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Am J Physiol Regul Integr Comp Physiol 275: R728-R734, 1998;
0363-6119/98 $5.00
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Vol. 275, Issue 3, R728-R734, September 1998

Effect of nitric oxide within the paraventricular nucleus on renal sympathetic nerve discharge: role of GABA

Kun Zhang and Kaushik P. Patel

Department of Physiology and Biophysics, University of Nebraska College of Medicine, Omaha, Nebraska 68198

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

Both nitric oxide (NO) and GABA are known to provide inhibitory inputs to the paraventricular nucleus (PVN) of the hypothalamus and are involved in the control of sympathetic outflow. The purpose of the present study was to examine the interaction of NO and GABA in the regulation of renal sympathetic nerve activity in rats. The responses of renal nerve activity, blood pressure, and heart rate to microinjection of sodium nitroprusside (SNP), an NO donor, into the PVN were measured in the presence and absence of blockade of the GABA system (bicuculline; 2 nmol). Microinjection of SNP (50, 100, and 200 nmol) into the PVN elicited significant decreases in renal nerve discharge, arterial blood pressure, and heart rate, reaching -36.4 ± 9.7%, -11 ± 5 mmHg, and -34 ± 14 beats/min, respectively, at the highest dose. These responses were eliminated by blockade of the GABA system. Conversely, microinjection of Nomega -nitro-L-arginine methyl ester (L-NAME; 50, 100, and 200 nmol) elicited significant increases in the renal sympathetic nerve discharge, arterial blood pressure, and heart rate, reaching 88.9 ± 16.6%, 9 ± 1 mmHg, and 29 ± 9 beats/min, respectively, at the highest dose. These sympathoexcitatory responses were masked by prior blockade of the GABA system with bicuculline. The sympathoexcitatory effect of L-NAME was also eliminated by activation of the GABA system with muscimol. In conclusion, our data indicate that the inhibitory effect of endogenous NO within the PVN on the renal sympathetic nerve activity is mediated by GABA.

blood pressure; heart rate; Nomega -nitro-L-arginine methyl ester; bicuculline

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

AS AN UNCONVENTIONAL neurotransmitter, nitric oxide (NO) is known to play a role in sympathetic regulation by central mechanisms (28, 34). Immunohistochemical and electrophysiological evidence suggest an effect of NO in some central nuclei that are known to be associated with sympathetic regulation (3, 8, 15, 20, 24, 29, 36). The presence of NO synthase in the paraventricular nucleus (PVN) of the hypothalamus suggests that NO may play a role in endocrine and autonomic regulation of cardiovascular responses. Blockade of NO synthesis potentiates excitatory neurotransmitter actions in the PVN (1). Recently, we have demonstrated that endogenous NO in the PVN has an inhibitory effect on renal sympathetic outflow (38). However, the mechanisms by which NO regulates renal sympathetic nerve activity in the PVN are unclear. The PVN is a nucleus in which ~30 different neurotransmitters converge. A number of these neurotransmitters have been shown to have an effect on sympathetic outflow (18, 19). Thus it is possible that the effect of NO on sympathetic outflow is mediated by the modulation of these neurotransmitters within the PVN. Recently, Horn et al. (12) reported that perfusion of the PVN with NO-containing cerebrospinal fluid or microinjection of sodium nitroprusside (SNP), an NO donor, elicited changes in the concentrations of some amino acids, including GABA. Immunocytochemical studies have reported extensive GABAergic synaptic connections in the PVN (7). GABAA receptor antagonists such as bicuculline methiodide within the PVN are known to produce an activation of sympathetic outflow, presumably via activation of neurons in the PVN projecting to autonomic nuclei in the brain stem and spinal cord (19). Thus it is possible that the sympathoinhibitory effect of NO within the PVN may be mediated by an intermediary GABA system.

The purpose of this study was to examine whether there is an interaction of NO and GABA within the PVN in regulating renal sympathetic nerve discharge (RSND). We studied the influences of blockade of the GABA system within the PVN on the renal sympathoinhibitory effect of SNP and the renal sympathoexcitatory effect of Nomega -nitro-L-arginine methyl ester (L-NAME). We also examined the influence of the activation of the GABA system in the PVN on the renal sympathoexcitatory effect of L-NAME.

