(Hypertension. 2001;37:1292.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
AT1 Antisense Distinguishes Receptors Mediating Angiotensin II Actions in Solitary Tract Nucleus
From the Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC.
Correspondence to Debra I. Diz, PhD, The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1032. E-mail ddiz{at}wfubmc.edu
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Abstract |
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Abstract—Angiotensin (Ang) II receptors in the solitary tract nucleus (nTS) are located on vagal sensory-afferent fiber terminals as well as on neuronal cell bodies. Results from in vitro slice preparations indicate that
50%
of the neuronal excitatory actions of Ang II result from actions at
presynaptic receptors. The differential contribution of actions on
fiber terminals versus neuronal cell soma to the
cardiovascular effects of Ang II in the nTS is not
known. We used antisense oligonucleotides to the
angiotensin type 1 (AT1) receptor,
which should reduce receptors on neurons within the injection site but
not those on fiber terminals projecting to the nTS. Ang II
injections (250 fmol/30 nL) into the nTS reduced blood pressure by
14±1 mm Hg and heart rate by 13±1 bpm (n=8) in male
Sprague-Dawley rats anesthetized with chloralose/urethane.
Although there was still a significant fall in pressure that was
induced by Ang II at 90 and 150 minutes after
AT1 antisense (164 pmol/120 nL) was injected
into the nTS, the response was blunted 50%
(P<0.01). Heart rate responses
were completely blocked at the 150-minute time point. Scrambled
sequence oligonucleotides did not alter Ang II
responses at any time. There was a 40% reduction in
125I[Sar1Thr8]-Ang
II binding when antisense-injected and noninjected sides of the nTS
were compared with receptor autoradiography. This
finding is consistent with the continued presence of
AT1 receptors on afferent fibers. This unique
strategy illustrates that both presynaptic fiber terminals and nTS
neurons are involved in the blood pressure lowering actions of Ang II,
whereas heart rate responses are largely due to actions directly on nTS
neurons and activation of vagal efferent pathways.
Key Words: solitary tract nucleus • medulla oblongata • circulation • angiotensin II • microinjections • oligodeoxynucleotides, antisense • receptors, angiotensin
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Introduction |
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Angiotensin (Ang) II receptors are present on vagal sensory-afferent fiber terminals in the nucleus of the solitary tract (nTS), consistent with the known localization of receptors on neuronal cell bodies in the nodose ganglion.1 2 In addition, neurons in the medial nTS and in the dorsal motor nucleus of the vagus (dmnX) also express Ang II receptors.1 2 3 4 5 6 While it is not known whether the hemodynamic actions of Ang II are mediated by actions at fiber terminals or neuronal cells within the nTS, electrophysiological evidence supports actions at both sites. Ang II elicits excitation of nodose ganglion neurons7 8 as well as neurons of the medial nTS and the dmnX.9 Other studies lend support to the idea that
50% of the responses to Ang II in the nTS
may be a result of actions at presynaptic
receptors.10 11 In
fact, unilateral nodose ganglionectomy results in a 36% to 48%
reduction in the density of Ang II receptors in the nTS of
rats.12 Antisense oligodeoxynucleotides have been used to examine the role of Ang II in neural control of the cardiovascular system. Recently, we showed that local paraventricular nucleus administration of angiotensin type 1 (AT1) receptor antisense oligonucleotides could reverse the excess hypertension caused by drinking hypertonic sodium chloride for 4 days in (mRen2)27 transgenic rats.13 A unique feature of using antisense techniques to block receptors is that distinct receptor populations (those on cell bodies versus those on nerve terminals) can be targeted. The antisense oligomer is taken up locally to interfere with synthesis of receptors in cell bodies at the injection site. However, receptors synthesized at remote locations and transported to the site via cells with fiber terminals projecting to the area are spared. Thus, unlike receptor antagonists that block all receptors in the area of the injection, antisense treatment affords a window of selectivity. We took advantage of this ability of AT1 antisense oligonucleotides to decipher whether exogenous Ang II produces its depressor and bradycardic effects in the nTS through receptors made in local nTS neurons or those synthesized elsewhere (ie, vagal afferent neurons of the nodose ganglion).
