(Hypertension. 1998;31:27.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Role of Endogenous Nitric Oxide in the Brain Stem on the Rapid AdaptatKion of Baroreflex
From the Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka, Japan.
Correspondence to Yoshitaka Hirooka, MD, PhD, Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, 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—It has been shown that nitric oxide in the brain stem plays an important role in the control of sympathetic nerve activity. We examined the role of endogenous nitric oxide in the brain stem in the rapid central adaptation of baroreflex control of sympathetic nerve activity in anesthetized rabbits. Bilateral carotid sinuses were isolated, and a stepwise increase in pressure of 25 or 50 mm Hg for 50 to 60 seconds was applied to the carotid sinuses while the arterial pressure and renal sympathetic nerve activity were recorded. The renal sympathetic nerve activity was inhibited by the stepwise increase in carotid sinus pressure, but thereafter it gradually returned toward the baseline level despite the fact that carotid sinus pressure was kept constant. This procedure was performed after intracisternal injection of N
-nitro-L-arginine methyl
ester (L-NAME, 8 µmol),
N-nitro-D-arginine methyl
ester (D-NAME, 8 µmol), L-arginine (40 µmol),
or the vehicle solution. The magnitude of the immediate and maximal
inhibition of renal sympathetic nerve activity caused by a stepwise
increase in carotid sinus pressure was similar between the vehicle and
L-NAME treatment, but the rate of recovery of the renal sympathetic
nerve activity after immediate inhibition was faster after L-NAME than
after vehicle. L-Arginine reversed the effects of L-NAME.
However, D-NAME or L-arginine alone had no such effects on
the rate of recovery of the nerve activity. These results thus suggest
that endogenous nitric oxide in the brain stem attenuates
rapid adaptation of the arterial baroreflex control of the
sympathetic nerve activity in rabbits.
Key Words: nitric oxide • L-arginine • baroreflex • nervous system, sympathetic • brain stem
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Introduction |
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There is now considerable evidence that NO in the brain stem is involved in the regulation of the activity of sympathetic nerves supplying the cardiovascular system.1 2 3 4 5 6 7 8 For example, it has been shown that microinjections of L-NMMA into the NTS increase both the arterial pressure and renal sympathetic nerve activity in anesthetized rabbits or rats.3 5 Microinjections of L-NMMA into the rostral VLM increase arterial pressure and sympathetic nerve activity in anesthetized cats and rats but not rabbits.4 5 7 8 Microinjections of L-NMMA into the caudal VLM decrease arterial pressure and sympathetic nerve activity in anesthetized cats.7 A depressor response evoked by L-glutamate into the NTS is attenuated by either L-NMMA, methylene blue (an inhibitor of soluble guanylate cyclase), or NMDA receptor antagonist.9 Furthermore, the inhibition of NO synthase decreases, but an NO donor increases, the neuronal activity of the NTS neurons both in vivo and in vitro.10 11 These observations suggest that endogenous NO within the brain stem may act to influence the sympathetic outflow. In addition, immunohistochemical studies have demonstrated the existence of NO synthase in the NTS and VLM.8 12 13 14 15
Arterial baroreceptor stimulation inhibits sympathetic nerve activity by reflex mechanisms,16 17 but sympathetic nerve activity may recover or "escape" from inhibition and, thus, again approach the baseline level even though the increase in baroreceptor activity is maintained.18 This phenomenon is referred to as central adaptation. It is possible that every site in the baroreflex pathway contributes to central adaptation, and it has been shown to occur at least at the level of the NTS.18 19 However, the mechanisms involved in central adaptation are not known. It is suggested that stimulation of NMDA receptors activates NO synthase and then the NO that is produced stimulates the release of glutamate as a positive feedback mechanism.20 21 We therefore considered the possibility that endogenous NO within the brain stem may be involved in the central adaptation of the arterial baroreflex control of sympathetic nerve activity. The aim of this study was thus to examine whether an intracisternal injection of L-NAME alters the rate of central adaptation of renal sympathetic nerve activity during sustained elevation of carotid sinus pressure in the rabbit.
