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1 Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824; and 2 Department of Pharmacology, Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study was designed to test the
hypothesis that the medullary lateral tegmental field (LTF) is an
important synaptic relay in the baroreceptor reflex pathway controlling
sympathetic nerve discharge (SND) of urethan-anesthetized cats. We
determined the effects of blockade of excitatory amino acid-mediated
neurotransmission in the LTF on three indexes of baroreceptor reflex
function: cardiac-related power in SND, strength of linear correlation
(coherence value) of SND to the arterial pulse (AP), and inhibition of
SND during increased arterial pressure produced by abrupt obstruction
of the abdominal aorta. Bilateral microinjection of
D-(
)-2-amino-5-phosphonopentanoic acid, an
N-methyl-D-aspartate
(NMDA) receptor antagonist, abolished cardiac-related power and
coherence of SND to the AP, and it prevented inhibition of SND during
aortic obstruction. These data support the view that NMDA
receptor-mediated neurotransmission in the LTF is critical for
baroreceptor reflex control of SND. Bilateral microinjection of
1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo-[f]-quinoxaline-7-sulfonamide, a non-NMDA receptor antagonist, decreased cardiac-related power and
total power in the 0- to 6-Hz band of SND; however, the AP-SND coherence value remained high, and inhibition of SND during aortic obstruction was preserved. These data imply that non-NMDA
receptor-mediated neurotransmission in the LTF is involved in setting
the level of excitatory drive to sympathetic nerves.
D-()-2-amino-5-phosphonopentanoic
acid; caudal ventrolateral medulla; excitatory amino acid-mediated
neurotransmission; 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo-[f]-quinoxaline-7-sulfonamide; nucleus of the tractus solitarius; sympathetic nerve discharge
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A CARDIAC-RELATED RHYTHM is commonly observed in the discharges of sympathetic nerves with cardiovascular targets in baroreceptor-innervated animals (5-8, 20, 23, 30, 34, 37, 41). The organization of the central network responsible for the cardiac-related rhythm in sympathetic nerve discharge (SND) and baroreceptor-induced inhibition of SND has been the subject of much investigation. Largely on the basis of work in rats and rabbits, one popular model (16, 34, 49) suggests that baroreceptor-induced sympathoinhibition is relayed over a pathway in which baroreceptor afferent fibers terminate in the nucleus of the tractus solitarius (NTS), and neurons in this region project to and excite caudal ventrolateral medullary (CVLM) neurons. These CVLM neurons then project to and inhibit rostral ventrolateral medullary (RVLM) neurons that serve as the major source of excitatory drive to preganglionic sympathetic neurons. There is anatomic and electrophysiological evidence to support the existence of each element of this pathway (1, 2, 16, 35, 40, 49).
At least in the cat, there is evidence for the involvement of an additional brain stem region in the control of the cardiac-related rhythm in SND. The medullary lateral tegmental field (LTF) contains neurons, the naturally occurring discharges of which are correlated to this component of SND (6-8, 30, 50, 51). Two observations suggest that these LTF neurons are contained in the network responsible for SND and that their discharges are entrained to pulse-synchronous baroreceptor afferent nerve activity. First, their discharges are correlated to the irregular 0- to 6-Hz oscillations in SND that replace the cardiac-related rhythm during baroreceptor unloading (29, 30). Second, their activity remains locked in time to the peak of the cardiac-related slow wave in SND during changes in heart rate that shift the phase relations between the arterial pulse (AP, a reflection of baroreceptor afferent nerve activity) and SND (6). Such LTF neurons were classified into two groups on the basis of their responses to baroreceptor reflex activation produced by an increase in arterial pressure. The firing rates of neurons in the first group decrease in parallel to SND during baroreceptor reflex activation; thus they are classified as putative sympathoexcitatory neurons (7, 30). LTF sympathoexcitatory neurons fire significantly earlier than RVLM neurons during the inferior cardiac sympathetic nerve slow wave, and their axons project to and appear to terminate in the RVLM (7). Taken together, these data led Barman and Gebber (7) to propose that these LTF neurons are a source of excitatory drive to RVLM-spinal neurons. The second group of LTF neurons with cardiac-related activity are referred to as putative sympathoinhibitory neurons, because their firing rates increase during the inhibition of SND produced by baroreceptor reflex activation (8, 30). The axons of these LTF neurons appear to terminate in the vicinity of raphespinal sympathoinhibitory neurons (8).
Clement and McCall (19) and Vayssettes-Courchay et al. (51) reported that bilateral microinjection of high concentrations of kainic acid (5-25 nmol/100 nl injection) into the LTF eliminated the cardiac-related rhythm in SND and blocked the inhibition of SND during the pressor response produced by an intravenous injection of phenylephrine. Although the results were presumed to reflect the destruction of neuronal cell bodies in the LTF, the authors were unable to rule out the possibility that they had damaged fibers of passage from the NTS. Moreover, spread of the injectate to adjacent regions, such as the CVLM, was not considered. Thus a definitive role for LTF neurons in control of SND is still in question.