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

All rats were fed and housed according to institutional guidelines at the University of Nebraska Medical Center. This study was approved by the University of Nebraska Medical Center 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.

General Surgical Preparation

On the day of the experiment, the rat was anesthetized with urethan (0.75 g/kg ip) and alpha -chloralose (70 mg/kg ip), and the left femoral vein was cannulated for administration of supplemental anesthesia. The left femoral artery was cannulated and connected to a computer-based data acquisition system (MacLab) via a pressure transducer (Gould P23 1D) for recording arterial blood pressure and heart rate.

Recording of the Efferent RSND

The left kidney was exposed through a left retroperitoneal flank incision. A branch of the renal nerve was isolated from the adipose and connective tissues. The distal end of the nerve was ligated, and the nerve was placed on a thin bipolar platinum electrode. The nerve-electrode junction was insulated electrically from the surrounding tissues with mineral oil. The electrical signal from the electrode was amplified with a Grass amplifier (HIP5) with a high- and a low-frequency cutoff of 1,000 and 100 Hz, respectively. The output from the Grass amplifier was directed to a Grass Integrator, which rectifies the signal and integrates the raw nerve discharge. The output of the Grass Integrator was displayed as an integrated voltage that is proportional to the renal nerve discharge. The average rectified signal (RC filtered, time constant, 0.5 s) was then recorded and stored for later analysis in a computer-based data acquisition system (MacLab). Efferent RSND at the beginning of the experiment was defined as basal nerve discharge. The nerve discharge recorded at the end of the experiment after the rat was injected with hexamethonium (30 mg/kg iv) was deemed background noise. During the experiment, the value of nerve discharge was calculated by subtracting the background noise from the actual recorded value. The change in nerve discharge during the experiment was subsequently expressed as a percentage from the basal value.

Placement of Cannula Into the PVN

The 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 right PVN were determined from an atlas (25), 1.3 mm posterior, 0.4 mm lateral to the bregma, and 7.8 mm ventral to the dura. A small burr hole was placed in the skull, and a thin needle (0.5 mm OD; 0.1 mm ID) that was connected to a microsyringe (0.5 µl, Hamilton microsyringe) was lowered into the PVN. At the end of the experiment, monastral blue dye was injected into the brain for histological verification.

Brain Histology

After the rat was killed, the brain was removed and fixed in 4% formaldehyde for at least 24 h. The brain was then frozen, and serial transverse sections (30 µm) were cut using a cryostat (-20°C). The sections were thaw mounted on microscope slides and then stained with 1% aqueous neutral red staining procedures. The presence of blue dye within the PVN was verified under a microscope with ×40 magnification. Those injections with termination in the PVN or within 0.5 mm away from the boundaries of the PVN were considered to be histologically targeted (Fig. 1).


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  		Fig. 1.   Schematic representations of serial sections from rostral (-1.4) to caudal (-2.12) extent of the region of the paraventricular nucleus (PVN). Distance, in millimeters, posterior to bregma is shown for each section. bullet , Sites of termination of injection considered to be within the PVN region; open circle , sites of termination of injection outside the PVN; AH, anterior hypothalamus; 3V, third ventricle; f, fornix.

Experimental Protocols

Responses to SNP. In the first group of rats (n = 6), an NO donor (SNP) was consecutively injected (50, 100, and 200 nmol of SNP in 50-200 nl) into the PVN at intervals of 15 min. Maximum changes in blood pressure, heart rate, and RSND over 15 min were recorded after each dose of SNP. In the second group of rats (n = 6), 5 min after a GABAA receptor antagonist (bicuculline; 2 nmol in 50 nl) was injected into the PVN, SNP was consecutively injected (50, 100, and 200 nmol of SNP in 50-200 nl) into the PVN at intervals of 15 min. Maximum changes in blood pressure, heart rate, and RSND over 15 min were recorded after each dose of SNP.

