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(Circulation Research. 1997;80:565-571.)
© 1997 American Heart Association, Inc.

Articles

Neuronal Nitric Oxide Reduces Sympathetic Excitability by Modulation of Central Glutamate Effects in Pigs

Johannes Zanzinger, Jürgen Czachurski, , Horst Seller

From the I. Physiologisches Institut, Universität Heidelberg (Germany).

	Abstract

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Abstract Mechanisms of the modulation of sympathetic activity by neuronal NO were studied in vagotomized anesthetized pigs. Inhibition of neuronal NO synthase (nNOS) within the brain stem by intracerebroventricular (ICV) administration of 7-nitroindazole (7-NI, 1 mmol/L) or S-methyl-L-thiocitrulline (MeTC, 0.1 mmol/L) caused slight increases in renal sympathetic nerve activity (RSNA) but did not affect arterial blood pressure (BP) or cardiac output (CO). However, the sympathoexcitatory effects of glutamate (0.5 mL, 0.1 mol/L ICV) that were associated with marked increases in BP, CO, and heart rate were potentiated by both nNOS inhibitors. Furthermore, 7-NI and MeTC significantly enhanced the responses of RSNA, BP, and CO to activation of somatosympathetic reflexes via stimulation of the left greater sciatic nerve (nervus ischiadicus, 10 to 20 V, 30 Hz, 1-millisecond pulses). Subsequent systemic inhibition of either the neuronal (by 7-NI) or all isoforms of NOS by N^G-nitro-L-arginine-methyl ester (20 mg/kg) had no significant additional effects on these responses. The effects of NOS inhibition were effectively counteracted by the endogenous NOS substrate L-arginine and by S-nitroso-N-acetyl-penicillamine (SNAP), a stable analogue of endogenous S-nitroso factors. Disruption of sympathoinhibitory baroreflex mechanisms by bilateral cutting of the carotid sinus nerves caused increases in RSNA and slightly increased responses to all excitatory stimuli but had no effects on the actions of the NOS inhibitors or SNAP. These results suggest that modulation of glutamate effects by nNOS-derived NO may be an important mechanism by which NO affects sympathetic activity in pigs.

Key Words: sympathetic activity • 7-nitroindazole • nitro-L-arginine • S-nitroso-N-acetyl-penicillamine • nitric oxide

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
A number of heterogeneous effects of NO on sympathetic functions at different sites within the autonomic nervous system have been reported recently. Inhibitory effects are consistently evoked by NO within the RVLM,^{1 2} which integrates sympathetic outflow onto preganglionic SPNs in the spinal cord.³ In contrast, the opposite action (ie, NO-mediated excitation) has been reported for cardiovascular neurons within the nucleus of the solitary tract.^{4 5} SPNs as well can be excited or inhibited by NO, apparently dependent on their location within the spinal cord and dependent on their functional roles.^{6 7 8} However, despite the variety of possible actions of NO on sympathetic functions reported in these studies, no significant changes in resting sympathetic tone occurred when NO synthesis was acutely blocked by systemic treatment with nonspecific NOS inhibitors in conscious rabbits⁹ or men.¹⁰ The present study was undertaken to characterize the mechanisms by which the central control of sympathetic functions within the medulla oblongata is influenced by NO and to determine whether primarily endothelial or neuronal NO sources account for the observed effects in vivo. In vagotomized anesthetized pigs, we studied the effects of 7-NI or MeTC, which are selective inhibitors of nNOS^{11 12} on tonic and reflex-modulated sympathetic activity within the brain stem. In addition, we tested the reversibility of nNOS inhibition by excess administration of L-arginine, which is the endogenous substrate for NOS, and by injections of the nitrosothiol SNAP, a stable analogue of endogenous S-nitroso compounds that are formed from NO in vivo. SNAP releases NO and, in addition, may act by nitrosation of amino acids and by nitrosylation of heme iron.^{13 14} As a test for tonic activation of presympathetic neurons, we used ICV injections of glutamate. Excitatory reflex modulation of sympathetic activity was tested by electrical stimulation of the left greater sciatic nerve. To test whether NO may modulate sympathetic tone via actions on the transmission of sympathoinhibitory baroreflex responses, we performed additional experiments on pigs that were completely baroreceptor-denervated by cutting both carotid sinus nerves after the vagotomy.

