Vol. 278, Issue 6, R1391-R1400, June 2000
INVITED REVIEW
Mechanisms regulating hypoxic respiratory depression during fetal
and postnatal life
John M.
Bissonnette
Departments of Obstetrics and Gynecology and Cell and
Developmental Biology, Oregon Health Sciences University, Portland,
Oregon 97201-3098
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ABSTRACT |
Selected topics in the respiratory
response to acute hypoxia in the fetus and newborn are reviewed.
Peripheral chemoreceptors acting through ionotrophic glutamate
receptors play an important role in affecting the initial augmentation
phase. Whether fall off in peripheral chemoreceptor activity
contributes to the secondary depressive phase remains controversial. A
number of approaches including permanent electrolytic and reversible
cooling lesions, Fos protein activation, and double-labeling
immunohistochemistry has converged to show that an area in and around
the locus ceruleus in the rostral pons affects the central depression.
There is evidence that this is mediated by catecholamines acting at
2-adrenergic receptors. Tonic activity in early
expiratory (postinspiratory) neurons may contribute to hypoxia-induced
apneic episodes in the fetus and newborn. Desensitization of
-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors has
been demonstrated in respiratory-related neurons both in vivo and in
vitro. The role that this process might play in the depressive phase of
the hypoxic ventilatory response has not been established. In
vitro experiments with isolated brain stem-spinal cord preparations or
transverse brain stem slices usually involve anoxia, whereas whole
animal experiments use 8-15% O2. Therefore, caution
must be exercised in attempting to construct a unifying framework from
these two approaches.
biphasic ventilatory response; control of respiration; fetal
breathing movements
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INTRODUCTION |
NEARLY FIFTY YEARS AGO Cross and co-workers
(24, 25) demonstrated that both term and preterm infants exposed to an
acute hypoxic environment show an initial increase in minute
ventilation that, after the second minute, declined toward baseline in
term and below baseline in preterm neonates. Twenty years later, in unanesthetized fetal sheep, it was observed that acute hypoxia resulted
in an immediate decline in breathing movements, usually to apnea (15).
The mechanisms underlying this hypoxic respiratory depression in the
fetus and newborn have received a large amount of attention in
subsequent years and have been the subject of a number of comprehensive
reviews (7, 26, 43, 71, 75, 78, 88, 100). The present paper is an
attempt to review selected aspects of this topic that have appeared
recently and/or received less emphasis in the past. Except where
contributions from work in adults address unique aspects, the review is
confined to the fetus and newborn. In addition, only the response to
short-term (5-15 min) hypoxia is reviewed.
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INTEGRATED RESPONSE TO HYPOXIA |
Figure 1 is a composite of a number of
studies in various species at early postnatal and juvenile stages of
development. All show an initial increase in minute ventilation
(
E) followed usually within 1 or 2 min by
a relative decline. These two components of the biphasic response to
hypoxia are usually termed the augmentation or first phase and the
depressive or second phase, respectively. Two common features are seen
across species: the initial augmentation in
E is less, relative to the baseline
value, at the earlier postnatal ages, and the magnitude of the later
depressive phase (whether expressed relative to baseline or as the
difference between the augmentation level and that observed in the
depressed phase) declines with advancing age. In situations in which
the level of inspired oxygen has been varied, usually between 0.14 and
0.06, the augmentation phase has been greater at the lower
fractional inspired oxygen
(FIO2) level (17, 18, 31,
61, 67, 103). The increase in
E during the augmentation phase results
from a combination of a rise in tidal volume and respiratory frequency.
In general, during the depressive phase, tidal volume falls to a
greater extent than frequency, and in some instances, respiratory rate
continues near the level reached during augmentation (18, 31, 67). In
preterm human infants, however, a decline in respiratory frequency is
the major contributor to the depression seen in the later stages of the
hypoxic challenge (24, 86). These studies in infants were carried out
at an FIO2 of 0.15. In
neonatal rats, Eden and Hanson (31) have shown that at this degree of
hypoxia, the depressive phase is characterized by a decline in
frequency, whereas at lower fractional oxygen concentration, tidal
volume plays a larger role. Thus the observations in
humans may be related to oxygen concentration. The differences in
response to hypoxia during the augmentation and depression phases seen
in Fig. 1 are probably not related to species differences. Rather, they
most likely represent the relative maturity of the respiratory center
at the time of birth. Thus 1- to 5-day-old rats and cats resemble
preterm humans, and 7- to 8-day-old monkeys resemble 14- to 15-day-old
rats and cats.