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Methods |
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Male Japanese white rabbits (3.0 to 3.7 kg) were anesthetized with thiamylal sodium (25 mg/kg IV) and
-chloralose (80 mg/kg IV, followed by a maintenance dose of
20 mg · kg-1 ·
h-1). Pancuronium bromide (0.5mg/kg IV) was
given to eliminate muscular activity. The rabbits were tracheotomized
and ventilated (model SN-480–6 ventilator; Shinano) with room air
supplemented with oxygen at a tidal volume of 10 mL/kg at a rate of 25
cycles per minute. A catheter was introduced into the
inferior vena cava through the left femoral vein for the
administration of anesthetic. Another catheter was then introduced into
the aorta through the left femoral artery to monitor and record
systemic arterial pressure. This experiment was reviewed by the Committee on Ethics in Animal Experiments of Kyushu University School of Medicine and was carried out according to the Guidelines for Animal Experiments of the Kyushu University School of Medicine and the Law (No. 105) and Notification (No. 6) of the Japanese Government.
Isolated Carotid Sinus Preparation
Bilateral carotid sinuses were surgically exposed, and all
arteries near the sinuses were ligated. Catheters (PE-90) were placed
in the external carotid arteries. The common carotid arteries were
clamped. The isolated sinuses were flushed and filled with
physiological saline solution equilibrated with
100% O2 and warmed to 37°C. Both carotid
sinuses were connected to a pressure reservoir through the external
carotid arteries, and the carotid sinus pressure was measured. The
cannulas of external carotid arteries were connected with a three-way
stopcock. The mean level of pressure in the carotid sinuses was
controlled by adjusting a regulator valve connected to a pressurized
air source. The carotid sinus isolation was confirmed by disappearance
of a pressure waveform in carotid sinus pressure recordings
when the common carotid arteries were clipped. The bilateral aortic
depressor nerves were identified by recording the typical
activity of each nerve and then were cut.
Recording Efferent Renal Sympathetic Nerve
Activity
The left kidney was exposed retroperitoneally, and the renal
nerve was isolated. A pair of stainless steel bipolar electrodes was
then placed beneath the renal nerves. The renal nerve around the
recording electrode was covered with silicone gel (Sil-Gel,
Wacker-Chemie). Multifiber renal nerve activity was recorded and
preamplified with a high-gain differential amplifier (bandwidth, 150 to
1000 Hz; model MEG-1100, Nihon-Kohden).
Intracisternal Injection
The head of the rabbit was placed in a head holder attached to a
stereotaxic frame and flexed forward at an angle of 45°.
The atlanto-occipital membrane was exposed, and the tip of a
polyethylene tube (PE-10) placed into the cisterna magna through a
small hole made in the membrane. Bolus injections of drugs (volume of
injected solution, 100 µL) were made through this catheter. The drugs
(L-NAME, D-NAME, L-arginine hydrochloride, all from Sigma
Chemical Co) were dissolved in artificial cerebrospinal fluid (NaCl
123 mmol/L, CaCl2 0.86 mmol/L, KCl
3.0 mmol/L, MgCl2 0.89 mmol/L,
NaHCO3 25 mmol/L,
NaHPO4 0.5 mmol/L, and
Na2HPO4 0.25 mmol/L)
and then gassed with 95% O2 and 5%
CO2.
Protocol and Data Analysis
Bilateral carotid sinuses were exposed to the same pressure,
which was at a level close to the mean systemic arterial
pressure, for approximately 10 minutes after the intracisternal
injection of either the vehicle (artificial cerebrospinal fluid),
L-NAME, D-NAME, or L-arginine. Then both carotid sinuses
were exposed to a stepwise increase in pressure of 25 or 50
mm Hg. At each level of pressure, the static pressure was held for 50
to 60 seconds. The renal sympathetic nerve activity was continuously
recorded. We tabulated the activity at 10 seconds before,
immediately before, and every 10 seconds after the sudden increase in
carotid sinus pressure and normalized it to the nerve activity
immediately before applying a sudden increase in the carotid sinus
pressure.
Protocol 1
We examined the effects of the intracisternal injection of
vehicle, L-NAME, or L-NAME plus L-arginine on the rapid
adaptation of the reflex inhibition of renal sympathetic nerve activity
(n=8). L-Arginine was injected approximately 30 minutes
after L-NAME, when the effects of L-NAME on the arterial
pressure and renal sympathetic nerve activity remained stable. A
stepwise increase in carotid sinus pressure of 25 or 50 mm Hg was
made approximately 10 minutes after the intracisternal injection of
either vehicle, L-NAME (8 µmol), or L-arginine
(40 µmol). The effects of the intracisternal injection of L-NAME
were confirmed by the increases in baseline arterial
pressure and renal sympathetic nerve activity. L-Arginine
after L-NAME reversed the increases in the baseline
arterial pressure and renal sympathetic nerve activity
caused by L-NAME alone.