	Materials and Methods

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General Procedures
Experiments were performed on pigs (16 to 20 kg body weight) that were initially sedated by ketamine (20 mg/kg IM). Anesthesia was maintained by isoflurane (0.6% to 1.2%) in the inspired air, consisting of 2:1 N₂O/O₂. For infusion of drugs and for measurement of BP, catheters were placed into a femoral vein and artery (advanced in the abdominal aorta) and in the right atrium, respectively. Antibiotics (100 mg/kg ampicillin) were given to prevent possible influences of infections, such as the induction of expression of inducible NOS by bacterial endotoxins. The pigs were paralyzed by 0.2 mg/kg per hour pancuronium bromide and artificially ventilated via a tracheal tube. End-tidal CO₂ was kept at normal levels by adjustment of ventilatory depth and rate. Arterial blood gases were monitored with a blood gas analyzer (AVL 990, AVL List) and maintained in the normal range by administration of sodium bicarbonate solutions or adjustment of ventilation. Rectal temperature was maintained at 38.5°C by a thermostatically controlled infrared lamp. All pigs were bilaterally vagotomized. In addition, five pigs were completely baroreceptor-denervated by cutting both carotid sinus nerves after the vagotomy. For measurements of CO, a biluminal 5F Swan-Ganz thermodilution catheter (Baxter) was inserted through a jugular vein and advanced through the right ventricle in the arteria pulmonalis under BP control in 10 animals. In 8 other pigs, active redirection transient time flow probes (ART, Triton) were placed around the pulmonary artery for continuous measurement of CO. For this purpose, a thoracotomy was performed in the left fourth intercostal space. The chest was closed before the measurements. The similarity of CO data was checked by simultaneous measurements using both methods in separate experiments (data not shown). For recording of RSNA, the left renal nerve was retroperitoneally exposed, placed on bipolar platinum electrodes, and kept in a mixture of Vaseline and paraffin oil. Neural signals were amplified (x20 000 to x50 000, Tektronix AM 502), filtered (2 Hz to 3 kHz), and stored and analyzed with a CED 1401 interface connected to an 80486 PC computer. RSNA was full wave–rectified, and then RC-integrated with a time constant between 7 and 10 milliseconds. To activate somatosympathetic reflex responses, the left great sciatic nerve (nervus ischiadicus) was placed on bipolar platinum electrodes, embedded in Vaseline, and connected to an isolated stimulator (Digitimer). Stimulation was performed to produce reproducible submaximal excitatory effects on RSNA using consecutive trains of 20-second length using 10 to 20 V, 30 Hz, and 0.5- to 1-millisecond pulse duration at intervals of 120 seconds.

Drugs and Infusions
7-NI and MeTC were from Alexis Chemicals. All other drugs were from Sigma Chemical Co. 7-NI was dissolved in DMSO. All other drugs were dissolved in distilled water. For preparation of the final concentrations, the substances were further diluted in Ringer's solution. For ICV administrations, a catheter was inserted into the cerebroventricular space from the dorsal surface of the medulla at the level of the obex and advanced to the ventral surface of the medulla. The position of the catheter was functionally verified by instantaneous excitatory sympathetic responses to injections (0.3 mL) of glutamate, which are finally integrated within the brain stem by pre-SPNs within the RVLM.³ Central NOS inhibition was carried out by short-term infusion (within 5 minutes, 1 mL/min) of 7-NI (1 mmol/L, 5% DMSO), MeTC (0.1 mmol/L), or L-NNA (0.3 mmol/L). The reversibility of the effects of NOS inhibition was tested by short-term infusion of L-arginine (3.0 mmol/L) or SNAP (100 µmol/L) after NOS inhibition. As a test for central sympathetic excitability, 0.5 mL of 0.1 mol/L glutamate was injected (ICV) subsequent to the above pretreatments or sham control. Systemically, inhibition of NOS was carried out by 7-NI and/or L-NAME at doses of 20 mg/kg IV, respectively. The NO donor SNAP was infused systemically at a rate of 2 µg/kg per minute.

