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(Hypertension. 1997;30:1499-1503.)
© 1997 American Heart Association, Inc.

Articles

Cardiovascular Effects of Nitric Oxide and N-Methyl-D-Aspartate Receptors in the Nucleus Tractus Solitarii of Rats

Wan-Chen Lo; Hui-Ching Lin; Luo-Ping Ger; Che-Se Tung; ; Ching-Jiunn Tseng

From the Department of Medical Education and Research (W.-C.L., L.-P.G., C.-J.T.), Veterans General Hospital–Kaohsiung, Kaohsiung, Taiwan, and the Departments of Pharmacology (H.-C.L., C.-J.T.) and Physiology and Biophysics (C.-S.T.), National Defense Medical Center, Taipei, Taiwan, Republic of China.

	Abstract

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Abstract Nitric oxide (NO) is an endogenously synthesized effector molecule that acts as a neurotransmitter with novel properties in both the central and peripheral nervous systems. We previously reported that NO was involved in central cardiovascular regulation and modulated the baroreflex in the nucleus tractus solitarii (NTS) of rats. The aim of the present study was to determine whether NO and excitatory amino acids reciprocally release each other in the NTS. In normotensive Sprague-Dawley rats, intra-NTS microinjection of L-arginine (1 to 100 nmol/60 nL) produced a dose-dependent decrease in blood pressure and heart rate. Microinjection of excitatory amino acids L-glutamate and NMDA also produced depressor and bradycardic effects. These effects of L-glutamate or NMDA were blocked by prior administration of NO synthase inhibitor N^G-methyl-L-arginine or N^G-nitro-L-arginine methyl ester. Similarly, prior administration of N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione significantly attenuated the depressor and bradycardic effect of L-arginine. These results demonstrated a reciprocal attenuation of NO synthase inhibitor and NMDA receptor antagonist on NMDA and L-arginine responses, respectively, in the NTS and suggest that NO and NMDA receptors may interact in central cardiovascular regulation.

Key Words: nitric oxide • N-methylaspartate • L-arginine • solitary nucleus • regulation, cardiovascular • L-NAME

	Introduction

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L-Arginine is converted to NO and citrulline in a variety of mammalian cell types, including vascular endothelial cells.¹ NO increases cGMP levels in the cells that produce this free radical through the activation of sGC. On release, NO also increases cGMP in neighboring cells via the activation of sGC.² As such, NO has the capacity to act as an intracellular and intercellular signaling molecule. The conversion of L-arginine to NO is catalyzed by a family of NO synthases.³ The NTS plays a vital role in baroreceptor, chemoreceptor, and cardiopulmonary afferent-mediated regulation of cardiovascular function.⁴ NO synthase exists in intrinsic neurons within the NTS⁵ and in central and primary afferent terminals within this nucleus.⁶ We have reported that unilateral microinjection of L-arginine into the NTS of anesthetized rats produced pronounce concentration-dependent falls in MBP, HR, and renal sympathetic nerve activity.⁷ We also found that the microinjection of the NO synthase inhibitors L-NMMA and L-NAME attenuated the hemodynamic effects produced by activation of the baroreceptor reflex.⁸ Taken together, these findings suggest that NO within the NTS may play an important role in the regulation of cardiovascular function.

Excitatory amino acids such as glutamate and aspartate are the most abundant excitatory neurotransmitters in the CNS. Glutamate acts through a variety of receptors, including the NMDA receptor.⁹ The microinjection of glutamate and glutamate receptor antagonists produces pronounced cardiovascular effects.¹⁰ Both NMDA and non-NMDA receptors in the NTS are involved in processing baroreceptor afferent information.¹¹ It has been reported that the stimulation of NMDA receptors increases the formation of NO in the CNS.^12,13 More specifically, stimulation of these receptors increases cGMP levels via activation of sGC, and this increase in cGMP can be prevented by NO synthase inhibitors.^14,15 In addition, NO increases the release of excitatory amino acids in the dorsomedial medulla by cGMP-dependent processes.¹⁶ There is evidence that in hippocampal slices, NO may mediate the release of the excitatory amino acid aspartate through the activation of release-regulating NMDA receptors on presynaptic terminals.¹⁷ Taken together, it appears that NO and excitatory amino acids release each other in the CNS.

