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1 Departamento de Fisiologia, Universidade Federal de São Paulo, Brazil CEP: 04023; and Departments of 2 Medicine, 3 Pediatrics, and 4 Neuroscience, Case Western Reserve University, Cleveland, Ohio 44106
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We studied the respiratory and
blood pressure responses to chemical stimulation of two regions of the
ventral brainstem in mice: the rostral and caudal ventrolateral medulla
(RVLM and CVLM, respectively). Stimulation of the RVLM by
microinjections of the excitatory amino acid L-glutamate
induced increases in diaphragm activity and breathing frequency,
elevation of blood pressure (BP), and a slight increase in heart rate
(HR). However, activation of the CVLM induced a decrease in breathing
frequency, mainly due to prolongation of expiratory time
(TE), and hypotension associated with a slight slowing of
HR. Because adrenergic mechanisms are known to participate in the
control of respiratory timing, we examined the role of
2-adrenergic receptors in the RVLM region in mediating
these inhibitory effects. The findings demonstrated that blockade of
the 2-adrenergic receptors within the RVLM by prior
microinjection of SKF-86466 (an 2-adrenergic receptor
blocker) significantly reduced changes in TE induced by
CVLM stimulation but had little effect on BP responses. These results
indicate that, in mice, activation of the RVLM increases respiratory
drive associated with an elevation of BP, but stimulation of CVLM
induces prolongation of TE via an
2-adrenergic signal transduction pathway.
respiratory timing; rostral ventrolateral medulla; caudal
ventrolateral medulla; L-glutamate; 2-adrenergic receptors
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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NEUROANATOMICAL AND PHYSIOLOGICAL studies have demonstrated that two connected groups of neurons within the ventrolateral medulla (VLM) play an important role in the control of respiration and vasomotor tone: a rostral (R) region and a more caudal (C) area. Neurons in the RVLM are involved in respiratory rhythm generation (11, 31), in maintaining resting sympathetic tone (4, 8, 28, 29), and in sympatho-respiratory and defense reaction integration (7, 14, 21, 25). The subset of neurons in the CVLM provides tonic inhibitory inputs to the respiratory-related neuronal network (6, 32) and modifies vasomotor tone via inhibition of the RVLM neurons (1, 2, 5, 8, 13). The interrelationships between the neuronal networks regulating respiratory and cardiovascular functions, and the neurotransmitters and receptors involved in these interlocking networks, are still largely unknown.
In the CVLM region of most mammals, a prominent group of
norepinephrine-containing neurons (the A1 cell group) is found.
Norepinephrine, when released at targeted sites, may elicit a variety
of ventilatory and cardiovascular effects, depending on the specific
region and receptor subtype that is present. The
2-adrenergic receptors are widely distributed and are
present on both neuronal terminals and cell bodies in the RVLM
(15). Activation of prejunctional 2-adrenergic receptors inhibits neurotransmitter
release, whereas stimulation of receptors located on neuronal cell
bodies mediates hyperpolarization and inhibition of firing rate
(16). Systemic administration of
2-adrenergic agonists induces alterations in breathing
pattern, such as prolonged and variable expiratory time (TE) intervals (20).
Recently, the mouse has been used as an experimental animal because of
its short gestation time, rapid growth, and the availability of a large
number of genetically modified strains that can provide valuable
information on the neurochemical mechanisms controlling the respiratory
and cardiovascular systems (27). However, important interspecies differences may exist between mice and the more frequently studied animal models. Thus we sought to determine the respiratory and
cardiovascular effects of selective stimulation of the CVLM and RVLM to
better characterize the mouse model in relation to other animal models.
In addition, we examined the role 2-adrenergic receptors
play in the function of these medullary centers.
