Regulation of type 1 ANG II receptor in
vascular tissue: role of a1-adrenoreceptor
YONG DU, JINGXIN QIU, SHARON H. NELSON, AND DONNA H. WANG
Department of Internal Medicine, Hypertension and Vascular Research,
University of Texas Medical Branch, Galveston, Texas 77555–1065
renin-angiotensin system; sympathetic nervous system; gene
regulation
THE RENIN-ANGIOTENSIN SYSTEM and the sympathetic
nervous system have each been implicated in the
primary causes of certain forms of clinical hypertension
and congestive heart failure. Of the effects on cardiovascular tissues, these two systems influence vascular
tone and growth of smooth muscle cells (24, 28, 29). The
effects of the pressor substances of these two systems,
angiotensin II (ANG II) and norepinephrine (NE), are
triggered by their interaction with specific receptors on
the vascular wall. It has been demonstrated that the
a1-adrenergic receptor mediates sympathetic vasoconstriction of the blood vessel (12), whereas most vascular
ANG II receptors in all species studied to date are
mainly of the type 1 ANG II receptor (AT1 ) (4, 7, 30) that
mediates contractile and growth effects of ANG II in
vascular smooth muscle (5, 31, 32).
It is well known that there are multiple interactions
between the renin-angiotensin system and the sympathetic nervous system. For example, ANG II facilitates
R1224
sympathetic neurotransmission at several sites, including the central nervous system (22), adrenal medulla
(21), sympathetic ganglia (17), and presynaptic noradrenergic nerve terminals (1, 14, 18). On the other hand,
stimulation of the sympathetic nervous system leads to
renin secretion and ANG II generation (11). It is
conceivable that these two systems interact at or
beyond the receptor levels. Indeed, it has been shown
that NE negatively regulates ANG II receptors in
cultured brain neurons through its interaction with
a1-adrenergic receptors (25). However, it is unknown
whether NE, the primary pressor substance of sympathetic innervation of blood vessels, participates in ANG
II receptor regulation in the vascular tissues. An understanding of vascular ANG II receptor regulation by the
sympathetic nervous system may provide insights into
the overall mechanisms by which these two pressor
systems interact. Therefore, the present study was
designed 1) to investigate the effect of NE on AT1 gene
expression and AT1 receptor density in the aorta and
cultured vascular smooth muscle cells (VSMC) of rats
and 2) to identify the specific pathway responsible for
NE-induced regulation of the vascular AT1 receptor.
MATERIALS AND METHODS
Animal groups. Seven-week-old male Wistar rats weighing
179 6 4 g (Charles River Laboratories, Wilmington, MA) were
randomly divided into four groups. Group 1 received 0.9%
NaCl (C1, n 5 6), group 2 received NE dissolved in 0.9% NaCl
(NE, n 5 8), group 3 received 50% dimethyl sulfoxide (DMSO)
(C2, n 5 6), and group 4 received prazosin 1 50% DMSO (Pr,
n 5 6). All the rats were anesthetized with a single intraperitoneal injection of ketamine hydrochloride (80 mg/kg) and
xylazine (1 mg/kg), and osmotic minipumps were implanted
subcutaneously between the scapulae. Physiological saline or
NE (0.5 µg · kg21 · min21 ) was infused continuously for 2 wk by
osmotic minipumps (Alzet model 2002, Alza, Palo Alto, CA). It
was reported that this dose of NE did not increase blood
pressure in the conscious dog (15). Similarly, DMSO or a
nondepressor dose of prazosin (3.5 µg · kg21 · min21 ) (26) was
infused continuously for 2 wk by osmotic minipumps (Alzet
model 2ML2, Alza). At the end of the 2-wk treatment period,
rats infused with NE and saline were decapitated. Blood
samples (,3 ml) were collected in heparinized tubes containing 5 ml of sodium metabisulfite at 4°C and were centrifuged
at 3,000 revolutions/min for 15 min. Plasma was then frozen
at 220°C for measurement of plasma NE levels with the use
of high-performance liquid chromatography (8). Rats infused
with prazosin and DMSO were anesthetized with the dose of
ketamine and xylazine described above, and the left carotid
artery was catheterized for the measurement of mean arterial
pressure (MAP). MAP responses to bolus injections of 3 µg/kg
a1-adrenoreceptor agonist phenylephrine were assessed to
evaluate the effectiveness of blockade of a1-adrenoreceptors
with prazosin. All animal procedures were in accordance with
0363-6119/97 $5.00 Copyright r 1997 the American Physiological Society
Downloaded from http://ajpregu.physiology.org/ by 10.220.32.246 on June 15, 2017
Du, Yong, Jingxin Qiu, Sharon H. Nelson, and Donna
H. Wang. Regulation of type 1 ANG II receptor in vascular
tissue: role of a1-adrenoreceptor. Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R1224–R1229, 1997.—
Angiotensin II (ANG II) and norepinephrine (NE) are important regulators of vascular function and structure. Recent
studies showed that there are multiple interactions between
these two potent vasoconstrictor agents. The present experiment was designed to investigate the effect of NE on the
expression of the type 1 ANG II receptor (AT1 ) in the aorta
and cultured vascular smooth muscle cells (VSMC) of rats.
