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Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska 68198-4575
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The paraventricular nucleus (PVN) of the hypothalamus is an important site of integration in the central nervous system for sympathetic outflow. Both glutamate and nitric oxide (NO) play an important role in the regulation of sympathetic nerve activity. The purpose of the present study was to examine the interaction of NO and glutamate within the PVN in the regulation of renal sympathetic nerve activity in rats. Renal sympathetic nerve discharge (RSND), arterial blood pressure (BP), and heart rate (HR) were measured in response to administration of N-methyl-D-aspartic acid (NMDA) and NG-monomethyl-L-arginine (L-NMMA) into the PVN. We found that microinjection of NMDA (25, 50, and 100 pmol) into the PVN increased RSND, BP, and HR in a dose-dependent manner, reaching 53 ± 9%, 19 ± 3 mmHg, and 32 ± 12 beats/min, respectively, at the highest dose. These responses were significantly enhanced by prior microinjection of L-NMMA. On the other hand, inhibition of NO within the PVN by microinjection of L-NMMA also induced increases in RSND, BP, and HR in a dose-dependent manner, reaching 48 ± 6.5%, 11 ± 4 mmHg, and 55 ± 16 beats/min, respectively, at the highest dose. This sympathoexcitatory response was eliminated by prior microinjection of DL-2-amino-5-phosphonovaleric acid, an antagonist of the NMDA receptor. Furthermore, with the use of the push-pull technique, perfusion of glutamate (0.5 µmol) or NMDA (0.1 nmol) into the PVN induced an increase in NO release. In conclusion, our data indicate that NMDA receptors within the PVN mediate an excitatory effect on renal sympathetic nerve activity, arterial BP, and HR. NO in the PVN, which is released by activation of the NMDA receptor, also inhibits NMDA-mediated increases in sympathetic nerve activity. This negative feedback of NO on the glutamate system within the PVN may play an important role in maintaining the overall balance and tone of sympathetic outflow in normal and pathophysiological conditions known to have increased sympathetic tone.
sympathetic nerve activity; N-methyl-L-arginine receptor; paraventricular nucleus
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE PARAVENTRICULAR NUCLEUS (PVN) of the hypothalamus is an important central site for the integration of sympathetic nerve activity (34, 35). Morphological and electrophysiological studies have shown that the PVN is reciprocally connected to other areas of the central nervous system that are involved in cardiovascular function (21, 34). With the use of retrograde tracing techniques, various studies have shown that the PVN is a major source of forebrain input to the sympathetic nervous system (30, 33). Functional studies have also implicated an important role for the PVN in cardiovascular regulation (14, 29). However, the interacting mechanisms within the PVN involved in regulating sympathetic nervous activity are still unknown.
In the PVN a number of neurotransmitters, excitatory and inhibitory, converge to influence its neuronal activity (35, 36). Among them are nitric oxide (NO) and glutamate. In the hypothalamus, NO synthase (NOS) positive neurons are found primarily in the PVN and supraoptic nucleus (4, 23, 39). Introduction of a NO donor, sodium nitroprusside (SNP), into the PVN has been shown to elicit a decrease in renal sympathetic nerve activity, arterial blood pressure (BP), and heart rate (HR) (13, 41). Consistent with this observation, administration of NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine (L-NNA), inhibitors of NOS, within the PVN increases renal sympathetic nerve discharge (RSND) (41). These data suggest that NO in the PVN is inhibitory to sympathetic outflow. Glutamate is a well-known excitatory neurotransmitter in the central nervous system. It has been reported that glutamate receptors exist in the PVN (11). Functional studies have shown that glutamate receptors within the PVN are involved in cardiovascular reflexes (6, 24), suggesting that a glutamatergic system within the PVN may play a role in regulating sympathetic nerve activity, and thus cardiovascular function.