The results showed that in mice, as in most mammalian species that are
studied, activation of the RVLM causes an increase in the respiratory
drive associated with arterial pressure elevation, but stimulation of
CVLM induces the opposite effect. Data from mice indicate, for the
first time, that prolongation of expiratory duration caused by CVLM
stimulation requires the participation of 2-adrenergic
receptors in the RVLM, whereas the accompanying hypotension is mediated
through other inhibitory mechanisms.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The studies were performed on 26 normotensive C57BL/6 mice (23 ± 3.6 g, mean ± SD). Anesthesia was induced by inhalation of methoxyflurane in air and maintained with urethane (1.0 g/kg iv). The level of anesthesia was assessed every 30 min. Supplemental doses of urethane (0.1 g/kg iv) were administered if noxious paw pinch evoked an increase in arterial blood pressure (BP) or withdrawal reflex. The study protocol was approved by the Case Western Reserve University School of Medicine Institutional Animal Care and Use Committee and was in agreement with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Animals were tracheotomized, vagotomized, and artificially ventilated with oxygen at arterial PCO2 above the apneic point (PaCO2 = 34 ± 2.4 Torr, 7.4 ± 0.1 pH). At the end of the studies, 0.2 ml of blood were withdrawn from the carotid artery for measurements of arterial blood gases and pH). Body temperature was maintained at 37°C with a heating lamp. The carotid artery and the external jugular vein were cannulated to measure BP and heart rate (HR) and for the administration of fluids and drugs.
Respiratory output was measured by recording the electromyographic activity of the diaphragm (DEMG) using bipolar, stainless steel, twisted wires that were implanted via a thoracic incision in the costal portion of the diaphragm. The electrical activity was amplified and filtered (0.1 Hz to 3 kHz, Grass P511K), rectified, and integrated (Paynter filter, time constant = 50 ms) using a moving averager (Charles Ward). The integrated moving average DEMG signal was recorded directly onto the computer for subsequent analysis. Mean (M), systolic (S), and diastolic (D) BP and HR were also recorded.
After instrumentation, mice were placed in a stereotaxic apparatus in a prone position. The occipital bone was removed, and the atlanto-occipital membrane was opened. Bregma and the midline served as stereotaxic zeros for rostrocaudal and lateral coordinates. The intramedullary bilateral microinjections of buffered saline vehicle (10 nl), L-glutamate (0.12 nmol, 10 nl), and SKF-86466 (0.4 nmol, 10 nl) were made simultaneously through glass micropipettes with a tip diameter of 40 µm, using a pneumatic pressure system (model PPS-2; Medical Systems, Greenvale, NY). The volume of injectate (10 nl) was calibrated at a controlled duration and pressure. This method was described previously by McCrimmon et al. (24), but we scaled the method down for use in the mouse. Briefly, the micropipettes were directed to the desired stereotaxic position using the bregma and midline as references. Dorsoventral positioning was achieved by slowly lowering the micropipettes at targeted sites. This method allowed the microinjectate to be consistently administered into the parenchyma of the RVLM or CVLM.
L-Glutamate and SKF-86466 were dissolved in saline, and the
pH was adjusted to 7.3. In studies examining the role of the
noradrenaline 2-adrenoreceptor signaling pathway,
microinjections of L-glutamate were made into the CVLM 10 min after microinjections of SKF-86466 into the RVLM.
To localize injection sites, the micropipettes were removed at the end of each experiment, filled with Evans blue dye (2%, 10 nl), and reinserted at the same sites, and the dye was microinjected. Animals were deeply anesthetized with an additional dose of urethane and perfused through the heart with saline (50 ml), followed by 4% paraformaldehyde in 0.1 M phosphate buffer. To identify injection sites, the brain stem was sectioned coronally in 50 µm thicknesses, mounted, and stained with 1% neutral red.