Rats were subcutaneously infused with either NE (0.5
µg · kg21 · min21, n 5 6) or the a1-adrenoreceptor antagonist
prazosin (3.5 µg · kg21 · min21, n 5 6) for 2 wk. Body weight
and tail cuff systolic blood pressure were not modified compared with the vehicle control (P . 0.05). Northern blot
analysis showed that AT1 mRNA levels in aorta were decreased by 38% in NE-treated rats and increased 117% in
prazosin-treated rats (P , 0.05) compared with control. To
determine whether NE directly regulates expression of vascular AT1 mRNA and AT1 receptor density, Northern blot
analysis and radioligand binding experiments were performed in cultured VSMC. Incubation of VSMC with NE (1027
M) led to 44% decrease in AT1 mRNA levels (P , 0.05) and
39% decrease in AT1 receptor density (P , 0.05). Prazosin, but
not the a2-adrenoreceptor antagonist yohimbine, prevented
NE-induced decrease in AT1 mRNA and AT1 receptor density
in these cells. Taken together, our results indicate that
vascular AT1 gene expression and receptor protein are regulated by ambient NE levels, and NE-induced downregulation
of AT1 mRNA and receptor protein is mediated, at least in
part, by activating a1-adrenoreceptors.
REGULATION OF ANG II RECEPTOR IN VASCULAR TISSUE
(20 mM sodium phosphate, pH 7.1–7.2). Homogenates were
then centrifuged at 48,000 g for 20 min at 40°C. Cell
membrane was resuspended in assay buffer [50 mM sodium
phosphate, 150 mM NaCl, 1 mM EDTA, and 0.1 mM bacitracin, pH 7.2] and recentrifuged. After resuspension in assay
buffer, an aliquot of the cell membrane suspension was used
for protein assay with the use of modified Bradford method
(Bio-Rad, Hercules, CA) (3). To measure total ANG II receptors, 10 µg protein were incubated with 125 pM to 2 nM
125I-labeled [Sar,Ile]ANG II (kindly provided by Dr. Robert C.
Speth, Washington State University, Pullman, WA) in a final
volume of 200 µl assay buffer containing 0.1% bovine serum
albumin. To measure the AT1 receptor density, 0.5 nM 125I[Sar,Ile]ANG II was used in the presence or absence of the
specific AT1 antagonist losartan (1 µM). Nonspecific binding
was measured in the presence of 1 µM unlabeled ANG II.
Binding assay was performed for 120 min at room temperature and was followed by immediate filtration through glass
fiber filters (Whatman GF/C, Hillsboro, OR). The filter-bound
radioactivity was counted in a gamma spectrometer (Beckman, LS 3801, Irvine, CA). Receptor affinity and concentration were calculated by Scatchard analysis using the GraphPAD InStat software.
Statistical analysis. Results are means 6 SE. The data
were analyzed either by unpaired Student’s t-test (between 2
groups) or by one-way analysis of variance followed by
Tukey-Kramer multiple comparison tests (for multiple
groups). Differences were considered statistically significant
at P , 0.05.
RESULTS
There were no significant differences in the body
weights of the rats in the different groups at the end of
the experiments [(in g) C1, 270 6 6; NE, 263 6 6; C2,
283 6 7; Pr, 300 6 12]. Systolic blood pressures were
not modified by the infusion of NE or prazosin compared with respective controls [before implantation of
osmotic pumps (in mmHg): C1, 117 6 5; NE, 118 6 4;
C2, 117 6 4; Pr, 110 6 5 and at the end of the
experiments: C1, 109 6 5; NE, 114 6 7; C2, 115 6 5; Pr,
118 6 4]. We did not measure MAP in rats infused with
NE and saline because these rats were decapitated for
the measurement of plasma NE levels at the end of the
experiments. The MAP at the end of the experiments
for prazosin- and DMSO-infused rats was 95 6 3
mmHg and 97 6 5 mmHg (P . 0.05), respectively.
