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(Hypertension. 1997;30:704.)
© 1997 American Heart Association, Inc.

Articles

Excitatory Effects of Nitric Oxide Within the Rostral Ventrolateral Medulla of Freely Moving Rats

Marli C. Martins-Pinge; Izabel Baraldi-Passy; 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 The aim of the present study was to examine the participation of NO in the rostral ventrolateral medulla (RVLM) of freely moving rats. We utilized NO donors and L-arginine, which were microinjected into the RVLM. Unilateral microinjection (100 nL) of 2.5 nmol sodium nitroprusside produced a biphasic response consisting of an initial, rapid increase in arterial pressure (AP) from 125±5 to 161±8 mm Hg (P<.01) and a second, long-lasting response with a progressive increase in AP (maximum peak, 34±9 mm Hg; P<.01). Another NO donor, S-nitroso-N-acetylpenicillamine (SNAP; 2.5 nmol), also produced immediate hypertension from 118±5 mm Hg to 168±7 mm Hg (P<.01) but without the second, long-lasting response. L-Arginine (5, 24, and 140 nmol) produced a gradual increase in AP. L-Glutamate (5 nmol) microinjected into the RVLM produced an increase in AP from 122±9 mm Hg to 171±8 mm Hg (P<.01) and bradycardia from 342±10 to 315±8 beats/min. This AP response was significantly attenuated, from 115±7 to 128±9 mm Hg (P<.05), after microinjection of methylene blue (3 nmol) without alterations in heart rate. These results indicate that NO may have an excitatory effect on the RVLM of freely moving rats, probably in association with glutamatergic synapses via cGMP mechanisms.

Key Words: amino acids • blood pressure, arterial • brain • nitric oxide • rostral ventrolateral medulla

	Introduction

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There is now a substantial body of evidence that nitric oxide (NO) is a signal molecule in both the peripheral and central nervous systems.¹ Although the role of NO in the brain has not been fully elucidated, it seems clear that there is a functional link between NO and glutamatergic neurotransmission in the central nervous system.^{2 3 4 5} The activation of N-methyl-D-aspartate receptors by glutamate induces an influx of Ca²⁺, which forms a complex with calmodulin and activates NO synthase in postsynaptic cells. The NO formed diffuses out to neighboring neurons or to the presynaptic terminal, where it activates a soluble form of guanylate cyclase that causes an accumulation of cGMP.⁶

It is generally agreed that the sympathoexcitatory neurons of the RVLM are the major tonic source of supraspinal sympathoexcitatory outflow and also are the efferent connection of reflex control of cardiovascular functions,^{7 8} with glutamate playing a very important role in this control.⁹ Many studies using microinjections have reported glutamate as one of the neurotransmitters in different pathways of cardiovascular reflexes, although another excitatory amino acid acting as a neurotransmitter cannot be ruled out.^{10 11} In anesthetized rats, the microinjection of L-glutamate into the RVLM produced an increase in AP and tachycardia, whereas the same concentration of L-glutamate microinjected into the RVLM of awake animals produced a much higher increase in AP and bradycardia¹²

A role for NO in the central regulation of cardiovascular function has been proposed by several groups who observed increases in sympathetic nerve activity and AP when NO synthase inhibitors were applied intracisternally, microinjected into the nucleus tractus solitarii (NTS), or infused intracerebroventricularly.^{13 14 15 16} In the case of NTS, the role for NO itself has been contested in favor of a direct role of S-nitrosothiols.¹⁷ However, these studies were conducted on anesthetized animals, a condition that may be a limiting factor in the interpretation and analysis of the results.

The aim of the present study was to examine the participation of NO in the RVLM by microinjecting NO donors and L-arginine into this structure and to analyze the participation of cGMP mechanisms in glutamatergic activation in freely moving rats.