The effects of the solvent of 7-NI (ie, DMSO, 5%) were tested in 4 pigs. Infusion (ICV) of DMSO had no direct effects on RSNA and MAP but transiently increased CO (change, 0.37±0.16 L/min) and HR (change, 35±9 bpm). Furthermore, the responses to sciatic nerve stimulation of RSNA (298±21% versus 235±16%) and MAP (change, 27.4±5.2 versus 18.2±6.3 mm Hg) but not those to glutamate (ICV) were significantly increased by DMSO. The duration of these DMSO effects was 3 to 6 minutes. Thereafter, baseline RSNA and hemodynamics and responses to nerve stimulation returned to normal values. To prevent influences of DMSO on other experiments, we observed a period of at least 10 minutes before measurements after 7-NI treatments.

Data Analysis
HR was derived from the BP signal. TPR was calculated as follows: (MAP-CVP)/CO, expressed in mm Hg·L^-1·min^-1. RSNA was RC-integrated and measured in aU. For presentation in summarizing figures and for statistical evaluation, these data were normalized and expressed in percent of control values (% RSNA). All direct measurements were stored on a linear recorder (Gould) and on DAT tape (Sony DT-120RN) for further computing. Responses to drugs were separately calculated as individual differences from pretreatment values. Responses to electrical stimulation were calculated as average peak values derived from three consecutive stimuli, respectively. All data were analyzed by ANOVA (for repeated measurements where appropriate). Comparison of means was carried out with Tukey's studentized range test. Differences of P<.05 were considered to be significant. Values are reported as mean±SEM.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Effects of ICV and Systemic Inhibition of NOS on Baseline Values
Changes in baseline RSNA and hemodynamics in response to ICV and systemic inhibition of nNOS by 7-NI and of all NOS isoforms by L-NAME are listed in Table 1. 7-NI had no significant effects on RSNA either after ICV or systemic administration but caused significant increases in HR upon ICV administration. MeTC, which was administered (ICV) in five other pigs increased RSNA (to 132±12% of control, P<.05), slightly increased CO (from 2.65±0.18 to 3.01±0.22 L/min), but had no significant effect on MAP (from 103.6±7.4 to 92.0±8.1 mm Hg) or HR (from 131±11 to 143±13 bpm). In contrast, systemic blockade of all NOS isoforms resulted in large increases in TPR and BP and reductions in CO that were associated with decreased RSNA (Table 1). The ICV administration of SNAP counteracted all of the effects of nNOS blockade except for the increases in HR caused by ICV administration of 7-NI.

View this table: [in this window] [in a new window]   Table 1. Changes in Baseline Sympathetic Activity and Hemodynamics Upon ICV or Intravenous Variation of NO Availability in Vagotomized Pigs

Modulation of Glutamate Responses
Original recordings of the responses to glutamate (ICV) before and after ICV inhibition of all NOS isoforms by L-NNA (0.3 mmol/L) and subsequent to the administration of the NO donor SNAP (100 µmol/L ICV) are shown in Fig 1. Glutamate caused reproducible sympathoexcitatory responses with latencies to onset of excitation between 10 and 30 seconds. The duration of the responses was 4 to 8 minutes. Inhibition of NOS increased the responses to glutamate, whereas SNAP attenuated them below control values. Fig 2A shows mean data for the changes in RSNA and MAP caused by glutamate before and after inhibition of nNOS by 7-NI compared with the effects of global NOS inhibition and the effect of subsequent treatment by the S-nitrosothiol SNAP. The correspondent hemodynamic changes are shown in Table 2.

View larger version (14K): [in this window] [in a new window]   Figure 1. Variation of glutamate responses by NO. Original tracings show changes in BP, RSNA, and HR. L-NNA (0.3 mmol/L) and SNAP (100 µmol/L) were administered by short-term ICV infusion. Control indicates sham infusion (Ringer's solution). Glutamate responses were evoked by intracerebroventricular (i.c.v.) injection of 0.5 mL of 0.1 mol/L glutamate.