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Methods |
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Animals
Experiments were performed in male Sprague-Dawley rats (Harlan Sprague-Dawley, Indianapolis, Ind [n=6 antisense and n=3 scrambled] and Hannover Sprague-Dawley rats from the Hypertension and Vascular Disease Center Colony, Wake Forest University School of Medicine, Winston-Salem, NC [n=2 antisense and n=2 scrambled]; 9 to 12 weeks of age). Rats were housed in group cages with free access to standard rat chow and water in a temperature- and humidity-controlled room (12:12 hour light:dark cycle). Anesthesia was induced by urethane/chloralose (750 mg/35 mg per kg, intraperitoneal administration) with supplemental doses given intravenously. Catheters were inserted into a femoral artery and vein. Rats were placed in a stereotaxic frame with the head flexed downward at 45° for exposure of the dorsal medulla via atlanto-occipital membrane incision. The pipette was placed into the nTS (0.4-mm rostral and 0.4-mm lateral to calamus scriptorius, and 0.4- to 0.6-mm below the dorsal surface). Arterial pressure was monitored by a strain gauge transducer (Model DTX, Spectramed, Inc) connected to the femoral arterial catheter. Heart rate was determined from the arterial pressure wave. Pressure and heart rate were digitized and recorded with a computerized acquisition system as published previously.14 15 Depth of anesthesia throughout the experiment was monitored by corneal reflexes, respiratory rhythm, arterial pressure, and heart rate stability.
AT1 Antisense and
Scrambled Sequence Oligodeoxynucleotides
In this study, we used the same sequence oligomers as
in a previous report.13 The
sequence of the 15-mer antisense to the AT1
receptor was 5'-AGAGTTAAGGGCCAT-3'. The scrambled sequence used as a
control was 5'-CCCTTTGAAGGTTCC-3'. The DNA Synthesis Core Laboratory of
the Comprehensive Cancer Center of the Wake Forest University School of
Medicine synthesized both oligomers.
Protocol
Microinjections of 30 to 60 nL were made with either
3- or 4-barreled glass micropipettes (50- to 100-µm outer diameter)
over a 40- to 60-second interval, as described
previously.14 15 16 17
Ang II (250 fmol, Bachem) was injected into the nTS in a volume of 30
nL to locate depressor sites. A second Ang II injection was given
several minutes before a 120-nL injection of AT1
receptor antisense (n=8) or scrambled sequence (n=5)
oligodeoxynucleotides in artificial cerebrospinal fluid.
The oligomers were given at a dose of 164 pmol/120 nL based on our
previous studies.13
Arterial blood pressure and heart rate responses to Ang II
injections were repeated 45, 90, and 150 minutes after injection of
the oligomer.
Ang II Receptor
Autoradiography
The medulla oblongata was removed at the end of the
experiment from rats that received scrambled sequence or
AT1 receptor antisense
oligonucleotide injections. The tissue was frozen and
sectioned. Consecutive adjacent 14-µm sections were preincubated in a
sodium phosphate buffer that contained 2.5 mmol/L EGTA, 5
mmol/L MgCl2, and 0.5% bovine serum
albumin. The sections were then incubated with 0.5 nmol/L
125I-Sarcosine,1 Threonine8 -Ang
II (Sarthran) in the same buffer. The presence of 5 µmol/L
losartan, 5 µmol/L PD123319, or the combination of the 2
competitors was used to determine the proportion of
AT1 or AT2 receptors and
nonspecific binding,
respectively.1 6 17 18
Slides were rinsed and dried according to published protocols, and then
placed against x-ray film (Kodak Biomax MR Scientific Imaging film,
Kodak) in cassettes for 2 days. After exposure and development, film
images were analyzed by computerized densitometry. Images were
measured on both the right and left sides of the nTS along the
rostro-caudal extent of the injection site as determined from the
injection tract and from the tissue damage that identified the
injection area in each rat. Values from all sections within the area of
the injection site were averaged to obtain 1 value for each rat for
each side of the brain (injected versus noninjected). Data are
expressed as the ratio of the injected to noninjected side as well as
in absolute values for binding for each side of the brain. To verify
the location of the injections, the injection tract was visually
identified in cresyl violet–stained brain stem sections for each
animal. All injections were localized within the intermediate portion
of the medial nTS within the rostro-caudal level -13.3 to -14
according to the atlas of Paxinos and
Watson.19
Analysis of Data
Baseline values for blood pressure and heart rate
were obtained in the minute preceding each injection. The maximum
change in pressure and heart rate was recorded after each
injection. Significant treatment and interaction terms were identified
by 2-way ANOVA. Therefore, further analyses were made with
1-way ANOVA for repeated measures (before versus after treatment) with
post hoc Dunnett’s multiple comparisons to identify the source of the
differences in each treatment group. For between-group differences,
unpaired t tests were used to
compare the scrambled-treated versus AT1
antisense-treated animals at each time point and for evaluation of the
binding data in antisense- versus scrambled-treated animals. Paired
comparisons were made between the injected and noninjected sides of the
brain for the binding data in each treatment group. Changes in blood
pressure or heart rate after scrambled or AT1
antisense treatments were also compared with a constant (0) to
determine whether significant changes in these variables occurred.