In three mice, we used immunohistochemistry to identify tyrosine hydroxylase (TH)-expressing neurons, as previously described (19). For this purpose, a one-in-five series of 50-µm- thick sections was exposed for 30 min to PBS-Triton solution containing 3% normal rabbit serum to block nonspecific binding sites. After a further wash, the tissue was placed overnight at room temperature in a primary polyclonal antibody solution (1:500 dilution of rabbit anti-tyrosine hydroxylase in PBS; Incstar). The sections were rinsed, incubated with biotinylated goat anti-rabbit secondary antiserum, and further processed using a standard biotin avidin-peroxidase kit (ABC-elite kit, Vector). The immunoreaction was visualized by incubating the section with 0.02% 3,3'-diaminobenzidine containing 0.01% hydrogen peroxide for 6 min. A purple-black reaction was obtained by adding 40 µl of 8% NiCl2 solution (per 100 ml of 3,3'-diaminobenzidine solution) to the peroxidase reaction. The sections were rinsed in PBS and then mounted on gelatin-coated glass slides, stained with neutral red, and coverslipped. Control studies were performed to determine whether the primary or secondary antibodies produced false-positive results. Omission of primary or secondary antibodies resulted in the absence of labeling. Slides were viewed with a Leitz Laborlux S microscope. The image was projected onto a television screen and processed through a video processor, and video copy was used to determine dye distribution. The labeled area was plotted on drawings of sections from the atlas of Franklin and Paxinos (12).
Data analysis. Integrated diaphragmatic activity was used to determine respiratory timing, as well as inspiratory and expiratory durations. The DEMG, inspiratory time (TI), and TE were analyzed, and respiratory frequency (f, breaths/min), and minute DEMG (DEMG × f) were calculated. To quantify the respiratory response, these parameters were averaged in the control period for 50 consecutive breaths and a minimum of 10 breaths at peak response after microinjection of the vehicle or L-glutamate. In addition, BP and HR were measured in the control period and when peak changes occurred after drug administration. Results obtained before and after microinjection of tested drugs were averaged, and percent changes from the control for each variable were calculated. Means and standard error (SE) of the analyzed variables as percent change from the control were compared, and differences were tested by Student's paired t-test. Criterion for statistical significance was P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The vehicle microinjections into the RVLM or the CVLM had slight transient or no effect on BP, HR, and respiratory parameters; however, microinjections of L-glutamate induced changes in respiratory output, BP, and HR.
Respiratory and cardiovascular effects of RVLM stimulation.
Figure 1 shows a coronal section of the
medulla oblongata depicting an actual injection site in the RVLM, in
parallel with TH staining. The inset shows an example of the response
to bilateral microinjections of L-glutamate into this
region. As can be seen, simultaneous bilateral microinjection of
L-glutamate into the RVLM elicited an increase in f that
was often followed by changes in the amplitude of inspiratory
discharge. Initially, during increases in BP, a transient decrease
followed by a gradual increase in DEMG occurred. On
average, in the 10 mice studied, L-glutamate produced a
significant rise in f, from 107 ± 13 to 122 ± 12 breaths/min (23 ± 5%, P < 0.05; Fig.
2A). The increase in breathing
frequency was mainly due to a reduction of TE;
TE decreased from 0.54 ± 0.17 to 0.35 ± 0.15 s (
20 ± 5%, P < 0.05; Fig.
2B). In addition, L-glutamate injection into the
RVLM caused an increase in inspiratory DEMG, with
consequent increases in the minute DEMG (56 ± 7.2 and 87 ± 13.4%, respectively, P < 0.05; Fig.
2A).
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6.48 to 7.20 mm caudal to bregma, 1.2 mm lateral to midline, and at
a depth of 1.7-2.0 mm from the dorsal surface of the medulla oblongata.
Respiratory and cardiovascular effects of CVLM stimulation.
Figure 3 shows a coronal section of the
medulla oblongata depicting the actual injection site in the CVLM
(3A), the injection site in parallel with TH staining
(3B), and an example of the effects elicited by bilateral
microinjections of L-glutamate (3C). The
response to bilateral microinjections of L-glutamate into the CVLM (n = 11) consisted of a decrease in frequency
of inspiratory discharge, and, in five of the 11 animals, there was a
slight increase in peak DEMG, as shown in this example. On
average, L-glutamate microinjected into the CVLM elicited a
significant reduction in frequency of inspiratory discharge, which
decreased from 93 ± 11 to 52 ± 5 breaths/min (38 ± 7%, P < 0.05; Fig.
