(Hypertension. 2000;36:259.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Angiotensin in the Nucleus Tractus Solitarii Contributes to Neurogenic Hypertension Caused by Chronic Nitric Oxide Synthase Inhibition
Presented in part at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8–11, 1998.
From the Department of Cardiovascular Medicine, Cardiovascular Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Correspondence to Yoshitaka Hirooka, MD, PhD, Department of Cardiovascular Medicine, Cardiovascular Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail hyoshi{at}cardiol.med.kyushu-u.ac.jp
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Abstract |
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Abstract—Activation of the sympathetic nervous system and renin-angiotensin system has been suggested to contribute to the hypertension caused by chronic nitric oxide synthase inhibition. The aim of the present study was to determine whether angiotensin within the nucleus tractus solitarii (NTS) plays a role in activation of the sympathetic nervous system in this model. Rats were treated with N
-nitro-L-arginine methyl
ester (L-NAME, 100 mg · kg-1 ·
d-1 in drinking water) for 2 weeks. Experiments were
performed on anesthetized rats with denervated
arterial and cardiopulmonary baroreceptors.
Arterial pressure, heart rate, and renal sympathetic nerve
activity (RSNA) were measured. Microinjection of an
angiotensin II type 1 (AT1) receptor
antagonist (CV11974) or an angiotensin II type
2 (AT2) receptor antagonist (PD123319) into the
depressor region within the NTS (identified by prior injection of
L-glutamate) was performed. Microinjection of CV11974, but
not of PD123319, produced greater decreases in arterial
pressure, heart rate, and RSNA in L-NAME–treated rats than in control
rats. The administration of hexamethonium resulted in a
larger fall in arterial pressure in L-NAME–treated rats
than in control rats. The ACE mRNA level in the brain stem was greater
in L-NAME–treated rats than in control rats. These results suggest
that increased sympathetic nerve activity plays a role in hypertension
caused by chronic nitric oxide synthase inhibition and that activation
of the renin-angiotensin system in the NTS is involved at
least in part in this increased sympathetic nerve activity via
AT1 receptors.
Key Words: nitric oxide • sympathetic nervous system • brain • angiotensin • blood pressure • heart rate
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Introduction |
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It is well established that pharmacological inhibition of nitric oxide (NO) synthesis produces acute and chronic hypertension in many animal species,1 2 but the underlying mechanisms that mediate this hypertension are not fully understood. Although this hypertension was initially attributed solely to the inhibition of endothelial NO synthase (eNOS), numerous studies have demonstrated that the inhibition of neuronal NO may also play a role.3 4 5 6 7 The administration of an NOS inhibitor, such as NG-monomethyl-L-arginine (L-NMMA) or N
-nitro-L-arginine
methyl ester (L-NAME), into the central nervous system evokes acute
increases in both arterial pressure and sympathetic nerve
activity.8 9 These results have been interpreted to
suggest that neuronal NO plays roles in the signal transduction
pathways involved in the tonic inhibition of sympathetic
vasoconstrictor outflow from the brain stem. The removal of this
inhibition by NOS inhibitors is postulated to
activate the sympathetic nervous system and thereby result in
hypertension. Several investigators have demonstrated a great effect of sympathectomy or ganglionic blockade on L-NAME–induced hypertension, suggesting that the sympathetic nervous system is involved primarily in the maintenance, rather than the initiation, of L-NAME–induced hypertension.10 11 12 However, the specific sites at which NOS inhibition produces progressive neurogenic hypertension are unknown. Neuronal NOS (nNOS) is expressed in the brain stem, including the nucleus tractus solitarii (NTS) and the ventrolateral medulla (VLM).13 The injection of L-NMMA into the NTS results in increases in arterial pressure and renal sympathetic nerve activity (RSNA).8 It was demonstrated that L-NAME treatment is accompanied by a progressive attenuation of baroreceptor reflex, which might contribute to neurogenic vasoconstriction and hypertension.14 It has also been suggested that hypertension induced by chronic NOS inhibition is mediated in part by activation of the sympathetic nervous system and the renin-angiotensin system.15 Plasma norepinephrine level, epinephrine level, and renin activity were increased in rats treated orally with L-NAME. The intravenous injection of both losartan and phentolamine reduced arterial pressure considerably in L-NAME–treated rats.15 Whole brain NOS activity was reduced by 84% in such rats.15
We recently reported that the chronic inhibition of NOS causes microvascular remodeling and cardiac hypertrophy associated with activation of the tissue renin-angiotensin system.16 17 18 19 An independent renin-angiotensin system exists in the brain,20 21 22 and the microinjection of angiotensin II into the NTS has been shown to increase arterial pressure and heart rate.23 The aim of this study was thus to determine whether brain angiotensin in the NTS plays a role in the hypertension caused by chronic NOS inhibition, which in turn activates the sympathetic nervous system. For this purpose, we examined the effects of an angiotensin II type 1 (AT1) receptor antagonist (CV11974) microinjected into the NTS on arterial pressure, heart rate, and RSNA in anesthetized rats treated with L-NAME.
