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Constance S. Kaufman Pediatric Pulmonary Research Laboratory, Departments of Pediatrics and Physiology, Tulane University School of Medicine, New Orleans, Louisiana 70112
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Nitric oxide
(NO) is an excitatory neurotransmitter in the hypoxic ventilatory
response (HVR). Furthermore, neuronal NO synthase (nNOS) activity in
the developing rat correlates with the magnitude of late hypoxic
ventilatory depression. To test the hypothesis that repeated short
exposures to hypoxia may modify late HVR characteristics in young rats,
we conducted 30-min hypoxic challenges in 2- to 3-day-old rat pups,
before (Pre) and 6 h after (Post) they completed a series of eight
cycles consisting of 5 min of hypoxia and 10 min of normoxia (Hyp-Norm)
or normoxia throughout (Norm-Norm). In an additional group, similar
challenges were performed after administration of either
intraperitoneal vehicle or 25 mg/kg 7-nitroindazole (7-NI). Ventilation
(
E) was measured using whole body
plethysmography. Although no changes in peak
E responses occurred with
episodic hypoxia (Pre vs. Post,
P = not significant), late
E reductions were markedly attenuated
in Post (
E from early to late: 7.2 ± 1.5 ml/min in Pre vs. 4.5 ± 1.1 ml/min in Post;
P < 0.002). Furthermore, 7-NI
treatment of Post animals was associated with late
E reductions to Pre levels in
Hyp-Norm-exposed animals. Western blots of protein equivalents from the
caudal brain stem revealed increased nNOS expression in Hyp-Norm
compared with Norm-Norm (P < 0.01).
Current findings suggest that repeated short hypoxic exposures improve
the ability to sustain E, which appears
to be mediated by increased nNOS expression and activity in brain stem
respiratory regions. We postulate that changes in nNOS may play a role
in respiratory control plasticity.
biphasic response; respiration; roll-off; peripheral chemoreceptor; brain stem; neural plasticity
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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IN MAMMALIAN SPECIES, the hypoxic ventilatory response (HVR) is the result of an elaborate interplay among multiple mechanisms that are activated on exposure to reduced inspired oxygen concentrations. Such mechanisms differ in their temporal characteristics (onset and duration), dependency on stimulus magnitude, overall effect on neuronal discharge (excitatory or inhibitory), specific effect on particular neuronal populations [tidal volume (VT) vs. frequency], and neurotransmitters and receptors that mediate their effects on ventilation. In this context, the concept of plasticity of respiratory control has emerged and increasingly gained acceptance in recent years. This notion implies that the ventilatory response characteristics to a particular stimulus may be modified by previous experiences with such stimulus, i.e., a memory effect (10).
Periodic isocapnic hypoxia will induce serotonin-dependent increases of phrenic nerve-integrated output in anesthetized vagotomized rats that persist for minutes to hours after the final hypoxic exposure and have been termed long-term facilitation (LTF) (2, 11, 31). It has been postulated that serotonergic raphe neurons mediate LTF because repeated carotid body stimulation induces persistent increases in raphe neuronal activity (33) and stimulation of the raphe elicits LTF of phrenic nerve discharge (30). More recently, Turner and Mitchell (49) have shown the presence of LTF in awake adult goats when imposing a series of 10 cycles consisting of 3-min isocapnic hypoxic exposures separated by 5 min of isocapnic normoxia (49). Interestingly, with advancing stimulus cycles, the HVR was also correspondingly enhanced, suggesting that LTF did not affect hypoxic sensitivity.
When developing rat pups are exposed to hypoxia, a very transient
initial minute ventilation (E) increase
will occur and is followed by E
reductions to levels below those measured in room air conditions (9,
34). We have previously shown that in addition to the neurotransmitters
adenosine (36) and GABA (23, 24), nitric oxide (NO) originating from
neuronal NO synthase (nNOS) activity plays a significant role in this
central inhibitory process (19). Indeed, the late component of the
biphasic HVR is highly correlated with the relative abundance of
nNOS-containing neurons in critical regions mediating the hypoxic
response in developing animals (15), such that reduced NO release and
the resultant constrained ability to sustain
E during hypoxia emerge as immediate
consequences of the developmental pattern of NOS expression within the
dorsocaudal brain stem. A substantial body of evidence indicates that
NO modulates important elements of neural function such as memory
formation and synaptic plasticity (43). In addition, the expression of
NOS genes can be influenced by oxygen tension, such that increased nNOS
expression will occur with tissue hypoxia (13, 42, 44). Thus we
hypothesized that application of repeated intermittent exposures to
hypoxia in developing rats could lead to upregulation of nNOS
expression within neural structures underlying the ventilatory response
to hypoxia and modify the stimulus-response characteristics to induce
ventilatory enhancements during the late phase of HVR.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The experimental protocols were approved by the Institutional Animal Use and Care Committee. Timed-pregnant Sprague-Dawley rats were obtained from a commercial breeder (Charles River), and delivery times were recorded. Only 2- to 3-day-old rat pups were studied because this is a postnatal age during which late hypoxic ventilatory depression is most prominent and nNOS expression in the dorsocaudal brain stem is lowest (15).