An increasing body of evidence indicates that the interaction of NO and the glutamate receptor is important for neuronal development and function (1, 31). On one hand, glutamate through N-methyl-D-aspartic acid (NMDA) receptors activates NOS in neurons and induces an increase in NO production (5, 31). On the other hand, NO elicits a regulatory effect on glutamate receptor activity (16, 17). In the PVN, NO and glutamate interact to regulate neuronal function (1, 7). However, whether the interaction of NO and glutamate in the PVN plays a role in regulating sympathetic nerve activity remains unclear.
The purpose of present study was to test the effect of the interaction between NO and the NMDA-glutamate receptor in the PVN on the subsequent regulation of sympathetic nerve activity and cardiovascular responses. This was investigated by determining: 1) the effect of microinjection of an NOS inhibitor, L-NMMA into the PVN on NMDA-induced changes in RSND, BP, and HR; 2) the effect of microinjection of NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP-5) into the PVN on L-NMMA-induced changes in RSND, BP, and HR; and 3) the effect of push-pull perfusion of glutamate and NMDA into PVN on NO release.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All rats were fed and housed according to institutional guidelines. This study was approved by the Institutional Animal Care and Use Committee and conformed to the guidelines for the care and use of laboratory animals of the National Institutes of Health and the American Physiological Society.
On the day of the experiment, the rat was anesthetized with urethane
(0.75 g/kg ip) and 
-chloralose (70 mg/kg ip), and the left femoral
vein was cannulated with polyethylene tubing (PE-50) for injection of
supplemental anesthesia. The left femoral artery was cannulated and
connected to a computer-driven data recording and analyzing system
(MacLab) via a pressure transducer (Gould P23 1D) for recording
arterial BP and HR. The trachea was intubated to facilitate spontaneous ventilation.
Placement of Microinjection and Push-Pull Perfusion Cannulas into PVN
The anesthetized rat was placed in a stereotaxic apparatus (Davis Kopf Instruments; Tujanga, CA). A longitudinal incision was made on the head, and the bregma was exposed. The coordinates for the PVN were determined from the Paxinos and Watson Atlas (28). They were 1.5 mm posterior to bregma, 0.4 mm lateral to the midline, and 7.8 mm ventral to the dura. A small burr hole was made in the skull. For the microinjections, a thin needle (0.5 mm OD and 0.1 mm ID) connected to a microsyringe (0.5 µl; model 7000.5, Hamilton microsyringe) was lowered into the PVN. For push-pull perfusion, a probe (0.7 mm OD and 0.2 mm ID) was lowered that led the inner (push) cannula into PVN and collected the perfusate into the outer (pull) cannula. Both the push and pull cannulas were connected to a pump that infused and returned artificial cerebrospinal fluid (aCSF, composition in mM: 145 NaCl, 3.5 KCl, 1.0 MgCl2, and 1.3 CaCl2, pH 7.2) at a constant flow rate of 2-5 µl/min. The returned perfusate was collected as a fraction every 10 min. The samples were rapidly frozen in
70°C for nitrate/nitrite
(NOx) measurement.