The criterion for statistical significance was
P<0.05, and all tests were
performed using InStat or Prism (GraphPad Software). Numerical values
are given as mean±SEM.
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Results |
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Baseline Hemodynamics
Mean arterial pressure and heart rate at various time points during the experiment are shown in the Table. Baseline values did not differ between AT1 antisense and scrambled-sequence treatment groups before Ang II injections at any time point. There was no long-term change in blood pressure or heart rate as a result of AT1 antisense or scrambled-sequence injections relative to the initial values (the before value).
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Effects of AT1 Antisense
on Cardiovascular Responses to Ang II Injected into the
nTS
Ang II (250 fmol/30 nL) injected into the nTS produced
a significant decrease in blood pressure of 14±1 mm Hg and heart
rate of 15±3 bpm in 8 rats before injection of
AT1 receptor antisense into the nTS. The fall in
blood pressure was reduced by 50% at 90 and 150 minutes after the
injection of AT1 antisense
(Figure 1, top). The reductions in blood pressure at 90 and
150 minutes (-9±1 mm Hg and -7±1 mm Hg) were
significantly less compared with values before treatment (F=6.80,
P<0.002;
P<0.05 at 90 and 150 minutes,
respectively), but were significantly >0
(P<0.01). In contrast, the
reduction in heart rate caused by Ang II was completely abolished at
both the 90- and 150-minute time point (heart rate changes not
different from 0;
Figure 1, bottom).
Figure 2A illustrates a typical response to Ang II before
and at several time points after the AT1
antisense injection. There were no effects of nTS injection of
scrambled-sequence oligomer on either blood pressure (F=0.58,
P=0.65) or heart rate (F=2.25,
P=0.18) responses to Ang II
(Figure 1 and
Figure 2B).
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Effects of the AT1
Receptor Antisense on Ang II Receptor Binding in the Dorsal
Medulla
As illustrated in
Figure 3, there was a unilateral reduction in
125I-Sarthran binding in the dorsal medulla
of animals given the AT1 antisense injections
into the nTS. The density of 125I-Sarthran
binding was 218±49 fmol/mg protein on the antisense-injected side and
389±84 fmol/mg protein on the noninjected side of medulla
(P<0.03). The loss in binding
did not occur in the nTS of animals injected with scrambled-sequence
oligonucleotides compared with the noninjected side of
the brain (402±122 fmol/mg protein versus 430±144 fmol/mg protein,
respectively). The ratio of binding on the injected to noninjected side
of the medulla averaged 0.61±0.04 (n=8) in
AT1 antisense-treated rats. In comparison, the
ratio of binding in the injected to noninjected side of the animals
receiving the scrambled sequence oligonucleotide was
0.98±0.07 fmol/mg protein (n=4). Thus, there was a significant
(P<0.05,
AT1 antisense versus scrambled
oligonucleotide) reduction of 38% in
angiotensin binding 3 hours after the
AT1 antisense injections. The rostro-caudal
extent of the injection site in which the receptors were measured
averaged 248±26 µm. In the presence of losartan, there was
no residual specific binding in the nTS of antisense- or
scrambled-treated animals. This confirms that
AT1 receptors predominate in the intermediate
region of the nTS of rats, which is consistent with previous
reports.20
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Discussion |
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Ang II lowers blood pressure and heart rate after injection of low (fmol) doses in the nTS, as previously reported by us and others in several strains of rats.14 15 16 17 21 This response can be blocked completely by the nTS injection of an AT1 receptor antagonist.22 We found that the bradycardia in response to Ang II was totally abolished at 150 minutes after injection of AT1 receptor antisense into the nTS. At this time, the depressor response induced by Ang II was reduced by only 50%. The reduction in cardiovascular responses was associated with a 40% decrease in the density of Ang II receptors in the nTS.
