Hypertension. 1997;30:953-956
(Hypertension. 1997;30:953-956.)
© 1997 American Heart Association, Inc.
Brain Nitric Oxide Synthase Messenger RNA in Central Mineralocorticoid Hypertension
Yoshiyu Takeda;
Isamu Miyamori;
Takashi Yoneda;
Kenji Furukawa;
Satoru Inaba;
Ryoyu Takeda;
;
Hiroshi Mabuchi
From the Second Department of Internal Medicine (Y.T., I.M., T.Y., K.F.,
S.I., H.M.) and Department of Health Sciences (Y.T.), School of Medicine,
Kanazawa University, and the KKR Hokuriku Hospital (R.T.), Izumigaoka,
Kanazawa 920, Japan.
Correspondence to Yoshiyu Takeda, MD, Second Department of Internal Medicine, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920, Japan.
 |
Abstract
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Abstract The mechanism underlying the central
hypertensinogenic
effects of mineralocorticoids remains unclear. Given
that nitric
oxide (NO) is thought to act at autonomic sites in the
brain
to regulate arterial blood pressure, the effects of
the potent
mineralocorticoids aldosterone and
19-noraldosterone on the
abundance of neuronal NO synthase
(nNOS) mRNA in the brain were
investigated. Wistar-Kyoto rats received
a continuous intracerebroventricular
infusion
of aldosterone or 19-noraldosterone (5
ng/h) from an implanted
osmotic minipump for 4 weeks. Total RNA was
purified from microdissected
tissue blocks containing the hypothalamus,
dorsal medulla, rostral
ventrolateral medulla, or caudal ventrolateral
medulla, and
changes in the abundance of nNOS mRNA were determined with
a
semiquantitative competitive polymerase chain reaction method.
Blood
pressure was significantly increased in rats 2, 3, and
4 weeks after
the onset of intracerebroventricular
aldosterone
or 19-noraldosterone infusion
compared with that in animals
receiving vehicle. Subcutaneous infusion
of either mineralocorticoid
had no effect on blood pressure. Compared
with controls, rats
treated with aldosterone or
19-noraldosterone for 4 weeks showed
significant decreases
in the amount of nNOS mRNA in the hypothalamus
and rostral and caudal
ventrolateral medulla. These data suggest
that reduced nNOS activity
may contribute to the increase in
blood pressure in rats with central
mineralocorticoid-induced
hypertension.
Key Words: mineralocorticoid RNA nitric oxide nitric oxide synthase aldosterone
 |
Introduction
|
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Nitric
oxide, an important regulatory molecule produced by
endothelial
cells, neurons, macrophages, and
other cell types,
1 is generated
from
L-arginine in a reaction catalyzed by the enzyme NOS. The
cytokine-inducible
isoform of NOS is activated by
various immunological stimuli,
which results in the production
of large quantities of NO that
can be cytotoxic.
2 The
endothelial isoform of NOS is thought
to be a
physiological regulator of basal vascular
tone.
3 Thus,
mice lacking the gene for this isozyme are
hypertensive.
4 nNOS
also plays an important role in
cardiovascular homeostasis.
5
The steroid 19-noraldosterone, like
aldosterone, possesses potent mineralocorticoid and
hypertensinogenic activity.6 We previously have shown that
19-noraldosterone is synthesized by human adrenal glands
and that urinary excretion of this mineralocorticoid is increased in
individuals with primary aldosteronism and in some patients with
essential hypertension.7 8 9 However, urinary excretion of
19-noraldosterone is lower than that of
aldosterone.
The mineralocorticoid receptor is distributed widely; it is present
in the colon, parotid, vasculature, and specific areas of the
brain.10 In addition to classical sites of steroid
synthesis, brain is also a steroidogenic tissue.11 12
Although the pathophysiological role of central
mineralocorticoids is unclear, ICV infusion of aldosterone
induces hypertension in rats.13
19-Noraldosterone possesses more hypertensinogenic potency
than aldosterone.14 To clarify the mechanism
underlying the central hypertensinogenic effect of mineralocorticoid,
we have examined the concentration of nNOS mRNA in the brains of
normotensive rats and rats with hypertension induced by ICV infusion of
aldosterone and compared them with rats treated with ICV
infusion of 19-noraldosterone. The amount of nNOS mRNA was
measured in regions of the brain important in regulation of
arterial blood pressure with the use of semiquantitative
PCR assay.