Responses to L-NAME. In the first group of rats (n = 6), an NO synthase inhibitor (L-NAME) was consecutively injected (50, 100, and 200 nmol of L-NAME in 50-200 nl) into the PVN at an interval of 15 min. Maximum changes in blood pressure, heart rate, and RSND over 15 min were recorded after each dose of L-NAME. In the second group of rats (n = 6), 15 min after a GABA agonist (muscimol, 1.6 nmol in 100 nl) was injected into the PVN, L-NAME (50, 100, and 200 nmol in 50-200 nl) was consecutively injected into the PVN with an interval of 15 min. Maximum changes in blood pressure, heart rate, and RSND over 15 min were recorded after each dose of L-NAME. In the third group of rats (n = 6), 10 min after bicuculline (2 nmol in 50 nl) was injected into the PVN, L-NAME (50, 100, and 200 nmol in 50-200 nl) was consecutively injected into the PVN with an interval of 15 min. Maximum changes in blood pressure, heart rate, and RSND over 15 min were recorded after each dose of L-NAME.

Responses to N-methyl-D-aspartic acid. In a group of rats (n = 5), we examined the specificity of responses to L-NAME in the experiment above by injecting another sympathoexcitatory agent, N-methyl-D-aspartic acid (NMDA), after similar activation of the GABA system. Fifteen minutes after a GABA agonist (muscimol, 1.6 nmol in 100 nl) was injected into the PVN, NMDA (5 nmol in 50 nl) was injected into the PVN. Maximum changes in blood pressure, heart rate, and RSND over 15 min were recorded after NMDA.

Analysis of Data

Responses of renal nerve to the various doses of drugs were expressed as percent change over the basal value. Responses of arterial blood pressure and heart rate to drugs were expressed as differences between the basal value and the value after each dose of drugs. The data were subject to analysis of variance within the group followed by the comparison between the groups (Fisher); P < 0.05 indicated significant difference.

    RESULTS
Top
Abstract
Introduction
Methods
Results
Discussion
References

General Data

There were no significant differences in basal RSND (not withstanding caveats for comparing multifiber recordings between animals), mean blood pressure, and heart rate among the groups before microinjection of any substances into the PVN (Table 1). These parameters did not change significantly over the time frame of these experiments independent of microinjections of substances into the PVN. Furthermore administration of similar volumes of vehicle (saline) into the PVN used in this study did not produce any changes in RSND (8.0 ± 8.4%), mean blood pressure (2 ± 1 mmHg), and heart rate (17 ± 8 beats/min).

                              
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  		Table 1.   Basal renal nerve discharge, basal arterial blood pressure, and heart rate

Responses Following Microinjections Into the PVN

Responses to SNP. Microinjection of the NO donor SNP (50, 100, and 200 nmol) produced a significant reduction (1-way ANOVA) in efferent RSND, arterial blood pressure, and heart rate, reaching -36.4 ± 9.7%, -11 ± 5 mmHg, and -34 ± 14 beats/min, respectively, at the highest dose (Fig. 2). As expected, blockade of endogenous GABA system with bicuculline produced increases in RSND (42%), arterial blood pressure (18%), and heart rate (6%) (Table 1). After administration of bicuculline, microinjections of SNP (50, 100, and 200 nmol) no longer produced significant changes in efferent RSND, arterial blood pressure, and heart rate (Fig. 2). There were significant differences in the responses of efferent RSND, arterial blood pressure, and heart rate to SNP between before and after blockade of the endogenous GABA system (Fig. 2). Injection of SNP (200 nmol) and bicuculline (2 nmol) simultaneously (n = 5) produced increases in RSND (64 ± 11%), arterial blood pressure (23 ± 8%), and heart rate (24 ± 5%) that were not statistically different from injection of bicuculline (2 nmol) alone (RSND, 47 ± 6%; blood pressure, 23 ± 8%; and heart rate, 15 ± 12%; n = 8). A ten times higher dose of SNP (2,000 nmol) still failed to significantly decrease RSND or heart rate after bicuculline, but decreased arterial pressure by 20 ± 5% (n = 5).


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  		Fig. 2.   Change of efferent renal sympathetic nerve discharge (RSND; A), blood pressure (B), and heart rate (C) to microinjection of sodium nitroprusside into the PVN both in absence (open bars) and presence (hatched bars) of blockade of endogenous GABA system with bicuculline in the PVN. Graphs represent mean value for each group ± SE. * P < 0.05 compared with control.