The aim of the present study was to provide pharmacological evidence regarding whether NO and excitatory amino acids reciprocally release each other in the NTS.

	Methods

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Male Sprague-Dawley rats (weight, 250 to 350 g; Charles River) were obtained and housed in the animal room of the National Defense Medical Center (Taipei, Taiwan, ROC). The rats were kept in individual cages in a room in which lighting was controlled (12 hours on/12 hours off) and temperature was maintained between 23° and 24°C. The rats were given Purina Laboratory Chow and tap water ad libitum.

Rats were anesthetized with urethane (1.0 g/kg IP and 300 mg/kg IV if necessary). A polyethylene cannula was inserted into the femoral vein for administration of drugs, and BP was measured directly via a cannula placed into the femoral artery and connected to a pressure transducer (P23 ID; Gould) and a polygraph (AT5000; Gould). HR was monitored continuously with a tachograph preamplifier (13–4615-65; Gould). Tracheostomy was performed to keep the airway patent.

The animals were then placed in a stereotaxic instrument (Kopf) with the head downward at a 45° angle. The dorsal surface of the medulla was exposed via limited craniotomy, and the animals were allowed to rest for 1 hour before experiments. For microinjections into the NTS, a glass cannula was prepared (0.031-in OD, 0.006-in ID; Richland Glass) with an external tip diameter of 40 µm. The cannula was connected to a Hamilton microsyringe through polyvinyl tubing. The cannula was filled with L-glutamate (78 pmol/60 nL) to functionally identify the NTS. The cannula was lowered into the NTS with A-P coordinates of 0.0 mm; M-L, 0.5 mm; and V, 0.4 mm with the obex used as reference.^18,19 Injections were given over 10 seconds by air pressure generated by a hand-held syringe while the pipette tip was positioned in the NTS.

During the experiment, the injection sites in the NTS were confirmed by responsiveness to L-glutamate administration. A specific decrease in BP and HR (-35 mm Hg and -50 bpm) was demonstrated after microinjection of 2.3 nmol L-glutamate in the NTS. The response was restricted to the intermediate third of the NTS, and the administration of the same dose of L-glutamate in adjacent areas to the NTS failed to elicit the response. In agreement with our previous study,^18,19 we did not observe significant effects on mean BP or HR after the administration of 60 nL sterile saline in NTS; therefore, we used saline for the control experiments in this study.

BP and HR were observed through microinjection of excitatory amino acids L-glutamate (2.3 nmol) and NMDA (1 nmol) and L-arginine (33 nmol) before and 10 minutes after intra-NTS administration with NO synthase inhibitors L-NMMA (10 nmol), L-NAME (10 nmol), and D-NAME (10 nmol); NMDA antagonist MK-801 (1 nmol); and non-NMDA antagonist DNQX (1 nmol). In addition, to study the recovery effects of these agonists (L-glutamate, NMDA, and L-arginine), the cardiovascular effects were observed for >60 minutes.

After completion of the experiment, ink was injected through the cannula, and the rats were perfused with saline, followed by a solution of 4% formaldehyde, and finally with 30% sucrose solution. Sections (40 µm) of the brainstem were stained with cresyl violet, and proper placement of the pipette tip in the NTS was verified with histological sections under the microscope (the injection sites in the NTS are presented in Fig 1).

View larger version (22K): [in this window] [in a new window]   Figure 1. Representation of some individual injection sites in the brainstem nuclei of rats in coronal section 14.08 mm caudal to the bregma. Arrowheads indicate the sites of injections in NTS. Maps and coordinates (from bregma) are taken from the atlas of Paxinos and Watson. Scale bar, 1 mm. Gr indicates gracile nucleus; Sol, nucleus solitary tract; 12, hypoglossal nucleus; Sp5, spinal trigeminal tract; LRN, lateral reticular nucleus; and ION, inferior olive nucleus.

