From the Department of Physiology, College of Medicine, University of
Florida (Gainesville).
Correspondence to Dr M. Ian Phillips, Department of Physiology, Box 100274, College of Medicine, University of Florida, Gainesville, FL 32610. E-mail MIP{at}phys.med.ufl.edu
Surgical Procedures
Drinking Responses
Intracardiac Administration
Oligodeoxynucleotides
Autoradiography
Statistical Analysis
Effect of Central Injection of AS-ODN to AGT mRNA on SBP and
Spontaneous Drinking Response
Drinking Response
Effect of Central Injection of AS-ODN to AT1-R mRNA on
SBP and Drinking Response
Blood Pressure
Drinking Response
Effect of Peripheral Injection of AS-ODN to
AT1-R mRNA on SBP and AT1-R Binding
Autoradiography of Peripheral Tissues
The results provide evidence that the brain RAS is involved in CIH. The
AS-ODN to AT1-R mRNA inhibited the
physiological effects, pressor and drinking
responses, produced by central administration of Ang II. The results of
this study are in keeping with the hypothesis that inhibition of mRNA
translation for Ang II or AT1-R in the brain can
reduce BP of rats with CIH. When coupled with our previous results
showing that mRNA for the Ang II, AT1-R,
spontaneous-drinking, and dipsogenic responses to administration of Ang
II is increased in cold-treated rats, a role for the central RAS in
this type of experimentally induced hypertension is indicated.
The data presented here confirm the effectiveness of antisense
inhibition in reducing hypertension. In previous studies, we have used
the same AS-ODN designs to lower BP in a genetic model of hypertension,
the SHR. Gyurko et al14 showed that central
injection of AS-ODN decreased BP in SHR by blocking the protein
synthesis of central AT1-R. Wielbo et
al17 showed that AS-ODN targeted to AGT mRNA
reduced hypertension in SHR when given centrally or systemically.
Morishita et al23 also found similar AS-ODN to
AGT mRNA to be effective in transient reduction of BP in SHR. The
prolonged reduction in high BP in the present experiment confirms
the pattern of effect of AS-ODN to AT1-R ICV
observed in SHR.18 The present results expand
on these studies by demonstrating the effectiveness of antisense
inhibition in a different model of hypertension. The CIH model is
nonsurgical and nongenetic; it is an environmentally induced model of
hypertension. Thus, antisense administration lowers BP in genetic- and
cold-induced hypertension. The results also confirm the findings of
Meng et al24 and Sakai et
al25 that the drinking response to Ang II (ICV)
can be inhibited by AS-ODN to AT1-R mRNA. The
data suggest that the mechanism of hypertension development on exposure
to cold is via increased production of AGT in the brain and
consequently Ang II. Furthermore, the mechanism of CIH involves
upregulated AT1-R. Increased Ang II synthesis and
increased AT1-R induce the elevation of BP in
cold-exposed rats and maintains it, once elevated.
Injections of AS-ODN into the heart produced a significant decrease in
BP compared with injections of SCR-ODN. We used the intracardiac route
for rapid dispersal of antisense in arterial blood. The
results indicate that peripheral
AT1-R contributes to the hypertension in parallel
with changes in brain RAS. Control injections of SCR-ODN had no effect
in central or peripheral injections. Thus, the results
demonstrated that systemic administration of AS-ODN is also a viable
route and is effective for antihypertensive action.
To show that the mechanism of action responsible for these
physiological effects is due to sequence-specific
antisense inhibition, the amount of the targeted gene product, the
AT1-R, should be decreased. The results of the
autoradiography experiments confirm a significant
decrease in the number of AT1-R in aorta, adrenal
glands, and kidneys. Whether these are the sites of action for the
effect on BP or other sites are involved cannot be resolved by this
analysis. The results are not due to nonspecific effects. We
have used every type of control in prior experiments, including
scrambled, sense, vehicle, mismatch, inverted, and even antisense to
ANP to produce the opposite effects of antisense to Ang II. In every
case, the antisense to AT1-R or to AGT mRNA
produces a unique, specific response resulting in both
physiological and molecular changes, indicating
antisense inhibition. Earlier work by others using long oligos (22 mer
or longer) with multiple repeats of G bases led to nonspecific
binding.15 26 Sequences of 4 G cause
self-annealing and misleading results.26 Our
oligo design avoids these pitfalls by using shorter ODN (15 mer) and by
excluding sequences with 4 or more G repeats.