Responses to L-NAME. Microinjections of L-NAME (50, 100, and 200 nmol) elicited a significant increase (1-way ANOVA) in efferent RSND, arterial blood pressure, and heart rate, reaching 88.9 ± 16.6%, 9 ± 1 mmHg, and 29 ± 9 beats/min, respectively, at the highest dose (Fig. 3). As expected, microinjection of muscimol produced decreased RSND (-39%), arterial blood pressure (-28%), and heart rate (-11%) (Table 1). However, after administration of muscimol into the PVN, microinjections of L-NAME (50, 100, and 200 nmol) no longer elicited significant changes in efferent RSND, arterial blood pressure, and heart rate (Fig. 3). There were significant differences in the responses of efferent RSND, arterial blood pressure, and heart rate to microinjection of L-NAME between before and after administration of muscimol into the PVN. Again as expected, administration of bicuculline produced increases in RSND (40%), arterial blood pressure (15%), and heart rate (8%) (Table 1). Furthermore, after administration of bicuculline into the PVN, microinjection of L-NAME (50, 100, and 200 nmol) no longer produced significant changes in efferent RSND, arterial blood pressure, and heart rate (Fig. 3). There were significant differences in the responses of efferent RSND, arterial blood pressure, and heart rate to the microinjection of L-NAME into the PVN between before and after administration of bicuculline into the PVN (Fig. 3).


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  		Fig. 3.   Change of efferent RSND (A), arterial blood pressure (B), and heart rate (C) to microinjection of L-NAME into the PVN in absence (open bars) of muscimol or bicuculline and presence of muscimol (solid bars) or bicuculline (hatched bars) into the PVN. Graphs represent mean value for each group ± SE. * P < 0.05 compared with control.

Responses to NMDA. Microinjection of muscimol produced decreases in RSND (42 ± 6%), arterial blood pressure (19 ± 11%), and heart rate (19 ± 3%) (Table 1). After the administration of muscimol into the PVN, microinjection of NMDA (5 nmol) into the PVN elicited significant increases in efferent RSND, arterial blood pressure, and heart rate (Fig. 4). These results demonstrate that RSND, arterial pressure, and heart rate are capable of significant changes (increase) after administration of muscimol (Fig. 4).


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  		Fig. 4.   Changes of efferent RSND (A), arterial blood pressure (B), and heart rate (C) to microinjection of Nomega -nitro-L-arginine methyl ester (L-NAME) and N-methyl-D-aspartic acid (NMDA) after administration of muscimol into the PVN. Graphs represent mean value for each group ± SE. * P < 0.05 compared with basal values.

    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

The results of the present study indicate that the inhibitory effect of SNP on renal sympathetic nerve activity is eliminated by blockade of the GABA system within the PVN. Conversely, the effect of L-NAME to increase renal sympathetic nerve activity is also blocked by both activation and blockade of the GABA system. Our results suggest that the effect of NO on renal sympathetic nerve activity is mediated by GABA within the PVN.