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Methods |
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General Procedures
These experiments were reviewed and approved by the Committee on Ethics of Animal Experiments, Kyushu University Faculty of Medicine, and were conducted according to the guidelines for animal experiments of the Kyushu University Faculty of Medicine.
Experiments were performed on male Wistar-Kyoto rats weighing 300 to
350 g. Anesthesia was induced with pentobarbital
sodium (50 mg/kg IP), and an intravenous infusion of
propofol (
20 to 30 mg · kg-1 ·
h-1) was begun as the effect of the
pentobarbital diminished, as previously described.24 The
adequacy of anesthesia was verified by the absence of a
withdrawal response to nociceptive stimulation of a hindpaw and by a
stable baseline arterial pressure and heart rate. The right
femoral artery and vein were cannulated to record
arterial blood pressure and to administer drugs. Rats were
artificially ventilated. The carotid sinus bifurcations were
denervated, and the aortic and vagal nerves were cut to eliminate
arterial and cardiopulmonary baroreceptor reflexes.
The rats were placed in a stereotaxic frame, and the dorsal
medulla was exposed. The left renal nerve was exposed with a flank
incision and placed on a stainless steel bipolar electrode to
record multifiber RSNA. Microinjections of various compounds into
the NTS were performed with a micropipette held in a micromanipulator.
The compounds injected were L-glutamate (20 nL of 1
mmol/L), an AT1 receptor antagonist
(CV11974; Takeda Chemical Industries Ltd), and an
angiotensin II type 2 (AT2) receptor
antagonist (PD123319; Parke-Davis).
Animal Model of Chronic Inhibition of NO Synthesis
The rats were randomly separated into 2 groups. The first group
(control) received untreated drinking water for 2 weeks. The second
group received L-NAME (Sigma Chemical Co) in drinking water (1 mg/mL)
for 2 weeks as previously described.16 17 18 19 At the
concentration administered, the daily intake of L-NAME was 30 to 40
mg. All rats were fed a normal diet and housed singly in a special
pyrogen-free facility.
RNA Isolation and Northern Blot Analysis
Total RNA was prepared from the brain stem with ISOGEN (Nippon
Gene), followed by poly(A)+ RNA purification with
an oligo(dT)/cellulose column (Takara Shuzo).
Poly(A)+ RNA (5 µg/lane) was separated with
electrophoresis and transferred onto a nylon membrane (Hybond
N+; Amersham). Hybridization was carried out with
a 32P-labeled EcoRV/EcoRI
fragment of rat ACE cDNA,25 rat
AT1 receptor cDNA,26 or mouse GAPDH
cDNA, followed by autoradiography.
Autoradiograms were scanned with a Fuji phosphorimaging
system to measure amounts of ACE and AT1 receptor
mRNAs normalized against those of GAPDH mRNA.
Experimental Protocols
Protocol 1
Microinjections of 2 doses of CV11974 (0.1 and 1 nmol) into the
NTS were made in L-NAME–treated rats as well as in control rats (15
rats of each group) to examine the effect of AT1
receptor blockade on arterial pressure, heart rate, and
RSNA.
Protocol 2
A microinjection of PD123319 (0.1 nmol) into the NTS was made in
L-NAME–treated rats as well as in control rats (15 rats of each group)
to examine the effect of AT2 receptor blockade on
arterial pressure, heart rate, and RSNA.