Recording RSND
The left kidney was exposed through a retroperitoneal flank incision. A branch of the renal nerve was isolated from the fat and connective tissue. The nerve was placed on a pair of thin bipolar platinum electrodes. The nerve-electrode junction was insulated electrically from the surrounding tissue with a silicone gel (Wacker Sil-Gel, 604 A B). The electrical signal was amplified (10,000 times) with a Grass amplifier (P55) with a high- and a low-frequency cutoff of 1,000 and 100 Hz, respectively. The output signal from the Grass amplifier was directed to a computer-run data acquisition system (MacLab) to record and integrate the raw nerve discharge. The signal recorded at the end of the experiment (after the rat was dead) was deemed as background noise. During the experiment, the value of nerve discharge was calculated by subtracting the background noise from the actual recorded value. The basal value of the nerve discharge was defined by subtracting the background noise from the actual nerve discharge value before the administration of drugs into the PVN. The peak response of RSND to the administration of drugs into the PVN during the experiment (averaged over a period of 20-30 s) was subsequently expressed as a percent change from baseline.Measurement of NO Release in Perfusates from PVN
NO in the samples of perfusates drawn from the PVN was measured as its NOx metabolites using a chemiluminescence detector (model 280, Sievers Nitric Oxide Analyzer). A standard curve for NaNO3 concentration (100 µl of 0.1, 0.5, 1, 2.5, 5, and 10 µM) was generated for each experiment, and unknown samples were compared with the standard curve using the software provided with the Sievers Nitric Oxide Analyzer. This program takes into account both the peak response and the total area of the curve generated by standard and unknown samples. All measurements were performed, at least in duplicate, and then averaged to represent the mean for each sample.Experimental Protocols
Experiment 1: Determine effect of microinjection of NOS inhibitor L-NMMA into PVN on NMDA-induced changes in RSND, BP, and HR. In the first group of rats (n = 7), NMDA (25, 50, and 100 pmol in 25, 50, and 100 nl of 1 mM of NMDA in aCSF, respectively) was injected into the PVN at 30-min intervals. In the second group (n = 7), each dose of NMDA administered followed 2 min after the injection of 100 pmol (50 nl of 2 mM of L-NMMA in aCSF) of L-NMMA into the PVN. These volumes of aCSF injections in the PVN did not produce any significant changes in RSND, BP, or HR [a change of: RSND = 1.2 ± 0.4%, BP = 2.1 ± 0.2 mmHg, and HR = 2.8 ± 1.2 for a 50-nl microinjection; RSND = 2.4 ± 0.5%, BP = 2.8 ± 0.4 mmHg, and HR = 5.6 ± 2.0 for a 100-nl microinjection; RSND = 2.6 ± 0.8%, BP = 3.4 ± 0.7 mmHg, and HR = 6.2 ± 3.0 for a 200-nl microinjection (n = 5)] over the time frame of these experiments. Furthermore, we have previously shown that microinjections of this vehicle with vasoactive substances (of similar volumes) do not produce a change in RSND, BP, or HR (41). The responses in RSND, BP, and HR were recorded after each application. To validate that responses in RSND, BP, and HR to NMDA or L-NMMA were not due to a peripheral action, in five normal rats, responses to intravenous injections of 200 pmol of NMDA with or without 200 pmol of L-NMMA were examined.
Experiment 2: Determine effect of microinjection of NMDA receptor antagonist AP-5 into PVN on change in RSND, BP, and HR induced by L-NMMA. In the first group of rats (n = 6), L-NMMA (50, 100, and 200 pmol in 25, 50, and 100 nl of 2 mM of L-NMMA in aCSF, respectively; intervals of 30 min) was injected into the PVN. In the second group (n = 7), each dose of L-NMMA administered followed 2 min after the injection of 8 nmol (in 50 nl of 0.16 M of AP-5 in aCSF) of AP-5 into the PVN. The responses in RSND, BP, and HR were recorded after each application.
Experiment 3: Determine effect of perfusion of glutamate and NMDA into PVN on NO release. With the use of the push-pull technique and after a 40-min equilibration period, the perfusate from the PVN was collected for a 30-min control period. Then 0.5 nmol of glutamate in aCSF (n = 5) or 0.1 nmol of NMDA in aCSF (n = 6) was infused into the PVN within a 1-min time period. After 30 min and after the perfusion of the drugs, perfusate from the PVN was collected. NO concentration in the perfusate was measured as described above.
Brain Histology
After the experiment, the rat was killed and the brain was removed and fixed in 10% formalin for at least 24 h. The brain was then frozen, and serial transverse sections (30 µm) were cut with a cryostat (18°C). The sections were mounted on microscope slides
and then stained using 1% neutral red. The location of the injection
within the PVN was verified under a microscope with ×40 magnification.
Those injections with termination in the boundaries of the PVN were
considered to be effective injections. Figure 1 illustrates the histological data of
the termination site of microinjection and push-pull perfusion into the
PVN. Among 35 effective injection sites, 14 sites belong to
experiment 1; 13 sites belong to experiment 2;
and 8 sites belong to experiment 3. Eight sites were outside
the PVN and did not elicit changes in RSND to NMDA administration.