The pattern of distribution of Ang II receptors in the dorsal medulla is known to overlap that of the vagal sensory and motor systems.1 3 5 Receptors have been identified on local neurons of the nodose ganglion, nTS, and dmnX as well as fiber terminals that project to these sites by anatomical,2 molecular,23 24 or electrophysiological9 25 26 techniques. Knowledge of the role of each of these populations of receptors in the fall in blood pressure and heart rate in response to Ang II was limited previously. This was because techniques using receptor antagonists did not allow the selective interruption of each component, whereas selective denervations did not maintain the necessary efferent pathways as functional. The present study takes advantage of the unique features of antisense technology, which would include sparing receptors on neurons with fiber terminals projecting to the area of the injection. We reveal that the actions of Ang II on heart rate may be mediated entirely by angiotensin receptors made in nTS cells within the injection site. The fall in pressure, however, results from actions at receptors on both local nTS cells and terminal processes projecting to the area.
The mechanism by which antisense oligodeoxynucleotides interfere with synthesis of the protein products of a certain gene allows for their use in the central nervous system to dissect out actions at local elements versus pathway components with neuronal cell bodies in remote locations.27 28 We previously used a similar approach to illustrate the role of AT1 receptors in the paraventricular nucleus in the blood pressure response of (mRen2)27 transgenic rats to sodium loading.13 In that study and in earlier work by Phillips et al,29 the maximal effects of the AT1 receptor antisense were observed within 2 to 3 hours. A similar time course of action occurred in the present study, because the effects of the antisense took at least 90 minutes to develop, and the responses remained suppressed at 150 minutes postinjection. AT1 receptors exhibit rapid turnover apparently explained by the internalization and loss of receptors after exposure to Ang II, even before any change in mRNA.30 Thus, our study and at least 2 other reports using AT1 receptor antisense indicate that after interruption of synthesis, there is also a relatively rapid loss of surface AT1 receptors developing over a 3-hour time period. We cannot completely rule out, however, that additional actions might develop over a longer time period that leads to complete inhibition of the blood pressure as well as heart rate responses in our study.
To assess the reduction of Ang II receptors after treatment
with the AT1 antisense injections, we used the
in vitro receptor autoradiographic technique to quantify
125I-Sarthran-labeled receptors in the nTS
at the end of the experiments. There was a reduction in receptors of
40% in the nTS of the antisense-treated rats with no reduction seen in
the nTS of the animals treated with scrambled-sequence
oligonucleotides. This indicates that the reduction in
binding is not simply a result of damage in the area of the injections,
given that the ratio of the injected and noninjected sides of
scrambled-treated rats was 0.98. The magnitude of reduction of Ang II
receptors in the nTS after unilateral nodose ganglionectomy in the rat,
which would remove afferent fibers, is 40% to
50%.12 This implies that at
least 50% of the receptors in this brain area are located on nTS
neurons. Because we observed a reduction of 40% after antisense
injections, the data indicate that the majority of the binding
remaining is not due to incomplete effects of the antisense but rather
reflects the remaining receptors located on afferent fibers. The
reduction in binding appeared limited to the vicinity of the injection
sites, which averaged 250 µmol/L in the rostro-caudal direction.
This area of distribution for the 120-nL injection volume of antisense
is less than what we estimated after
125I-Sarthran injections into the nTS in a
volume of 100 nL in a previous
study.31 While the area of
reduction in receptors appeared to be confined to the nTS, it is
possible that the actions of Ang II before or after the antisense
injections were a result of actions at both nTS and dmnX sites. The
remaining fall in blood pressure may then result from actions on
receptors outside the area of the loss of binding. This possibility is
not likely, because the volume of the Ang II injection was only 30 nL;
previous studies indicate that this volume does not reach the dmnX from
injection sites in the nTS.22
Finally, we saw no residual non-AT1
angiotensin receptor binding in the nTS in the present
study. Thus, there is no strong evidence for AT2
receptors in the medial nTS of the rat that would account for the
residual actions of Ang II.