 |
Methods
|
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Animals and Experimental Protocol
All experiments were performed according to guidelines for the
use
of experimental animals of the Animal Research Committee of
Kanazawa
University. Wistar-Kyoto (WKY)/Izm rats
15 (body
weight, 160
to 180 g), donated by the Disease Model Cooperative
Research
Association (Kyoto, Japan), were housed in
metabolic cages with
free access to tap water and normal
rat chow (0.1 mmol/g Na,
0.24 mmol/g K; Nippon
Charles River, Kanagawa, Japan). Animals
were maintained in a
constant-temperature environment, with
a 12-h-light/12-h-dark
cycle.
Blood pressure was determined by the plethysmographic tail-cuff method
as previously described.16 Plasma concentrations of
aldosterone and corticosterone were determined by
radioimmunoassay after extraction with a Sep-Pak C18 cartridge (Waters
Assoc).
The rats were anesthetized with sodium pentobarbital 50
mg/kg, intraperitoneally. With aseptic
surgical techniques, a cannula was placed into the right lateral
cerebral ventricle of the rats under anesthesia and was
connected to an implanted miniosmotic pump (Alzet 2002, Alza) that
delivered 0.49±0.02 µL/h for 14 days. Alternatively, the pump was
implanted subcutaneously. Pumps were changed on day 14 under isoflurane
anesthesia, and pumps of the same lot were used throughout
the experiment to ensure consistency. Artificial CSF
(Na+, 152 mmol/L; K+, 3
mmol/L; Mg+, 1.6 mmol/L;
HCO3-, 25 mmol/L;
PO43-, 0.5 mmol/L;
Cl-, 135 mmol/L) was prepared as previously
described.13 The rats were divided into five experimental
groups, with 8 animals per group. Group 1 received ICV CSF containing
aldosterone in 5% (vol/vol) ethanol at a rate of 5
ng/h. Group 2 received ICV CSF containing
19-noraldosterone in 5% ethanol at a rate of 5
ng/h. Group 3 received subcutaneous CSF containing
aldosterone in 5% ethanol at a rate of 5 ng/h.
Group 4 received subcutaneous CSF containing
19-noraldosterone in 5% ethanol at a rate of 5
ng/h. Group 5 received ICV CSF containing vehicle in 5%
ethanol. All solutions were prepared and sterilized by filtration
through 0.22-µm filters (Nihon Millipore Ltd) immediately before
filling and implanting the pumps.
Brains were removed immediately after animals were killed by
decapitation, and necropsies, including dye infusions to check cannula
placement, were performed. Animals in which there was doubt about the
correct delivery of solution or that showed evidence of illness or high
levels of stress were excluded from data analysis. Brains were
frozen rapidly in liquid nitrogen and stored at -80°C until RNA
isolation.
Isolation of RNA and PCR Analysis
Frozen brains were dissected into tissue blocks that included
the hypothalamus, dorsal medulla, RVLM, or CVLM. The extent of tissue
blocks according to coordinates from Paxinos and Watson17
was as follows: hypothalamus (rostral, 0.2 mm caudal to the optic
chiasm; caudal, 1.8 mm caudal to the optic chiasm; dorsal, 4
mm from the ventral surface; ventral, ventral surface of the brain; and
lateral, 3.5 mm lateral to the midline), dorsal medulla (rostral,
12.1 mm caudal to the optic chiasm; caudal, 14.4 mm caudal to
the optic chiasm; dorsal, dorsal surface of the brain stem; ventral,
2 mm from the dorsal surface of the brain stem; and lateral,
2 mm lateral to the midline), RVLM (rostral, 11.1 mm caudal
to the optic chiasm; caudal, 13.0 mm caudal to the optic chiasm;
dorsal, 2 mm from the dorsal surface of the brain stem; ventral,
ventral surface of the brain stem; and lateral, lateral edge of the
brain stem), and CVLM (rostral, 13.0 mm caudal to the optic
chiasm; caudal, 14.4 mm caudal to the optic chiasm; dorsal,
1.5 mm from the dorsal surface of the brain stem; ventral, ventral
surface of the brain stem; and lateral, lateral edge of the brain
stem).