Protocol 3
A microinjection of vehicle (the solution dissolved CV11974)
into the NTS was made in both groups of rats (15 rats of each group) to
rule out nonspecific effects of microinjection on arterial
pressure, heart rate, and RSNA.
Protocol 4
A microinjection of CV11974 (1 nmol) into the area postrema was
made to examine the effect of AT1 receptor
blockade on arterial pressure, heart rate, and RSNA.
Protocol 5
To determine whether basal sympathetic nerve activity is
activated in L-NAME–treated rats,
hexamethonium chloride was administered
intravenously (40 mg/kg) at the end of the microinjection
experiments.
Protocol 6
To determine whether the brain stem
renin-angiotensin system is activated in
L-NAME–treated rats, we assayed brain stem levels of ACE and
AT1 receptor mRNA in L-NAME–treated and control
rats.
Histological Examination
At the end of experiments, the micropipette containing Evans’
blue was positioned at the site of the drug injection, and Evans’ blue
(100 nL) was injected to determine the site of injection at postmortem
examination. After completion of the experiments, the rat was deeply
anesthetized with an overdose of pentobarbital, and the brain
was perfused with 0.9% saline followed by 4%
paraformaldehyde solution through the heart. The brain
stem was removed, and frozen sections (50 µm) were cut serially.
The location of the injection site was identified under a
microscope.
Statistical Analysis
All values are expressed as mean±SEM. The unpaired t
test was used to compare the baseline values between the groups. The
paired t test was used to examine the effects of each
intervention within a group. ANOVA followed by Bonferroni’s multiple
comparison test was used to compare the values of changes in
differences between groups. Differences were considered significant for
values of P<0.05.
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Results |
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Baseline Levels of Arterial Pressure and Heart Rate
The Table shows the baseline levels of mean arterial pressure and heart rate in the L-NAME–treated and control rats before and after sinoaortic denervation and vagotomy. Mean arterial pressure in L-NAME–treated rats was higher than that in control rats (P<0.01). Heart rate did not differ between the 2 groups after sinoaortic denervation and vagotomy.
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Effects on Arterial Pressure, Heart Rate, and RSNA of
Microinjection of AT1 Receptor Antagonist,
AT2 Receptor Antagonist, or Vehicle Injected
Into the NTS
Prior microinjection of L-glutamate into the NTS (0.5
nmol) decreased mean arterial pressure (-28±8 versus
-34±12 mm Hg) and heart rate (-18±2 versus -18±2 bpm) in
both control and L-NAME–treated rats. The magnitudes of the decreases
in these variables did not differ between the 2 groups.
Microinjections of CV11974 (0.1 and 1 nmol) into the depressor regions in the NTS (identified prior injection of L-glutamate) decreased arterial pressure, heart rate, and RSNA (Figure 1). The magnitudes of decreases in arterial pressure, heart rate, and RSNA evoked by CV11974 were greater in L-NAME–treated rats than in control rats (Figure 1). On the other hand, the microinjection of PD123319 (0.1 nmol) into the NTS produced no changes in these variables in either group. The microinjection of vehicle into the NTS also did not produce changes in these variables.
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Effects of on Arterial Pressure and Heart Rate
AT1 Receptor Antagonist Injected Into the
Area Postrema
The microinjection of CV11974 (1 nmol) into the area postrema
produced no changes in arterial pressure or heart rate in
either group.
Effects of Systemic Administration of Hexamethonium
Figure 2 shows the effects on mean
arterial pressure of the intravenous injection
of hexamethonium. The mean arterial
pressure of L-NAME–treated rats was significantly higher than that of
control rats before the injections of hexamethonium.
After the intravenous injection of
hexamethonium, mean arterial pressure
decreased to the same levels, and the change in mean
arterial pressure of L-NAME–treated rats was significantly
greater than that of control rats (-100.0±7.3 versus -43.7±4.1
mm Hg, P<0.01).
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ACE and AT1 Receptor Expression in the Brain
Stem
As shown in Figure 3, the ACE mRNA
level in the brain stem of L-NAME–treated rats was higher than that in
brain stem of control rats. On the other hand, the
AT1 receptor mRNA level did not differ between
the 2 groups.