In summary, we have shown that AS-ODN, targeted to the RAS,
significantly reduced BP in a rat model of hypertension that is not
genetically, surgically, or pharmacologically induced. The antisense
administration centrally reduces BP for 3 to 4 days after a single
injection in CIH rats, and peripheral administration was
effective 24 hours after a single injection. These results demonstrate
that both the central and peripheral RAS are involved in
CIH.
Received August 20, 1997;
first decision September 19, 1997;
accepted January 19, 1998.
© 1998 American Heart Association, Inc.
Scientific Contributions
Reduction of Cold-Induced Hypertension by Antisense Oligodeoxynucleotides to Angiotensinogen mRNA and AT1-Receptor mRNA in Brain and Blood
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—Rats exposed chronically to
mild cold (5°C/41°F) develop hypertension and cardiac
hypertrophy. This provides a unique model of hypertension
that is environmentally induced. The blood
renin-angiotensin system (RAS) has been shown to play a
role in both initiating and maintaining the high blood pressure (BP) in
cold-induced hypertension. The mechanism also appears to involve both
the tissue and brain RAS because there is increased mRNA for
angiotensinogen (AGT) and angiotensin type 1
(AT1) receptors in brain and peripheral
tissues, an increased spontaneous drinking response, and an increased
dipsogenic response to acute administration of angiotensin
II (Ang II) in cold-treated rats. Antisense
oligodeoxynucleotides (AS-ODN), targeted to the RAS, have
been shown to reduce BP in spontaneously hypertensive rats. Therefore,
we injected AS-ODN in rats with cold-induced hypertension to test
whether antisense inhibition was effective in reducing this nongenetic
nonsurgical hypertension. Sprague-Dawley rats were made hypertensive by
cold exposure and injected
intracerebroventricularly with AS-ODN
to AGT mRNA (n=6) or AT1 receptor mRNA (n=6).
Systolic BP was recorded by tail cuff 24 hours later for 2
or 7 days, respectively. Systolic BP decreased significantly in
response to AGT–AS-ODN (40±6 mm Hg, P<0.01)
within 1 day after injection and to AT1 receptor–AS-ODN
(P<0.05) for 3 days after injection. The maximum
decrease was 41±10 mm Hg. Systolic BP then gradually
increased to the preinjection level. The spontaneous drinking response
to cold treatment also decreased significantly (P<0.05)
after AGT–AS-ODN or AT1 receptor–AS-ODN
intracerebroventricular injection.
Intracardiac injection of AT1–AS-ODN (n=6) reduced
systolic BP by 36±8 mm Hg (P<0.05) and
decreased AT1 receptor as measured by
autoradiography in aorta, adrenal glands, and kidneys
24 hours after injection. These data show that AS-ODN reduces BP in
cold-induced hypertension and that the hypertension involves both
peripheral tissues and central RAS in addition to
blood-borne RAS mechanisms.