N-methyl-D-aspartate (NMDA) and non-NMDA excitatory amino acid (EAA) receptors have been localized on neurons within caudal brain stem regions of the cat involved in control of cardiovascular function, including the LTF (4). Thus, in the present study, we microinjected EAA receptor antagonists into the LTF to test the hypothesis that this region is an important synaptic relay in the baroreceptor reflex pathway controlling SND. We determined the effects of bilateral microinjection of NMDA or non-NMDA receptor antagonists into the LTF on three indexes of baroreceptor reflex function: cardiac-related power in SND, strength of linear correlation (coherence value) of SND to the AP at the frequency of the heartbeat, and inhibition of SND during increased arterial pressure produced by abrupt obstruction of the abdominal aorta. To rule out the possibility that the changes in SND produced by these injections resulted from spread of the injectate to adjacent medullary regions that are part of the baroreceptor reflex pathway (16, 49), we microinjected the EAA receptor antagonists bilaterally into the CVLM and NTS. The results of the present study support the hypothesis that NMDA receptor-mediated synaptic transmission in the LTF plays a pivotal role in the baroreceptor reflex control of SND. Moreover, the data obtained support the view that non-NMDA receptor-mediated synaptic transmission in the LTF is involved in setting the level of excitatory drive to sympathetic nerves.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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General Procedures
The protocols used in these studies on 28 adult cats (1.8-4.2 kg) were approved by the All-University Committee on Animal Use and Care of Michigan State University. Cats were initially anesthetized with 2.5% isoflurane mixed with 100% O2. The right brachial artery and the left and right femoral veins were cannulated to measure arterial pressure and to administer drugs, respectively. Urethan (1.1-1.8 g/kg iv initial dose) was then administered, and isoflurane inhalation was terminated. Supplemental doses (0.2 g/kg iv) of urethan were given every 4-6 h for the duration of the experiment (up to 9 h). The initial dose of urethan has been shown to maintain a surgical level of anesthesia for 8-10 h in cats (27). The frontal-parietal electroencephalogram (EEG) showed a mixture of 7- to 13-Hz spindles and
-slow waves, indicative of
unconsciousness and blockade of information transfer through the
thalamus (47, 48). Noxious stimuli (e.g., pinch, cauterizing muscle)
did not change the EEG pattern. As reported by Barman et al. (11),
coherence analysis showed no correlation between SND and either the EEG
spindles or -slow waves in urethan-anesthetized cats.
Cats were paralyzed (gallamine triethiodide, 4 mg/kg iv initial dose), pneumothoracotomized, and artificially respired with room air. End-tidal CO2 was held near 4% (model 2200 capnometer, Traverse Medical Monitors) by adjusting the volume and rate of artificial respiration, and rectal temperature was kept near 38°C with a heat lamp.
Mean arterial pressure (MAP) was maintained at the same level throughout the analysis period (i.e., before and after microinjection of EAA receptor antagonists). At the start of each experiment, an intravenous infusion of a mixture of dextran (6% in saline) and norepinephrine (1-3 µg/min) was used to set MAP at a level (~120 mmHg) adequate to produce a prominent cardiac-related rhythm in SND (10, 12, 53). The rate of infusion was raised or lowered during the experiment to keep MAP constant. This was done to avoid changes in cardiac-related power in SND that might have occurred as the result of a change in the level of baroreceptor afferent nerve activity.
Neural Recordings
The methods used to make monophasic recordings of left inferior cardiac postganglionic SND and the EEG can be found in earlier reports (31). The preamplifier band pass was 1-1,000 Hz. The synchronized discharges of sympathetic fibers appear as slow waves (i.e., envelopes of spikes) when this band pass is used (30).Microinjections
The general procedures used for microinjections into the brain stem were similar to those used by us to chemically inactivate medullary or pontine neurons with muscimol microinjections (9, 11, 12). The competitive NMDA receptor antagonist D-()-2-amino-5-phosphonopentanoic acid (D-AP5) or the competitive
non-NMDA receptor antagonist
1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo-[f]-quinoxaline-7-sulfonamide (NBQX) was microinjected bilaterally into the medulla (sites defined below) through a glass micropipette (~40-µm tip diameter) that was
glued (cyanoacrylate) to the needle of a 5-µl Hamilton syringe. The
syringe and micropipette were filled with a 3 mM solution of
D-AP5 or a 1 mM solution of
NBQX. All drugs were diluted in 0.9% saline, and the solution was
adjusted to pH 6-8 (litmus paper test), which ensured solubility
of the antagonists. The syringe and micropipette were mounted on a
microinjection unit (model 5000, David Kopf Instruments). Each 100-nl
injection of D-AP5 (300 pmol) or
NBQX (100 pmol) was made slowly (30-60 s) into the medulla by
turning the calibrated micrometer on the microinjection unit.
D-AP5 and NBQX were purchased
from Research Biochemicals International (Natick, MA).
