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Hypertension. 1999;34:748-751

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(Hypertension. 1999;34:748-751.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Nitric Oxide–Dependent Guanylyl Cyclase Participates in the Glutamatergic Neurotransmission Within the Rostral Ventrolateral Medulla of Awake Rats

Marli C. Martins-Pinge; Gessi C. Araújo; Oswaldo U. Lopes

From the Department of Physiology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil.

Correspondence to Oswaldo U. Lopes, MD, Departamento de Fisiologia, Universidade Federal de São Paulo, Escola Paulista de Medicina, Rua Botucatu, 862, CEP 04023-060, São Paulo, SP, Brazil. E-mail LopesU.Fisi{at}epm.br


*    Abstract
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 *Abstract
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Abstract—A well-known action of nitric oxide (NO) is to stimulate the soluble form of guanylyl cyclase, evoking an accumulation of cyclic GMP in target cells. The aim of the present study was to examine the effects of inhibition of guanylyl cyclase dependent on NO during cardiovascular responses induced by L-glutamate and S-nitrosoglutathione (SNOG) microinjected into the rostral ventrolateral medulla (RVLM) of awake rats. Three days before the experiments, adult male Wistar rats (280 to 320 g) were anesthetized for implantation of guide cannulas to the desired stereotaxic position (AP=-2.5 mm, L=1.8 mm) in relation to lambda. The cannulas were fixed to the skull with acrylic cement. Twenty-four hours before the experiments, a femoral artery and vein were cannulated for recording arterial pressure (AP) and heart rate (HR) and injection of anesthetic. Unilateral microinjections (100 nL) of L-glutamate (5 nmol/L) and SNOG (2.5 nmol/L) were made into the histologically confirmed RVLM. The cardiovascular responses to these drugs were evaluated before and after microinjection (3 nmol/L, 200 nL) of either methylene blue or oxodiazoloquinoxaline (ODQ). The hypertensive effect of L-glutamate was attenuated by 74% after methylene blue ({Delta}AP=49±8 to 13±4 mm Hg) and by 80.5% after ODQ ({Delta}AP=30±2 to 6±2 mm Hg). The increase in AP produced by SNOG was fully blocked by ODQ ({Delta}AP=39±8 to 1±2 mm Hg). These data indicate that cyclic GMP mechanisms have a key role in glutamatergic neurotransmission in the RVLM of awake rats, and it is most probable that NO participates in this response.


Key Words: glutamic acid • blood pressure, arterial • brain • nitric oxide • rostral ventrolateral medulla • guanylate cyclase


*    Introduction
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It is well known that sympathoexcitatory neurons of the rostral ventrolateral medulla (RVLM) directly innervate sympathetic preganglionic neurons in the intermediolateral cell columns of the spinal cord, which are involved in the regulation of vasomotor and cardiac tone. In its turn, the RVLM is highly connected to other areas of the central nervous system. In these vasomotor pathways, the major neurotransmitter used for fast synaptic transmission seems to be glutamate. In support of its importance in regulating blood pressure, glutamate microinjected into the RVLM produces an increase in arterial pressure (AP).1

The concept that nitric oxide (NO) has a role, during stimulation of N-methyl-D-aspartate (NMDA) receptors, through activation of guanylyl cyclase (GC) is now well established.2 3 4 5 6 7 8 9 The molecular mechanism of this NO-induced stimulation of cyclic GMP formation has been the subject of detailed investigations, and it has been suggested that NO interacts with the heme group bound to soluble GC in various tissues.8 10

Although inhibitory effects evoked by NO have been described within the RVLM,11 12 13 an opposite action, ie, excitatory effects, began to emerge in the literature, either in anesthetized as well as unanesthetized animals.14 15 The microinjection of the nitrosothiols sodium nitroprusside and S-nitroso-N-acetylpenicillamine produced hypertension and bradycardia in awake rats,15 a response very similar to that produced by L-glutamate. In addition, there are a great number of reports, especially studies of the higher structures of the central nervous system, suggesting that NO may participate in glutamatergic neurotransmission.4 5 Methylene blue was found to inhibit the stimulation of soluble GC by NO and nitrovasodilators in cell systems and has been extensively used to demonstrate the involvement of cyclic GMP accumulation in vascular relaxation, platelet aggregation, and neurotransmission.2 16 17