4A). This resulted in a
decrease in minute DEMG (44 ± 4%,
P < 0.05) without significant changes in peak
DEMG (3 ± 2%; P > 0.05; Fig.
4A). The decrease in frequency was mainly due to
prolongation of TE. Expiratory duration increased from
0.54 ± 0.12 to 1.01 ± 0.16 s (122 ± 18%, P < 0.05; Fig. 4B). Furthermore,
TI increased from 0.24 ± 0.02 to 0.34 ± 0.04 s (42 ± 8%, P < 0.05; Fig.
4B). Hence, ventilatory depression was due to changes in
respiratory timing; the rate of DEMG increase tended to
decrease because of prolongation of TI. Decreases in BP and
HR after CVLM stimulation were significant. MBP, SBP, and DBP decreased
from 80 ± 3 to 54 ± 2 (33 ± 3%), from 89 ± 3 to 66 ± 2 (26 ± 3%), and from 70 ± 4 to 43 ± 2 mmHg (37 ± 3%), respectively (P < 0.05 for all
values; Fig. 4C). Furthermore, there was a slight but
significant slowing of HR, decreasing from 623 ± 11 to 575 ± 22 beats/min (8 ± 3%, P < 0.05; Fig.
4C).
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Effects of 2-adrenergic receptor blockade on
respiratory and cardiovascular changes induced by CVLM stimulation.
In a separate group of five mice, we studied the possible role of
2-adrenergic mechanisms in respiratory and
cardiovascular changes observed with CVLM stimulation by prior
microinjection of SKF-86466 (an 2-adrenergic receptor
blocker) into the RVLM. Administration of SKF-86466 into the RVLM
caused a slight transient increase in f (12 ± 6%,
P > 0.05). As can be seen in Fig.
5, after blockade of
2-adrenergic receptors in the RVLM, activation of the
CVLM produced insignificant changes in respiratory timing and peak
DEMG but induced a decrease in BP and HR comparable to that
observed in untreated mice. Thus bilateral microinjections of
L-glutamate into the CVLM slightly shortened TE
and TI (5 ± 13% and 2 ± 12%,
respectively, P > 0.05; Fig. 5B),
insignificantly increased f and minute DEMG (16 ± 12% and 10 ± 10, respectively, P > 0.05), and
had no significant effect on peak DEMG (4 ± 4%, P > 0.05; Fig. 5A).
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2-receptors
induced significant decreases in MBP and HR (23 ± 3 and
9 ± 2%, respectively, P < 0.05; Fig.
5C) that were comparable to those observed in untreated mice.
Histological analysis of injection sites revealed that, in the mouse,
the CVLM inhibitory region is located at the level of the caudal end of
the area postrema, extending from the ventral compact portion of the
nucleus ambiguus to the ventral medullary surface, medial to the spinal
trigeminal tract, and lateral to the lateral tip of the dorsal
accessory nucleus of the inferior olive. Noradrenergic neurons of the
A1 cell group are present in this region. The
coordinates of the vasodepressor region are 7.32-7.48 mm caudal to
the bregma, 1.2-1.3 mm lateral to the midline, and 1.6-1.8 mm
from the dorsal surface of the medulla oblongata.