	Methods

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The study was performed on 49 male Wistar rats weighing 280 to 320 g from the Central Animal House of the Universidade Federal de São Paulo, Escola Paulista de Medicina. The procedure for microinjections of drugs in awake animals was a development of the method already used in our laboratory for anesthetized rats.^{9 18 19} Three to five 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. To implant the guide cannulas, a small window was opened caudal to the lambda through which a stainless steel cannula was directed to the desired stereotaxic position in relation to lambda (AP=-2.5 mm, L=1.8 mm). Due to the small size of the guide cannulas (0.7-mm OD, 10-mm length), their handling was facilitated by coupling then to a support cannula made with the same needle but having a length of 26 mm, inserted on another stainless steel tube (1.5 mm OD), fixed on the side of an electrode holder. Experiments were done according to the Policy on Use of Laboratory Animals (PHS Policy). Injections into RVLM were performed with the rats showing no external signals of discomfort.

A stainless steel micropipette (0.3 mm OD) was placed inside the set of guide and support cannulas. The lengths of the micropipette and guide cannula were adjusted to allow only the micropipette to be inserted into the brain tissue. Vertical positioning was obtained by slowly lowering both the micropipette and the guide cannula until a slight displacement between them was observed. Postmortem histology demonstrated that this procedure consistently permitted the placement of the micropipette tip juxtaposed to the surface of the ventral medulla, otherwise intact. The guide cannula was then fixed to the skull with acrylic cement and closed with an occluder until the time for the microinjections.

Twenty-four hours before the experiments, the femoral artery was cannulated, and the catheter was dorsally exteriorized to record AP and HR. On the day of the experiment, the animals were kept in their cages and the basal recordings were obtained for at least 30 minutes. The pulsatile ABP was recorded using a Statham P23XL transducer (Statham Instruments) connected to a Beckman R511A recorder. MAP was obtained by filtering the ABP signal, and HR was recorded with a cardiotachometer (SensorMedias, 9857 B) triggered by the pulse wave. A micropipette was connected to a Hamilton (7101) 1-µL syringe and positioned into the guide cannula. Just prior to infusion, all drugs were dissolved in physiological saline, and the pH of the solutions was adjusted to 7.4. SNP (2.5 nmol), SNAP (2.5 nmol), L-arginine (5, 24, and 140 nmol), L-glutamate (5 nmol), methylene blue (3 nmol), and physiological saline were unilaterally microinjected into the RVLM in a 100-nL volume, and the cardiovascular response was analyzed for at least 1 hour after drug microinjection. Only one drug (SNP, SNAP, or L-arginine) was injected in each experiment. In the case of L-glutamate, it was repeated once, after methylene blue or normal saline. At the end of experiments, 100 nL of 2% Evans blue dye was injected into the RVLM. The rats were killed with an overdose of urethane, and the brainstem was removed and fixed in 10% formaldehyde. Injection sites were evaluated, as a screen test, by dye diffusion seen by transparency on the ventral surface and plotted on schematic diagrams. For histological identification of the injection sites, the brainstem was cut coronally into 40-µm thick sections and stained with 1% neutral red. A typical histological site is shown in Fig 1. L-Arginine hydrochloride, L-glutamate, methylene blue, and SNP were obtained from Sigma Chemical Co; SNAP was obtained from Research Biochemicals International.

View larger version (63K): [in this window] [in a new window]   Figure 1. Left, Photomicrograph of transverse section stained with 1% neutral red at the level of the center of the microinjection in the RVLM (dark area). Right, Schematic outline of nuclear groups present. nA indicates nucleus ambiguus; py, pyramidal tract; Sp5, spinal trigeminal nucleus. Horizontal bar, 0.5 mm.

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<.05.

	Results

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SNP is an NO donor that releases NO spontaneously. When microinjected into the RVLM of freely moving rats (n=8), it produced a significant hypertensive biphasic response consisting of an initial and rapid increase in AP (125±5 to 161±8 mm Hg, P<.01) and HR (294±6 to 326±7 beats/min, P<.01) and a second, gradual, long-lasting response (peak AP, 34±9 mm Hg, P<.01), as shown in Fig 2. This second response lasted for about 90 minutes with a peak at 60 minutes.

View larger version (23K): [in this window] [in a new window]   Figure 2. Bar graph shows the effects of unilateral microinjection of SNP (2.5 nmol/L, 100 nL, n=8) and SNAP (2.5 nmol/L, 100 nL, n=6) into the RVLM on MAP in freely moving rats. *P<.05 compared with respective basal value at zero time.