Protocol. In a first stage, ventilatory challenges with 10% O2-5% CO2-balance N2 lasting for 30 min were initially performed in each rat pup (Pre). Addition of 5% CO2 to the hypoxic gas aimed to maintain arterial partial pressure of CO2 levels within isocapnia (14). Gas switches were performed by rapidly bleeding the premixed gas mixture into the recording chamber. Animals were then allowed to recover with their dam in room air for at least 3 h and were then subjected to a series of eight cycles consisting of 5 min in 10% O2-5% CO2-balance N2 followed by 10 min in 5% CO2-balance room air (Hyp-Norm). Pups were returned to the litter, and 6 h later, 30-min hypoxic challenges were repeated (Post). As a control group, littermates underwent identical hypoxic challenges before and after eight cycles in which the hypoxic gas was replaced with 5% CO2-balance room air (Norm-Norm).
In a second stage, an additional group of 2- to 3-day-old rat pups underwent an identical protocol except that they received 0.2 ml of a mixture containing either vehicle (1:5 DMSO:saline) or the selective nNOS inhibitor 7-nitroindazole (7-NI, 25 mg/kg ip; Research Biochemicals International, Natick, MA) 6 h after completion of either Norm-Norm or Hyp-Norm cycles. The selected dosage of 7-NI has been previously validated in the rat (6, 14, 22). In a third stage, grouped animals were subjected to an identical protocol as described above, but ventilatory recordings were not measured, and instead animals were euthanized with a pentobarbital sodium overdose for assessment of nNOS expression in the caudal brain stem on completion of the second 30-min hypoxic challenge.Ventilatory recordings.
Respiratory measures were continuously acquired in the freely behaving,
unrestrained animal placed in a previously calibrated 0.5-liter
barometric chamber (Buxco Electronics, Troy, NY) using the methods
described by Bartlett and Tenney (3) and Pappenheimer (40). To minimize
the effect of signal drift due to temperature and pressure changes
outside the chamber, we used a reference chamber of similar size in
which temperature was measured using a T-type thermocouple.
Environmental temperature was maintained within 29-32°C, which
corresponds to usual temperatures recorded in the dam. A calibration
volume of 0.5 ml of air was repeatedly introduced into the chamber
before and on completion of recordings. At least 30 min before the
start of each protocol, animals were allowed to acclimate to the
chamber, in which humidified air (90% relative humidity) warmed at
30°C was passed through at a rate of 2 l/min using a precision flow
pump-reservoir system. Pressure changes in the chamber due to the
inspiratory and expiratory temperature changes (7) were measured using
a high-gain differential pressure transducer (model MP45-1,
Validyne). Analog signals were continuously digitized and analyzed
online by a microcomputer software program (Buxco Electronics). A
rejection algorithm was included in the breath-by-breath analysis
routine and allowed for accurate rejection of motion-induced artifacts.
VT, respiratory frequency, and
E were computed and stored for
subsequent offline analysis.
Immunoblot analysis.
After a pentobarbital sodium overdose, the skull was rapidly opened and
the brain was extracted, immediately placed on dry ice, and surgically
dissected. The obex was visually identified, and a coronal section 1.5 mm caudal to 0.5 mm rostral to the obex was performed. Tissues
corresponding to three to five animals were pooled and homogenized at
0°C with a tissue blender in 20 mM Tris-HCl buffer, pH 7.5, containing 2 mM EDTA, 0.5 mM EGTA, 25 µg/ml leupeptin, 25 µg/ml
aprotinin, and 1 mM phenylmethylsulfonyl fluoride. The homogenate was
centrifuged for 10 min at 1,000 g at
4°C to remove cell debris. To separate soluble and particulate fractions, we performed subcellular fractionation by 1 h of
centrifugation at 30,000 g at 4°C
using a modification of the technique described by Lehel et al. (26).
Supernatants were removed and considered representative of the
nNOS-containing soluble fraction. Protein content was measured in each
soluble fraction using the Bradford method (DC-Biorad protein assay;
Bio-Rad, Richmond, CA), and samples were frozen at 
70°C
until analysis.
Data analysis.