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Discussion |
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The major finding of the present study was that AT1 receptor blockade, but not AT2 receptor blockade, in the NTS reduced arterial pressure, heart rate, and RSNA in rats chronically treated with L-NAME, suggesting that activation of the renin-angiotensin system in the NTS via AT1 receptors plays a role in the neurogenic hypertension in this model. The intravenous injection of hexamethonium produced a greater fall in arterial pressure in rats treated with L-NAME. After hexamethonium injection, the arterial pressure of rats treated with L-NAME was similar to that of control rats. These results indicate that activation of the sympathetic nervous system contributes to the hypertension in this model. Furthermore, we found an increase in ACE mRNA level in the brain stem of the L-NAME–treated rats, which supports the hypothesis of activation of the renin-angiotensin system in the brain stem in this model.
We first consider the possibility that the greater response to microinjection of CV11974 on arterial pressure in the L-NAME–treated rats was nonspecific due to the presence of a higher baseline arterial pressure. However, this is unlikely because the prior injection of L-glutamate produced similar depressor responses in the 2 groups. In addition, we also found a greater decrease in RSNA in the L-NAME–treated rats than in the control rats. Furthermore, we ruled out the possibility of a nonspecific effect of vehicle solution– dissolved CV11974.
Sander et al10 11 found that once L-NAME–induced
hypertension developed, it can be completely reversed by acute
ganglionic blockade, suggesting that the sympathetic nervous system
plays a role in L-NAME–induced hypertension in the chronic phase. They
demonstrated that L-NAME treatment induced smaller (by 50%)
increases in arterial pressure in rats with than in those
without sympathectomy. Furthermore, in rats without
sympathectomy that received chlorisondamine, ganglion
blockade produced larger decreases in arterial pressure in
L-NAME–treated than in vehicle-treated rats. Thus, although
arterial pressure was higher in L-NAME–treated than in
vehicle-treated rats before ganglionic blockade, the values of
arterial pressure in the 2 groups were comparable after
ganglionic blockade. It has also been shown that ganglionic blockade
induced by trimethaphan caused a greater decrease in
arterial pressure in L-NAME–treated rats than in control
rats.12 Our results are consistent with the
results of these studies, indicating that an increase in central
sympathetic drive contributes to the hypertension induced by the
chronic inhibition of NOS.
There is evidence that L-NAME crosses the blood-brain barrier when administered orally. It has been demonstrated that NOS activity in the cerebral tissue was reduced by 84% with L-NAME.15 Previous studies have indicated that 120 minutes is required for intravenous L-NAME to cross the blood-brain barrier and reach a concentration in the central nervous system sufficient to nearly completely inhibit NOS activity, as measured in brain homogenates in many species.27 28
The relationship between the renin-angiotensin system and
the sympathetic nervous system is complex. It has been demonstrated
that intravenous injection of the AT1
receptor antagonist losartan alone causes a small
decrease in arterial pressure in L-NAME–treated rats but
that the combination of 
1-adrenoceptor and
AT1 receptor blockade was potently
antihypertensive, resulting in normalization of arterial
pressure in chronically NO blockade hypertensive rats.29
On the other hand, the intravenous injection of
losartan caused a greater decrease in arterial
pressure in rats treated with L-NAME than in normotensive
rats.30 The reason for the discrepancy in results between
these studies is not clear. Because an AT1
receptor antagonist was administered
intravenously in those studies, activation of the
renin-angiotensin system in the brain stem may be more
important for increased sympathetic nerve activity, which in turn
produces hypertension.