The dorsal surface of the brain stem was exposed by removing portions
of the occipital bone and cerebellum. The midline and obex were used as
landmarks for placement of the micropipette. The EAA receptor
antagonists were microinjected into one of four medullary regions: the
LTF, the rostral or caudal portion of the CVLM (CVLM-r or CVLM-c), or
the intermediate portion of the NTS. The target sites around which
these injections were made are shown in Fig.
1. Actual injection sites
were within 250 µm of the target sites. The micropipette was
positioned into the LTF in tracks located 2 and 3 mm rostral to the
obex and 2.8-3 mm lateral to the midline (sections P12 and P11 in
Fig. 1). Microinjections were made bilaterally at depths of 3 and 4.5 mm from the dorsal surface. This region contains putative
sympathoexcitatory and sympathoinhibitory neurons (7, 8, 30, 50, 51).
The micropipette was positioned into the CVLM-r in tracks located 1 and
2.5 mm rostral to the obex and 4 mm lateral to the midline (sections
P13 and P12 in Fig. 1). Microinjections were made bilaterally at depths
of 4 and 5.5 mm from the dorsal surface. This region contains neurons
with activity correlated to the cardiac-related rhythm in SND; the
firing rates of these neurons are increased during baroreceptor reflex
activation (12, 50). The micropipette was positioned into the CVLM-c in
tracks located 0 and 1.0 mm caudal to the obex and 3.5-4 mm
lateral to the midline (sections P14 and P15 in Fig. 1).
Microinjections were made bilaterally at depths of 4 and 5 mm from the
dorsal surface. This region also contains neurons with cardiac-related
activity; the firing rates of these neurons are increased during
elevations in arterial pressure (46). Chemical stimulation of neurons
in the CVLM-r and CVLM-c produces a fall in arterial pressure (25). The
micropipette was positioned into the NTS in tracks located 1.0 mm
rostral to the obex and 1.6 mm lateral to the midline, at the level of
the obex and 1.4 mm lateral to the midline, and 1.0 mm caudal to the obex and 1 mm lateral to the midline (sections P13, P14, and P15 in
Fig. 1). Microinjections were made bilaterally at depths of 1.0-1.2 mm from the dorsal surface. Electrolytic lesion of this portion of the NTS blocks the baroreceptor reflex in the cat (5).
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The protocol used in these studies was as follows. An 80-s control data sample was collected after the micropipette was positioned at the first site to be injected. A complete set of injections was then made on the left and right sides of the medulla. Test 80-s data blocks were collected as soon as MAP had been adjusted to the preinjection steady-state level (within 1-2 min after the injection), 10-20 min later, and then at 15- to 30-min intervals for up to 2 h to allow for recovery. Because the maximum effects of the drugs were noted 10-20 min after the microinjections were completed, this data block was used to quantify the effects of D-AP5 or NBQX on SND and the baroreceptor reflex. With the exception noted below, microinjections were not placed into another medullary region until SND had recovered from the first set of injections. In two cats, only 15-20 min elapsed between microinjection of D-AP5 into the CVLM-r and CVLM-c.
Two types of control experiments were performed. In three cats, vehicle (saline adjusted to pH 6-8) was microinjected bilaterally into the LTF, CVLM-r, CVLM-c, and NTS; sites of vehicle injection were the same as those for D-AP5 and NBQX microinjections. In two experiments, D-AP5 was microinjected into tracks 1.2 mm medial to the LTF; the sites of injection were at the same rostral-caudal and dorsal-ventral levels as injection sites within the LTF. Neither of these procedures produced significant changes in any of the indexes of baroreceptor reflex control of SND evaluated in this study.
Data Analysis
Before all analyses on a Zenith 486 Z-Station 510 computer, SND was low-pass filtered at 100 Hz; the Butterworth analog filter (model 260-5, AP Circuit) has unity gain and a roll-off rate of 24 dB/octave. Data were acquired (5-ms sampling interval) with software and an analog-to-digital converter board (RC Electronics, Santa Barbara, CA). Frequency-domain analysis used a modified version (31) of the software of Cohen et al. (21) and Kocsis et al. (37).Fast Fourier transform was performed on 32 5-s windows of data with
50% overlap (80-s data block) to construct autospectra of left
inferior cardiac SND and the AP and coherence functions relating SND to
the AP. Spectral analyses were done over a frequency band of 0-100
Hz with a resolution of 0.2 Hz/bin. Figures 2-9 show only
frequencies 
20 Hz, because 
90% of the total power in SND was
within this band. The autospectrum of a signal shows how much power
(voltage squared) is present at each frequency. The coherence function
(normalized cross-spectrum) is a measure of the strength of linear
correlation of two signals at each frequency. The squared coherence
value (referred to as coherence value) is 1 in the case of a perfect
linear relationship and 0 if two signals are unrelated. A coherence
value 0.1 reflects a statistically significant relationship when 32 windows are averaged (13).