SNAP is another NO donor that releases NO spontaneously, and its microinjection (n=6) also produced an immediate increase in AP (118±5 to 168±7 mm Hg, P<.01) and a significant decrease in heart rate (336±24 to 267±25 beats/min, P<.05) as shown in Fig 2. The response to SNAP was similar to the initial phase of the response to SNP but was not followed by a second, long-lasting response. An example of response to both NO donors is shown in Fig 3.

View larger version (13K): [in this window] [in a new window]   Figure 3. Pulsatile (AP), MAP, and HR recorded from a freely moving rat. Left, Microinjection of SNAP (2.5 nmol, 100 nL) showing the cardiovascular effects at 0, 30, and 50 minutes. Right, Microinjection of SNP (2.5 nmol, 100 nL) on a different animal (same parameters). Numbers at the top of the tracings indicate time in minutes between successive records.

L-Arginine is the substrate for NO synthase that ultimately produces NO. Microinjection of three different concentrations of L-arginine (5 nmol, n=6; 24 nmol, n=6; 140 nmol, n=7) produced gradual increases in AP for all concentrations, with a maximum effect at 30 minutes (113±4 to 126±6 mm Hg at 5 nmol, 114±6 to 129±6 mm Hg at 24 nmol, 121±8 to 146±6 mm Hg at 140 nmol; P<.05). Despite changing significantly, the AP for each dose was not accomplished in a dose-dependent manner.

L-Glutamate microinjected into the RVLM (n=6) of freely moving rats produced an increase in AP (122±9 to 171±8 mm Hg, P<.01) and bradycardia (342±10 to 315±8 beats/min, P<.05). When we microinjected methylene blue (3 nmol/200 nL), which blocks the activation of soluble guanylate cyclase, before a second injection of L-glutamate, the AP response was significantly attenuated (115±7 to 128±9 mm Hg, P<.05), as shown in Fig 4. If normal saline (200 nL) was injected instead of methylene blue, no significant reduction in AP response was observed with the second L-glutamate microinjection. The microinjection of physiological saline alone (100 nL) did not produce any significant effect in basal AP or HR (102±4 to 104±4 mm Hg and 385±16 to 402±16 beats/min).

View larger version (11K): [in this window] [in a new window]   Figure 4. Effects of unilateral microinjection of L-glutamate (2.5 nmol, 100 nL, n=6) before (A) and after (B) microinjection of methylene blue (3 nmol, 200 nL) into the RVLM on MAP in freely moving rats. *Different from control, P<.01; **different from control and from first microinjection of L-glutamate, P<.05.

In our experience, with the method described, the number of failures or missing experiments is 15%, ie, the tip of the micropipette in the vicinity of RVLM but definitely not within the RVLM. Under these conditions we observed (1) with glutamate, always a hypertensive response, although of less intensity; (2) with SNP, no first component, but sometimes the second one (long-lasting response) was present; and (3) with SNAP, no effect at all if the tip was outside the RVLM.

	Discussion

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The role for NO in the cardiovascular functions of the RVLM has been studied by different groups but always using anesthetized animals, a condition that can interfere with the sensitivity of the neurons or even qualitatively with the pattern of the response.¹² In the CNS, the increased activity in excitatory pathways has long been known to cause increases in the levels of cGMP. Although in the CNS and blood vessels NO acts via cGMP, the NO system in the central glutamatergic synapses appears to operate differently than in peripheral nonadrenergic/noncholinergic nerves. In the blood vessels, NO is presumed to be formed in presynaptic elements and then to diffuse to its target, ie, smooth muscle cells. In the CNS, the NO system appears to be formed in postsynaptic cells, by the activation of N-methyl-D-aspartate receptors by glutamate.⁶

The results of the present study demonstrate that microinjection of SNP directly into the RVLM of freely moving rats produced an increase in AP in a biphasic way. The initial fast response to SNP is closely similar to that obtained with glutamate stimulation of the RVLM, and the NO released by SNP may mediate the synaptic actions of glutamate on cGMP, as suggested by Bredt and Snyder.²⁰ The second long-lasting response to SNP that also produced hypertension is not clear. A possible explanation for this gradual increase in AP may be found in the fact that SNP breakdown generates cyanide molecules, and there is some evidence that cyanide produces hypertension when injected into the RVLM.²¹ This long-lasting increase in AP may have been a excitatory effect of cyanide.