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Fig. 1.
Maturation of hypoxic ventilatory response in various species. Data
represent minute ventilation expressed relative to baseline for
augmentation and depression phases. Fractional inspired
O2 (FIO2) used
for hypoxic study. Figure is a composite of a number of studies in
human (24, 25, 86, 90, 91), rat (31, 42), cat (67), monkey (103), and
sheep (18).
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In fetal sheep, the majority of studies have used a design in which
arterial oxygen saturation is reduced from its baseline value of
>60% to levels <30%. Koos and co-workers, using the hourly incidence during which breathing movements were present as the index of
respiratory drive, showed no change with saturation reduced to 45% and
then a progressive linear decline at saturations of 37 and 28% (59).
More detailed analysis at fetal O2 saturation of 33%
showed no change in either amplitude or frequency in the residual fetal
breathing (94). Rurak and Cooper (93) employed an alternate design in
which fetal oxygen tension was raised by having the ewe breathe 50%
O2 in N2 and then room air. Making allowances
for the time lag for the changes to occur in fetal arterial oxygen
tension, the results are qualitatively similar to those seen in the
newborn. Whereas there was no change in respiratory rate, amplitude
increased for ~2 min and then declined to baseline. Thus under
conditions nearer those used for the neonate, the fetal integrated
responses to hypoxia are similar. To place the depressive phase in
context, a brief discussion of the augmentation phase is indicted.
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AUGMENTATION PHASE |
In newborn sheep (17) and rats (37), carotid body denervation
eliminates the augmentation phase of the hypoxic ventilatory response,
indicating the prominent role of peripheral chemoreceptors. Activity of
carotid chemoreceptors in fetal sheep increases on exposure to hypoxia
(13), suggesting that the failure to show an augmentation phase is not
due to immaturity of peripheral afferents. The sensitivity of neural
responses of the carotid chemoreceptors to hypoxia increases with
postnatal age in cat (20, 65, 102), sheep (13), and term infants (19).
This maturation of the response to hypoxia has also been demonstrated
in rat carotid body in vitro (53). The mechanisms underlying this
resetting of the carotid body chemoreceptors have been reviewed (22,
44, 47). To examine the central processing of carotid body afferents, Lawson and Long (64) compared phrenic neural activity responses to
electrical stimulation of the carotid sinus nerve in piglets age
1.5-11 days to those 19 days and older. The phrenic equivalent of
E (peak phrenic neuronal activity × frequency) showed a sustained increase that was not different during
the 60-s carotid sinus nerve stimulation in these two age groups. There
was, however, a difference in the components of minute output. The
younger animals showed a decline in frequency coupled with an increase
in peak phrenic activity, whereas the older piglets increased frequency for 10 s, but then it returned to baseline level. This response at both
ages is different from the integrated response to hypoxia, in which
both frequency and tidal volume increase during the augmentation phase. In adult rat and cat, it has been shown that the
caudal hypothalamus modulates the respiratory response to hypoxia (see Refs. 48 and 49 for recent reviews). The excitatory output from this
area takes place in the absence of input from the carotid sinus nerve.
If similar suprapontine responses to hypoxia are present in the
newborn, this may explain the difference between carotid nerve
stimulation and the augmentation phase of the integrated hypoxic response.
Studies to determine the central neuronal groups to which carotid
afferents project and the neurotransmitters involved in the
chemoreceptor reflex have been primarily carried out in adult animals.
Erickson and Milhorn (33) used immunohistochemical double labeling to
identify rat brain stem neurons, which were activated by hypoxia or
electrical stimulation of the carotid sinus nerve. Fos protein
expression was induced in catecholaminergic neurons in the
ventrolateral medulla oblongata and the dorsal vagal complex as well as
the locus ceruleus and A5 cell group in the pons. Activity was seen in
serotoninergic neurons in the nucleus raphe pallidus, nucleus raphe
magnus, and along the ventral medullary surface. Fos-like
immunoreactivity also appeared in a number of regions, including the
lateral parabrachial and Kölliker-Fuse nuclei, but there, cells
did not colocalize for either catecholamines or serotonin.