Recently, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) was identified to potently and selectively inhibit NO-stimulated GC activity in slices of cerebellum.18 Increasing concentrations of ODQ caused concentration-dependent reductions in cyclic GMP production during relaxation of isolated cerebral arteries induced by NO.19 This suggests that under physiological conditions, GC may be a key mediator in cerebral vasodilation. This drug is, in fact, thought to be the first inhibitor acting on the NO "receptor," soluble GC. The aim of the present study was to investigate the participation of cyclic GMP mechanisms in glutamate and NO responses in the RVLM during cardiovascular analysis of awake rats.


*    Methods
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All experiments were performed in conscious, freely moving, adult male Wistar rats (280 to 320 g, n=42) supplied by the central Animal House of the Universidade Federal de São Paulo, Escola Paulista de Medicina (UNIFESP-EPM). Experiments were approved by the animal experimentation Ethics Committee of the UNIFESP-EPM. The animals were housed individually in Perspex cages in a room with a 12:12-hour light/dark cycle. Food and water were always available except during the experiments. Three to 5 days before the experiments, the rats were anesthetized with sodium pentobarbital (40 mg/kg IP) and placed prone in a stereotaxic apparatus (David Kopf Institute) with the incisor bar 5 mm below the interaural line. The methodology for implantation of guide cannulas and their fixation was the same as described previously.15

Twenty-four hours before the experiments, the femoral artery and vein were cannulated, and the catheters were dorsally externalized to record AP and heart rate (HR) and for anesthetic injection when necessary. On the day of the experiment, the animals were kept in their cages, and basal recordings were obtained for at least 30 minutes. The pulsatile arterial blood pressure was recorded by using a Statham A23XL transducer (Statham Instruments) connected to a Beckman R511A recorder. Mean arterial pressure (MAP) was obtained by filtering the arterial blood pressure signal, and HR was recorded with a cardiotachometer (Sensor Medias, 9857B) triggered by the pulse wave. A micropipette was connected to a Hamilton (7101) 1-µL syringe and positioned into the guide cannula. Just before infusion, all drugs were dissolved in physiological saline, except that ODQ was first dissolved in dimethyl sulfoxide and then diluted in saline. The pH of the solutions was adjusted to 7.4 when necessary. L-Glutamate (5 nmol/L, 100 nL) was unilaterally microinjected into the RVLM before and after using the GC blockers methylene blue (3 nmol/L, 200 nL) or ODQ (3 nmol/L, 200 nL). S-Nitrosoglutathione (SNOG) was also compared before and after GC blockade.

At the end of the experiments, 100 nL of 2% Evans blue dye was injected into the same site. The rats were killed with an overdose of urethane, and the brain stem was removed and fixed in 10% formaldehyde. Injection sites were evaluated at the conclusion of each experiment by observing the dye diffusion on the ventral surface of the brain and plotting them on schematic diagrams. For histological identification of the injection sites, the brain stem was cut coronally into 40-µm-thick sections and stained with 1% neutral red. L-Glutamate and methylene blue were obtained from Sigma Chemical Co. SNOG and ODQ were obtained from Tocris Cookson.

All data are reported as mean±SEM. Changes in maximal responses induced by microinjection of drugs into the RVLM were analyzed by paired Student's t test. One-way ANOVA followed by Dunnett's test was used to test whether the values changed with time after drug microinjection. The criterion for statistical significance was P<0.05.