Plasma NE levels were measured in rats infused
with saline or NE to evaluate the effectiveness of NE
administration. Plasma NE levels were about three
times higher in NE-infused rats (107 6 43 pmol/ml)
than in saline-infused rats (30 6 5 pmol/ml), but this
difference did not reach statistical significance (P .
0.05). Plasma NE levels in NE-infused rats were 1.07 3
1027 M, which were almost equal to the concentration
used in the in vitro experiments (1027 M). To evaluate
the efficacy of a1-adrenergic receptor blockade by prazosin, intra-arterial blood pressure responses to bolus
injection of a1-adrenoreceptor agonist phenylephrine
were measured in rats infused with DMSO or prazosin.
The pressor response to 3 µg/kg phenylephrine was
44 6 7 mmHg in DMSO-infused rats but was undetectable in prazosin-treated rats, indicating that a1-
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the National Institutes of Health Guidelines for the Care and
Use of Laboratory Animals.
Blood pressure measurement. Indirect tail cuff systolic
blood pressures were routinely obtained in all rats by use of a
Narco Bio-Systems Electro-Sphygmomanometer (Houston,
TX). The pressures were measured in conscious rats every 3
days for 14 days, beginning 1 day before surgery. The blood
pressure value for each rat was calculated as the average of
three separate measurements at each session.
Cell culture. Seven to fifteen passages of VSMC from the
thoracic aorta of male Sprague-Dawley rats (kindly provided
by Dr. Marschall Runge, University of Texas Medical Branch)
were cultured in Dulbecco’s modified Eagle’s medium (DMEM)
containing 10% fetal calf serum, 0.68 mM L-glutamine, 100
U/ml penicillin, and 100 µg/ml streptomycin in a humidified
incubator with a 95% air-5% CO2 atmosphere at 37°C. After
70% confluence was reached, the medium was replaced by
serum-free DMEM, and the cells were cultured for 48 h to
become quiescent (10). The cells were divided and treated
with phosphate-buffered saline (PBS) (control), NE (1027 M),
prazosin (Pr, 1027 M), NE 1 Pr, yohimbine (Yo, 1027 M) and
NE 1 Yo (20). The cells were then collected and used for RNA
extraction (after 12-h treatment) or radioligand binding
assay (after 24-h treatment).
cDNA probes. To make AT1 cDNA probes, a clone pUC19
containing a 2.3-kb fragment of the rat AT1a receptor cDNA
was digested with Kpn I and EcoR I to obtain a 790-bp
fragment (2180 to 1610) (kindly provided by Dr. Tadashi
Inagami, Vanderbilt University, Nashville, TN) (13). Because
this fragment contains the AT1a coding region where AT1a and
AT1b cDNAs exhibit high nucleotide sequence identity, it was
used as a template for making AT1 cDNA probes that hybridize to both AT1a and AT1b mRNA. Probes were labeled with
32P-labeled dCTP using a Multiprime DNA labeling system
(Amersham, Arlington, IL) to a specific activity of 3 3 108
counts · min21 · µg21. The labeled probes were separated from
unincorporated nucleotide using Mini-Spin G-50 DNA purification spin columns (Worthington Bio, Freehold, NJ).
RNA extraction and Northern blots. Total RNA of aorta and
VSMC was extracted with use of the guanidine thiocyanatephenol-chloroform extraction protocol (6). Electrophoresis of
30 µg of denatured RNA from each preparation was carried
out in a 1% agarose gel containing 2.2 M formaldehyde. RNA
was transferred to a positively charged nylon membrane. The
membrane was baked at 80°C for 2 h in a vacuum oven. After
prehybridization for 5 h at 42°C in 50% deionized formamide,
53 Denhart’s solution, 53 saline sodium citrate (SSC), 0.5%
sodium dodecyl sulfate (SDS), and 200 µg/ml of denatured
salmon sperm DNA, the membrane was hybridized with the
32P-labeled probes for 18–20 h. The membrane was then
washed successively in 23, 13, and 0.53 SSC (2 times, 10
min each) containing 0.1% SDS. The washing temperature
was 65°C for each probe. Blots were exposed to XAR-5 X-ray
film (Eastman Kodak, Rochester, NY). To correct the differences in RNA loading, Northern blots were incubated at 90°C
for 10 min in 20 mM tris(hydroxymethyl)aminomethane
(Tris)-HCl (pH 8.0) to strip off the AT1 cDNA probes and
rehybridized with 32P-labeled probe for 18S rRNA. Autoradiographic signals were scanned with a laser densitometer
(Ultrascan XL Laser Densitometer, Bromma, Sweden). Relative gene expression was calculated as the ratio of AT1 mRNA
to 18S rRNA and expressed as a percentage of the respective
control group.