Microdialysis has been used to demonstrate, in unanesthetized rats,
that hypoxia induces an increase in extracellular glutamate in the
caudal nucleus of the solitary tract (NTS) during the increase in
E (69). These studies were extended to
show that 1) after carotid body denervation, there was neither
glutamate increase nor hyperpnea; 2) NTS glutamate injections
increased E, and the broad-spectrum
excitatory amino acid antagonist kynurenate reduced the hypoxic
ventilatory response (69); and 3) kynurenate application
reduced the activation of NTS neurons induced by carotid sinus nerve
stimulation (104). In anesthetized rats, more specific antagonists have
shown that both the N-methyl-D-aspartate (NMDA) and
non-NMDA subtypes of glutamate ionotropic receptors mediate the
increase in phrenic burst amplitude evoked by hypoxia (23). The
increase in burst frequency, however, was not changed by application of
these antagonists to the phrenic motor nucleus. In contrast, systemic
administration of an NMDA antagonist to unanesthetized rats markedly
blunted the hypoxic ventilatory response by reducing the frequency
rise, whereas tidal volume was unaffected (79). Afferents from the lung
also play a role in the pattern of respiratory response during the
augmentation phase. In awake sheep (12-18 days of age) with
vagotomy, breath frequency was little affected by hypoxia due to an
inability to shorten expiratory time (28). Tidal volume in
these experiments did increase so that the overall response matched
that of intact sheep.
Although carotid chemoreceptor and pulmonary afferents input play an
important role in the augmentation phase of the hypoxic ventilatory
response, in vitro studies have demonstrated a biphasic pattern in
neonatal brain stems. These in vitro studies are generally carried out
with anoxia, in which O2 is completely replaced by N2 so that the mechanisms responsible for changes in
neuronal function may not be the same as that seen in intact
unanesthetized preparations subjected to an
FIO2 of 0.08-0.15. In
an isolated neonatal rat brain stem preparation, anoxia resulted in a
transient resting membrane potential depolarization of inspiratory neurons, which was followed by a hyperpolarization (88). Mironov and
Richter (68) have extended these observations in 4- to 12-day-old mice
using medullary slice preparations to show that hypoxia induced glutamate release, acting at postsynaptic metabotropic receptors, activates L-type Ca2+ channels. Blocking
L-type Ca+ channels eliminated the augmentation phase of
the hypoxic response. The in vitro preparations have also been shown to
have a developmental pattern in the response to hypoxia. In transverse
brain stem slices, which contain the hypoglossal nerve rootlets,
hypoxia results in an initial increase in the frequency of rhythmic
bursts for early neonatal mice [postnatal day 0-7
(P0-P7)], whereas older mice (P8-P22) demonstrated an increase in
both frequency and amplitude (84). Thus the in vitro
preparation shows some of the developmental changes observed in intact
preparations (see Fig. 1 in which E in
rat is greater at P7-P10 compared with P3-P5). In this same transverse brain stem slice preparation, whole cell patch recordings from inspiratory neurons (defined by discharging in phase with hypoglossal rootlet activity) have shown that during augmentation, the
amplitude of synaptic drive potentials increased in slices from mice
older than P8. In contrast, slices from P0-P4 mice showed no
change in drive potential during anoxia (85).
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DEPRESSION PHASE |
A number of mechanisms have been put forward to explain the secondary
or depression phase of the hypoxic ventilatory response in the newborn,
some of which apply to the hypoxic respiratory depression seen in the
fetus. These include a time-dependent decrease in carotid body
stimulation, a time-dependent increase in cerebral blood flow with
central carbon dioxide washout, a time-dependent decline in metabolic
rate and therefore CO2 production, changes in pulmonary
mechanics, and depression in respiratory-related central neurons
affected either or both by neurotransmitters or neuromodulators or by
membrane properties of the neurons involved (43, 71-73, 75, 88,
101). In this section, emphasis is placed on the role of the peripheral
chemoreceptors, the site(s) of central neuronal inhibition, the
reciprocal inhibition by early expiratory (postinspiratory) neurons,
and the role of catecholamines, and of adenosine.
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PERIPHERAL CHEMORECEPTORS |
The contribution of the peripheral chemoreceptors to the depressive
phase of the hypoxic ventilatory response has been considered from two
aspects. 1) Does the afferent output from the carotid body in
particular decline over a similar time span as the drop off in
E, and 2) are carotid body
afferents necessary to evoke the depression of central neurons.