Protocol 2
We examined the effect of intracisternal injection of vehicle or
D-NAME on the rapid adaptation of reflex inhibition of the renal
sympathetic nerve activity (n=4). A stepwise increase in the carotid
sinus pressure of 25 or 50 mm Hg was made 10 to 20 minutes after
the intracisternal injection of vehicle or D-NAME (8 µmol).
Protocol 3
We examined the effects of intracisternal injections of vehicle
or L-arginine (40 µmol) alone on the rapid
adaptation of the reflex inhibition of the renal sympathetic nerve
activity (n=5).
Protocol 4
We injected either L-NAME (8 µmol) or
L-arginine (8 µmol) intravenously to
examine their systemic effects on baseline arterial
pressure, heart rate, and renal sympathetic nerve activity (n=5). Each
injection was given at an interval of at least 1 hour.
Statistical Analysis
A one-way ANOVA for repeated measures was used to compare the
baseline values. Comparisons between any two mean values were made
using Student’s t test for paired measurements while using
the Bonferroni multiple procedure for repeated measures. The
Wilcoxon signed rank test was used to compare the percentage
changes in the sympathetic nerve activity during a stepwise increase in
the carotid sinus pressure between vehicle and L-NAME, D-NAME, or
L-arginine. All values are expressed as
mean±SEM, and the differences were considered to be significant when
P<.05.
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Results |
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Effects of Intracisternal or Intravenous Injection of Vehicle, L-NAME, D-NAME, or L-Arginine on the Baseline Arterial Pressure, Heart Rate, and Renal Sympathetic Nerve Activity
The Table shows the baseline values of the mean arterial pressure, heart rate, and renal sympathetic nerve activity after the intracisternal injection of vehicle, L-NAME, or L-NAME plus L-arginine. Mean arterial pressure and renal sympathetic nerve activity after L-NAME injection were higher than those after vehicle injection, and both returned to baseline values after injection of L-arginine. There were no significant differences among the baseline values of mean arterial pressure, heart rate, and renal sympathetic nerve activity after intracisternal injection of D-NAME, L-arginine alone, or vehicle. The intravenous injection of either L-NAME (8 µmol) or L-arginine (8 µmol) did not alter mean arterial pressure, heart rate, or renal sympathetic nerve activity (data not shown).
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Effects of Intracisternal Injections of L-NAME, D-NAME, or
L-Arginine on the Reflex Inhibition of Renal Sympathetic
Nerve Activity
As illustrated in Fig 1, the rate of
recovery of the reflex inhibition of renal sympathetic nerve activity
was faster after intracisternal injection of L-NAME than after the
injection of vehicle. Fig 2 shows the
grouped data for this protocol. The sudden increase in carotid sinus
pressure by 25 and 50 mm Hg caused a sudden decrease in the renal
sympathetic nerve activity, which thereafter gradually increased toward
the baseline level during the following 50 seconds despite the fact
that the carotid sinus pressure was maintained at the higher level. The
magnitudes of the immediate decreases in renal sympathetic nerve
activity caused by increasing the carotid sinus pressure by 25 or
50 mm Hg were similar after injection of L-NAME or vehicle
solution (23±5% versus 28±7%, respectively, of the baseline values
in response to the increase in carotid sinus pressure by 25
mm Hg, NS; 13±5% versus 7±3%, respectively, in response to the
increase in carotid sinus pressure by 50 mm Hg, NS). However, the
magnitude of the recovery in renal sympathetic nerve activity was
greater after the injection of L-NAME than after the injection of
vehicle. The renal sympathetic nerve activities at 30, 40, and 50
seconds after the increase in carotid sinus pressure of 25 mm Hg
and those at 40 and 50 seconds after the increase in carotid sinus
pressure of 50 mm Hg were significantly greater
(P<.05) after the injection of L-NAME than after the
injection of vehicle (Fig 2). Thus, the recovery of the renal
sympathetic nerve activity was significantly faster after the injection
of L-NAME (P<.001 for carotid sinus pressure increases of
both 25 and 50 mm Hg) than after vehicle. However, the recovery
of the renal sympathetic nerve activity was similar after the injection
of L-NAME plus L-arginine and after the injection of
vehicle (48±13% versus 43±12%, respectively, of the baseline values
at 50 seconds after the increase in carotid sinus pressure by 25
mm Hg, NS; 15±8% versus 17±9%, respectively, at 50 seconds after
the increase in carotid sinus pressure by 50 mm Hg, NS).