Values are reported as means ± SD unless indicated otherwise. For
ventilatory challenges, early and late responses were assessed as the
average of the first and last 3-min periods of each 30-min challenge,
whereas baseline ventilation was defined as the average of the 3 min
immediately preceding the hypoxic gas switch. Although the initial 3 min of a hypoxic challenge may not always correspond to the peak
E response in a particular animal, they
are primarily representative of the peripheral chemoreceptor-mediated
E component, with little contamination
from central sources, and were therefore selected for comparative
analyses (41). Differences in ventilatory data among Pre and Post
hypoxic ventilatory challenges were compared by paired Student's
t-tests. Differences between vehicle
and 7-NI treatments for Hyp-Norm and Norm-Norm exposures were compared by ANOVA (2-way ANOVA for repeated measures) and the Newman-Keuls test.
To normalize across film exposure times for the various Western blots,
we expressed densitometry readings for each lane as percentage from
corresponding control lysate lane. Unpaired t-tests were then used to compare nNOS
ratiometric density readings in animals undergoing Hyp-Norm cycles vs.
Norm-Norm cycles. A P value <0.05
was considered statistically significant.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Ventilatory measurements.
A prominent biphasic response was present in all pups during Pre runs
(Fig. 1). E
increased during the early stages of hypoxia from 8.4 ± 1.4 to 11.9 ± 2.0 ml/min in control animals and decreased to 5.5 ± 0.9 ml/min at the end of the hypoxic challenge
(P < 0.02). Such responses remained
unaltered in Post when the rat pups were subjected to Norm-Norm (Fig.
1; n = 12). Indeed, the
E differences between early and late
E
(Eearly-late)
in control animals were similar in Pre (6.4 ± 1.4 ml/min) and Post
runs (6.8 ± 1.5 ml/min; P = not
significant). However, when Hyp-Norm cycles were applied,
Eearly-late
were markedly attenuated in Post (7.2 ± 1.5 ml/min in Pre vs. 4.5 ± 1.1 ml/min in Post; n = 12, P < 0.002). The attenuation of late
hypoxic ventilatory depression was primarily mediated by sustained
frequency response, with no significant contribution by
VT
(P = not significant).
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Eearly-late
increased from 3.1 ± 1.0 ml/min in vehicle to 9.0 ± 1.7 ml/min
after 7-NI (P < 0.001).
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Immunoblots of nNOS in caudal brain stem. Western blotting of protein equivalents from the soluble fraction of five different samples derived from pooled caudal brain stem tissue corresponding to a total of 20 rat pups per treatment group revealed increased nNOS expression with Hyp-Norm exposures compared with Norm-Norm exposures (Fig. 3; P < 0.01).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The present study shows that episodic hypoxic exposure of young rat pups does not modify the early component of HVR when assessed 6 h later but markedly attenuates the magnitude of the late hypoxic ventilatory depression. Furthermore, such changes in the late HVR are abolished by pretreatment with the selective nNOS inhibitor 7-NI. In agreement with such findings, we have also found that nNOS expression within the caudal brain stem is significantly increased in Hyp-Norm-exposed pups.
Our ventilatory measurements during both early and late respiratory
responses to hypoxia in Pre conditions are similar to those reported by
previous investigators (9). Although potential errors in ventilatory
measures could have been introduced in the absence of corrections for
body temperature changes, such concerns are alleviated by the presence
of the Norm-Norm control group. In addition, changes in oxygenation may
induce significant alterations in oxygen consumption
(O2) (35), and because
metabolic rates were not specifically measured, we cannot exclude that
Hyp-Norm exposures were not associated with elevated metabolic rates
compared with Norm-Norm. However, this is highly unlikely because
baseline E were similar in Pre and Post
conditions. In addition, thermal conditions were similar before and
after 7-NI administration, such that E
differences during hypoxia after nNOS inhibition are also unlikely to
result from O2 changes.
Nonetheless, because O2 was
not measured, one cannot exclude with certainty that intraperitoneal
administration of an nNOS blocker did not affect the ability to mount a
metabolic response (5), although the absence of any effect on early and
late HVR by 7-NI in the Norm-Norm group argues against such a contention.
To the best of our knowledge, this is the first study demonstrating long-lasting effects of episodic hypoxia on the hypoxic response properties of the respiratory system in developing mammals. It has now become evident that LTF will occur after repeated carotid sinus nerve stimulation in anesthetized cats (12, 31) as well as anesthetized rats (21, 28). There is also evidence that LTF occurs in waking preparations, albeit to a lesser extent than during anesthesia, and that serotonin plays a critical role in LTF (2, 4, 31). On the basis of such previously described relationships between LTF and serotonin and our current findings of nNOS increased expression modulating the late hypoxic depression of developing rat pups, potential colocalization of these two neurotransmitters should be present. Indeed, serotonin and NOS were found to colocalize in 40-60% of neurons within the dorsal raphe nucleus of the rat (50, 51). In addition, the majority of cholinergic and serotonergic neurons in the pons are NOS positive, whereas the immunoreactivity is lower or undetectable in most of the serotonergic, aminergic, and cholinergic neurons in the medulla (8). Thus the ventilatory enhancements reported herein could be attributable to a mechanism such as LTF, in which serotonergic neurons modulate or receive modulatory inputs from NOS-positive cells.