Key Words: hypertension, cold-induced • angiotensinogen • angiotensin II • RNA • receptors • antisense elements
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Rats exposed to mild
cold (5°C/41°F) develop hypertension.1 2 3 4
This CIH is a nongenetic, nonsurgical model for studying hypertension
in rats. Our previous studies have shown that the blood-borne RAS
either prevents or attenuates CIH.5 6 The
mechanism also appears to involve both peripheral tissue
and central RAS because there is increased mRNA for AGT and/or
AT1-R in brain and peripheral
tissues,7 increased spontaneous drinking
response, and increased dipsogenic response to acute administration of
Ang II either centrally or subcutaneously.8 The
receptors for Ang II in the diencephalon of rats have been correlated
directly with the drinking response to Ang
II.9 10 Furthermore, studies also suggest that
there is a direct correlation between the state of receptors for Ang II
in the diencephalon and development of hypertension, ie, upregulation
of receptors for Ang II has been linked to the induction of both
deoxycorticosterone acetate–salt and spontaneously induced
hypertension.9 10 11 12 13 Tests of the dipsogenic
responsiveness to Ang II, spontaneous drinking response to cold, and
AT1-R mRNA in brain show much greater responses
in cold-treated rats.8 This suggests that the
receptors for Ang II are upregulated in rats exposed chronically to
cold. Additional studies have shown an increased amount of mRNA for
AGT, the substrate for the RAS, in the brains of cold-treated rats
compared with rats kept at room temperature as controls. This raises
the possibility that both increased production of Ang II and
upregulation of Ang II receptors contribute to the elevation of BP
during exposure to cold. An increased amount of mRNA of AGT and/or
AT1-R in peripheral tissues (liver,
adrenal glands, and aorta) of cold-treated rats suggests that an
overactive peripheral tissue RAS is involved in CIH as
well. AS-ODN, targeted to AGT mRNA or AT1-R mRNA,
have been shown to reduce BP in SHR, which demonstrates that AS-ODN are
specific and reduce an overactive RAS.14 15 16 17 18
Therefore, to assess more directly the role of the central RAS in CIH,
AS-ODN to AGT mRNA and to AT1-R mRNA were
administrated centrally, and their effects on BP and spontaneous
drinking in chronically cold-exposed rats were determined. To assess
the role of the peripheral RAS in CIH, AS-ODN to
AT1-R mRNA was administered by intracardiac
injection, and its effect on BP and AT1-R in
chronically cold-exposed rats was determined. We hypothesized that
central injection of AS-ODN to AGT or AT1-R mRNA
would decrease BP and spontaneous drinking response, and that a
peripheral injection of AS-ODN to
AT1-R mRNA would decrease BP and
AT1-R binding in cold-treated rats.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Animal Model
Forty-two adult male Sprague-Dawley rats (225 to 250 g)
were acquired from Harlan. The rats were kept in individual cages in a
room with a 12-hour light/dark cycle. They were given tap water to
drink and standard rat chow to eat ad libitum. For a 2-week control
period, the rats were kept at room temperature (25°C). During this
time, SBP and body weight of each rat were measured weekly. SBP was
recorded by tail cuff. After 2 weeks, all rats were transferred to
ventilated chambers kept at 5±1°C. SBP and body weight were measured
twice weekly by tail cuff until a significant and stable increase in
SBP was noted compared with SBP before cold exposure. At the end of 5
weeks, the rats were divided randomly into seven groups (n=6 per
group). Two groups received either AS-ODN or SCR-ODN to AGT mRNA. Two
groups received either AS-ODN or SCR-ODN to AT1-R
mRNA. One control group received ICV injection of 2 µL artificial
CSF. The last two groups received either AS-ODN or SCR-ODN to
AT1-R mRNA by intracardiac injection. Before
injection, the ODN were dissolved in 2 µL artificial CSF at a
concentration of 25 µg/µL. This dose has been used previously
without side effects or toxicity.14
Each rat was anesthetized with sodium pentobarbital (65
mg/kg body wt IP). Rats were mounted in a Kopf stereotaxic
apparatus, and the skull was exposed. A burr hole was made,
and an injector connected to a 10-µL Hamilton microsyringe was
lowered into place. For ICV injection, a single injection of ODN was
administered into the right lateral cerebral ventricle (coordinates:
1.0 mm lateral, 1.0 mm caudal to the bregma, 5.0 mm
below the skull surface). Each rat was injected with either 50 µg
AS-ODN or 50 µg SCR-ODN (dissolved in 2 µL artificial CSF) or with
2 µL artificial CSF alone. SBP was recorded 24 hours later and
daily until pressure had returned to the preinjection level.
Water intakes were measured gravimetrically at 24 hours for 3
days before injection and for 2 or 7 days after rats received the ICV
injection of AGT-ODN or AT1- R-ODN mRNA.