View larger version (47K): [in this window] [in a new window]   Figure 2. Modulation of the pressor effects (MAP) and sympathoexcitatory responses (% RSNA) to glutamate by NO within the brain stem. Glutamate tests and pretreatments were carried out as described in Fig 1. A, Responses to glutamate following pretreatments with sham control, 7-NI (1 mmol/L), L-NNA (0.3 mmol/L), and SNAP (100 µmol/L) (n=7). B, Responses to glutamate following pretreatments with sham control, MeTC (0.1 mmol/L), and L-arginine (L-Arg, 3.0 mmol/L) (n=5). *P<.05, **P<.01 vs control values.

View this table: [in this window] [in a new window]   Table 2. Responses to Glu and Stim During Variation of Central NO Availability in Vagotomized Contol Pigs (n=8) and Baroreceptor-Denervated Pigs (n=5)

The responses of RSNA and MAP to glutamate before and after ICV inhibition of nNOS by MeTC and subsequent to the additional treatments by L-arginine and SNAP are shown in Fig 2B. The correspondent hemodynamic responses are listed in Table 3. MeTC and 7-NI had qualitatively similar effects on the responses to glutamate. After the recovery of endogenous nNOS activity by L-arginine, almost normal responses to glutamate were observed. Nevertheless, SNAP also caused further inhibition of glutamate responses in the experiments with MeTC.

View this table: [in this window] [in a new window]   Table 3. Hemodynamic Responses to Glu and Stim During Variation of Central NO Availability by the nNOS Inhibitor MeTC, L-Arg, and SNAP in Vagotomized Pigs (n=5)

Modulation of Somatosympathetic Reflexes
Examples of the effects of ICV administration of MeTC and L-arginine after MeTC on the responses to sciatic nerve stimulation are shown in Fig 3. The mean data for stimulation experiments with 7-NI and MeTC are summarized in Fig 4. The respective hemodynamic data are summarized in Tables 2 and 3. Inhibition of neuronal NOS by both compounds potentiated somatosympathetic reflex responses significantly. Systemic inhibition of nNOS by 7-NI or of all NOS isoforms by L-NNA/L-NAME had no significant additional effects. Similarly, when L-NNA/L-NAME was given first, there were no further neuronal or hemodynamic effects of ICV or intravenous 7-NI (n=3 each, data not shown). Effects of nNOS inhibition by MeTC were significantly reduced by L-arginine and antagonized even more pronouncedly by the S-nitrosothiol SNAP, which was similarly effective in the experiments with 7-NI or L-NNA/L-NAME.

View larger version (17K): [in this window] [in a new window]   Figure 3. Effects of NO on somatosympathetic reflex responses. Original tracings show changes in BP, RSNA, and HR in response to electrical stimulation of the left greater sciatic nerve (nervus ischiadicus) in a representative pig. Pretreatments by sham control and intracerebroventricular (i.c.v.) MeTC, and L-arginine are as described in Figs 1 and 2.

View larger version (49K): [in this window] [in a new window]   Figure 4. Effects of intracerebroventricular (i.c.v.) or intravenous (i.v.) treatment with sham control, 7-NI (1 mmol/L i.c.v., 20 mg/kg i.v.), L-NNA (0.3 mmol/L i.c.v.), L-NAME (20 mg/kg i.v.), and SNAP (100 µmol/L i.c.v., 2 µg·kg-1·min-1 i.v.) (n=8, i.c.v.; n=6, i.v.) (A) or sham control, MeTC (0.1 mmol/L i.c.v.), L-arginine (L-Arg, 3.0 mmol/L i.c.v.), and SNAP (100 µmol/L i.c.v.) (n=5) (B) on the responses of mean BP (MAP) and RSNA (% RSNA) to electrical stimulation of the left greater sciatic nerve (10 to 20 V, 1-millisecond pulse duration, 30 Hz for 20 seconds every 2 minutes). *P<.05, **P<.01 vs control values.