ASCII files of the spectra were saved for transfer to spreadsheet, graphics, and statistical programs (Statmost for Windows version 3.0, DataMost). The autospectra of SND before and after microinjection of D-AP5 or NBQX were displayed on the same power scale. In this study we limited our quantification of SND to the frequency band from 0 to 6 Hz, which includes the cardiac-related rhythm and irregular low-frequency oscillations. The cardiac-related band of SND is defined as the range of frequencies surrounding the sharp peak in the autospectrum of SND at the frequency of the heartbeat. A macro written in Microsoft Excel version 7.0 was used to measure cardiac-related power. Briefly, a hypothetical line was fitted to connect the left and right limits of the cardiac-related band of SND (Fig. 2A, top); cardiac-related power was calculated as the area above this hypothetical line. The 0- to 6-Hz total power was calculated by arithmetically summing the values for the bins in this frequency range. The 0- to 6-Hz background power was defined as 0- to 6-Hz total power minus cardiac-related power. Cardiac-related power divided by 0- to 6-Hz total power was multiplied by 100 to determine the percentage of 0- to 6-Hz total power that was cardiac related.
Indexes of Baroreceptor Influences on SND
The present study monitored three indexes of baroreceptor reflex control of SND. First, we compared cardiac-related power in SND before and after microinjection of EAA receptor antagonists at the same level of MAP. Second, we compared the magnitude of the AP-SND coherence value at the frequency of the heartbeat. These two indexes provide measures of the strength of 1:1 locking (i.e., entrainment) of SND to pulse-synchronous baroreceptor afferent nerve activity. Third, we monitored changes in SND during an increase in brachial arterial pressure produced when the abdominal aorta was obstructed for 5-10 s by rapid inflation of the balloon-tipped end of the Fogarty embolectomy catheter (abrupt aortic obstruction). After complete baroreceptor denervation [i.e., bilateral section of the carotid sinus, aortic depressor (ADN), and vagus nerves], there is no cardiac-related power in SND, the AP-SND coherence value at the frequency of the heartbeat is0.1 (not significantly different from
zero), and abrupt aortic obstruction does not inhibit SND (9, 12, 29,
53).
Statistical Analysis
Values are means ± SE. Student's paired t-test was used to compare power in specific frequency bands of SND and AP-SND coherence values at the frequency of the heartbeat before and after microinjection of EAA receptor antagonists into the brain stem. Coherence values were subjected to z transformation before this analysis (42). Student's unpaired t-test was used to compare the effects produced by microinjection of D-AP5 and NBQX into the LTF. Also, to address the issue of spread of injectate from the LTF to the CVLM or NTS, we also used the unpaired t-test to compare the effects produced by microinjection of a drug into the LTF and these other medullary regions. P 0.05 indicated
statistical significance.
Histology
The brain stem was removed and fixed in 10% buffered Formalin. Frontal sections of 30 µm thickness were cut and stained with cresyl violet. Sites of microinjection were identified with reference to the bottom of the tracks made with the micropipette and the stereotaxic planes of Berman (14).| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of D-AP5 and NBQX Microinjections Into the LTF
D-AP5 microinjections.
The competitive NMDA receptor antagonist
D-AP5 (300 pmol/100 nl) was
microinjected bilaterally into the LTF of seven cats with an MAP of 128 ± 9 mmHg. The target sites of these injections are shown in
sections P11 and P12 in Fig. 1. The data in Fig. 2 are representative of the results from
these experiments. The control autospectra of SND and the AP (Fig.
2A,
top and
middle) show a prominent peak at the
frequency of the heartbeat. The coherence value relating SND to the AP
at this frequency was 0.84 (Fig. 2A,
bottom). The coherence of these
signals was also significant at the second and third harmonics of the
heart rate. Within 15 min after bilateral microinjection of
D-AP5 into the LTF, the cardiac-related rhythm in SND was eliminated (Fig. 2B,
top), as evidenced by an AP-SND coherence value near 0 at
the frequency of the heartbeat (Fig.
2B,
bottom). Because cardiac-related
power in SND is dependent on the level of MAP (10, 12, 53), extreme care was taken to maintain the same MAP before and after drug injection
(see METHODS). The elimination of
the cardiac-related rhythm was accompanied by an increase (141% of
control) in 0- to 6-Hz background power in SND in this
experiment. As shown in Fig. 2C,
partial recovery of the cardiac-related rhythm in SND occurred within 1 h, at which time the AP-SND coherence value at the frequency of the
heartbeat was 0.65.
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NBQX microinjections.
The competitive non-NMDA EAA receptor antagonist NBQX (100 pmol/100 nl)
was microinjected bilaterally into the LTF of 11 cats with an MAP of
119 ± 5 mmHg. In the example shown in Fig.
5, cardiac-related power in SND was
decreased to 35% of control (A) and
the AP-SND coherence value at the frequency of the heartbeat was
reduced from 0.89 to 0.80 (B) 15 min
after bilateral microinjection of NBQX.
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Effects of D-AP5 and NBQX Microinjections Into the CVLM
D-AP5 microinjections.
D-AP5 was microinjected
bilaterally into the CVLM-r of six cats with an MAP of 115 ± 7 mmHg. The target sites of these injections are shown in sections P12
and P13 in Fig. 1. In the example shown in Fig.