Total RNA was extracted with guanidinium thiocyanate and isolated by
centrifugation in a CsCl gradient as previously
described.18 RNA (200 ng) was then incubated at 42°C for
60 minutes with 2.5 U of Moloney murine leukemia virus reverse
transcriptase (Takara) in a 20-µL reaction volume containing 10
mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 5
mmol/L MgCl2, 1 mmol/L each of
deoxynucleoside triphosphate, and 2.5 mmol/L of a random
hexanucleotide primer (Takara). After subsequent incubation
for 5 minutes at 99°C, the resulting single-stranded cDNA was
subjected to competitive PCR analysis. The sequences of the
sense and antisense primers for nNOS were 5'-TCAACAGCGTCTCCT-CCTA-3'
and 5'-GTCGATCGGCTGAACTTAGG-3', respectively, as described by Krukoff
et al,19 and correspond to nucleotides 2882 to
2990 and 3364 to 3383, respectively, of the cDNA.20 The
competitive template was prepared with a PCR MIMIC Construction kit
(Clontech). After quantification, a series dilution was used as an
internal standard for competitive PCR as previously
described.21 Competitive PCR was performed with 2.5 µL
of cDNA, 2 µL of various concentrations of the competitive template,
0.5 µmol/L each of the sense and antisense primers, and
0.5 U of Taq DNA polymerase (Perkin-Elmer Japan) in a total
volume of 50 µL containing 10 mmol/L Tris-HCl (pH 8.3),
50 mmol/L KCl, 2 mmol/L MgCl2, and
0.2 mmol/L of each deoxynucleoside triphosphate. The
amplification protocol consisted of 30 cycles of 1 minute at 94°C, 1
minute at 59°C, and 2 minutes at 72°C. The reaction products
(10 µL) were subjected to electrophoresis on a 3.0% agarose gel,
which was then stained with ethidium bromide and photographed.
Signal intensity was quantified by computerized densitometry with the
BIO-PROFIL BIO-1D system (Compak). The intensities of the products
from each cDNA and the competitive template were plotted as a function
of the known amounts of the competitive template. The intra-assay and
interassay variabilities of the competitive PCR assay were 11.2% and
13.6%, respectively. The amount of nNOS mRNA was expressed as
attomoles per 100 ng of RNA.
Statistical Analysis
Data are expressed as mean±SD. The statistical significance of
differences was assessed by one-way ANOVA and multiple comparison test.
A value of P<.05 was considered statistically
significant.
 |
Results
|
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There were no signs of illness, infection, or behavioral deficits
in
any of the rats in the five study groups. The blood pressure
of rats
infused ICV with aldosterone (5 ng/h) or
19-noraldosterone
(5 ng/h) was significantly higher
than that of controls (vehicle,
ICV) by day 14 and remained so until
the end of the experiment
on day 28 (Fig 1

); there was no significant difference
between
rats receiving aldosterone and those receiving
19-noraldosterone.
The blood pressure of animals infused
subcutaneously with aldosterone
or
19-noraldosterone did not differ significantly from that
of
controls throughout the 28-day experiment period.
The plasma concentrations of aldosterone,
corticosterone, K, and Na did not differ among rats treated ICV with
aldosterone, 19-noraldosterone, or vehicle
(Table
).
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Table 1. Plasma Concentration of Aldosterone,
Corticosterone, Na, and K in Rats After ICV Infusion of
Aldosterone, 19-Noraldosterone, or Vehicle for
4 Weeks
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Fig 2
shows that the competitive template
for nNOS inhibited the amplification by PCR of brain nNOS cDNA in a
concentration-dependent manner.

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Figure 2. Effect of concentration of the competitive template
on the amplification of PCR products derived from brain nNOS cDNA
and the competitive template (Mimic).
|
|
The amount of nNOS mRNA in the dorsal medulla did not differ
significantly between controls and rats infused ICV with either
aldosterone or 19-noraldosterone for 4 weeks
(Fig 3
). In contrast, the amount of nNOS
mRNA in the hypothalamus, RVLM, or CVLM of rats treated ICV with either
aldosterone or 19-noraldosterone was
significantly reduced compared with that in the corresponding brain
region of controls (P<.05). There were no significant
differences in the amount of nNOS mRNA in the hypothalamus, RVLM, or
CVLM between rats treated with aldosterone or
19-noraldosterone.