*    Results
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The effects of L-glutamate microinjected into the RVLM of awake rats were similar to those previously reported. In this study, both unilateral and bilateral microinjections of L-glutamate into the RVLM were made. Unilateral microinjection of L-glutamate elicited an increase in MAP from 119±3 to 180±6 mm Hg (P<0.05) in all rats that was accompanied by bradycardia from 329±11 to 249±5 bpm (P<0.05) However, in some cases, bradycardia was followed by tachycardia. A typical record of these effects is shown in Figure 1. Bilateral microinjections produced an increase in MAP from 118±3 to 193±7 mm Hg (P<0.05) with no significant alterations in HR (from 279±15 to 327±39 bpm).



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  		Figure 1. MAP, pulsatile AP, and HR recorded from a freely moving rat. A, Unilateral microinjection of L-glutamate (GLU) (6.5 nmol/L, 100 nL) into the RVLM of an awake rat. B, Bilateral microinjection of L-glutamate (6.5 nmol/L, 100 nL per site) into the RVLM of the same rat.

To analyze the participation of NO in L-glutamate–mediated activation of the RVLM, we used the NO donor SNOG, which is present endogenously in the brain.20 Unilateral microinjection of SNOG into the RVLM of awake rats produced an increase in MAP from 123±5 to 167±9 mm Hg (P<0.05), with no significant alterations in HR. A typical response of SNOG microinjections is shown in Figure 2.



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  		Figure 2. MAP, pulsatile AP, and HR recorded from an awake rat. The arrow indicates the moment of unilateral microinjection of SNOG (2.5 nmol/L, 100 nL) into the RVLM. Numbers at the top of the tracings indicate time in minutes after microinjection.

The cardiovascular response of L-glutamate was analyzed before and after microinjection of the GC blockers methylene blue and ODQ. The effect of ODQ or methylene blue on L-glutamate response is shown in Figure 3. The hypertensive effect of L-glutamate was attenuated by 74% after methylene blue ({Delta}MAP49±8 to +13±4 mm Hg, P<0.05) and by 80.5% after ODQ ({Delta}MAP30±2 to +6±2 mm Hg, P<0.05).



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  		Figure 3. Bar graphs show the effects of unilateral microinjection of L-glutamate (glu) (5 nmol/L, 100 nL, n=12) into the RVLM on MAP in awake rats before (A) and after (B) microinjection of 1 of the GC inhibitors. Top, Effect of methylene blue (3 nmol/L, 200 nL) microinjected 10 minutes before. Bottom, Effect of ODQ (3 nmol/L, 200 nL) microinjected 10 minutes before. *P<0.05.

The increase in MAP produced by SNOG was also analyzed in the presence of ODQ. The hypertension was fully blocked by ODQ ({Delta}MAP=39±8 to 1±2 mm Hg, P<0.05). This effect is shown in Figure 4. No significant reduction in MAP with the second L-glutamate microinjection was observed when physiological saline was used instead of the GC blockers. Microinjections of GC inhibitors alone did not produce any significant effect on MAP or HR. Microinjection of ODQ vehicle (0.05% dimethyl sulfoxide) did not produce any change in AP or respiration.



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  		Figure 4. Bar graph shows the effects of unilateral microinjection of SNOG (2.5 nmol/L, 100 nL, n=6) before (A) and after (B) microinjection of ODQ (3 nmol/L, 200 nL) into the RVLM on MAP in awake rats. *P<0.05, comparison between black and white bars; +P<0.05, difference between black bars.

Methylene blue microinjected in the RVLM had such long-lasting inhibition that glutamate responses had not recovered as long as 2 hours after injection. However, when we used ODQ in this kind of experiment, the inhibitory effect disappeared after 20 minutes, when the cardiovascular responses to L-glutamate and SNOG could again be evoked.