For intracardiac injection, each rat was anesthetized
with Metafane. Rats were injected with 100 µg of either AS-ODN or
SCR-ODN to AT1-R mRNA (in 100 µL artificial
CSF) directly into the heart with a 0.4x12-mm needle (Monoject 250).
Twenty-four hours later, SBP was recorded, the rats were then
killed, and tissues were removed for
autoradiography.
The ODN was synthesized as a phosphorothioated 15-mer or 18-mer
ODN at the DNA Core, University of Florida, using designs based on cDNA
of AGT19 and AT1-R.20 The antisense
sequence to AGT mRNA was 5'-CGGTGGGAGGTCACGG-3', the 18-mer targeted to
bases -5 to +13 of AGT mRNA encompassing the AUG codon; and the
AT1-R mRNA was 5'-TAACTGTGGCTGCAA-3', 15-mer
complementary to bases +63 to +77 of the AT1-R
mRNA. Control injections contained SCR-ODN (the sequence for AGT is
5'-CAG GGA TCT CTG GCC GAC-3' and for AT1-R mRNA
it is 5'-CTT ACT AGC CTA GGC-3') or artificial CSF.
Rats were deeply anesthetized with sodium
pentobarbital (65 mg/kg body wt IP) and perfused transcardially with
0.9% saline. The tissues were removed and kept frozen at -20°C
until cryostat sectioning into 20-µm sections. The sections were
mounted onto gelatin-coated slides. The slides were preincubated in
assay buffer (150 mmol/L NaCl, 50 mmol/L sodium phosphate,
1 mmol/L EDTA, 0.1 mmol/L bacitracin, pH 7.2) for 30 minutes
and then incubated with the same buffer with the addition of 500 pmol/L
125I-Sar1,Ile8-Ang
II for 2 hours. The sections were incubated with the
radioligand in the presence or absence of 1 µmol/L
Ang II to determine nonspecific and total receptor binding.
AT1-R or AT2-R binding was
determined in the presence of 1 µmol/L of either PD123319 or
losartan. The sections were washed and dried.
Autoradiograms were generated by exposing the slides to
x-ray films for 1 to 4 weeks. They were analyzed by
autoradiographic densitometry (Image Systems Inc). The
photos were taken directly from the image analysis system.
Optical densities of the autoradiograms were determined
by computerized microdensitometry, and the results are expressed in
femtomoles per gram of protein after comparison with the
125I-standard.21
The data for SBP were analyzed by repeated measures
one-way ANOVA using the Newman-Keuls procedure to assess the
significance of differences between two means. For ICV injection, the
data for SBP and water intakes were analyzed by a repeated
measures two-way ANOVA using the Newman-Keuls procedure to assess the
significance of differences between two means. For intracardiac
injection, SBP and AT1-R and
AT2-R binding were compared by Student's
t test. A value of P<0.05 was considered
significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Cold-Induced Hypertension
SBP increased during 5 weeks of exposure to cold (Figure 1
). At 1, 2, 3, 4, and 5 weeks of cold
exposure, SBP was 121±1, 146±3, 149±3, 157±3, and 165±3
mm Hg, respectively. By the second week of cold exposure, SBP was
significantly greater than that before cold exposure
(P<0.01). The difference was pronounced during the fifth
week of cold exposure. This result is consistent with previous
studies from this laboratory in which rats exposed to chronic cold
developed hypertension.1 2 3 4
View larger version (13K):
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Figure 1. SBP of 42 unanesthetized rats before
exposure to cold (5oC/41oF) and at weekly
intervals thereafter for 5 weeks. One standard error is set off at each
mean; when standard error is not shown, it falls within the symbol.
**P<0.01 compared with before cold exposure.
Blood Pressure
A highly significant decrease in SBP was observed in the
AS-ODN–treated rats. The result of injecting AS-ODN to AGT mRNA was
that SBP was reduced from a hypertensive level (157±6 mm Hg) to
a normotensive level (117±3 mm Hg) at 24 hours after injection
in the AS-ODN–treated rats. Figure 2
shows the effect of central injection of AS-ODN on SBP in cold-treated
rats. The SBP of AS-ODN–treated rats was significantly decreased to
117±3 mm Hg at 24 hours after injection (P<0.01) and
to 139±5 mm Hg at 48 hours after injection (P<0.05).