7A,
cardiac-related power in SND was reduced to 32% of control 10 min
after microinjection of D-AP5
(top), and the AP-SND coherence
value at the frequency of the heartbeat was reduced from 0.89 to 0.5 (bottom).
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NBQX microinjections.
NBQX was microinjected bilaterally into the CVLM-r of five cats with an
MAP of 120 ± 8 mmHg. In the example shown in Fig. 8A,
top, cardiac-related power in SND was
increased to 319% of control 15 min after microinjection of NBQX. The
AP-SND coherence value at the frequency of the heartbeat was not
changed by this injection (Fig. 8A,
bottom).
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Effects of D-AP5 and NBQX Microinjections Into the NTS
D-AP5 microinjections.
D-AP5 was microinjected
bilaterally into the NTS of six cats with an MAP of 123 ± 4 mmHg.
The target sites of these injections are shown in sections P13, P14,
and P15 in Fig. 1. In the example shown in Fig.
9A,
cardiac-related power in SND was reduced to 55% of control
(top) and the AP-SND coherence value
at the frequency of the heartbeat was reduced from 0.87 to 0.72 (bottom) 15 min after microinjection
of D-AP5.
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NBQX microinjections. NBQX was microinjected bilaterally into the NTS of five cats with an MAP of 119 ± 4 mmHg. In the example shown in Fig. 9B, the cardiac-related rhythm in SND was eliminated (top) 15 min after microinjection of NBQX, as evidenced by an AP-SND coherence value near zero at the frequency of the heartbeat (bottom).
Figure 3B and Table 1 summarize the effects of bilateral microinjection of NBQX into the NTS of five cats. NBQX essentially eliminated the cardiac-related rhythm in SND. This was shown by the significant decrease in cardiac-related power in SND (Fig. 3B, top), the low coherence value relating SND to the AP at the frequency of the heartbeat (Table 1), and the significant decrease in the percentage of 0- to 6-Hz total power that was cardiac related (Table 1). There was a tendency for 0- to 6-Hz background power to increase (Fig. 3B, middle), but this change was not statistically significant; 0- to 6-Hz total power was also not significantly changed (Fig. 3B, bottom). Microinjection of NBQX into the NTS eliminated baroreceptor reflex-induced sympathoinhibition in four cats in which brachial MAP was elevated from 120 ± 6 to 201 ± 6 mmHg by abrupt aortic obstruction. As shown by the example in Fig. 6, C and D, before drug administration, SND was inhibited during the pressor response; however, 15 min after microinjection of NBQX, SND was essentially unaffected during a comparable increase in arterial pressure.| |
DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of the present study point to two distinct roles of the medullary LTF in the control of SND in anesthetized cats. First, the effects produced by bilateral microinjection of D-AP5 into this region support the hypothesis that the baroreceptor reflex pathway controlling SND includes an obligatory synapse in the LTF. Second, the effects produced by microinjection of NBQX into the LTF support the view that this region is involved in setting the level of excitatory drive to sympathetic nerves.
There are at least two ways to explain how blockade of EAA receptors in the LTF could reversibly reduce or abolish cardiac-related power in SND. First, if EAA neurotransmission in this region is involved in the entrainment of irregular low-frequency oscillations in SND to pulse-synchronous baroreceptor afferent nerve activity, microinjection of an EAA receptor antagonist should convert the cardiac-related rhythm to irregular 0- to 6-Hz oscillations and, thus, would disrupt the 1:1 locking of bursts of SND to the AP. This is what happened when D-AP5 was microinjected bilaterally into the LTF: cardiac-related power in SND was significantly reduced and 0-to 6-Hz background power was significantly increased. D-AP5 also prevented the reflex-induced inhibition of SND that occurs during the pressor response produced by abrupt aortic obstruction. This observation also supports the view that NMDA receptor-mediated synaptic transmission in the LTF plays a pivotal role in the baroreceptor reflex pathway controlling SND. Barman and Gebber (8, 30) reported that baroreceptor reflex activation increased the firing rate of one group of LTF neurons, the naturally occurring discharges of which were correlated to the cardiac-related rhythm in SND; they proposed that activation of such neurons leads to inhibition of SND. The effects of D-AP5 microinjection into the LTF are consistent with the possibility that baroreceptor-induced activation of these neurons is mediated by EAAs acting through NMDA receptors.