Since the first demonstration of NO acting as a neuronal messenger (9, 10), NO has been reported to be involved in the function of a wide variety of central and peripheral processes, such as neurotoxicity (6), secretion (26, 39), and animal learning (5). As an unconventional neurotransmitter, NO has been shown to participate in the regulation of the sympathetic nervous system via a central inhibitory mechanism (28, 34). The presence of NO synthase in several central nuclei that are known to process autonomic outflow (3, 8, 15, 20, 24, 29, 36) suggests that this central inhibitory effect of NO on sympathetic nerve activity may be mediated by its action at those same sites. In addition, electrophysiological studies similarly suggest that NO has an inhibitory effect on sympathetic outflow by its action in some of these central nuclei (31, 35). Horn et al. (12) reported that the microdialysis of the PVN with NO-containing cerebrospinal fluid elicited a decrease in arterial blood pressure. Because the PVN is known to be an integrative center for the sympathetic nervous system, it was proposed that this cardiovascular effect of NO is mediated by the inhibition of sympathetic nerve activity (12). Consistent with the study by Horn et al. (12), our recent study indicated that the administration of NG-monomethyl-L-arginine (L-NMMA) into the PVN elicited significant increases in renal sympathetic nerve activity and arterial blood pressure, which suggests that blockade of endogenous NO in the PVN has an excitatory effect on sympathetic outflow (38). However, the mechanisms by which NO exerts its effect in the PVN remain undetermined. NO has a very short half-life (3-5 s) and is an unconventional modulator that is not packaged in vesicles but rather diffuses from its site of production in the absence of any specialized release machinery. On its formation, it reacts with superoxide immediately to form peroxynitrite (2, 30). The independence of the release apparatus raises the possibility that NO can be released from both pre- and postsynaptic neuronal elements. In addition, because NO is gaseous and membrane permeable (32), it can bypass normal signal transduction routes involving interactions with synaptic membrane receptors. The targets of NO have not yet been completely understood. It is known that NO can bind to the iron contained in heme groups, leading to conformational changes in associated proteins, such as guanylate cyclase (37). The resulting increase in cGMP may, in turn, modulate ion channel or phosphodiesterase activity or lead to the activation of a cascade of cGMP-dependent protein kinase activity. This can then lead to various possibilities for the action of NO.

One way through which NO may modulate sympathetic nerve activity is to interact with some other neurotransmitters within the PVN. Several studies have shown that NO can modulate Ca2+ influx, which is required for the release of a number of neurotransmitters. Thus this function may enable NO to interact with a number of neurotransmitters in the neural processes within the PVN. The PVN is a nucleus that is reciprocally connected to a number of nuclei associated with sympathetic function in the central nervous system (4, 13, 16, 33). Furthermore, there are ~30 different neurotransmitters converging within the PVN (33). A number of these neurotransmitters are known to have an effect on sympathetic outflow, such as GABA, known to have an sympathoinhibitory effect (19), and sympathoexcitatory substances such as angiotensin II and glutamate (1, 18). It is possible that the effect of NO is mediated by the modulation of the activity of these neurotransmitters within the PVN.

NO may activate an inhibitory system in the PVN, such as the endogenous GABA system (Fig. 5). It has been reported that NO can cause the release of GABA from the neurons via peroxynitrate (22, 23). GABA is a dominant neurotransmitter in the PVN (7) and well known as an important sympathoinhibitory input within the PVN (19). The activation of the GABA system may play an important role in mediating the renal sympathoinhibitory effect of NO in the PVN. This interaction between NO and GABA at the level of neurons may exist within the PVN, because it has been reported that perfusion of the PVN with NO-containing cerebrospinal fluid elicited an increase in the concentration of GABA in the perfusate (12).


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  		Fig. 5.   Schematic representations of our working model of interaction between nitric oxide (NO) and GABA systems to influence RSND. NO is formed from L-arginine (L-Arg) with action of NO synthase (NOS). NO then stimulates (+) release of GABA, which in turn inhibits (-) PVN neurons responsible for producing activation of RSND. Bic, bicuculline; SNP, sodium nitroprusside; v, third ventricle.

As we reported earlier (38), administration of an NO donor into the PVN caused a similar decrease in renal sympathetic nerve activity and arterial blood pressure as observed in this study. This response was probably not mediated by the direct effect of NO but rather by an indirect effect of NO. The sympathoinhibitory effect of NO was eliminated by blockade of the GABA system in the PVN with bicuculline, a GABAA receptor antagonist. We speculate that the effect of NO is mediated by GABA in the PVN (12, 22, 23). Consistent with this notion, the increase in sympathetic nerve activity as a result of NO synthase inhibitor (38) would also be expected to be mediated by the GABA system in the PVN. In our current study, the administration of L-NAME into the PVN elicited significant increases in efferent RSND, arterial blood pressure, and heart rate that were abolished by blockade of the GABA system. It may be postulated that blockade of GABA produces a maximal increase in RSND that cannot be attenuated any further by the administration of L-NAME. To investigate this possibility, we examined the sympathoexcitatory effect of L-NAME in the presence of an activated GABA system with muscimol. The sympathoexcitatory effect of L-NAME was still absent, although muscimol produced a fairly large sympathoinhibition of renal nerve discharge. These data demonstrate that either blockade or activation of the GABA system eliminates the effects of upstream manipulations of the NO system, consistent with our overall working model shown in Fig. 5. Furthermore, this blocking effect of muscimol on sympathoexcitatory response to L-NAME is unique because microinjection of NMDA, a glutamate agonist, into the PVN elicited significant increases in efferent RSND, arterial blood pressure, and heart rate. These data demonstrate that the lack of the effect of L-NAME within the PVN after blockade of the GABA system is not due to a maximally increased RSND that cannot be augmented any further. Overall, these data taken together indicate that the sympathoinhibitory effect of NO within the PVN is mediated by the GABA system. However, it should be noted that the sympathoinhibitory response mediated via GABA system is not exclusively by the NO system. The NO system is one of the components of the various inputs responsible for the activation of the GABA system.