Different results have been reported in experiments examining the
temporal response of the carotid sinus nerve to hypoxia. In
pentobarbital sodium anesthetized cats, both Marchal et al. (65) and
Carroll et al. (20) showed a time-dependent decline in chemoreceptor
function in animals <10 days of age. The timing of the decline was
somewhat shorter than that observed to reach the peak increase in
minute volume in unanesthetized cats of the same age (67) from a
separate study. In contrast, Blanco et al. (14), also using
pentobarbital sodium, found that carotid chemoreceptor discharge
reached a peak at the same time as the peak rise in
E and remained elevated, whereas minute
volume decreased primarily by a decrease in respiratory
frequency. Studies in piglets between P1 and P20 support a
role for declining carotid afferents in the depression phase. The
unsustained response to hypoxia was found more often in younger piglets
(74) and occurred over a similar time course as the decline in
E shown in this species in a separate
study (63). Carroll and Bureau (21) used breaths of 100%
O2 to assess chemoreceptor function during hypoxia
(FIO2 = 0.08) and found that
in 2- to 3-day-old lambs, it was reduced after 15 min of hypoxia but
not at 7 min. Older lambs (10-11 days) showed no decline in the
response to hyperoxia.
Fetal sheep studied with carotid denervation and vagotomy became apneic
with hypoxia (60) similar to intact animals. The onset of the apnea,
however, was delayed compared with fetuses with intact chemoreceptors,
suggesting that these afferents play a role in the respiratory
depression. In chemodenervated 4-day-old lambs, there was little
depression when breathing 0.07 O2, again supporting a role
of the carotid body (17). In neonatal rats, however, a depression phase
characterized by declines in both peak integrated phrenic activity and
respiratory frequency was seen in animals with bilateral sectioned
carotid sinus nerves (37). Thus whether carotid body input is essential
for the expression of the depressive phase has not been unequivocally established.
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SITE(S) THAT MEDIATE CENTRAL RESPIRATORY DEPRESSION |
In 1983, Dawes and co-workers demonstrated that transverse section of
fetal sheep brain stem at the upper pons or midcollicular altered the
response to hypoxia (27). In place of the expected respiratory depression, often to apnea, these transected fetuses showed
an increase in both respiratory frequency and breath amplitude measured
from a tracheal pressure catheter. This hyperpnea was maintained for
the 10-min hypoxic challenge. Martin-Body and Johnston (66), in
unanesthetized (5-10 day old) rabbits, showed that this result was
not confined to the fetus. Transected (at the midbrain-pontine
junction) animals showed a maintained stimulation of
E during 15 min of exposure to 7%
oxygen, which was characterized by an increase in both frequency and
tidal volume. Gluckman and Johnston (41) used electrolytic lesions in
fetal sheep to localize the site that mediates the hypoxic depression
to the region of the upper lateral pons at, and slightly rostral to,
the sensory and motor nuclei of the trigeminal nerve. Walker and
associates have further established the importance of the dorsolateral
pons by examining Fos immunoreactivity as an index of neuronal activity in hypoxic fetal and newborn (7-18 day old) sheep.
An area just ventral to the medial parabrachial nucleus near the
Kölliker-Fuse nucleus, which they have termed the subceruleus
nucleus (Fig. 2) was shown to be unique in
that hypoxia induced Fos immunoreactivity in fetal but not newborn
sheep (16). This suggests that this area may be important for the more
profound hypoxia-induced respiratory depression in the fetus.
Interestingly, in newborns with carotid body denervation, hypoxia
resulted in Fos immunoreactivity in the subceruleus consistent with the
proposal that in neonates, peripheral afferents inhibit neuronal
activity in this area. The ventilatory response, however, is not
supportive in that chemodenervated newborn sheep show little depression
to hypoxia (17). The interpretation is complex in that these animals
also fail to have a significant augmentation. Nitsos and Walker (76)
have further defined the function of the subceruleus neurons that are
Fos immunoreactive by demonstrating that 1) they are
catecholaminergic, but not cholinergic or GABAergic, and 2)
cholera toxin B conjugated to colloidal gold particles demonstrated
that a proportion of them project to the C5-C8 ventral horn. In 3- to 8-day-old sheep, cooling in the area of the locus ceruleus prevented
hypoxic depression (70). In an exacting experimental protocol, Koos et
al. (55) transected the brain stem (at varied locations between the
rostral midbrain and the pontomedullary junction), and, after these
fetal sheep had been shown to increase the rate and amplitude of
breathing during hypoxia, they were chemodenervated at a second
surgical procedure. Hypoxia no longer stimulated breathing after
removal of carotid and aortic afferents. These experiments add
considerably to the conclusion that the fetus has intact peripheral
chemoreceptors whose excitatory activity during hypoxia is suppressed
by central mechanisms. These results were confirmed by Johnston and
Gluckman (50) using a similar two-stage protocol, in which electrolytic lesions in the rostral lateral pons were followed by chemodenervation. It should be pointed out that these brain stem transection and rostral
lateral pontine lesion preparations in fetal sheep disrupt the normal
respiratory pattern. Under basal conditions, the lesioned fetuses have
a respiratory frequency of 15-20 per minute, less than one-third
that of intact sheep. Hypoxia increases frequency to 30-40 breaths
per minute, a value still below the eupneic level of intact animals
(27, 41, 50, 55). This alteration in eupneic respiratory rate was not
seen in unanesthetized neonatal rabbits transected at the
midbrain-pontine junction (66).