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Data Analysis
Responses of RSND to the various doses of drugs were expressed as percent change from the baseline value. Responses of arterial BP and HR to drugs were expressed as the difference between the basal value and the value after each dose of drug. The data were subjected to two-way repeated measures ANOVA, followed by comparison for individual differences using the Newman-Keuls test (40). P < 0.05 was considered to indicate statistical significance. All data are presented as means ± SE.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1. Effect of Microinjection of NOS Inhibitor L-NMMA Into PVN on NMDA-Induced Change in RSND, BP, and HR
The administration of NMDA or NMDA + L-NMMA into the PVN induced a significant increase in RSND, BP, and HR. The NMDA-induced increase of RSND usually peaked within 3 min after microinjection followed by a recovery within 20 min. In most cases, after the NMDA-induced increase, the level of RSND went lower than baseline (i.e., before NMDA administration), indicative of a possible inhibitory effect (Fig. 2). Coadministration of L-NMMA enhanced the increase of RSND induced by NMDA as well as diminished the decrease of the RSND level after the increase during the peak. Figure 2 illustrates typical responses of BP and RSND to the administration of NMDA or NMDA + L-NMMA. Figure 3 shows the time course of the change in RSND to administration of NMDA (50 pmol) and NMDA (50 pmol) + L-NMMA (100 pmol) into the PVN.
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An example of the responses in RSND, BP, and HR to different doses of
NMDA or NMDA + L-NMMA is illustrated in Fig.
4. Microinjection of NMDA (25, 50, and
100 pmol) induced significant increases in RSND, BP, and HR in a
dose-dependent manner, reaching 53 ± 9%, 19 ± 3 mmHg, and
32 ± 12 beats/min, respectively, at the highest dose (Fig.
5). Microinjection of NMDA (25, 50, and
100 pmol) with prior microinjection of L-NMMA (100 pmol in
50 nl) induced a significantly larger increase in RSND than the
response to microinjection of NMDA by itself, reaching 77 ± 13%
at the highest dose of NMDA (Fig. 5). Blockade of endogenous NO in the
PVN enhanced the NMDA-induced increase in renal sympathetic nerve
activity. These data indicate that endogenous NO elicits a inhibitory
effect on the NMDA-induced increase of sympathetic activity. Peripheral
intravenous injections of 200 pmol of NMDA with or without 200 pmol of
L-NMMA had no effect on RSND, BP, or HR (data not shown),
indicating the above responses are not due to peripheral effect of the
drug when it is administered centrally within the PVN.
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Experiment 2. Effect of NMDA Receptor Antagonist AP-5 on L-NMMA-Induced Change in RSND, BP, and HR
Microinjection of L-NMMA (50, 100, and 200 pmol) into the PVN induced significant increases in RSND, BP, and HR in a dose-dependent manner, reaching 48 ± 7%, 11 ± 4 mmHg, and 55 ± 15 beats/min, respectively, at the highest dose. When the NMDA receptor was blocked by prior administration of AP-5 (8 nmol) within the PVN, microinjection of L-NMMA no longer induced the increase in RSND or HR (Fig. 6). This result suggest that the effect of an increase in RSND induced by L-NMMA is mediated by the NMDA receptor and may be due to the reduction in inhibition of NMDA receptor activity by endogenous NO.
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Experiment 3. Effect of Perfusion of Glutamate and NMDA Into PVN on NO Release
In the 30 min after perfusion of glutamate (0.5 nmol) or NMDA (0.1 nmol) into the PVN, the concentration of NOx in the push-pull samples was significantly greater than before glutamate or NMDA perfusion (Fig. 7). This suggests that in the PVN, the excitation of glutamatergic-NMDA receptors induces an increase in NO synthesis and release.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of the present study indicate that activation of NMDA receptors in the PVN elicits an excitatory effect on renal sympathetic nerve activity. This action of NMDA can be enhanced by the inhibition of endogenous NO synthesis by L-NMMA, suggesting that NO produced during NMDA receptor activation is involved in inhibiting NMDA-mediated increases in RSND. Consistent with this, perfusion of either glutamate or NMDA into PVN induced an increase in NO release, suggesting that the activation of NMDA receptors in the PVN increases the synthesis and release of NO. The results also show that a NMDA receptor antagonist AP-5 abrogated L-NMMA-induced increases in RSND, suggesting that the increase in RSND evoked by blockade of endogenous NO is mediated by activation of NMDA receptors.