Ligand binding assay. Cultured VSMC cells were divided
into four groups and treated with the same doses of NE,
prazosin, NE 1 prazosin, and PBS as described above. After
24 h, cells were collected and homogenized in hypotonic buffer
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R1226
REGULATION OF ANG II RECEPTOR IN VASCULAR TISSUE
Fig. 1. Northern blot analysis of type I ANG II receptor (AT1 ) mRNA
in the aorta of rats infused with 0.9% NaCl (control) or norepinephrine (NE). Results were calculated as the ratio AT1 mRNA/18S rRNA
and expressed as percentage of control. Values are means 6 SE. * P ,
0.05.
Fig. 2. Northern blot of AT1 mRNA in the aorta of rats infused with
50% DMSO in 0.9% NaCl (control) or prazosin. Results were calculated as the ratio AT1 mRNA/18S rRNA and expressed as percentage
of control. Values are means 6 SE. * P , 0.05.
NE-treated group than in the other three groups, but
this difference did not reach statistical significance.
Figure 4 shows AT1-specific binding sites that were
calculated by measuring the difference in 0.5 nM
Fig. 3. A: Northern blot analysis of AT1 mRNA and 18S rRNA in
cultured vascular smooth muscle cells (VSMC). Ten micrograms of
total RNA were isolated after 12 h of incubation with phosphatebuffered saline (PBS) (control, lane 1), norepinephrine (NE, 1027 M,
lane 2), prazosin (Pr, 1027 M, lane 3), NE 1 Pr (lane 4), yohimbine
(Yoh, 1027 M, lane 5), and NE 1 Yoh (lane 6). B: densitometric
analyses of Northern blots in which AT1 mRNA levels were normalized by 18S rRNA and expressed as percentage of control. Results are
means 6 SE of 5 separate experiments. * P , 0.05 vs. control; 1 P ,
0.05 vs. NE; # P , 0.05 vs. Yoh.
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adrenergic receptors were effectively blocked by prazosin.
AT1 mRNA content in the rat aorta was determined
by Northern blot analysis in all four experimental
groups. Blots were then stripped and rehybridized to
18S rRNA probes. To determine if DMSO treatment has
an effect on aortic AT1 mRNA levels, RNA samples from
the aorta of DMSO- or saline-infused rats were analyzed first. We found that there was no significant
difference in aortic AT1 mRNA levels between DMSOinfused (AT1 mRNA/18S rRNA, 0.8 6 0.1) and salineinfused (1.1 6 0.1, P . 0.05) rats. Aortic AT1 mRNA
levels were significantly decreased in NE-infused rats
compared with saline-infused rats (Fig. 1). Conversely,
aortic AT1 mRNA levels were significantly increased in
prazosin-infused rats compared with DMSO-infused
rats (Fig. 2).
To determine whether NE has a direct effect on AT1
gene expression in VSMC, AT1 mRNA levels were
determined by Northern blot analysis in cultured VSMC
treated with NE and/or a-adrenergic receptor antagonists (Fig. 3A). Northern blot analysis (Fig. 3B) indicated that AT1 mRNA levels were decreased by 44% in
NE-treated cells compared with PBS-treated cells.
Prazosin and yohimbine did not modify the expression
of AT1 mRNA compared with that of PBS-treated cells,
which may reflect that there was no basal NE level in
the culture medium. However, NE-induced downregulation of AT1 mRNA expression was fully prevented by
the addition of prazosin, indicating that an a1-adrenergic receptor-mediated mechanism is operating. In contrast, NE-induced downregulation of AT1 mRNA was
not modified by the addition of yohimbine, indicating
that the a2-adrenergic receptor may not participate in
NE-induced regulation of AT1 mRNA expression.