The differential effects of the AT1
receptor antisense treatment on blood pressure and heart rate are
similar to what we observed in early studies investigating the
peripheral mechanisms responsible for the Ang II–induced
effects. Vagotomy or treatment with methylatropine blocked the
bradycardia by 80% but only reduced the hypotension by
50%.16 Thus, Ang II acts
directly on nTS neurons to stimulate efferent pathways responsible for
parasympathetic control of heart rate. In contrast, at least 50% of
the Ang II–mediated effect on the blood pressure results from
inhibition of sympathetic nervous system activity. The data in the
present study indicate that receptors on presynaptic fiber sites
not affected by the AT1 receptor antisense might
account for these actions. There are direct connections of vagal
sensory afferent fibers with cells in the A2-catecholamine
cell group in the ventral
nTS.32 The A2 cells
project to ventral medullary sites involved in control of
sympathetic outflow. Thus, the remaining actions of Ang II appear to be
mediated by receptors on presynaptic afferent-fiber terminals in the
nTS most likely of vagal origin.
The data obtained in the current experiments are
consistent with previous electrophysiology studies noting both
a presynaptic and postsynaptic contribution to the neuronal excitatory
actions of Ang II. The percentage of Ang II excitatory responses linked
to presynaptic effects of the peptide in the nTS is
50%.10 Moreover, with the
use of high-resolution autoradiography, we were able to
see Ang II receptors overlying nTS
neurons.2 Combined with the
findings after AT1 receptor antisense treatment,
it appears that at least 50% of the actions of Ang II on blood
pressure and most of the heart rate effects involve actions directly on
neurons within the nTS. However, the remaining fall in blood pressure
obtained after AT1 receptor antisense treatment
suggests additional actions on fiber terminals projecting to the
region. Unilateral denervation of the sino-aortic nerves (which
contribute 2% of the primary sensory afferent input to the nTS) is
accompanied by an 11% to 15% reduction in Ang II receptors in the nTS
at an intermediate rostro-caudal
level.12 17 The
reduction in receptors after unilateral sino-aortic denervation was not
associated with significant changes in the
cardiovascular response to Ang II injected into the
nTS.17 On the basis of the
available electrophysiological and
anatomical evidence, presynaptic vagal sensory afferent fibers other
than those carrying baroreceptor reflex input would be likely
candidates to mediate the residual blood pressure component of the
response. However, the only way to test this will be to use the
antisense approach to inhibit AT1 receptors in
the nodose ganglion.
The physiological significance of the acute depressor and bradycardic actions of Ang II are not known. We previously showed that the entire blood pressure and heart rate response elicited by Ang II in the nTS is blocked by either of 2 different substance P antagonists.14 15 Substance P is contained in both vagal sensory afferent fiber terminals projecting to the nTS and in nTS interneurons projecting to the dmnX.33 34 35 36 Thus, substance P–containing cells within the nTS appear to be responsible for the direct actions of Ang II. In addition, the nerve fibers within the nTS that result in the Ang II–induced actions must also contain substance P. A link has been made recently between substance P–containing pathways and the effects of Ang II on the chemoreceptor reflex.37 38 39
Ang II is present in nerve terminals projecting to the nTS from forebrain sites and may access the nTS by blood-borne routes via the area postrema or cerebrospinal fluid routes (see reviews).40 41 Regardless of the source of the angiotensin acting in the nTS, it is well accepted that endogenous Ang II plays a tonic role in modulation of the baroreceptor reflex control of heart rate and the response to activation of cardio-pulmonary vagal chemoreceptors at the level of the nTS. The inhibitory role of the peptide on these predominantly vagally mediated responses is present in normotensive conscious42 or anesthetized31 43 animals and is even more pronounced in hypertensive rats.44 To conclude, the present studies show the utility of using AT1 antisense to discern the presynaptic versus postsynaptic sites for the acute hemodynamic actions of Ang II in the nTS. Future work using antisense technology can be used to establish the involvement of vagal sensory-afferent fibers or local nTS cell soma in the baroreceptor or chemoreceptor reflex actions of Ang II.
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Acknowledgments |
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This work was supported by grants HL-51952, HL-38535, and HL-07790 from the National Heart, Lung, and Blood Institute.
Received October 10, 2000; first decision November 7, 2000; accepted November 14, 2000.
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