These pressures were significantly lower than those of the SCR-ODN–or
artificial CSF–treated groups. There was no significant difference in
the response to SCR-ODN injection (from 152±3 to 155±5 mm Hg at
24 hours after injection, to 150±7 mm Hg at 48 hours after
injection, P>0.05) or to artificial CSF injection (from
163±5 to 155±4 mm Hg at 24 hours after injection, to
161±6 mm Hg at 48 hours after injection, P>0.05).
Thus, AS-ODN significantly reduced SBP compared with SCR-ODN or
artificial CSF administration at the same time intervals.
View larger version (14K):
[in a new window]
Figure 2. Effect of ICV AGT mRNA AS-ODN administration on
SBP in cold-treated rats. Rats were given 50 µg AS-ODN to AGT mRNA or
SCR-ODN, or 2 µL artificial CSF directly into the right lateral
ventricle. SBP of the antisense-treated rats was significantly
decreased to a normotensive level at 24 hours and at 48 hours after
injection compared with SCR-ODN or artificial CSF administration at the
same time intervals (day 1, **P<0.01; day 2,
*P<0.05) (n=6).
The spontaneous drinking response was also significantly decreased
by AS-ODN. Chronic cold exposure increases spontaneous drinking
response (the percent increase from control is 10% at 1 week, 19% at
3 weeks, and 41% at 5 weeks during cold exposure), probably due to the
increased activity of brain RAS.8 22 Figure 3 shows the effect of central injection
of AS-ODN on spontaneous drinking response in cold-treated rats. The
drinking response of AS-ODN–treated rats was significantly decreased
from 49±3 to 27±4 mL/d at 24 hours after injection
(P<0.01) and to 30±6 mL/d at 48 hours after injection
(P<0.01). There was no significant difference in the
response to SCR-ODN injection (from 59±14 to 65±6 mL/d at 24 hours
after injection, to 68±6 mL/d at 48 hours after injection,
P>0.05) or to artificial CSF injection (from 47±10 to
50±8 mL/d at 24 hours after injection, to 61±8 mL/d at 48 hours after
injection, P>0.05). The AS-ODN significantly reduced
spontaneous drinking compared with SCR-ODN or artificial CSF
administration at the same time intervals (P<0.05).
View larger version (15K):
[in a new window]
Figure 3. Effect of ICV AGT mRNA AS-ODN administration on
spontaneous drinking response in cold-treated rats (same rats as in
Figure 2 
). Spontaneous drinking response of the antisense-treated rats
was significantly decreased at 24 hours (**P<0.01) and
at 48 hours (**P<0.01) after injection compared with
SCR-ODN or artificial CSF administration at the same time intervals
(n=6).
The result of injecting AS-ODN to AT1-R mRNA
was that SBP and water intake were reduced in the AS-ODN–treated
rats.
Figure 4 shows the effect of central
injection of AS-ODN on SBP in cold-treated rats. The decrease in SBP
began 24 hours (from 172±6 to 138±5 mm Hg, P<0.05)
after the single dose of 50 µg (25 µg/µL). The SBP remained
decreased by >30 mm Hg, and the maximum effect was seen 72 hours
after the injection (to 131±5 mm Hg, P<0.01). The
SBP gradually increased and reached the control level by day 5 to 6
after injection. The controls, artificial CSF and SCR-ODN, produced no
significant reduction in SBP.
View larger version (18K):
[in a new window]
