Department of Pediatrics, The Johns Hopkins Children's Center, Baltimore, Maryland 21287
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The O2 sensitivity of carotid chemoreceptor type I cells is low just after birth and increases with postnatal age. Chronic hypoxia during postnatal maturation blunts ventilatory and carotid chemoreceptor neural responses to hypoxia, but the mechanism remains unknown. We tested the hypothesis that chronic hypoxia from birth impairs the postnatal increase in type I cell O2 sensitivity by comparing intracellular Ca2+ concentration ([Ca2+]i) responses to graded hypoxia in type I cell clusters from rats born and reared in room air or 12% O2. [Ca2+]i levels at 0, 1, 5, and 21% O2, as well as with 40 mM K+, were measured at 3, 11, and 18 days of age with use of fura 2 in freshly isolated cells. The [Ca2+]i response to elevated CO2/low pH was measured at 11 days. Chronic hypoxia from birth abolished the normal developmental increase in the type I cell [Ca2+]i response to hypoxia. Effects of chronic hypoxia on development of [Ca2+]i responses to elevated K+ were small, and [Ca2+]i responses to CO2 remained unaffected. Impairment of type I cell maturation was partially reversible on return to normoxic conditions. These results indicate that chronic hypoxia severely impairs the postnatal development of carotid chemoreceptor O2 sensitivity at the cellular level and leaves responses to other stimuli largely intact.
carotid chemoreceptors; maturation; calcium; birth
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
THE CAROTID CHEMORECEPTORS, located bilaterally at the carotid bifurcation, are the major sensors of arterial O2 concentration and are largely responsible for driving the important ventilatory, cardiovascular, and behavioral responses to hypoxia. Functioning carotid chemoreceptors appear to be critically important for survival in the neonatal period. Although carotid denervation is well tolerated by adults (41), newborn mammals deprived of carotid chemoreceptor function just after birth exhibit hypoventilation, abnormal breathing patterns, apnea, and high mortality rates (8, 10, 11, 21).
Despite its importance during postnatal development, carotid chemoreceptor sensitivity to O2 is not mature at birth. Neural activity from the fetal carotid chemoreceptors can be elicited only with extreme hypoxic stimuli, and the response to hypoxia is weak just after birth (4). Over the first few days of life, neonatal carotid chemoreceptor sensitivity to hypoxia increases, requiring weeks or even months in some species to reach full maturity (9, 24, 27). Although the mechanisms are poorly understood, the consensus view is that the fetal carotid chemoreceptors are adapted to the low levels of fetal arterial PO2 (PaO2) and, after birth, reset O2 sensitivity to the approximately fourfold higher PaO2 range seen during postnatal life (5).
The postnatal increase in carotid chemoreceptor O2 sensitivity is dependent on the rise in PaO2 after birth (5, 19), suggesting that postnatal chronic hypoxia could perpetuate the fetal/newborn state of low chemoreceptor O2 sensitivity. Chronic hypoxia from birth has been shown to impair postnatal development of carotid chemoreceptor O2 sensitivity and ventilatory responses to acute hypoxia in all species studied, including humans (12, 16, 23, 25, 33). However, the mechanisms underlying the effects of chronic hypoxia on peripheral chemoreceptor sensitivity are unknown.
The O2-sensing element of the carotid chemoreceptors is believed to be the type I cell, which responds to hypoxia with a rise in intracellular Ca2+ concentration ([Ca2+]i), leading to neurotransmitter release and excitation of apposed carotid sinus nerve (CSN) endings (13). Our previous work on rabbit and rat carotid chemoreceptors showed that [Ca2+]i responses to hypoxia were weak in type I cells from newborns and increased during postnatal maturation (35, 40). Furthermore, maturation of type I cell O2 sensitivity followed approximately the same time course as maturation of carotid chemoreceptor neural responses to hypoxia (24), consistent with the hypothesis that maturation of carotid chemoreceptor function is due, at least in part, to maturation of type I cell O2 sensitivity.
We hypothesized that impaired resetting or maturation of type I cell O2 sensitivity is responsible for the blunting of the postnatal increase in chemoreceptor sensitivity by chronic hypoxia from birth. We tested this hypothesis by comparing [Ca2+]i responses to graded hypoxia in type I cells from rats reared in room air with responses from rats reared in 12% O2. The results indicate that exposure to peri- and postnatal chronic hypoxia abolishes the normal postnatal increase in type I cell O2 sensitivity. Furthermore, impairment of type I cell development appears to be largely specific for hypoxia sensing, and suppression of type I cell maturation is partially reversible on return to normoxic conditions.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Type I cell isolation. Experiments were performed with carotid chemoreceptor type I cells isolated from Sprague-Dawley rats born and raised in normoxia or in a hypoxic chamber. The chamber was maintained at 12% O2 with CO2 removed by a soda lime canister. For chronic hypoxia, pregnant rats were transferred to the hypoxic chamber 1-2 days before delivery and maintained in the chamber up to 3 wk after birth of the pups. Rats in the normoxic and hypoxic groups were killed and studied at 3, 11, and 18 days of age. Glomus cells from seven litters of rats raised in normoxia and eight litters raised in hypoxia were studied. Several pups from two of the litters born into hypoxia were moved to normoxic conditions at 11 days of age and then killed for study at 18 days of age. Data for all other experimental and control groups were obtained from at least three litters (range 3-6 litters).