Catecholamine-containing neurons in the ventrolateral medulla oblongata. In mice, as in most mammals, catecholamine-containing neurons in the ventral medulla oblongata form paired longitudinal columns extending from the facial nucleus to the pyramidal decussation. As seen in Fig. 1, the TH-containing cells that presumably belong to the C1 epinephrine-containing cell group can be found in the RVLM region of the reticular formation. In the CVLM region, caudal to the area postrema and rostral to the pyramidal tract, TH-expressing neurons were localized in a group resembling the A1 norepinephrine-containing cell group in the rat (Fig. 3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This study showed that activation of the RVLM and CVLM in mice
elicits both respiratory and cardiovascular responses that are similar
to those seen in other mammalian species. Encompassed in these
regions are catecholamine-containing neuronal cell groups that are
identified by TH immunohistochemistry (19,
22). The cardiovascular responses elicited from the CVLM
have usually been attributed to noncatecholamine pathways, but the
respiratory responses to CVLM stimulation have not been previously
tested in any species. We found that 2-adrenergic
mechanisms in the RVLM are required for full expression of respiratory
responses from the CVLM of the mouse.
TH, an enzyme that catalyzes the initial rate-limiting step in the
catecholamine biosynthetic pathway, can be used as a generic marker to
identify catecholamine-containing cells (22). If TH immunohistochemistry is used alone, staining patterns do not allow differentiation among dopamine-, noradrenaline-, and
adrenaline-containing cells. However, on the basis of studies
comparing antibodies to TH to dopamine-
hydroxylase (DBH, the enzyme
that converts dopamine to norepinephrine) and
phenylethanolamine-N-methyl transferase (PNMT, the enzyme
that synthesizes epinephrine), the type of catecholamine expressed by
various catecholamine cell groups has been well defined (22). These studies have revealed that TH-immunoreactive
neurons in the RVLM are also immunopositive for PNMT and are usually
considered to be adrenergic. TH-immunoreactive neurons in the CVLM
region (A1 cell group) are DBH positive but PNMT negative and, hence, are noradrenergic cells.
In these studies, the pressure microinjection of L-glutamate was used to evoke responses from localized regions of the ventrolateral aspect of medulla oblongata containing C1 and A1 cell groups. To minimize the limitations of the method employed, the glutamate concentration and volume were carefully limited. The dose used (0.12 nmol/site) was more than 50 times lower than that found to induce depolarization blockade (23). Furthermore, the volume (10 nl/site) was kept below the range capable of reaching cell groups outside the studied regions of the medulla. Previously, Haxhiu et al. (17) found that the radiolabeled drug (4 nmol/80 nl) administered into the RVLM of the rat had diffused <1 mm from the site of injection at the time of peak response. In fact, 90% of the total radiolabeled concentration was recorded within 0.6 mm of the center of the target region. The concentration of the drug declined exponentially as a function of the distance, as was expected from simple diffusion. Full recovery of the injected radioactivity occurred, ruling out any significant leakage into the peripheral circulation (17). Thus it is unlikely that the changes observed after microinjection of drugs into the RVLM or CVLM are due to diffusion of the drugs to distant areas, to local depolarization blockade, or to leakage into the peripheral circulation.
RVLM stimulation caused a rise in f and peak integrated DEMG. In parallel with the respiratory changes, activation of the RVLM caused a concomitant increase in arterial pressure, with a slight but significant acceleration of HR. This cardiorespiratory excitatory area was located rostral to the area postrema, caudal to the facial nucleus, in the region that partially overlaps the ventrolateral portion of the paragigantocellular nucleus, and in the neurons ventral to the compact part of the nucleus ambiguus, including those just beneath the ventral medullary surface. This region contains the neuronal network involved in the generation of respiratory rhythmic activity (11, 31), sympathetic tone (4, 8, 22, 23), and sympatho-respiratory integration (7, 14, 25). Furthermore, this region plays an important role in central chemosensitivity (18, 30) and in mediating vasodepressor effects of centrally acting antihypertensive drugs (10, 17). Taken together, these results indicate that, as in most mammals, the RVLM of the mouse is a site that participates in respiratory and cardiovascular controls (14, 26, 28, 29, 31, 32). The species-related similarities in the cardiorespiratory responses to L-glutamate microinjections into the RVLM suggest that the mouse is an acceptable model for future studies in respiratory and cardiovascular control mechanisms.