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Fig. 2.
Hypoxia induced Fos immunoreactivity in fetal and newborn sheep. Line
drawings of sections through rostral pons of a sheep fetus
(left) and a newborn sheep (right). Each dot represents
a Fos-immunoreactive cell nucleus. Note area below and lateral to locus
ceruleus (LC) that shows hypoxia-induced Fos reactivity in fetus but
not in newborn. MPB, medial parabrachial nucleus; SC, subceruleus; KF,
Kölliker-Fuse; DTN, dorsal tegmental nucleus; MLF, medial
longitudinal fasciculus; SCP, superior cerebellar peduncle; LPB,
lateral parabrachial nucleus; MCP, middle cerebellar nucleus; TZ,
trapezoid body. [Reprinted from Brain Res 748, Breen S, Rees
S, and Walker D, Identification of brainstem neurons responding to
hypoxia in fetal and newborn sheep, p. 107-121, 1997, with
permission from Elsevier Science (16)].
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Whereas considerable emphasis has been placed on the rostral lateral
pons, a number of areas rostral to the pons has also been implicated in
affecting hypoxic respiratory depression. Building on the work of
Gallman and co-workers (39) in adult cats, Waites et al. (99) made
electrolytic lesions in the red nucleus of decerebrate rabbits
(28-35 days old) and observed that bilateral (but not unilateral)
lesions abolished the depressive phase of the hypoxic ventilatory
response. These studies were extended to show that neuronal stimulation
with nanoliter volumes of glutamate interrupted rhythmic phrenic
discharge (Fig. 3) (1). In addition, with
the use of midbrain slices, it was shown from extracellular recordings
that neurons within the red nucleus increase their firing rate when
O2 is reduced from 95% to 45% in the artificial cerebrospinal fluid (CSF) bathing the slice (1). In fetal sheep, hypoxia did not cause Fos immunoreactivity in the red nucleus, although
some was seen ventral to it (77). More recently, ibotenic acid has been
used to lesion neuronal populations in the diencephalon of fetal sheep
(56). This approach has the advantage of leaving fibers of passage and
vascular supply more intact than with thermal destruction. The
parafascicular nuclear complex in the thalamus was identified as a site
mediating the hypoxic ventilatory depression in sheep fetuses (56). In
contrast to brain stem-transected and rostral lateral pons-lesioned
sheep fetuses, these thalamic-lesioned animals had respiratory
frequencies nearer to intact animals [47 ± 12 breaths/min vs.
70 ± 7 (SE)], but hypoxia insignificantly reduced frequency and
amplitude compared with the increases seen in the more caudal lesions
or transections (see above). As with the red nucleus, no increase in
Fos immunoreactivity was observed after hypoxia in this parafascicular
nucleus region (77). These results indicate that, in contrast to the
dorsal lateral pontine sites, the thalmic region does not receive
excitatory input from peripheral chemoreceptors during hypoxia.
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Fig. 3.
Effect of glutamate injection within red nucleus on phrenic neurogram
in neonatal rabbit. At stimulus, 10 nl glutamate (10 mM) were injected.
[Reprinted from Respir Physiol 110, Ackland GL, Noble R, and
Hanson MA, Red nucleus inhibits breathing during hypoxia in neonates,
p. 251-260, 1997, with permission from Elsevier Science (1)].