The radioligand binding data are summarized in
Table 1. No significant difference in the binding constants was found among VSMC preparations from
control, NE, prazosin, and NE 1 prazosin-treated
groups. The total receptor number was lower in the
REGULATION OF ANG II RECEPTOR IN VASCULAR TISSUE
Table 1. Changes in ANG II receptors in cultured
VSMC in response to NE and/or prazosin treatment
Control
NE
Prazosin
NE 1 prazosin
Bmax , fmol/mg protein
Kd , pM
228 6 23
153 6 25
201 6 14
221 6 31
482 6 81
548 6 161
434 6 49
637 6 173
Values are means 6 SE; n 5 3 for each condition. Bmax , maximal
binding capacity; Kd , dissociation constant; VSMC, vascular smooth
muscle cells; NE, norepinephrine.
125I-[Sar,Ile]ANG
DISCUSSION
We examined the regulation of the AT1 receptor in the
aorta and cultured VSMC of rats treated with NE and
a-adrenergic receptor antagonists. The present study
contains several distinct observations. First, the data
from the in vivo study demonstrate that continuous
infusion of NE without alteration of the blood pressure
decreases AT1 mRNA levels in the aorta of the rats.
Conversely, infusion of a nondepressor dose of prazosin
increases aortic AT1 mRNA content. Furthermore, the
data from the in vitro study show that NE has a
negative effect on both AT1 mRNA expression and AT1
receptor density in cultured VSMC. This inhibitory
effect of NE can be prevented by the a1-adrenoreceptor
antagonist prazosin, but not by the a2-adrenoreceptor
antagonist yohimbine. To our knowledge, this is the
first direct evidence showing that NE negatively regulates AT1 receptor expression in the vascular tissue
Fig. 4. Bar graph showing AT1 receptor density in cultured VSMC
treated with PBS (control), NE (1027 M), prazosin (Pr, 1027 M), or
NE 1 Pr for 24 h. Values were obtained by measuring difference of
0.05 nM 125I-[Sar,Ile]ANG II binding in presence or absence of 1 µM
losartan. Results are expressed as means 6 SE of 3 experiments.
* P , 0.05 vs. control; 1 P , 0.05 vs. NE.
through an a1-adrenergic receptor-mediated mechanism.
The interactions between the renin-angiotensin system and the sympathetic nervous system have been
found in various tissues at different levels (1, 14, 19,
21). ANG II works within the central nervous system to
stimulate sympathetic outflow and promotes the release of catecholamines from the adrenal medulla (2).
ANG II also potentiates the pressor effects of the
peripheral sympathetic nervous system. This potentiation is achieved through facilitation of peripheral adrenergic neurotransmission, inhibition of NE reuptake,
and enhancement of postjunctional response of VSMC
to a1-adrenoreceptor stimulation (9). On the other
hand, low-frequency renal sympathetic nerve stimulation promotes renin release through activation of b1adrenoreceptors (19). All of this evidence indicates that
the renin-angiotensin and sympathetic nervous systems interact positively with each other.
In opposition to these positive interactions, our present results indicate that the sympathetic nervous system negatively regulates the vascular AT1 receptor in
vivo and in vitro. Our results are consistent with
observations reported in other tissues. For example, it
has been shown in brain neuronal cultures of WistarKyoto rats that NE decreases AT1 receptor density and
its gene expression (33). Also, renal denervation or
sympathetic blockade with guanethidine increases glomerular ANG II receptor density in normotensive and
hypertensive rats (23), suggesting that the sympathetic
nervous system exerts an inhibitory effect on AT1
receptor expression in glomeruli. These studies provide
clear evidence for heterologous downregulation of the
AT1 receptor by NE. As a cautionary note, because it is
well known that NE causes renin release and an
increase in circulating ANG II, the contribution of
activation of the renin-angiotensin system to NEinduced downregulation of AT1 mRNA in the present in
vivo experiments cannot be ruled out.