Similarly, after intracisternal injections of D-NAME or
L-arginine alone, the reflex inhibitions of renal
sympathetic nerve activity following the increase in carotid sinus
pressure were not different from those after injection of vehicle (Figs 3 and 4).
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Discussion |
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This study demonstrated that L-NAME injected into the cisterna magna increased the rate at which renal sympathetic nerve activity returned toward baseline levels after an initial reflex inhibition in response to a stepwise increase in carotid sinus pressure. This recovery occurred despite the fact that the increase in carotid sinus pressure was maintained. However, the magnitudes of the immediate and maximal inhibitions of renal sympathetic nerve activity in response to a stepwise increase in carotid sinus pressure did not differ after injection of L-NAME compared with the vehicle solution. These results thus indicate that inhibition of NO synthesis in the brain stem facilitates the central adaptation of the baroreflex inhibition of sympathetic nerve activity. We thus suggest that endogenous NO in the brain stem is involved in the mechanism or mechanisms of rapid central adaptation of baroreflex control of sympathetic nerve activity and therefore may play an important role in maintaining reflex inhibition of the sympathetic nerve activity in response to a sustained change in baroreceptor input.
The possibility must be considered that these findings resulted from some mechanism other than the inhibition of NO formation in the brain stem. For example, it has been shown that L-NAME has an antagonistic action of muscarinic cholinergic receptors.22 However, this possibility is unlikely because the effect of L-NAME was reversed by the injection of L-arginine. Second, D-NAME, a stereoisomer of L-NAME, was not found to affect adaptation. Therefore, it is likely that the effect of L-NAME is due specifically to inhibition of the L-arginine–NO pathway.
L-NAME was injected intracisternally so that it would have access to the essential medullary nuclei (NTS and caudal and rostral parts of the VLM) that subserve the baroreceptor reflex.23 A dose of 8 µmol was selected because a previous study demonstrated that the mean threshold intracisternal dose of L-NAME required to block the decompensatory phase of acute hypovolemia in rabbits was 4 µmol (range, 0.4 to 11 µmol).24 It is unlikely that this dose of intracisternal L-NAME had any systemic effects, because intravenous L-NAME at the same dose did not alter the baseline arterial pressure or renal sympathetic nerve activity.
We also need to consider the possibility that the increased rapid adaptation of the baroreflex inhibition of renal sympathetic nerve activity caused by intracisternal L-NAME might have resulted in part from baroreceptor adaptation.18 However, this possibility is unlikely because we applied L-NAME intracisternally and isolated the carotid sinuses. Therefore, L-NAME could not have affected directly the baroreceptors in our preparation. We therefore consider that the changes in rapid adaptation caused by intracisternal L-NAME mainly reflected the changes in the central adaptation of baroreflex inhibition.
The exact mechanisms of central adaptation have yet to be elucidated. It has been clearly shown that central adaptation of neuronal activity occurs in the NTS neurons and that it is greater when the solitary tract is stimulated with a high frequency.25 26 It has been hypothesized that NO functions in two main modes.20 21 First, it has been suggested that NO may work as a retrograde messenger, acting on presynaptic nerve terminals to increase their release of neurotransmitter. According to this model, the synthesis and release of NO is triggered by stimulation of postsynaptic NMDA receptors. It has been shown that NMDA receptors in the NTS and the caudal VLM participate in the baroreceptor reflex.16 17 27 28 Thus, if this mechanism is operative in the NTS and the caudal VLM, then one may speculate that the loss of the effect of NO as a retrograde messenger at synapses may explain the increased central adaptation that was observed after L-NAME administration. Second, it also has been suggested that NO may be generated presynaptically after the action potential–dependent influx of Ca2+ and that it then acts to increase the release of primary neurotransmitter.20 This mechanism also would explain the observations of the present study.
We did not address the question as to which are the specific sites of action of L-NAME in reducing rapid adaptation. In the brain stem, the existence of NO synthase has been demonstrated in the NTS, VLM, and medullary reticular formation.8 12 13 14 15 21 It is thus possible that every site within the central baroreflex pathway might contribute to the observed effect of L-NAME. NO has been shown to have a predominantly excitatory effect on NTS neuronal activity in vitro.10 11 L-NAME may also act on neurons in other regions such as the rostral and caudal VLMs, both of which, like the NTS are essential components of the central baroreflex pathway and contains NO synthase–positive neurons.8 12 13 14 15 Further studies are required to determine the precise site or sites at which endogenous NO acts to maintain reflexly evoked sympathoinhibition in response to a sustained baroreceptor stimulation.