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NEUROTRANSMITTERS AND NEUROMODULATORS MEDIATING THE DEPRESSION PHASE |
A number of both classical neurotransmitters and neuromodulators have
been put forward as important mediators of hypoxic respiratory depression in the fetus and newborn. Opioids, nitric oxide, and substance P show evidence of their roles and have been reviewed along
with other effectors (7, 75, 88, 95). In this section, the involvement
of catecholamines acting at 2-receptors and adenosine at
A1 receptors will be considered. The demonstration that
rostral lateral pontine (subceruleus) neurons implicated in respiratory depression in the fetus are catecholaminergic (see above) underscores the interest in this neurotransmitter. Systemic infusions of the 2-adrenergic-receptor agonist clonidine inhibited the
incidence of breathing in fetal sheep (3), and this was blocked by the antagonist idozoxan. The site of action for clonidine was further localized by administering clonidine into a lateral cerebral ventricle. These infusions reduced the incidence of breathing by 66%, and the
duration of breathing episodes was less than one-half that seen in the
control period (4). Systemic and lateral ventricular infusions of
2-adrenergic antagonists did not affect fetal breathing, indicating that these receptors are not tonically active under eupneic
conditions (2, 3). The importance of
2-adrenergic-receptor activation during hypoxia in the
fetus was studied during antagonist infusions into the lateral cerebral
ventricles. These experiments showed that in contrast to infusions of
CSF, fetal breathing was maintained in the 30-min hypoxic challenge
(2). Similar to brain-transected or pontine-lesioned fetuses, breath
amplitude was significantly augmented during hypoxia. These studies in
fetal sheep have been confirmed with systemic infusions of a combined 1- and 2-adrenergic-receptor antagonist
that prevented hypoxic respiratory depression (40). In vitro newborn
rat brain stem preparations, in which solutions bathing the pons can be
isolated from those bathing the medulla, have shown that
norepinepherine increases cervical root burst frequency when it acts at
the pontine level (34). In contrast, norepinepherine slows burst
frequency when it is applied to the medulla, and
2-adrenergic-receptor antagonists blocked this
depression. Studies in brain stem slice preparations from 18- to
32-day-old rats revealed that 2-adrenergic agonists
produce hyperpolarization in hypoglossal motoneurons by decreasing the
amplitude of a hyperpolarization- activated inward current (80).
Hypoxia has been shown to result in membrane hyperpolarization of most
respiratory neurons in the ventral respiratory group of neonatal rat
isolated brain stem preparations (88). In slice preparations from
neonatal mice, however, depolarization is seen in only a minority of
inspiratory neurons (85). In the brain stem preparation experiments
(88), removal of chloride from the whole cell patch pipette did not
affect the change in membrane potential, suggesting that hypoxia was
activating potassium channels. Activation of
2-adrenergic receptors stimulates K+
currents (96), which indicates that their role in hypoxic inhibition may involve multiple cellular mechanisms. Taken together, these observations are consistent with an important function of
2-adrenergic receptors in the depression phase of the
hypoxic ventilatory response.
Adenosine has been shown in the fetus and newborn to fulfill a number
of the criteria used to establish a significant role for a
neuromodulator in physiological functions. Adenosine A1 receptors are present in respiratory related regions of the brain stem
of fetal sheep (12). During the moderate hypoxia, which results in an
inhibition of the incidence of fetal breathing, microdialysis from
probes placed in the midbrain showed a 2.3-fold increase in perfusate
adenosine concentration (57). Adenosine or its analogs
administered either systemically or into the fourth cerebral cerebral
ventricle causes respiratory depression in newborns and fetuses (9, 58,
62), which can be overcome with adenosine-receptor blockade. In
addition, the hypoxia-induced depression can be abolished or attenuated
with these xanthine derivatves in both intact fetus (8) and newborn
(32, 92) and in isolated neonatal brain stem-spinal cord preparations
(52). Adenosine can inhibit neuronal activity by pre- and postsynaptic
mechanisms (97). Recordings from hypoglossal motoneurons in neonatal
rat brain stem slices demonstrated that adenosine-receptor agonists
decreased the amplitude of glutamate-evoked excitatory postsynaptic
potentials (EPSPs) (5), indicating a presynaptic mode of action. In
these same studies, adenosine did not change hypoglossal neuronal input
resistance or membrane potential, consistent with a lack of
postsynaptic activity. Similar approaches were used to examine the