For NTS microinjection, the drugs were dissolved in sterile saline to the final concentrations in a volume not exceeding 60 nL. For each drug, only 60 nL was pressure-microinjected into the NTS. The drugs that were used were urethane, L-arginine, L-glutamic acid, NMDA, MK-801, DNQX, L-NMMA, L-NAME, and D-NAME (Sigma Chemical).

For statistical analysis, paired t test (before and after intra-NTS microinjection) and unpaired t test (for control and study group comparisons) or repeated-measures analysis of variance followed by Dunnett's test for significant differences was used. Differences with a probability value of <.05 were taken as significant. All data were presented as mean±SEM.

	Results

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Unilateral microinjection of L-glutamate (2.3 nmol) into the NTS produced remarkable depressor and bradycardic effects. The falls in BP and HR averaged 47±4 mm Hg and 21±3 bpm, respectively (n=12). After pretreatment with NO synthase inhibitor L-NMMA (10 nmol) for 10 minutes, the depressor and bradycardic responses to L-glutamate were attenuated significantly (25±3 mm Hg and 11±2 bpm) (Figs 2 and 3). The cardiovascular effects of L-glutamate in the NTS can also be attenuated by 10-minute pretreatment with 10 nmol L-NAME (from -45±3 mm Hg and -19±2 bpm to -26±2 mm Hg and -11±2 bpm) (Fig 3). However, the pretreatment with 10 nmol D-NAME did not change the cardiovascular effects of L-glutamate. Microinjection of another excitatory amino acid, NMDA (1 nmol), into the NTS produced more conspicuous depressor and bradycardic effects (-84±15 mm Hg and -42±10 bpm) than L-glutamate. The cardiovascular effects of NMDA were significantly attenuated 10 minutes after 10 nmol L-NMMA (-37±8 mm Hg and -9±2 bpm) (Fig 4).

View larger version (15K): [in this window] [in a new window]   Figure 2. Cardiovascular effects of unilateral injection of L-glutamate (L-glu, 2.3 nmol) into the NTS before and after L-NMMA (10 nmol) in anesthetized rats. L-glu and L-NMMA were injected at the indicated time points. BP, MBP, and HR recordings were made at a paper speed of 3 mm/min. Horizontal bar represents recording during 5 minutes.

View larger version (23K): [in this window] [in a new window]   Figure 3. Comparative MBP and HR effects of L-glutamate (L-glu, 2.3 nmol) by NO synthase inhibitors L-NMMA (10 nmol) and L-NAME (10 nmol) on unilateral intra-NTS administration of the substances. L-glu was injected in the absence (open columns) or presence (10 nmol, top hatched column) of L-NMMA and of L-NAME (10 nmol, bottom hatched column). Vertical bars represent SEM change from baseline values, which were 103±4 and 107±5 mm Hg for MBP and 305±3 and 302± 3 bpm for HR. Each bar represents the average value from 8 rats. *Significant difference from corresponding control L-glu response.

View larger version (21K): [in this window] [in a new window]   Figure 4. A, Cardiovascular effects of unilateral injection of NMDA (1 nmol) into the NTS before and after L-NMMA (10 nmol) in anesthetized rats. NMDA and L-NMMA were injected at the indicated time points. BP, MBP, and HR recordings were made at a paper speed of 3 mm/min. Horizontal bar represents recording during 5 minutes. B, Bar graphs show comparative MBP and HR effects of NMDA (1 nmol) by L-NMMA (10 nmol) on unilateral intra-NTS administration of the substances. NMDA was injected in the absence (open columns) or present (hatched column) of L-NMMA (10 nmol). Vertical bars represent SEM change from baseline values, which were 108±5 mm Hg for MBP and 300±3 bpm for HR. Each bar represents the average value from 6 rats. *Significant difference from corresponding control NMDA response.