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|
Figure 3. Effect of ICV infusion of
aldosterone (solid bars), 19-noraldosterone
(striped bars), or vehicle (open bars) for 4 weeks on the amount of
nNOS mRNA in the dorsal medulla, hypothalamus, RVLM, and CVLM. Data are
presented as mean±SD (n=8). *P<.05 versus
vehicle-treated rats.
|
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 |
Discussion
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The central nervous system has been shown to be important in
the
development of mineralocorticoid-induced hypertension.
22
Mineralocorticoid receptors are present in the hippocampus,
amygdala,
lateral septum, and hypothalamus, especially in the
periventricular
regions, areas known or thought to be
important in the regulation
of ACTH release, arousal, fluid and
osmolality equilibrium,
and the maintenance of normal blood
pressure. Mineralocorticoids
also are synthesized outside the adrenal
gland, especially by
the vasculature
23 24 and
brain.
25 The expression of nNOS is
highly localized within
the brain, with many nNOS-containing
regions also important in
regulation of the cardiovascular system.
In the
hypothalamus, NOS-positive neurons are present primarily
in the
paraventricular nucleus and supraoptic
nucleus,
26 27 the former being an especially important
integrating center
for autonomic information.
28 In the
medulla, nNOS-containing
neurons
29 and nerve
terminals
30 are found in the nucleus of
the tractus
solitarius and the RVLM, an area known as a pressor
region.
30 In addition, the CVLM, the so-called depressor
area, contains
nNOS-expressing neurons, albeit in smaller numbers than
the
RVLM.
31
We have now shown that the amount of nNOS mRNA in the hypothalamus and
RVLM of rats with central mineralocorticoid-induced hypertension was
significantly reduced compared with that in normotensive controls.
Thus, reduced NO synthesis in these areas of the brain may contribute
to the increase in blood pressure in the mineralocorticoid-treated
animals. The central effects of 19-noraldosterone both on
the blood pressure and gene expression of nNOS are equal with those of
aldosterone. These results suggest that
19-noraldosterone possesses central hypertensinogenic
potency as well as aldosterone. However, urinary excretion
of 19-noraldosterone is much lower than that of
aldosterone.32 Local concentration of these
mineralocorticoids should be further studied.
L-Nitroarginine and other NOS inhibitors
increase the blood pressure of many species, including rats, guinea
pigs, rabbits, dogs,33 and mice.3 El Karib et
al34 showed that infusion of the NOS blocker L-NNA into
the lateral cerebral ventricle of rats increased arterial
pressure, whereas intravenous administration of the same
dose had no effect. These researchers concluded that L-NNA acts
directly in the central nervous system to increase blood pressure,
probably by increasing the activity of the sympathetic nervous system.
Increases in NO concentration produced by microinjecting sodium
nitroprusside into the RVLM resulted in a decrease in blood pressure.
Injection of L-NNA into the RVLM to block endogenous
production of NO increased the frequency of nerve activity and
blood pressure.35 Harada et al36 observed
that microinjection of an NOS inhibitor into the nucleus
tractus solitarius in the rabbit increased renal sympathetic nerve
activity and blood pressure. Changes in nNOS mRNA abundance in the
hypothalamus and the CVLM have been detected in two-kidney, one clip
hypertensive rats.19 These results, together with our
data, suggest that a decrease in NO production may contribute
to increases in blood pressure mediated by the central nervous
system.
We have also detected aldosterone synthase mRNA rat brain
(Takeda et al, unpublished data, 1996), and Gomez-Sanchez et
al25 have demonstrated presence of several steroid
synthases, including aldosterone synthase, in rat brain.
Further study is necessary to clarify the relation between brain
mineralocorticoid hormones and the NO system in the regulation of blood
pressure.
 |
Selected Abbreviations and Acronyms
|
|---|
| CVLM |
= |
caudal ventrolateral medulla |
| ICV |
= |
intracerebroventricular |
| L-NNA |
= |
N -nitro-L-arginine |
| nNOS |
= |
neuronal nitric oxide synthase |
| NO |
= |
nitric oxide |
| NOS |
= |
nitric oxide synthase |
| PCR |
= |
polymerase chain reaction |
| RVLM |
= |
rostral ventrolateral medulla |
|
Received January 16, 1997;
first decision February 12, 1997;
accepted March 11, 1997.
 |
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