To the best of our knowledge, this is the first study to demonstrate a role for NO in central adaptation of the baroreflex control of sympathetic nerve activity. Previous studies have examined the role of NO in arterial baroreflex control of sympathetic nerve activity and heart rate29 30 31 32 and have reported that NO either depresses or does not change the baroreflex control of heart rate and/or sympathetic nerve activity.29 30 31 However, in those studies, a NO synthase inhibitor was administered intravenously so it is not clear whether this compound had any action on the central nervous system. Interestingly, however, one of these studies demonstrated that intracerebroventricular injection of L-NAME inhibited the baroreflex function.32
Harada et al3 have shown that the reflex control of renal sympathetic nerve activity caused by a ramp (gradual) increase or decrease in arterial pressure with intravenous phenylephrine or nitroglycerin does not differ before or after the injection of L-NMMA into the NTS. However, the results of the present study are not necessarily contradictory to the results by Harada et al, since we found a similar immediate inhibition of renal sympathetic nerve activity between the injection of vehicle and the injection of L-NAME.
The physiological implications of the rapid central adaptation of the baroreflex control of the sympathetic nerve activity is still not well understood, especially in the conscious state. We did experiments in anesthetized animals because it was necessary to carefully control the carotid sinus pressure, which could not be done in conscious animals. It has been demonstrated in dogs that the initial inhibition of sympathetic nerve activity during an increase in the carotid sinus pressure and baroreceptor activity is similar in both old and young animals, but that in older animals sympathetic nerve activity escapes from inhibition and returns toward baseline levels despite the higher level of pressure.33 With aging, there may be a decreased density of the excitatory glutamate receptor subtype for NMDA.34 Recent studies have shown that NO synthase activity decreases with aging,35 36 thus suggesting a possible link between the glutamate receptors and the NO activity.
In summary, our results suggest that endogenous NO in the brain stem may attenuate the rapid central adaptation of the baroreflex control of the sympathetic nerve activity, thus helping to maintain the reflex inhibition of the sympathetic nerve activity in response to sustained baroreceptor stimulation. Further studies are needed, however, to clarify the precise sites and mechanisms of this action of NO.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants-in-aid for Scientific Research from the Japanese Ministry of Education, Science and Culture. We thank Dr Roger A.L. Dampney for valuable comments and Fumiko Amano for her technical assistance.
Received April 17, 1997; first decision May 21, 1997; accepted August 15, 1997.
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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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V. L. Brooks, K. A. Clow, and K. P. O'Hagan Pregnancy and acute baroreflex resetting in conscious rabbits Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2002; 283(2): R429 - R440. [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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I. Matsuo, Y. Hirooka, K. Hironaga, K. Eshima, H. Shigematsu, M. Shihara, K. Sakai, and A. Takeshita Glutamate release via NO production evoked by NMDA in the NTS enhances hypotension and bradycardia in vivo Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1285 - R1291. [Abstract] [Full Text] [PDF]
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 J. F R Paton, J. Deuchars, Z. Ahmad, L-F Wong, D. Murphy, and S. Kasparov Adenoviral vector demonstrates that angiotensin II-induced depression of the cardiac baroreflex is mediated by endothelial nitric oxide synthase in the nucleus tractus solitarii of the rat J. Physiol., March 1, 2001; 531(2): 445 - 458. [Abstract] [Full Text] [PDF]
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 K. Sakai, Y. Hirooka, I. Matsuo, K. Eshima, H. Shigematsu, H. Shimokawa, and A. Takeshita Overexpression of eNOS in NTS Causes Hypotension and Bradycardia In Vivo Hypertension, December 1, 2000; 36(6): 1023 - 1028. [Abstract] [Full Text] [PDF]
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K. Eshima, Y. Hirooka, H. Shigematsu, I. Matsuo, G. Koike, K. Sakai, and A. Takeshita Angiotensin in the Nucleus Tractus Solitarii Contributes to Neurogenic Hypertension Caused by Chronic Nitric Oxide Synthase Inhibition Hypertension, August 1, 2000; 36(2): 259 - 263. [Abstract] [Full Text] [PDF]
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