Conversely, we examined the effects of NMDA and non-NMDA receptor antagonists on L-arginine. Unilateral microinjection of different doses of L-arginine (1 to 33 nmol) into the NTS produced dose-dependent depressor and bradycardic effects. Pretreatment with MK-801 (1 nmol; a NMDA receptor antagonist) for 10 minutes significantly reduced depressor and bradycardic responses elicited by L-arginine (Fig 5). Prior administration of non-NMDA receptor antagonist DNQX (1 nmol) significantly reduced depressor responses elicited by L-arginine (Fig 5). In contrast, DNQX (1 nmol) failed to significantly modify the bradycardic responses to L-arginine.

View larger version (23K): [in this window] [in a new window]   Figure 5. Comparative MBP and HR effects of L-arginine (L-Arg, 33 nmol) by MK-801 (1 nmol) and DNQX (1 nmol) on unilateral intra-NTS administration of the substances. L-Arg was injected in the absence (open columns) or presence (1 nmol, top hatched column) of MK-801 and of DNQX (1 nmol, bottom hatched column). Vertical bars represent SEM change from baseline values, which were 98±3 and 99±4 mm Hg for MBP and 297±5 and 308±5 bpm for HR. Each bar represents the average value from 8 rats. *Significant difference from corresponding control L-Arg response.

The attenuated cardiovascular effects of NO synthase inhibitors and NMDA receptor antagonist on L-glutamate, NMDA, and L-arginine had recovered by 30 to 60 minutes.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The NO system and excitatory amino acids seem to have interrelated effects in the regulation of cardiovascular response. In this study, we demonstrated that microinjection of L-glutamate into the NTS induced depressor and bradycardic effects. These results were similar to those of a previous study that suggested that the excitatory amino acid L-glutamate may be a potential neurotransmitter of baroreceptor information in the rat NTS.^10,11 Unilateral microinjection of another excitatory amino acid, NMDA, has the same effects with greater intensity. Prior administration of NO synthase inhibitor L-NMMA or L-NAME significantly attenuated the cardiovascular effects of intra-NTS microinjection of L-glutamate and NMDA. Thus, the results of the present study suggest that the activation of NMDA receptors by excitatory amino acids is mediated through NO in the NTS of rats. These results are consistent with the previous finding of Di Paola et al.¹³

Excitatory amino acids such as glutamate or aspartate may be involved in the activation of NMDA receptors in the NTS.²⁰ The presence of NMDA receptors in the rat NTS has been demonstrated in autoradiographic²¹ and electrophysiological²² studies. It has been indicated that both NMDA and non-NMDA receptors in the rat NTS are responsible for the mediation of baroreflexes.¹¹ Microinjection of L-glutamate and other excitatory amino acid receptor agonists into the rat NTS produces decreases in BP and HR.¹⁰ We also reported that NO was involved in central cardiovascular regulation, and the depressor effect of NO in the NTS and rostral ventrolateral medulla may occur through inhibition of renal sympathetic nerve activity.⁷ Furthermore, the NO synthase inhibitor attenuated baroreflex activation in the NTS.⁸ These cardiovascular effects of NO are similar to those of the excitatory amino acids in the NTS. Also, there has been much evidence indicating that NMDA receptor activation is linked to synthesis of NO in the CNS.^13,23,24

The activation of NMDA receptors can increase in the intracellular levels of Ca²⁺ and activate Ca²⁺/calmodulin-dependent NO synthase, which converts L-arginine to NO, and L-citrulline,^12,14,25 which is able to activate sGC, thereby raising the cGMP level.^12,15 In addition, both methylene blue (inhibitor of guanylate cyclase activation) and L-NMMA (a specific inhibitor of NO synthesis) inhibited the elevation of cerebellar cGMP induced by the excitatory amino acid receptor agonist NMDA and kainate.^14,26 In the CNS, NO may link activation of postsynaptic NMDA receptors to functional modifications in neighboring presynaptic terminals and glial cells.²³ The NTS processes information from a visceral afferent receptor,^6,27 including the baroreceptor afferent nerves, and plays an important role in the reflex regulation of arterial pressure and heart rate. Moreover, it is not clear the extent to which stimulation of the excitatory amino acids can trigger NO formation on the central cardiovascular regulation of rats. In support of this hypothesis, the present study demonstrated that two different kinds of NO synthase inhibitors, L-NMMA and L-NAME, significantly attenuated the depressor and bradycardic response induced by the excitatory amino acids, L-glutamate and NMDA, and the attenuated effects can recover within 30 to 60 minutes. Although administration of D-NAME, an isomer of L-NAME did not produce any change in the cardiovascular effects of excitatory amino acids. These observations suggested that excitatory amino acids activate NMDA receptor, which further stimulates NO release from NOS-positive neurons in the NTS, which modulate the cardiovascular functions.