Effects of Baroreceptor Denervation
To test whether inhibitory baroreflex inputs to the RVLM might influence the modulation of RSNA by NO, we performed similar experiments in completely baroreceptor-denervated animals (n=5). The results are summarized in Table 2. Baseline RSNA (10.5±1.9 aU), CO (2.40±0.34 L/min), TPR (45.3±6.0 mm Hg·L^-1·min^-1), MAP (105.0±10.4 mm Hg), and HR (145±12 bpm) were not significantly different from those shown in Table 1 for control pigs. The responses to glutamate are 126±14%, and those to electrical reflex stimulation represent 122±16% of the responses in control animals. These changes in RSNA were paralleled by analogue effects on MAP, CO, TPR, and HR (Table 2). However, except for the increases in TPR, these changes were not statistically significant. Furthermore, there were no significant differences in the effects of NOS inhibition or SNAP on the responses to glutamate or sciatic nerve stimulation in these baroreceptor-denervated animals.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The two major findings of the present study are (1) that neuronal effects of NO on sympathetic functions appear to be mediated primarily by nNOS-derived NO and (2) that modulation of glutamatergic pathways represents a mechanism that is sufficient to explain the majority of NO effects on sympathetic activity in vivo. The absence of effects of baroreceptor denervation on NO actions is in accordance with previous observations suggesting that central sympathetic baroreflex transmission may be largely independent of NO effects.^{2 15 16} In a recent study on conscious and anesthetized rabbits, Liu et al⁹ found significant effects of NO on central baroreflex sensitivity that were, however, primarily mediated by modulation of vagal functions, whereas baroreflex inhibition of RSNA similarly remained almost unaffected by changes in NO availability. Arterial baroreceptor reflexes are transmitted by glutamate receptors in the NTS and in the CVLM, which mediates a GABA-ergic inhibition on the RVLM.^{17 18 19} Upon baroreceptor denervation, a strong tonic sympathoinhibition from the CVLM to the RVLM replaces the phasic baroreceptor-modulated inhibition as previously shown in rats²⁰ and cats.²¹ Therefore, attenuation by NO of glutamate effects in both the RVLM and the CVLM may limit the net effects observed at the level of RSNA. This could explain the considerably lower effect of NOS inhibition on sympathetic tone in the present study compared with our previous experiments, in which direct microinjections of L-NNA or SNAP were administered into the RVLM of cats.² Recent studies in conscious rabbits⁹ and men¹⁰ also provided evidence that significant modulation of baseline sympathetic tone may not be induced by acute systemic NOS inhibition. Therefore, since NOS inhibition and SNAP had relatively small effects on baseline RSNA (Table 1, Figs 1 and 3) in the present study as well, it appears that the modulation of glutamatergic pathways may be the primary mechanism of NO action. Glutamatergic afferents represent the majority of excitatory inputs to the RVLM from higher brain regions.³ Furthermore, the transmission of somatosympathetic reflexes within the brain stem is probably also glutamatergic, since reflex responses to stimulation of somatic nerves are completely blocked by inhibition of glutamate receptors in the ventrolateral medulla.^{22 23}

Local inhibition of NOS in the NTS causes decreases in baseline sympathetic activity,⁴ and NO donors applied to the NTS potentiate glutamate-mediated chemoreflex responses.⁵ This potentiation of glutamate effects by NO is in contrast to the reduction in baseline and reflex-activated sympathetic activity upon microinjections of NO donors in the RVLM.^{1 2} However, despite possibly different modes of action of NO in different brain regions, the overall sympathoinhibitory role of NO observed by several acute and chronic studies in vivo^{24 25 26 27} appears to be predominant at least under physiological conditions.

The molecular mechanisms by which NO or NO-related species such as nitrosyl factors mediate differential modulation of glutamate effects in the brain stem were not elucidated by these experiments. However, attenuation of glutamate effects by NO could be mediated by inactivation of N-methyl-D-aspartate receptors¹³ and perhaps also by NO-induced inhibition of protein kinase C activity.²⁸ Since, on the other hand, the activity of the neuronal NOS is upregulated by N-methyl-D-aspartate receptor activation,²⁹ NO may serve as a feedback inhibitor of sympathetic excitation at these neurons. Excitatory effects of NO in the NTS could be related to presynaptic enhancement of transmitter (eg, glutamate) release by NO as proposed for neurons in the NTS⁵ and other central nervous system regions²⁹ recently. Moreover, a variety of new cGMP-dependent and -independent actions of NO (including effects on ion channels and mitochondrial functions in neurons) that could contribute to a modulation of postsynaptic glutamate effects have been reported recently.³⁰ Moreover, it is possible that NO modulates effects of other transmitters as well. However, a possible contribution of other transmitters to the observed effects could be either inhibitory or excitatory or both if several transmitters were involved. Further investigations are required to address these questions. However, taking the complexity of NO actions into account, it is reasonable to propose that NO may elicit contrasting effects even in functionally and anatomically nearby structures. This raises the interesting possibility that seemingly paradoxical effects of NOS blockade observed in studies on nNOS gene knockout mice recently^{31 32} may be explained by an altered or disrupted balance between inhibitory and excitatory effects of NO within the brain.

