 1998.
|
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Editorial Comment
Gary L. Baumbach, , MD, Guest Editor
Department
of Pathology and Cardiovascular Center,
University of Iowa College of Medicine,
Iowa City, Iowa
|
Introduction
|
|---|
The importance of endothelium-derived factors to the
regulation of vascular relaxation and constriction has become widely
recognized since the original discovery of Furchgott and
Zawadzki1 almost 20 years ago. More recently,
endothelium-derived factors also have come to be recognized as
potential determinants of vascular structure. Their importance in this
regard, however, remains unclear. Thus, any effort to clarify the
actions of endothelium-derived factors on vascular structure, as in
this study, is particularly welcome and appreciated.
The goal of this study, as stated by the authors, was to determine the
effect of endogenous NO on Ang II–induced hypertrophy of small
arteries in vivo. Based on the finding that NO inhibits proliferation
of VSMC in tissue culture,2 one might anticipate that a
reduction in availability of NO to the vascular wall during treatment
with an NO synthase inhibitor would result in increased Ang II–induced
hypertrophy of small arteries as a consequence of reduced inhibition of
smooth muscle growth. Thus, the finding in this study that L-NAME did
not accentuate hypertrophy of basilar artery in Ang II–treated rats,
and in fact appeared to prevent hypertrophy, is surprising, if not
paradoxical.
One interpretation of this finding is that endogenous NO does not
inhibit Ang II–induced hypertrophy in vivo and may even be a necessary
factor for hypertrophy to develop. At least one other interpretation is
possible, however. NO synthase inhibitors may prevent hypertrophy
directly when given in sufficient doses, a possibility suggested by
findings in rat VSMCs grown in culture.3 This possibility
is further supported by the recent findings that (1) cerebral
arterioles in Sprague-Dawley rats undergo hypertrophy during
hypertension induced by L-NAME4 and (2) carotid clipping
does not prevent cerebral arteriolar hypertrophy induced by
L-NAME,4 even though clipping does prevent hypertrophy
in cerebral arterioles of stroke-prone spontaneously hypertensive
rats.5
In conclusion, the present study by Moreau et al provides significant
new information with regard to possible effects of NO on vascular
structure in vivo. The possibility that NO may be a necessary factor
for the development of vascular hypertrophy during chronic hypertension
is especially provocative, with important clinical implications
regarding reversal or prevention of alterations in vascular structure
during treatment of chronic hypertension. In addition, the
possibilities and questions raised by this study provide the
focus for future investigations in this important area.
|
Selected Abbreviations and Acronyms
|
|---|
| Ang II |
= |
angiotensin II |
| CSA |
= |
cross-sectional area |
| DOCA |
= |
deoxycorticosterone acetate |
| L-NAME |
= |
N-nitro-L-arginine methyl
ester |
| NO |
= |
nitric oxide |
| PRA |
= |
plasma renin activity |
| RAS |
= |
renin-angiotensin system |
| VSMC |
= |
vascular smooth muscle cells |
|
Received July 10, 1997;
revision received January 16, 1998;
accepted February 10, 1998.
|
References
|
|---|
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Clin Invest. 1989;83:1774–1777.
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Schiffrin EL. Vascular structure in
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Top
Abstract
Introduction
) and the control CSA
(CSAControl) divided by CSAControl
(CSATRx-CSAControl/CSAControl).2
Thus, the control group has a growth index of zero. A,
*P<0.05 compared with control (ANOVA+Bonferroni). The
Ang II+NAME group was not significantly different from the Ang II
group. B, *P<0.05 compared with zero (one-sample
analysis); 
P<0.05 compared with Ang II alone
(ANOVA+Bonferroni). A significant interaction was found for the growth
index (two-way ANOVA).