effect of adenosine on phrenic motoneurons in an in vitro isolated
brain stem-spinal cord preparation (29). Adenosine analogs
significantly decreased the frequency of spontaneous and of minature
EPSPs. These compounds, however, had no effect on phrenic input
resistance, and the inward currents produced by exogenous glutamate
also were unaffected, indicating a lack of postsynaptic effects. More
recently, adenosine neuromodulation has been studied in vitro in the
rostral ventrolateral medulla of neonatal rats (46). The type of
respiratory-related neuron was identified by the temporal relationship
of its membrane trajectory with activity in the cervical four (C4)
rootlet. Adenosine resulted in an slowing of burst rate from C4 and a
shortening of discharge duration in inspiratory neurons. Whole cell
recordings of inspiratory neurons revealed that neither membrane
potential nor input resistance were changed by adenosine; however,
spontaneous postsynaptic activities were decreased, indicating
a presynaptic mode of action. In contrast, expiratory neurons
responded to adenosine with a hyperpolarization of their membrane
potential and a reduction in input resistance. These membrane property
changes persisted in the presence of tetrodotoxin to block synaptic
activity consistent with postsynaptic action of adenosine on expiratory
neurons (46). Interestingly, C4 discharge continued, albeit at a slower
rate, despite expiratory neuron silencing (see RECIPROCAL
INHIBITION IN THE RESPIRATORY NETWORK). In juvenile rats,
recordings from CA1 neurons of the hippocampus demonstrated that an
adenosine A1 antagonist prevented the hypoxia-induced depression of
excitatory postsynaptic potentials (51).
Adenosine-receptor blockade during hypoxia did not, however, eliminate
hypoxia's depression of inhibitory potentials. In addition,
synaptic inhibition during the inspiratory phase persists in expiratory
neurons in the presence of adenosine (46). Therefore, this
neuromodulator does not account for all the cellular changes seen with hypoxia.
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RECIPROCAL INHIBITION IN THE RESPIRATORY NETWORK |
Models of the respiratory network include reciprocal inhibition, in
which the onset of activity in postinspiratory (or early expiratory)
neurons is associated with inhibition of inspiratory neurons (6, 30,
35, 36, 87). In this framework, it can be hypothesized that apnea seen
in the fetus and newborn is triggered or maintained by tonic activity
in postinspiratory neurons, leading to a long-lasting inhibition of
inspiration. Support for this suggestion is seen in a record from an
expiratory neuron in an isolated neonatal rat brain stem preparation.
The neuron was hyperpolarized by the electrode before hypoxia. During
the 4-min period of anoxia, the membrane potential gradually
depolarized and a prolonged train of action potentials was seen (Fig. 5 in Ref. 88). Recording from pre-Botzinger area neurons, which resemble in vivo postinspiratory neurons, Ramirez et al. (85) found, at
P0-P4, that there was hyperpolarization during the expiratory phase. The hyperpolarization usually seen during hypoglossal bursts in
these neurons was lost in the depressive phase of the hypoxic response
and replaced by a depolarization, indicating relative loss of
inhibition. In older mice, in which apnea developed during the
depression phase, expiratory neurons, however, are hyperpolarized and
inactive (85). The loss of inhibition, seen in expiratory neurons of
younger mice, supports the suggestion made in fetal sheep that hypoxia
results in tonic activity of expiratory neurons.
Recordings from expiratory neurons during hypoxia have not been made in
fetal sheep. Simultaneous recordings of electromyograms (EMG) from the
diaphragm and thyroarytenoid muscle (TA), however, indicate that the
latter may be an index of the activity in postinspiratory neurons (10,
45, 54). In eupnea, when phasic TA EMG activity is seen, it has an
onset concordant with the arrest of diaphragmatic EMG and its activity
stops well before the next diaphragm burst. Hypoxia, both isocapnic and
hypocapnic, has been shown to induce tonic activity in TA of fetal
sheep both during the expiratory pauses that precede apnea and during
the apnea itself (10). In newborn lambs (P0-P3), TA EMG
activity is seen in the apneic episodes induced by breathing 100%
O2 for 5 breaths after 6 min of 8% hypoxia (82). Unlike in
the fetus, this tonic TA activity was only seen in hypocapnic hypoxia.
In older lambs (P11-P18), tonic expiratory activity was seen in
the TA in the apneic episodes that occurred on returning the animals to
room air after a hypoxic episode (81). Thus, whereas they are not as
compelling as electrophysiological recordings from defined
postinspiratory neurons, these results using TA muscle activity as an
index of central neuronal activity suggest that expiratory neurons may
play a role in hypoxic respiratory depression in the fetus and newborn.