Actually, there is some controversy in the literature about the effects of SNP and other NO donors in the RVLM. The first report²² about the role of NO in the RVLM of anesthetized cats showed that SNP produced a decrease in AP and renal nerve sympathetic activity. Tseng et al²³ also reported a decrease in AP and renal nerve sympathetic activity in response to L-arginine and an opposite effect with L-NMMA. They did not employ NO donors. In the work of Liu et al²⁴ and Hirooka et al,²⁵ microinjection of SNP as well as S-nitrosoglutathione and SNAP into the RVLM produced an increase in AP. The former group used rats anesthetized with urethane, and the latter used anesthetized rabbits with denervated arterial and cardiopulmonary baroreceptors.

The second NO donor we used was SNAP. Microinjection of SNAP into the RVLM of conscious rats caused an increase in AP that was also closely similar to that obtained with glutamate microinjection into the RVLM. According to the theory about the operation of the NO system in the central glutamatergic synapses, the NO formed diffuses out to neighboring neurons and/or to the presynaptic terminals where it activates guanylate cyclase, which in turn produces more cGMP. This second messenger has been known to promote protein phosphorylation, with consequent cell activation.²⁶ The NO release by SNAP may act in the postsynaptic elements, causing excitation via cGMP. The similar results that we observed with NO donors and glutamate, in terms of blood pressure response, suggest that perhaps we are dealing with a maximum response; different doses and combinations of drugs could probably clarify the existing interaction.

When L-arginine was injected into the RVLM, it produced a gradual and long-lasting increase in AP but not in a dose-dependent manner. The hypertension produced by L-arginine was gradual (maximum at 30 minutes), and this may be due to the fact that as a substrate, its transformation needs to be activated by an enzyme (NO synthase); consequently, the NO formed by L-arginine is time dependent. A similar response was obtained by Tagawa et al,²⁷ who reported that L-arginine perfused into NTS slices produced a progressive increase in neuronal activity followed by a gradual decrease to baseline level. In contrast, Hirooka et al²⁵ observed only a nonspecific response employing L-arginine and D-arginine, which emphasizes the difficulty of approaching an enzymatic system in vivo. The NO formed by L-arginine may be dependent on the degree of activation of NO synthase and does not seem to be limited by the amount of L-arginine present.

The typical response to L-glutamate applied into the RVLM of either awake or anesthetized rats is an increase in AP and bradycardia.⁶ The present results showed exactly the same response, but after the microinjection of methylene blue, the hypertension was significantly attenuated without alterations in HR. Methylene blue appears to inhibit soluble guanylate cyclase stimulated by NO and has been widely used for inhibition of cGMP-mediated processes.^{28 2} However, there is a strong indication that methylene blue acts as a direct inhibitor of NO synthase.²⁹ In any event, the attenuation of the response to glutamate by methylene blue suggests that the NO system plays an important role in glutamatergic neurotransmission at the RVLM.

Although some controversy still exists about the role of NO in the cardiovascular centers, we believe that the use of unanesthetized animals can better demonstrate the physiological role of this peculiar neurotransmitter or neuromodulator. Our results indicate that NO may have an excitatory effect on the RVLM of freely moving rats, since the NO donors produced an increase in AP. At this stage, it is not possible to be sure that NO acts exclusively through glutamatergic synapses, but the similarity of the responses to NO donors and glutamate in the RVLM of freely moving rats is a good start. Clearly, the participation of the NO system in the glutamatergic synapses of the RVLM and in cardiovascular reflexes needs to be studied further.

	Selected Abbreviations and Acronyms

 

ABP = pulsatile arterial blood pressure AP = arterial pressure CNS = central nervous system HR = heart rate MAP = mean arterial pressure NTS = nucleus tractus solitarii RVLM = rostral ventrolateral medulla SNAP = S-nitroso-N-acetylpenicillamine SNP = sodium nitroprusside

Received March 15, 1997; first decision April 17, 1997; accepted May 7, 1997.

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