A second way in which cardiac-related power in SND could be decreased by blockade of EAA receptors in the LTF is by reducing the activity of LTF sympathoexcitatory neurons. Because these neurons are thought to be a source of excitatory drive to RVLM-spinal neurons (6, 7), reducing their activity would decrease SND. However, residual SND would still be cardiac related, provided that the mechanism for entrainment of SND to the AP was not blocked. This scenario is consistent with the effects produced by microinjection of the non-NMDA receptor antagonist NBQX into the LTF. Microinjection of NBQX into the LTF significantly decreased cardiac-related power and 0- to 6-Hz total power in SND. Two findings indicated that the baroreceptor reflex remained functional in these animals. First, the AP-SND coherence value at the frequency of the heartbeat remained high (0.65 ± 0.06). Second, microinjection of NBQX into the LTF did not diminish the sympathoinhibitory response to abrupt aortic obstruction. Thus, in contrast to the effects of D-AP5, NBQX appears to have lowered the level of excitatory output from the LTF without upsetting the baroreceptor reflex. The contention that the LTF contains sympathoexcitatory neurons is also supported by the observation of Barman and Gebber (9) that inactivation of this region by muscimol microinjection produced significant reductions in 0- to 6-Hz total power in SND and MAP in some baroreceptor-denervated cats. In the present study, one might have expected MAP to decrease if microinjection of NBQX reduced the activity of LTF sympathoexcitatory neurons. This possibility was not tested, because we purposely kept MAP constant by continually adjusting the rate of intravenous infusion of a mixture of norepinephrine and dextran. This was done to avoid changes in cardiac-related power in SND that might have occurred as the result of a change in the level of baroreceptor afferent nerve activity.
The decrease in cardiac-related power in SND produced by microinjection of NBQX into the LTF may also signify a role of non-NMDA receptors (although less important than that of NMDA receptors) in this region in mediating the baroreceptor reflex. If NBQX affected only transmission in the sympathoexcitatory pathway, injection of this drug into the LTF should have significantly decreased 0- to 6-Hz background power as well as cardiac-related and total power in SND. The failure to decrease 0- to 6-Hz background power could mean that NBQX interfered to some degree with the entrainment of SND to the AP. The conversion of some of the cardiac-related activity to irregular low-frequency oscillations would have offset the decrease in 0- to 6-Hz background power due to blockade of EAA-induced activation of LTF sympathoexcitatory neurons. A weak action of NBQX in the LTF on transmission in the baroreceptor reflex pathway might also explain the significant reduction in the AP-SND coherence value at the frequency of the heartbeat. Nonetheless, blockade of non-NMDA receptors in the LTF was not able to prevent baroreceptor reflex-induced sympathoinhibition during abrupt aortic obstruction.
An argument can also be made that D-AP5 acted not only on LTF neurons involved in mediating baroreceptor reflex-induced sympathoinhibition but also, to a lesser extent, on neurons responsible for sympathoexcitation. By blocking the baroreceptor reflex, microinjection of D-AP5 into the LTF should have significantly increased 0- to 6-Hz total power in SND as well as 0- to 6-Hz background power. The failure of 0- to 6-Hz total power to increase could mean that D-AP5 interfered to some extent with EAA-induced activation of LTF sympathoexcitatory neurons. This effect of D-AP5 would have counteracted some of the opposing effects of blockade of EAA-induced activation of LTF sympathoinhibitory neurons, resulting in no net change in 0- to 6-Hz total power. Thus, whereas the predominant actions of D-AP5 and NBQX in the LTF may be to block transmission in pathways mediating baroreceptor reflex-induced sympathoinhibition and excitatory drive to sympathetic nerves, respectively, each drug may also affect the other function.
D-AP5 and NBQX are classified as
selective NMDA and non-NMDA receptor antagonists, respectively (22). No
attempt was made in the present study to test directly the selectivity
of these drugs on different classes of EAA receptors. However, the
concentrations and doses of these drugs used here were similar to (or
even considerably lower than) those used in other studies in which
their ability to antagonize selectively NMDA and non-NMDA receptors,
respectively, was demonstrated (17, 18, 26, 38, 44). Also, the time courses of action of D-AP5 and
NBQX were similar to those reported by others (17, 26, 32, 36, 44, 45).
Because D-AP5 was more effective
than NBQX in disrupting the entrainment of SND to the AP and preventing
the inhibition of SND during abrupt aortic obstruction when
microinjected into the LTF, it is tempting to propose that NMDA
receptors in this region have a more significant role than non-NMDA
receptors in the baroreceptor reflex pathway. However, NBQX has a
higher affinity for the
-amino-3-hydroxy-5-methylisoxazole-4-propionic acid than the kainate
receptor subtype (39); thus a role for kainate receptors was not
adequately tested in the present study. We also did not construct
dose-response curves for D-AP5
and NBQX; the long duration of action of the drugs would have made it
difficult to do this in an individual experiment. Nonetheless, it seems likely that the doses of EAA receptor antagonists used were adequate to
block a significant proportion of the NMDA or non-NMDA receptors within
the medullary regions studied. This is because the doses of
D-AP5 and NBQX used were able to
abolish the baroreceptor reflex when microinjected into the LTF and
NTS, respectively. Despite the weaknesses in the pharmacological
aspects of this study, the effects produced by microinjection of
D-AP5 and NBQX into the LTF provide evidence for a physiological role of this region in mediating baroreceptor reflex control of SND and in providing excitatory drive to sympathetic nerves.