An alternative mechanism that could potentially underlie the attenuation of the late hypoxic ventilatory depression in Hyp-Norm-exposed pups could represent a form of respiratory control conditioning. Indeed, Thomas and colleagues (47, 48) have shown that when perturbations are presented to neonatal rats, long-lasting changes in respiratory patterning will occur and can be readily uncovered during adulthood. More recently, similar classic inhibitory conditioning of ventilation was described for application of a hypercapnic gas mixture as the unconditioned stimulus in adult rats (37), suggesting that similar to other neural networks, the respiratory control network is amenable to marked plasticity changes when conditioning perturbations are applied. However, the experimental protocol applied herein did not follow a typical paradigm from which associative interactions between a conditioning stimulus and a nonconditioning stimulus would be expected to elicit long-lasting conditioned responses.
Pharmacological nNOS inhibition did not modify HVR in Norm-Norm-exposed
rat pups, and this finding is in close concordance with the relative
paucity of nNOS-harboring neurons in brain stem regions mediating the
ventilatory response to hypoxia (15). In contrast, a marked enhancement
of the late hypoxic ventilatory depression occurred in Hyp-Norm-treated
animals, such that E during the last 3 min of the 30-min hypoxic run was similar to that measured before
application of the Hyp-Norm protocol (Fig. 2). This modification of the
HVR in Hyp-Norm rat pups by 7-NI paralleled increases in nNOS
expression within the caudal brain stem. Thus current studies lend
further support to our hypothesis favoring an important role for NO
derived from nNOS in sustaining ventilation during the second or late
phase of the hypoxic response (15, 19).
The relative contributions of the two elements involved in our
experimental paradigm, namely neural tissue hypoxia and increased peripheral chemoreceptor afferent input, remain unclear with respect to
the observed increase in nNOS expression. So far, the gene for nNOS has
demonstrated significant susceptibility to changes in oxygen tension,
and increased nNOS gene expression will occur in central neurons even
after short-lasting hypoxia (20, 29, 42). Hypoxia also induces the
release of glutamate (32); activation of glutamate receptors in
general, and more particularly of
N-methyl-D-aspartate (NMDA) glutamate receptors in brain stem neurons, is critical in
mounting a ventilatory response to hypoxia (27, 38, 46). On opening of
the NMDA receptor channel, intracellular calcium elevation ensues, with
concomitant activation of second messenger systems (16, 39); such
intracellular calcium changes and kinase activation have been shown to
play a critical role in nNOS activation (1, 45). Downstream recruitment
of particular transcriptional regulatory elements during activation of
the NMDA-NO pathway such as nuclear factor-
(18) or AP-1 (17)
could ultimately result in upregulation of specific spliced transcripts
of the nNOS gene (25) and provide the framework for improved functional
adaptations to the hypoxic stimulus.
In summary, the developing rat displays a characteristic biphasic ventilatory response to hypoxia, the late phase of which can be modified by application of episodic hypoxic exposures. Such experimental paradigms elicit significant alterations in nNOS expression within the caudal brain stem and appear to play a preponderant role in the attenuation of ventilatory depression during late HVR.
Perspectives
NOS has emerged in recent years as an important modulator of synaptic plasticity and has been implicated in memory formation and consolidation. In this context, it is possible that early life exposures to environmental stimuli that enhance or diminish nNOS expression may result in long-lasting modifications of the response characteristics of respiratory control networks. The present study opens the door to future research aiming to examine the modulation of synaptic relays, neurotransmitters, and receptor expression by well-controlled paradigms of pre- and postnatal stimulation.| |
ACKNOWLEDGEMENTS |
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We thank Elizabeth Lapeyre and José E. Torres for technical assistance.
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FOOTNOTES |
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This study was supported in part by grants from the National Institute of Child Health and Human Development (HD-01072), the Maternal and Child Health Bureau (MCJ-229163), and the American Lung Association (CI-002-N).
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: D. Gozal, Section of Pediatric Pulmonology, Dept. of Pediatrics, SL-37, Tulane Univ. School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112.
Received 2 June 1998; accepted in final form 1 September 1998.
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Top
Abstract
Introduction
Methods
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Discussion
References
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n = 12) or 5 min of normoxia and 10 min of normoxia (Norm-Norm; 
, n = 12). * P < 0.002 between Hyp-Norm and Norm-Norm treatments.