It has been suggested that retrograde signaling from the postsynaptic cell controls the presynaptic transmitter release in the hippocampus²⁸ and cerebral cortex.²⁹ For example, in the hippocampus, long-term potentiation is the most typical case of retrograde control of postsynaptic function, and NO has been proposed as a retrograde messenger in glutamatergic neurotransmission.^28,30 However, because such a retrograde signaling system of long-term potentiation has been demonstrated only in in vitro studies, it is unknown whether this system is involved in central cardiovascular regulation of rats. In the present study, unilateral microinjection of L-arginine into the NTS produced depressor and bradycardic effects; these results are consistent with our previous findings.⁷ Pretreatment with MK-801, the most potent and selective noncompetitive antagonist that blocks the NMDA receptor–associated ion channels, significantly attenuated the cardiovascular effects of L-arginine. Furthermore, we examined whether DNQX, a potent and selective antagonist of non-NMDA receptors, affected the effects of L-arginine. In our study, depressor but not bradycardic response evoked by L-arginine was significantly reduced by DNQX. These observations might suggest that cardiovascular responses of L-arginine were mediated through NMDA and non-NMDA receptors in the NTS.

Lawrence et al¹⁶ demonstrated that NO can act via sGC to affect excitatory amino acid release in the dorsomedial medulla oblongata. NO apparently subserves various roles as an intracellular and intercellular messenger molecule for neurons and glias in the CNS. An important corollary is that NO produced subsequent to activation of NMDA release-regulating receptors can act as an intracellular or intercellular messenger to modulate transmitter release.¹⁷ Jones et al³¹ found that a NO-sensitive mechanism regulates release subsequent to the activation of a number of different populations of NMDA receptors. NO not only acts as an intraterminal messenger after activation of presynaptic release-regulating receptors but also provides intraneuronal signaling for extrasynaptic NMDA release-regulating receptors. These extrasynaptic NMDA receptors could be located in various areas on the intermediary or local circuit neurons or somata, with NO arising from postsynaptic sites^32,33 and also acting as a retrograde messenger, as previously suggested for long-term potentiation.²⁸ Therefore, in our studies in which NMDA and non-NMDA antagonists attenuated the cardiovascular effects of NO in the NTS of rats, it is suggested that in the NTS, NO may have a retrograde effect on NMDA and non- NMDA receptors to modulate excitatory amino acid release.

In conclusion, NO and excitatory amino acids reciprocally release each other in the NTS and are likely to have subtle interactions in the central cardiovascular regulation of rats.

	Selected Abbreviations and Acronyms

 

BP = blood pressure CNS = central nervous system DNQX = 6,7-dinitroquinoxaline-2,3-dione D-NAME = NG-nitro-arginine methyl ester HR = heart rate L-NAME = NG-nitro-L-arginine methyl ester L-NMMA = NG-monomethyl-L-arginine MBP = mean blood pressure NO = nitric oxide NMDA = N-methyl-D-aspartate NTS = nucleus tractus solitarii sGC = soluble guanylate cyclase

	Acknowledgments

 
This work was supported by NSC grant 85–2331-B-075B-008 (Dr Tseng).

	Footnotes

 
Reprint requests to Ching-Jiunn Tseng, MD, PhD, Department of Medical Education and Research, Veterans General Hospital–Kaohsiung, 386 Ta-Chung 1st Rd, Kaohsiung. Taiwan, Republic of China.

Presented in part at the 25th Neuroscience Annual Meeting, November 11-16, 1995, San Diego, Calif.

Received January 28, 1997; first decision February 27, 1997; accepted June 13, 1997.

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