The effects on SND produced by microinjection of EAA receptor antagonists into the LTF cannot be explained by spread of the injectate into the NTS or CVLM regions identified as obligatory relays in the baroreceptor reflex pathway controlling SND (16, 49). First, the reductions in cardiac-related power in SND and in the AP-SND coherence value at the frequency of the heartbeat after microinjection of D-AP5 into the LTF were significantly greater than those produced by microinjection of D-AP5 into the NTS or the CVLM-r. Second, the inhibition of SND during abrupt aortic obstruction was blocked by microinjection of D-AP5 into the LTF but not into the NTS or CVLM-r. Third, NBQX microinjection into the LTF decreased cardiac-related power in SND, whereas cardiac-related power was increased when NBQX was injected into the CVLM-r. Fourth, microinjection of either EAA receptor antagonist into the CVLM-c did not significantly affect any of the three indexes of baroreflex control of SND.
There is compelling evidence that the baroreceptor reflex pathway in the rat and rabbit includes an obligatory synapse within the CVLM. First, the vasodepressor component of the baroreceptor reflex is abolished by chemical inactivation of CVLM neurons (microinjection of the GABA agonist muscimol) or kainic acid lesions of the CVLM (1, 23, 40). Second, neurons in the CVLM, the naturally occurring discharges of which are correlated to the AP, are activated by electrical stimulation of the ADN (35); the axons of these neurons project to the RVLM (2, 35). Third, anatomic studies show projections from the NTS to the CVLM (2, 16). The role of EAA receptors in the CVLM in mediating the baroreceptor reflex has been the focus of several studies in the rat and rabbit. In one of the earliest reports by Guyenet et al. (34), microinjection of kynurenate into the CVLM of the rat prevented the inhibition of SND produced by aortic constriction. Others have reported that microinjection of NMDA receptor antagonists into the CVLM produces complete or partial block of the ADN stimulus-induced depressor response (15, 16, 32, 36, 45, 49).
Similar to the CVLM of the rat and rabbit, the CVLM of the cat contains neurons with cardiac-related activity that are excited during the inhibition of SND produced by intravenous administration of a pressor dose of phenylephrine (12, 46, 50). Although Gatti et al. (28) did not directly assess the integrity of the baroreceptor reflex, they reported that muscimol microinjection into the CVLM of the cat did not induce a pressor response, as would have been expected if neurons in this region were contained in this reflex pathway. However, barring the possibility that D-AP5 diffused from the CVLM-r to the LTF, the results of the present study suggest that NMDA receptor-mediated transmission in the CVLM-r is involved to some extent in mediating baroreceptor reflex control of SND. This suggestion is based on the observation that microinjection of D-AP5 into this region significantly reduced cardiac-related power in SND. However, NMDA receptor-mediated transmission in the CVLM-r is not essential, because the sympathoinhibitory response to abrupt aortic obstruction was not impaired by this injection, and the AP-SND coherence value at the frequency of the heartbeat remained near control level. We also found that microinjection of NBQX into the CVLM-r increased, rather than decreased, cardiac-related power in SND and did not alter the other indexes of baroreceptor reflex control of SND. Thus non-NMDA receptor-mediated transmission in the CVLM-r does not appear to play a role in baroreceptor reflex control of SND. Finally, neither D-AP5 nor NBQX microinjection into the CVLM-c significantly changed any of the three indexes of baroreceptor reflex control of SND.
Masuda et al. (40) reported that chemical inactivation of the CVLM rostral and caudal to the obex was required to block the baroreceptor reflex in the rabbit. Thus we considered the possibility that simultaneous blockade of EAA neurotransmission in the CVLM-r and CVLM-c was required to interrupt baroreceptor reflex influences on SND. In two cats, D-AP5 was microinjected into the CVLM-c at a time when cardiac-related power in SND was reduced by an earlier injection of the drug into the CVLM-r. Cardiac-related power was not further reduced in these cases, and the inhibition of SND during abrupt aortic obstruction was maintained. It is possible that NMDA and non-NMDA receptors in the CVLM need to be blocked simultaneously to disrupt baroreceptor reflex control of SND. Miyawaki et al. (41), but not others (32, 36, 45), reported that blockade of both groups of EAA receptors in the CVLM of the rat was required to abolish baroreceptor reflex influences on SND. Additional studies are needed to evaluate more fully the role of the CVLM in mediating the baroreceptor reflex in the cat.
As already indicated, microinjection of NBQX into the CVLM-r increased cardiac-related power in SND and did not prevent baroreceptor reflex-induced sympathoinhibition. One explanation for these findings is that NBQX interrupted transmission in a pathway that inhibited SND by a mechanism independent of the baroreceptor reflex. A similar explanation was offered by Cravo et al. (23) for the increase in cardiac-related power in SND and persistence of the sympathoinhibitory response to ADN stimulation after kainic acid-induced lesions of the caudal CVLM of the rat. The results of the present study provide support for a role of non-NMDA receptors in the CVLM in this nonbaroreceptor sympathoinhibitory pathway.