Activation of the mouse CVLM invariably caused a decrease in breathing frequency and arterial hypotension, similar to results found in rats (6, 32). Our current findings showed that respiratory depression was entirely due to changes in respiratory timing. This cardiorespiratory depressor region is located at the level of the obex, medial to the spinal trigeminal nucleus, near the caudal lateral reticular nucleus, and ventral to the compact portion of the nucleus ambiguus. As in rats (19, 22), we found that this region of the mouse medulla oblongata also contains A1 norepinephrine-containing cells.
Recently, using subtype-specific antibodies against the two most
prevalent subtypes (A and C) of 2-adrenergic receptors
in the brain, Guyenet et al. (15) found that RVLM neurons
express only 2A- adrenergic receptor-like
immunoreactivity (15). The 2A-adrenergic
receptors are present on neuronal terminals and on neuronal cell
bodies, in which their activation inhibits neurotransmitter release and
mediates hyperpolarization and inhibition of firing rates, respectively
(16). We found that blockade of these receptors in the
mouse RVLM caused a slight increase in f, with no change in BP or HR,
suggesting that these receptors may be tonically activated on
respiratory, but not cardiovascular, neurons. Furthermore, blockade of
2-adrenergic receptors in the RVLM abolished the effects
of CVLM stimulation on respiratory timing.
It has been shown that A1 noradrenergic cells are activated by hypoxic
or hypercapnic loading (9, 19) and by
baroreceptor inputs (1, 2, 5,
13). Recently, Bach et al. (3) found that
oxygen deprivation induces prolongation of expiratory duration that can
be abolished by prior blockade of 2-adrenergic receptors. Conceivably, A1 cell group-activation by oxygen deprivation may have participated in the changes of respiratory timing.
Furthermore, systemic administration of 2-adrenergic
receptor agonists induced a highly dysrhythmic pattern of ventilation
that was characterized by alternating episodes of tachypnea and slow,
irregular breathing patterns, including the disruption of ventilation
and prolonged and variable TE intervals (20).
These changes suggest that 2-adrenergic receptors may
play an important role in the control of central respiratory rhythm,
and reflex activation of noradrenaline-containing neurons may lead to
respiratory dysrythmias.
Blockade of 2-adrenergic receptors in the RVLM did not
modify the vasodepressor response observed in CVLM stimulation,
suggesting that an independent pathway mediates arterial hypotension.
Given the presence of a heavy GABAergic projection from the CVLM to the
RVLM, this pathway may be responsible for cardiovascular changes in
response to CVLM stimulation, as has been previously suggested by
others (5).
In summary, the results obtained in this study indicate that along
the ventrolateral medulla of mice, as in other species, there are
two distinct areas that differentially modulate cardiorespiratory outputs. The RVLM region contains neurons that, when activated, increase respiratory activity and sympathetic outflow, and the CVLM
region possesses respiratory and sympatho-inhibitory cells. In
addition, our results demonstrated that the CVLM has the appropriate connections to produce coordinated changes in arterial pressure and
respiratory timing. Furthermore, our data showed, for the first time,
that 2-adrenergic signal transduction pathways play a
major role in respiratory, but not cardiovascular, changes induced by
activation of the CVLM.
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ACKNOWLEDGEMENTS |
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We thank Dr. Martha J. Miller for reviewing the manuscript and Cecily Lewis for secretarial support.
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FOOTNOTES |
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This work was supported by the Sao Paulo State Research Foundation, and by National Institute of Heart, Lung, and Blood Grant HL-50527.
Address for reprint requests and other correspondence: M. A. Haxhiu, Dept. of Pediatrics, School of Medicine, Case Western Reserve Univ., 10900 Euclid Ave., Cleveland, OH 44106 (E-mail: mah10{at}po.cwru.edu).
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.
Received 26 July 1999; accepted in final form 15 March 2000.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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) electromyographic
activity of the diaphragm (DEMG) and blood pressure (BP)
showing the response to bilateral microinjections of
L-glutamate (0.12 nmol, 10 nl/site). Arrow indicates time
of injections.