The PVN is one of the five major central nervous system sites that directly controls sympathetic outflow (32) and is the only one of these sites located in the hypothalamus. This fact, combined with the known role for the PVN in fluid balance and vasopressin release, makes the PVN a prime candidate within the forebrain for a central site responsible for mediating sympathetic outflow. Recent evidence, including our own, suggests that the parvocellular neurons of the PVN (pPVN) are involved in the mediation of the neural component of cardiovascular reflexes by influencing RSND (9, 19, 27). Specifically, these studies demonstrated that the PVN is involved in baroreflex regulation of lumbar sympathetic nerve activity (27). Stimulation of PVN has been shown to elicit an increased discharge from several sympathetic nerves, including renal (14), adrenal (15), and splanchnic (20). These observations suggest that the PVN plays an essential role in the mediation of RSND under rest and during autonomic reflex conditions (9, 19, 27). However, the interactions and possible neurotransmitters involved in regulating sympathetic function via the PVN have not been fully established.
Since the first demonstration of NO acting as a neuronal messenger in cerebellar granule cells (8), NO has been reported to be involved in various physiological activities as an nonconventional neurotransmitter, including sympathetic and cardiovascular functions (37, 38). NOS-positive neurons have been found in the PVN (4, 39), and functional studies from our laboratory indicate that NO in the PVN elicits an inhibitory effect on sympathetic nerve activity (41, 42). Thus we suggest that the NO mechanism within the PVN may serve a role in the physiological regulation of the sympathetic nervous system.
As a major excitatory neurotransmitter, glutamate has been found to
regulate sympathetic nerve activity in several brain areas, including
the lateral hypothalamic area (6) and the ventrolateral medulla (24, 26). It has been reported that NMDA and
-amino-3-hydroxy-5-methylisoxazole propionate receptors, the two
major ionotropic glutamate receptors mediating the excitatory signal of
glutamate, exist in the PVN (12), suggesting that both
receptors may mediate glutamate action in the PVN. Glutamate
receptor agonists activate PVN neurons (1). With the use
of whole cell recording from the hypothalamic slice preparations
obtained from the rat, it was observed that NMDA can induce
depolarization in both type I (mPVN) and type II (pPVN) neurons
(2, 3, 7). These observations indicate that glutamatergic synapses in the PVN may play a role in regulating sympathetic nerve activity.
Taken together, NO elicits an inhibitory effect, whereas glutamate
elicits an excitatory effect on sympathetic nerve activity within the
PVN. This fact led us to propose an interaction of NO and glutamate in
the PVN in the regulation of sympathetic nerve discharge. The results
of the present study provide the first direct in vivo experimental
evidence for the interaction of NO and glutamate in the PVN for
regulating sympathetic nerve activity. From these results, we
hypothesize that there is a negative feedback loop between
glutamatergic and NO systems in the PVN (Fig.
8): glutamate is an excitatory
neurotransmitter that excites higher-order neurons that project to
renal sympathetic nerve outflow within the PVN and increases renal
sympathetic nerve activity. Meanwhile, the excitation of NMDA receptors
produces NO release from excited neurons, which in turn elicits an
inhibitory action on the NMDA receptors to produce an inhibition of
sympathetic nerve activity.