In addition to activating an inhibitory system in the PVN via GABA, NO may be an inhibitory mechanism to excitatory neurotransmitters, such as the endogenous angiotensin II and glutamate (1, 18) systems. Consistent with this idea, it has been reported that NO can reduce the current through the NMDA receptor by oxidizing the redox site of the receptor (14, 17). The NMDA receptor is a specific type of inotropic receptor for glutamate. Thus it is possible that NO may modulate the action of glutamate by influencing the current through the NMDA receptor. Recently, Zanzinger et al. (37a) reported that the central sympathoexcitatory effect of glutamate was potentiated by the central inhibition of neuronal NO synthase, which suggests that NO inhibits the sympathoexcitatory effect of glutamate by a central mechanism.

It has also been suggested that NO may modulate the action of angiotensin II in the PVN. It was reported that the action of angiotensin II in the PVN was potentiated by L-NMMA (1). This indicates that endogenous NO may counter the action of angiotensin II in the PVN. It has been demonstrated that in cultured neurons, angiotensin II increases NO production, an effect blocked by either an inhibitor of NO synthase or an angiotensin II antagonist (27). According to Haberl et al. (11), one primary degradation product of angiotensin II is L-arginine, which is a precursor of NO. Because NO is very membrane permeable, it was proposed that the formation of postsynaptic NO diffuses back to the presynaptic terminal to inhibit the release of angiotensin II (1, 12). Glutamate and angiotensin II are both known as sympathoexcitatory neurotransmitters in the PVN (1, 18). The inhibitory effect of NO on sympathetic outflow may counter the actions of glutamate and angiotensin II within the PVN. The interactions between NO and sympathoexcitatory neurotransmitters glutamate and angiotensin II remain to be examined.

In conclusion, our data demonstrate that the sympathoinhibitory effect of NO in the PVN is mediated by GABA. However, the sympathoinhibitory response mediated via GABA is not exclusively by the NO system. These findings provide important new evidence supporting a role for GABA as an intermediary for the actions of NO within the PVN to regulate renal sympathoinhibition.

Perspectives

This PVN of the hypothalamus serves as a major forebrain structure involved in integrating autonomic function. Previously, we have demonstrated that endogenous NO in the PVN has an inhibitory effect on RSNA. This study demonstrates that the renal sympathoinhibitory effect of NO within the PVN is mediated by an intermediary GABA system. Future research will be necessary to establish the origin and nature of the stimuli that activate these mechanisms to regulate sympathetic outflow. Defining the precise nature of afferent signaling, interactions with sympathoexcitatory mechanisms such as glutamate and angiotensin II within the PVN, and the mechanisms of activation of the hypothesized NO-GABA-mediated sympathoinhibition require further investigation.

    ACKNOWLEDGEMENTS

This study was supported by National Heart, Lung, and Blood Institute Grant HL-48023 and a Grant-in Aid from the American Heart Association (no. 96006840).

    FOOTNOTES

Address for reprint requests: K. P. Patel, Dept. of Physiology and Biophysics, Univ. of Nebraska Medical Center, 600 South 42nd St., Omaha, NE 68198-4575.

Received 1 December 1997; accepted in final form 21 May 1998.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

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