Figure 4. Effect of ICV AT1-R mRNA AS-ODN
administration on SBP in cold-treated rats. Rats were given 50 µg
AS-ODN to AT1-R mRNA, or SCR-ODN, or 2 µL artificial CSF
directly into the right lateral ventricle. SBP of the antisense-treated
rats was significantly decreased 24 hours after injection; at day 3,
this decrease was even greater. From day 4, SBP gradually reached the
control level compared with SCR-ODN or artificial CSF administration at
the same time intervals (day 1, *P<0.05; days 2 and 3,
**P<0.01) (n=6).
Figure 5 shows the effect of
central injection of AS-ODN on water intake in cold-treated rats. Cold
increases spontaneous water intake. The drinking after AS-ODN
administration was significantly decreased from 58±4 to 41±5 mL/d at
24 hours after injection (P<0.05). This
inhibitory effect on drinking behavior was also present
at 48 hours after injection (41±4 mL/d, P<0.05). There was
no difference in water intake after SCR-ODN (from 60±4 to 51±4 mL/d
at 24 hours after injection, to 47±4 mL/d at 48 hours after injection,
P>0.05) or artificial CSF (from 58±6 to 50±6 mL/d at 24
hours after injection, to 61±6 mL/d at 48 hours after injection,
P>0.05). The AS-ODN significantly reduced drinking compared
with SCR-ODN or artificial CSF administration at the same time
intervals (P<0.05).
View larger version (20K):
[in a new window]
Figure 5. Effect of ICV AT1-R mRNA AS-ODN
administration on spontaneous drinking response in cold-treated rats
(same rats as in Figure 4 ). Spontaneous drinking response of the
antisense-treated rats was significantly decreased at 24 hours after
injection (*P<0.05). This effect on inhibiting drinking
behavior was also present at 48 hours after injection
(*P<0.05) compared with SCR-ODN or artificial CSF
administration at the same time intervals (n=6).
To test the effectiveness of antisense inhibition delivered
systemically, injections of AS-ODN to AT1-R mRNA
were given. The effect of this AS-ODN inhibition was a significant
reduction in SBP. A single injection with the receptor AS-ODN (100 µg
in 100 µL saline) resulted in a significant fall in SBP of 35±5
mm Hg (P<0.01) in cold-treated rats (Figure 6) 24 hours later. Injection with SCR-ODN
showed no significant decrease in SBP (3±8 mm Hg,
P>0.05). To examine the tissues for changes in
AT1-R binding at 24 hours after injection, no
further time points were measured.
View larger version (23K):
[in a new window]
Figure 6. Effect of peripheral injection of
AT1-R mRNA AS-ODN on SBP in cold-treated rats. Rats were
administered 100 µg AS-ODN or SCR-ODN intracardially. SBP of the
antisense-treated rats was significantly decreased to a normotensive
level 24 hours after injection compared with SCR-ODN administration at
the same time (**P<0.01) (n=6).
Autoradiography showed that treatment with
AS-ODN resulted in a significant decrease in
AT1-R binding in aorta, adrenal glands, and
kidneys when compared with the SCR-ODN treatment. These results are
summarized in Figure 7 and Figure 8A through 8F. The decreases observed
with 100 µg AS-ODN injection were 92% in aorta, 42% in adrenal
glands, and 28% in kidneys. No decrease in AT2-R
binding was observed (data not shown).
View larger version (28K):
[in a new window]
Figure 7. 125I-Sar1,Ile8-Ang II
autoradiography analysis of multiple transverse
sections of aorta, adrenal glands, and kidneys of cold-treated rats
that received intracardiac injection in Figure 6 . Columns indicate
AT1-R binding; error bars represent standard error.
*P<0.05.
View larger version (87K):
[in a new window]
Figure 8. Specific binding of AT1-R in
various tissues. After AT1-R mRNA AS-ODN administration,
AT1-R binding was decreased compared with after SCR-ODN
administration (color code shows calibration for femtomoles per gram).