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Bains and Ferguson (1, 3), using whole cell recording from the hypothalamic slice preparation in rats, observed that in addition to depolarizing PVN neurons initially, NMDA also induced inhibitory postsynaptic potentials (IPSP) later in the same neurons. Application of NO increased NMDA-induced IPSP. Conversely, blocking NO with NG-nitro-L-arginine methyl ester (L-NAME) elicited more pronounced NMDA-induced depolarization but no accompanying increase in IPSPs (1, 3). These results provide evidence suggesting that there is a negative feedback mechanism between the NO and glutamate systems within the PVN. We propose that this negative feedback mechanism plays an important role in the regulation of sympathetic nerve activity and prevents overexcitation and subsequent possibly increases in sympathetic outflow. We (18) recently observed that microinjection of NMDA into the PVN of rats with heart failure induced a greater increase in RSND than that in the normal rat. Rats with heart failure are known to have decreased NOS positive cells in the PVN (43). Therefore the functional balance of NO and NMDA in the PVN may play an important role in physiological and pathophysiological conditions with elevated sympathetic nervous outflow such as observed in hypertension or heart failure.
The results in this study also suggest that there is an ongoing endogenous inhibitory NO mechanism that opposes the excitatory NMDA mechanism in the PVN. Administration of L-NMMA elicited an increase in RSND that was abrogated by blockade of NMDA receptors with AP5. These results suggest that tonic NMDA (produced by glutamate release)-mediated NO release is constantly inhibiting ongoing NMDA-mediated increase in sympathetic outflow (Fig. 8).
The molecular mechanism of the interaction of NO and the NMDA receptor has been studied to some extent (5, 16, 31). It has been reported that NMDA and neuronal NOS are connected to each other through specific proteins called postsynaptic density proteins (PSD95) (5, 31). These observations suggest a strong link between NMDA receptor activation and NO production. Consistent with these results we observed an increase of NO release with perfusion of glutamate or NMDA into the PVN. With regard to the effect of NO on NMDA receptors, some recent studies (16) have shown that, as a radical molecule, NO and its derivative can redox glutamate-NMDA receptors and reduce the activity of the receptors, which are believed to be one of mechanisms of modulation of NO on the nervous system. The fact that blockade of NO with L-NMMA enhanced the actions of NMDA on RSND is consistent with an inhibitory action of NO on NMDA receptors. This does not exclude the possibility that NO may have an inhibitory effect on NMDA receptor via an indirect action as well. Some data suggest that NO may activate the endogenous GABA system in the PVN. It has been reported that NO can cause the release of GABA from neurons via peroxynitrite (25). This interaction may exist in the PVN because it has been reported that perfusion of the PVN with NO containing cerebrospinal fluid elicits an increase in the release of GABA (13). Furthermore, both NO and GABA (22) are sympathoinhibitory. Administration of an NO donor into the PVN causes decreases in RSND and BP that can be eliminated by blockade of the GABA receptor in the PVN with bicuculline (42). Thus the effect of NO is partly mediated by GABA in the PVN. Consistent with this concept, administration of L-NAME into the PVN elicited significant increases in RSND, BP, and HR, which were abolished by blockade of the GABA system with bicuculline (42). These data suggest that NO may have both a direct inhibitory effect on NMDA receptors and an indirect inhibitory effect via activation of a GABA mechanism.
In conclusion, our study demonstrates that NO inhibits NMDA-mediated increases in the renal sympathetic nerve activity. This indicates a short loop inhibition by NO of excitation by NMDA receptor activation to increase renal sympathetic nerve activity within the PVN. This may be an important interaction in dictating sympathetic outflow in disease states known to have altered NOS activity in the PVN with a concomitant increase in basal sympathetic tone, such as heart failure (43) and hypertension (10).
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ACKNOWLEDGEMENTS |
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The technical assistance of Phyllis Anding is greatly appreciated.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants PO1-HL-62222 and NS-39751.
Address for reprint requests and other correspondence: K. P. Patel, Dept. of Physiology and Biophysics, Univ. of Nebraska Medical Center, 984575 Nebraska Medical Center, Omaha, NE 68198-4575 (E-mail: kpatel{at}unmc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 June 2001; accepted in final form 5 September 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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