The role of angiotensin II in the NTS is not fully understood. The microinjection of angiotensin II into the NTS has been reported to have both pressor and depressor effects.20 22 The microinjection of angiotensin antagonist into the NTS has been shown to facilitate arterial baroreceptor reflex control of heart rate, suggesting that endogenous angiotensin within the NTS reduces arterial baroreflex control.31 The intracisternal infusion of angiotensin II caused pressor effects and activated the neurons in the NTS, VLM, and area postrema, as determined with c-fos immunohistochemistry.32 However, we found no effect on arterial pressure of the microinjection of AT1 receptor antagonist into the area postrema. The microinjection of L-NMMA into the area postrema has been shown to have no effect on arterial pressure and RSNA.8 The role played by the VLM in the increase in sympathetic nervous system caused by chronic NOS inhibition cannot be determined on the basis of the results of our study. It was recently suggested that rostral VLM neurons are activated in chronic NOS inhibition.33 Further studies will be needed to determine whether the renin-angiotensin system in the rostral VLM is also activated by chronic inhibition of NOS or whether the increase in neuronal activity of the rostral VLM is related to activation of the renin-angiotensin system of NTS neurons caused by chronic inhibition of NOS.
The mechanisms by which the renin-angiotensin system is activated by chronic NOS inhibition cannot be determined on the basis of the results of our study. A decrease in NO synthesis induces the synthesis of growth-promoting factors from the endothelium.34 It has been hypothesized that vascular and myocardial structural changes in rats treated with L-NAME are mediated by the local elaboration of growth-promoting factors, which in turn are induced by activation of the renin-angiotensin system, including ACE. Further studies are needed to clarify the mechanism of an activation of renin-angiotensin system caused by chronic NO inhibition.
In summary, our results suggest that the chronic inhibition of NOS activates the sympathetic nervous system and that activation of the renin-angiotensin system via AT1 receptors in the NTS contributes at least in part to this neurogenic hypertension.
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Acknowledgments |
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This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (09770489) and a Grant for Research on Autonomic Nervous System and Hypertension from Kimura Memorial Heart Foundation/Pfizer Pharmaceuticals, Inc.
Received January 3, 2000; first decision January 31, 2000; accepted February 21, 2000.
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K. Ito, Y. Hirooka, T. Kishi, Y. Kimura, K. Kaibuchi, H. Shimokawa, and A. Takeshita Rho/Rho-Kinase Pathway in the Brainstem Contributes to Hypertension Caused by Chronic Nitric Oxide Synthase Inhibition Hypertension, February 1, 2004; 43(2): 156 - 162. [Abstract] [Full Text] [PDF]
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H. L. Xu, R. A. Santizo, V. L. Baughman, and D. A. Pelligrino Nascent EDHF-mediated cerebral vasodilation in ovariectomized rats is not induced by eNOS dysfunction Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2045 - H2053. [Abstract] [Full Text] [PDF]
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Y. Wang, K. P. Patel, K. G. Cornish, K. M. Channon, and I. H. Zucker nNOS gene transfer to RVLM improves baroreflex function in rats with chronic heart failure Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1660 - H1667. [Abstract] [Full Text] [PDF]
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 K. Ito, Y. Hirooka, K. Sakai, T. Kishi, K. Kaibuchi, H. Shimokawa, and A. Takeshita Rho/Rho-Kinase Pathway in Brain Stem Contributes to Blood Pressure Regulation via Sympathetic Nervous System: Possible Involvement in Neural Mechanisms of Hypertension Circ. Res., June 27, 2003; 92(12): 1337 - 1343. [Abstract] [Full Text] [PDF]
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 N. Toda and T. Okamura The Pharmacology of Nitric Oxide in the Peripheral Nervous System of Blood Vessels Pharmacol. Rev., June 1, 2003; 55(2): 271 - 324. [Abstract] [Full Text] [PDF]
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A. Dendorfer, A. Thornagel, W. Raasch, O. Grisk, K. Tempel, and P. Dominiak Angiotensin II Induces Catecholamine Release by Direct Ganglionic Excitation Hypertension, September 1, 2002; 40(3): 348 - 354. [Abstract] [Full Text] [PDF]
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 K. P. Patel, Y.-F. Li, and Y. Hirooka Role of Nitric Oxide in Central Sympathetic Outflow Experimental Biology and Medicine, October 1, 2001; 226(9): 814 - 824. [Abstract] [Full Text] [PDF]
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H. Shigematsu, Y. Hirooka, K. Eshima, M. Shihara, T. Tagawa, and A. Takeshita Endogenous angiotensin II in the NTS contributes to sympathetic activation in rats with aortocaval shunt Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2001; 280(6): R1665 - R1673. [Abstract] [Full Text] [PDF]
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