There is substantial evidence for involvement of NMDA and non-NMDA receptors in the integration of baroreceptor afferent nerve activity in the NTS of rats (3, 24, 33, 38, 42, 52). To our knowledge, however, the present study is the first to show the effects of blockade of EAA receptors in the NTS on baroreceptor reflex control of SND in the cat. In general, our results are consistent with those obtained in rats. NBQX microinjection into the NTS essentially abolished cardiac-related power in SND; the reduction produced by D-AP5 was not as pronounced. Also, NBQX, but not D-AP5, microinjection into the NTS abolished the reflex inhibition of SND during abrupt aortic obstruction and produced a significant reduction in the AP-SND coherence value at the frequency of the heartbeat. Gordon and Leone (33) reported that blockade of non-NMDA, but not NMDA, receptors in the NTS abolished the depressor response to electrical stimulation of the ADN in the rat. The results of a study by Zhang and Mifflin (52) may explain why blockade of non-NMDA, but not NMDA, receptors in the NTS abolished the baroreceptor reflex. They showed that non-NMDA receptors mediate the monosynaptic activation of NTS neurons by stimulation of baroreceptor afferents, whereas NMDA and non-NMDA receptors mediate the excitation of higher-order NTS neurons in the baroreceptor reflex arc. When D-AP5 was microinjected into the NTS, non-NMDA-mediated activation of higher-order NTS neurons may have overridden the effects of blockade of NMDA receptors on these neurons, thus preserving baroreceptor reflex control of SND. On the other hand, when NBQX was microinjected into the NTS, synaptic transmission would have been blocked at the first synapse in the NTS, thus preventing baroreceptor reflex effects on SND. Somewhat surprisingly, microinjection of NBQX into the NTS did not increase 0- to 6-Hz total power in SND, as would be expected with baroreceptor denervation. This finding is consistent with that reported by Guyenet et al. (34); they showed that microinjection of the broad-spectrum glutamate receptor antagonist kynurenate into the NTS blocked the reflex-induced inhibition of SND during a pressor response to intravenous norepinephrine but did not increase the resting level of arterial pressure or SND in the rat.
Perspectives
A role for the medullary LTF is frequently ignored in reviews on central components of the baroreceptor reflex pathway (16, 49). The present study provides compelling evidence that this region serves as a critical synaptic relay in mediating baroreceptor reflex control of SND in the cat. In the rat, CVLM neurons that relay baroreceptor input from the NTS to the RVLM are viewed as simple interneurons in the afferent limb of the baroreceptor reflex arc (35). In contrast, the role of the LTF in control of SND in the cat is considerably more complex. Together with data obtained from earlier studies from this laboratory (6, 30), the results of the present study support the hypothesis that the LTF contains a synaptic relay in the pathway responsible for entrainment of irregular low-frequency oscillations in SND to pulse-synchronous baroreceptor afferent nerve activity. This function is illustrated by the conversion of the cardiac-related rhythm to irregular 0- to 6-Hz activity after blockade of NMDA receptors with the microinjection of D-AP5 into the LTF. Moreover, NMDA receptor-mediated synaptic transmission in the LTF was required for the reflex-induced inhibition of SND during abrupt aortic obstruction. A challenge for the future is to identify the cell types within the LTF that responded directly to the NMDA receptor antagonist, leading to disruption of baroreceptor reflex control of SND. The results of the present study are also consistent with the view that input from LTF neurons is a source of the naturally occurring discharges of RVLM-spinal sympathoexcitatory neurons (6, 7). This follows from the observation that cardiac-related and 0- to 6-Hz total power in SND were significantly reduced after blockade of non-NMDA receptors with the microinjection of NBQX into the LTF. The degree to which LTF neurons are responsible for the discharges of RVLM sympathoexcitatory neurons, however, remains to be determined. The results from the present study should stimulate new interest in the role of the LTF in control of SND.| |
ACKNOWLEDGEMENTS |
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This study was supported by National Heart, Lung, and Blood Institute Grants HL-33266 and HL-13187.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S. M. Barman, Dept. of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317 (E-mail: barman{at}msu.edu).
Received 11 March 1999; accepted in final form 28 June 1999.
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TOP
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 S. M. Barman and G. L. Gebber "Rapid" Rhythmic Discharges of Sympathetic Nerves: Sources, Mechanisms of Generation, and Physiological Relevance J Biol Rhythms, October 1, 2000; 15(5): 365 - 379. [Abstract] [PDF]
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S. M. Barman, G. L. Gebber, and H. S. Orer Medullary lateral tegmental field: an important source of basal sympathetic nerve discharge in the cat Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2000; 278(4): R995 - R1004. [Abstract] [Full Text] [PDF]
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, Target sites around which these injections were made in 4 medullary regions: medullary lateral tegmental field (LTF), rostral and
caudal portions of caudal ventrolateral medulla (CVLM-r and CVLM-c),
and nucleus of tractus solitarius (NTS). Although sites are shown on
only 1 side of brain stem, injections were placed symmetrically on left
and right sides. P11-P15 refer to approximate stereotaxic planes
of Berman (