The differences between the unanesthetized whole animal and in vitro
reduced preparations may be related to relative hypoxia compared with anoxia.
| |
DESENSITIZATION IN EXCITATORY AMINO ACID RECEPTORS |
As discussed in AUGMENTATION PHASE, glutamate is the
principal neurotransmitter mediating the afferent input from peripheral chemoreceptors in the augmentation phase of the hypoxic ventilatory response. The
-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) subtype
of non-NMDA inotropic glutamate receptor studied in single neurons or
excised membrane patches has been shown to rapidly desensitize in the
presence of ligand (83, 98). AMPA receptors are desensitized by
steady-state glutamate concentrations (EC50 = 5-10
µM) much lower than that necessary for activation of the receptor
(83, 98). With the use of microdialysis to determine interstitial
concentrations in the area of the nucleus ambiguous, Richter et al.
(89) have recently measured changes in glutamate during hypoxia in
anesthetized adult cats. Samples were determined at 1-min intervals and
showed an almost 10-fold rise from baseline levels of 9.5 µM in the
first minute. If the kinetics for desensitization in respiratory
neurons are similar to those determined in chicken spinal neurons (98)
and nucleus magnocellularis (83), then a high proportion of AMPA
receptors would be in the desensitized state, leading to a loss of
excitability. Cyclothiazide, a drug that blocks AMPA desensitization,
has been used to examine this question in medullary slices from 1- to
4-day-old rats and in unanesthetized fetal sheep. Cyclothiazide
increased both the frequency and amplitude of hypoglossal rootlet
bursting in slice proportions (38). Voltage-clamp whole
cell recordings from hypoglossal motoneurons in these preparations
demonstrated that inward current was enhanced in the presence of
cyclothiazide. In fetal sheep, instillation of cyclothiazide into the
CSF of the fourth ventricle resulted in an increase in both amplitude and frequency of fetal breathing (11). The latter result suggests that
under in vivo conditions, the steady-state interstitial concentrations of glutamate render a portion of AMPA receptors in the desensitized state. It is not unreasonable to suggest that hypoxia-induced increases
in glutamate would lead to further desensitization of these excitatory receptors.
Whereas ligand-induced desensitization of AMPA receptors may contribute
to hypoxic respiratory depression in other areas of the medulla, there
is evidence that this process does not have an effect in the NTS.
Low-frequency stimulation at 5 Hz for 5 min of the solitary tract in
transverse brain stem slices from 3- to 21-day-old rats is
characterized by a rapidly developing loss of EPSP amplitude.
Excitability in NTS neurons declines to less than one-half the
prestimulus level (105). Whereas the NTS neurons in this study were not
identified as respiratory, the time course of their depression fits
very well with the changes in E seen in
intact preparations. Zhou et al. (105) considered AMPA-receptor
desensitization as a mechanism for this decrease in EPSP amplitude, but
cyclothiazide failed to reverse the process. Because the hypoxic
ventilatory response in the fetus and newborn has not been examined in
the presence of cyclothiazide, the role of AMPA-receptor
desensitization at this time remains undetermined.
| |
CONCLUSIONS |
The understanding of the mechanisms underlying the hypoxic ventilatory
response continues to evolve. There is considerable evidence that
central mechanisms, especially in the fetus, overcome the excitatory
input from peripheral chemoreceptors, resulting in respiratory
depression. A goal for future investigation is to determine whether
these central mechanisms result from hypoxic activation of discrete
neuronal populations that exert an active inhibition or from loss of
reciprocal inhibition leading to tonic activation of expiratory neurons.
| |
ACKNOWLEDGEMENTS |
I thank Drs. C.-S. Poon and D. W. Walker for making manuscripts
available before publication and Keri Stepper for the preparation of
the manuscript.
| |
FOOTNOTES |
Work from the author's laboratory has been supported by the National
Institutes of Health, Medical Research Foundation of Oregon, and
American Lung Association.
Address for reprint requests and other correspondence: J. M. Bissonnette, Rm. 822B, Medical Research Bldg., L-458, Oregon
Health Sciences Univ., Portland, OR 97201-3098 (E-mail:
bissonne{at}ohsu.edu).
| |
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ABSTRACT
INTRODUCTION