*    Discussion
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 *Discussion
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The participation of L-glutamate as a neurotransmitter in cardiovascular centers has been reported by many authors.21 22 23 24 25 It has also been suggested to be involved in the modulation of different cardiovascular reflexes, including baroreflexes and chemoreflexes.26 27 In such situations, L-glutamate can be released or inhibited, depending on the quality of information and location of the response. During baroreflex activation for example, L-glutamate seems to be released in the nucleus tractus solitarii and inhibited in the RVLM.28 Glutamate is generally accepted to be an excitatory neurotransmitter in the central nervous system. Its action within the RVLM is an increase in AP.15 29

The action of NO in the brain has been suggested to be associated with glutamatergic neurotransmission.4 6 The activation of NMDA receptors can increase the intracellular levels of Ca2+ and activate Ca2+/calmodulin-dependent NO synthase, which converts L-arginine to NO and L-citrulline. The NO formed is able to activate soluble CG, thereby raising the cyclic GMP level.4 30 31 32 In addition, methylene blue and N-monomethyl-L-arginine inhibit the elevation of cerebellar cyclic GMP induced by the NMDA receptor agonist kainate.4 30 In the central nervous system, NO may link activation of postsynaptic NMDA receptors to functional modifications in neighboring presynaptic terminals and glial cells.2

Methylene blue is known to affect iron-containing enzymes like soluble GC and NO synthase.33 34 Therefore, it has been used frequently as an inhibitor of soluble GC. However, there are indications that methylene blue can also be an inhibitor of NO synthase and produce reductions in the conversion of L-arginine to L-citrulline. This action of methylene blue is more effective than its blocking of purified soluble GC.35 In fact, methylene blue is actually believed to be a weak GC inhibitor that more effectively generates superoxide anions and inhibits NO synthase. In our experiments, the inhibition of glutamatergic responses by methylene blue was irreversible, even 2 hours after its microinjection into the RVLM. This could be an unspecified response of methylene blue or an effect caused by its double blocking action.

ODQ is a potent and selective inhibitor of NO-stimulated GC activity in incubated slices of cerebellum,18 and it also blocks glutamate receptor–mediated increases in cyclic GMP in rat hippocampal slices.19 However, there are no previous reports of ODQ use in the RVLM before these studies. In the present experiments in awake rats, the cardiovascular response to microinjections of L-glutamate into the RVLM was greatly attenuated after microinjection of ODQ. This effect indicates that cyclic GMP mechanisms are important for glutamate neurotransmission.

There has been much controversy about the way NO is released from cells. The chemical identity of the endothelium-derived relaxing factor in particular is still a matter of dispute, with the major contenders being NO and an S-nitrosothiol compound. Because of the extreme lability and the facile inactivation of NO with many reactive biochemical species, it has been suggested that some intermediate compounds, S-nitrosothiols for example, may act to stabilize NO and at the same time preserve its biological activity. To investigate the participation of these compounds, we used the S-nitrosothiol SNOG, which is the predominant low-molecular-weight thiol present in the central nervous system of the rat and which may be the "package" form in which NO could be stored.36 Microinjection of SNOG into the RVLM of awake rats produced an increase in AP similar to that produced by L-glutamate. This response was also similar to that produced by S-nitroso-N-acetylpenicillamine15 and again suggests an excitatory effect for NO. When we used ODQ, the increase in AP produced by SNOG was fully blocked. This clearly shows that SNOG produces its effects through cyclic GMP mechanisms.

The physiological significance for the interaction of glutamate and NO in the RVLM is, however, not clear. In the higher structures of the central nervous system, a physiological link between both NO and glutamate has been proposed. Electrical stimulation of cerebellar parallel fibers induces an increase in cerebellar blood flow, and this response can be attenuated by glutamate receptor antagonists and NO synthase inhibitors.37 In other experiments, the release of NO by cortical neurons in response to activation of the NMDA receptor site has been shown to be responsible for the local vasodilation observed after this activation.38 These findings suggest that NO may mediate increases in local blood flow during increases in neuronal activity in response to excitatory amino acids.

In summary, the present experiments support the idea that the major part of the glutamate response when microinjected into the RVLM of awake rats is produced by GC mechanisms involving NO. This involvement could represent more than a simple supporting participation. Because the RVLM is a very active area, the production of NO during glutamate neurotransmission may be necessary to allow adequate blood flow during activation of RVLM neurons. This hypothesis remains to be investigated.

Received May 8, 1999; first decision July 1, 1999; accepted July 9, 1999.


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 *References
 

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