A, Aorta section of rats given SCR-ODN; B, aorta section of rats given
AS-ODN to AT1-R mRNA; C, adrenal gland section of rats
given SCR-ODN; D, adrenal gland section of rats given AS-ODN to
AT1-R mRNA; E, kidney section of rats given SCR-ODN; and F,
kidney section of rats given AS-ODN to AT1-R
mRNA.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Rats exposed to cold for several weeks develop a significant BP
elevation. This takes 3 to 4 weeks of chronic exposure to
cold.1 2 3 4 The mechanism(s) for induction of
hypertension after chronic exposure to cold is incompletely understood
and is presently under study. However, recent studies have
implicated both the central RAS and peripheral RAS as a
contributors. The peripheral RAS includes both the classic
blood-borne RAS and the tissue RAS. There is an increase in mRNA for
AGT and AT1-R in brain and peripheral
tissues7 and increased spontaneous drinking
response in cold-exposed rats that respond to Ang II administration
with an increased dipsogenic response.8 The
results of the present study support a role for the central and
peripheral tissue RAS in the maintenance of CIH in
that these experiments illustrate the viability of antisense inhibition
in vivo for reduction of BP in a nongenetic, environmentally induced
model of hypertension. Both antisense to AT1-R
and AGT mRNA were successful in reducing BP centrally and antisense to
AT1-R mRNA in reducing BP
peripherally. Reduction in BP was correlated to an
inhibition of spontaneous drinking response and to a reduction of
AT1-R binding in peripheral tissues,
respectively.
Selected Abbreviations and Acronyms
AGT
=
angiotensinogen
Ang II
=
angiotensin II
AS-ODN
=
antisense oligodeoxynucleotides
AT1-R
=
angiotensin II type 1 receptor
CIH
=
cold-induced hypertension
CSF
=
cerebrospinal fluid
ICV
=
intracerebroventricular
RAS
=
renin-angiotensin system
SBP
=
systolic blood pressure
SCR-ODN
=
scrambled oligodeoxynucleotides
SHR
=
spontaneously hypertensive rats
Acknowledgments
This study was supported by National Institutes of Health MERIT
award HL27334 and HL39154 (Dr Phillips). We wish to thank Howard Clark
and Leping Shen for their expert technical assistance.
Footnotes
1 Deceased. 
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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Z. Sun, R. Cade, Z. Zhang, J. Alouidor, and H. Van Angiotensinogen Gene Knockout Delays and Attenuates Cold-Induced Hypertension Hypertension, February 1, 2003; 41(2): 322 - 327. [Abstract] [Full Text] [PDF]
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M. I. Phillips Gene Therapy for Hypertension: The Preclinical Data Hypertension, September 1, 2001; 38(3): 543 - 548. [Abstract] [Full Text] [PDF]
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S. M. Galli and M. I. Phillips Angiotensin II AT1A Receptor Antisense Lowers Blood Pressure in Acute 2-Kidney, 1-Clip Hypertension Hypertension, September 1, 2001; 38(3): 674 - 678. [Abstract] [Full Text] [PDF]
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A. F. Moore, N. T. Heiderstadt, E. Huang, N. L. Howell, Z.-Q. Wang, H. M. Siragy, and R. M. Carey Selective Inhibition of the Renal Angiotensin Type 2 Receptor Increases Blood Pressure in Conscious Rats Hypertension, May 1, 2001; 37(5): 1285 - 1291. [Abstract] [Full Text] [PDF]
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S. Kagiyama, A. Varela, M. I. Phillips, and S. M. Galli Antisense Inhibition of Brain Renin-Angiotensin System Decreased Blood Pressure in Chronic 2-Kidney, 1 Clip Hypertensive Rats Hypertension, February 1, 2001; 37(2): 371 - 375. [Abstract] [Full Text] [PDF]
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J. B. Chambers, T. D. Williams, A. Nakamura, R. P. Henderson, J. M. Overton, and M. E. Rashotte Cardiovascular and metabolic responses of hypertensive and normotensive rats to one week of cold exposure Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2000; 279(4): R1486 - R1494. [Abstract] [Full Text] [PDF]
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M. K. Raizada, M. J. Katovich, H. Wang, K. H. Berecek, and C. H. Gelband Is antisense gene therapy a step in the right direction in the control of hypertension? Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H423 - H432. [Full Text] [PDF]
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M. I. Phillips Is Gene Therapy for Hypertension Possible? Hypertension, January 1, 1999; 33(1): 8 - 13. [Full Text] [PDF]
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Z.-Q. Wang, R. A. Felder, and R. M. Carey Selective Inhibition of the Renal Dopamine Subtype D1A Receptor Induces Antinatriuresis in Conscious Rats Hypertension, January 1, 1999; 33(1): 504 - 510. [Abstract] [Full Text] [PDF]
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