The question arises as to the possible mechanisms by
which NE induces downregulation of the AT1 receptor
in the vascular tissue. Among the many possibilities is
that NE activates a1-adrenergic receptors and, through
modulation of one or more signaling pathways, downregulates AT1 receptor gene expression. Support of this
hypothesis comes from our observations that 1) blockade of the a1-adrenoreceptor with prazosin increases
AT1 mRNA levels in the aorta of the rat; this increase
does not appear to be an artifact of the effect of DMSO
because our preliminary experiments showed that there
is no significant difference in aortic AT1 mRNA levels
between DMSO and saline-infused rats, and 2) the
inhibitory effect of NE on both AT1 mRNA and receptor
protein in cultured VSMC was prevented by cotreatment with prazosin but not with the a2-adrenoreceptor
antagonist yohimbine. It is possible that yohimbine at
0.1 µM may not be sufficient to completely block
a2-adrenoreceptors. However, the fact that yohimbine
had no effect whatsoever does serve to rule out involvement of this receptor type. We have shown that a
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II binding in the presence or absence
of 1 µM losartan. AT1 receptor density was decreased by
39% in NE-treated compared with PBS-treated VSMC
(P , 0.05). This decrease was abolished by the addition
of prazosin, indicating that activation of the a1adrenoreceptor by NE downregulates the AT1 receptor
in cultured VSMC.
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REGULATION OF ANG II RECEPTOR IN VASCULAR TISSUE
feedback on AT1 receptor by ANG II and/or NE may
exist in hypertensive rats.
We express our thanks to Wilma Frye for expert secretarial skills.
This study was supported in part by National Institutes of Health
Grant HL-52279 and a grant to D. H. Wang from the John Sealy
Endowment Fund for Biomedical Research.
The first two authors contributed equally to this study.
Address for reprint requests: D. H. Wang, Dept. of Internal
Medicine, 8.104 Medical Research Bldg., Univ. of Texas Medical
Branch, Galveston, TX 77555–1065.
Received 21 February 1997; accepted in final form 23 June 1997.
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nonpressor dose of ANG II infusion (25 ng · kg21 · min21 )
for 2 wk downregulates AT1 mRNA levels in both the
aorta and mesenteric resistance arteries (27). This
homologous downregulation of the AT1 receptor in the
vascular tissue seems to be mediated by both transcriptional and posttranscriptional mechanisms (16). The
results from the present study showed that the changes
in AT1 receptor density parallel the changes in AT1
mRNA levels in cultured VSMC, indicating that NEmediated downregulation of AT1 receptors occurs, at
least partially, via a diminished AT1 receptor mRNA
level. Although it is unknown whether NE-induced
heterologous downregulation of AT1 receptors occurs at
transcriptional or posttranscriptional levels, the data
represent a clear example of cross talk between the two
plasma membrane receptors.
The physiological and pathophysiological significance of NE on AT1 receptor expression in the circulatory system of the rats is that the vascular AT1 receptor
is a central component of the renin-angiotensin system,
and regulation of its expression is likely to be important
in cardiovascular responsiveness. On the basis of our
data and those of others, we propose the following
events: a positive interaction between ANG II and NE
through an action on the vascular AT1 and a1-adrenergic receptor to produce a greater vasoconstriction than
that produced by either alone. At the same time,
persistent increased ANG II and NE will downregulate
the AT1 receptor, providing a ‘‘negative feedback’’ mechanism to attenuate the action of ANG II. Thus cyclic
upregulation of ANG II and NE, a ‘‘feed-forward’’
mechanism, followed by downregulation of AT1 receptor
by a negative feedback mechanism may play an important homeostatic role between the renin-angiotensin
and sympathetic nervous systems in blood pressure
regulation in the normotensive rat. Conversely, in
hypertensive rats, disruption of the negative feedback
mechanism will prevent downregulation of AT1 receptor. This ultimately leads to hyperactive renin-angiotensin and sympathetic nervous systems that may contribute to blood pressure increase in hypertensive rats.
Support of this hypothesis comes from the study showing that the inhibitory effect of NE on the AT1 receptor
expression in brain neurons of Wistar-Kyoto rats is
absent in neurons of spontaneously hypertensive rats
(33). Obviously, whether such an alteration occurs in
the vascular tissue and leads to overactivity of the
effect of ANG II in hypertensive animal models remains
to be explored.
In conclusion, we have provided the first direct
evidence that NE regulates the vascular AT1 receptor
through a negative feedback mechanism both in vivo
and in vitro. The mechanisms underlying this regulation are through the a1-adrenoreceptor. These studies
suggest that, in vasculature, AT1 expression is regulated by ambient NE levels. Reciprocal regulation
between the renin-angiotensin system and sympathetic
nervous systems may play an important role in the
control of blood pressure hemostasis. By extension, it
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