The exact site of glutamate action could not be determined. However, the observed changes in RSNA probably result from glutamate-mediated excitation of RVLM neurons either directly or by activation of glutamatergic afferents to the RVLM. Similarly, the effective concentrations of NOS inhibitors and NO donors are unknown. We used substances and concentrations that evoked near-maximal responses in our previous studies on cats.^{2 16} Since systemic application of these substances at doses that are known to be effective^{33 34} had no further significant effects, sufficient local concentrations can be assumed. The selectivity of 7-NI, which is widely used as a blocker of nNOS,^{11 33 35} has been questioned recently.^{36 37} However, in the present experiments, 7-NI probably acted rather selectively, since no vasoconstrictor responses (measurable as increases in TPR) were observed in response to systemic 7-NI. Systemic inhibition of endothelial NOS by L-NAME, in contrast, caused large increases in TPR (Table 1) that were independent of coadministrations of 7-NI. Mayer et al¹¹ have demonstrated that 7-NI has only in vivo selectivity for nNOS, which may be explained by low neuronal L-arginine and/or H4-biopterin concentrations and by the cell-specific properties that determine cellular uptake and metabolism of 7-NI. These properties, however, could be different between species as well. Furthermore, the other compound used (ie, the competitive nNOS-inhibitor MeTC, with 17-fold higher selectivity for nNOS than for endothelial NOS in vivo¹² ) had similar effects. Therefore, it is reasonable to suggest that the observed effects were mediated by neuronal rather than endothelial NOS.

The treatment with 7-NI but not with MeTC caused increases in HR that were not reversed by SNAP. At present, we have no consistent explanation for this effect, since all other parameters reacted in a different way. It could be, however, that DMSO, which is required for the solution of 7-NI, had persistent effects in combination with 7-NI that were not apparent when given alone (see "Materials and Methods").

In conclusion, we have shown that the modulation of sympathetic activity by NO in vivo is primarily mediated by central actions of nNOS-derived NO. Modulation of glutamate effects is a mechanism that could explain the majority of the NO effects on sympathetic activity. The overall inhibitory modulation of sympathetic functions by NO may consist of simultaneous potentiation of glutamate effects in the NTS as well. Therefore, the role of NO in the regulation of sympathetic functions may be determined by the balance between its inhibitory and excitatory effects in different brain regions, which may be subject to changes with age or during diseases and therapeutic interventions.

	Selected Abbreviations and Acronyms

 

7-NI = 7-nitroindazole aU = arbitrary units BP = blood pressure CO = cardiac output CVLM = caudal ventrolateral medulla DMSO = dimethyl sulfoxide HR = heart rate ICV = intracerebroventricular(ly) L-NAME = NG-nitro-L-arginine methyl ester L-NNA = nitro-L-arginine MAP = mean arterial pressure MeTC = S-methyl-L-thiocitrulline nNOS = neuronal NOS NOS = NO synthase NTS = nucleus of the solitary tract RC = resistance capacity RSNA = renal sympathetic nerve activity RVLM = rostral ventrolateral medulla SNAP = S-nitroso-N-acetyl-penicillamine SPN = sympathetic neuron TPR = total peripheral resistance

	Acknowledgments

 
This study was supported by the German Research Foundation (DFG, grant Za 176/3-1).

	Footnotes

 
Reprint requests to Dr J. Zanzinger, I. Physiologisches Institut, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany.

Received August 16, 1996; accepted December 19, 1996.

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