After rapid decapitation under surgical anesthesia (methoxyflurane), carotid bifurcations were excised and placed in ice-cold PBS. The cell isolation procedure was based on the method described by Buckler and Vaughan-Jones (6). The carotid bodies were dissected free from the bifurcation, cut in half, and placed in a solution containing 0.02% trypsin (Sigma) and 0.1% collagenase type II (Sigma) in PBS with 50 µM Ca2+. The carotid bodies were incubated for 20 min at 37°C, teased apart with forceps, then digested for an additional 5 min. After dispersion by gentle rocking, the tissue was pelleted at 2,000 g for 2 min and then resuspended in a nutritive medium composed of Ham's F-12 (Mediatech) with 10% FCS, 33 mM glucose, 2 mM L-glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, and 0.08 U/ml insulin. The cells were then centrifuged as described above and resuspended in the nutritive medium. Cells were plated on poly-D-lysine-coated coverslips and maintained in a 5% CO2, 37°C incubator. Cells were studiedMeasurement of [Ca2+]i. Type I cells attached to coverslips were loaded with fura 2 by incubation for 8 min at 37°C with 4 µM fura 2-AM (Molecular Probes). Cells were studied on a Zeiss Axiovert microscope with a ×40 Fluar (Zeiss) objective. Fura 2 fluorescence emission was measured at 505-540 nm in response to alternating excitation wavelengths of 340 and 380 nm. Pairs of images were collected every 8 s and stored on a computer using Metafluor (Universal Imaging). A charge-coupled device camera and image intensifier (Videoscope) at constant intensifier and camera gain detected fluorescence. Background images were acquired at the end of each experiment from an area of the coverslip with no cells and subtracted, pixel by pixel, from the experimental images before the calculation of a fluorescence ratio of 340 to 380 nm. In separate experiments, autofluorescence values were measured for type I cells treated in an identical manner but not loaded with fura 2. On our system, autofluorescence was negligible under control and 0% O2 conditions. The fluorescence ratio of 340 to 380 nm was used to calculate [Ca2+]i from
![]() |
Experimental protocol.
Coverslips were mounted in a small-volume (0.2 ml) closed microscope
chamber and perfused at 35°C with a BSS containing (in mM) 118 NaCl, 23 NaHCO3, 3 KCl, 2 KH2PO4,
1.2 CaCl2, 1 MgCl2, and 10 glucose equilibrated
with 21% O2 and 5%
CO2 at pH 7.32-7.36 (normoxic
solution). After baseline
[Ca2+]i
was recorded under normoxic conditions, cells were challenged in random
order to BSS equilibrated with 5%
CO2 and 5, 1, or 0% O2. Cells were also challenged
with 40 mM K+ made from BSS with
equimolar substitution of KCl for NaCl. At 11 days, a subset of cells
was challenged with BSS equilibrated with 15%
CO2 and 21%
O2. Hypoxia and
CO2 challenges lasted 1.5 min, and
challenges with elevated extracellular KCl lasted ~1 min;
[Ca2+]i
responses reached maximum within these time frames. Cells were allowed
to recover in the normoxic perfusate for 5 min between stimuli.
Data analysis.
Baseline
[Ca2+]i
was calculated as the average
[Ca2+]i
over the 1 min before the stimulus and peak
[Ca2+]i
as the maximum value obtained during the 1- to 2-min challenge. Responses were calculated for each cell as the
[Ca2+]i
between the baseline and peak
[Ca2+]i
values. For baseline, peak, and
[Ca2+]i,
data from cells in a single cluster were averaged and treated as one
independent observation. Values are means ± SE;
n refers to number of clusters.
Statistical analysis for age-related effects was performed using ANOVA
with Tukey's honestly significant difference post hoc testing.
Comparisons in the 3- and 11-day age groups between room air and
chronic hypoxia conditions were made using an unpaired
t-test. In the 18-day age group,
comparison between control, chronic hypoxia, and recovery groups was
made using ANOVA with Dunnett's T3 post hoc testing (for unequal
variance). P < 0.05 was considered significant.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Figure 1 shows typical
[Ca2+]i
responses of a type I cell cluster isolated from 11-day-old rats reared
in normoxia (CON) and in chronic hypoxia (CH). In CON clusters, acute
exposure to 0 and 1% O2 induced
significant and consistent increases in
[Ca2+]i
(Fig. 1A). Cell clusters from CH
rats at the same age show only small increases in
[Ca2+]i
in response to acute hypoxia challenge, whereas responses to K+ are largely unaffected by
chronic hypoxia (Fig. 1B).
|
Hypoxia.
The mean
[Ca2+]i
responses of CON and CH type I cell clusters to 0%
O2 at 3, 11, and 18 days are shown
in Fig. 2. Consistent with our previous
work (35, 40),
[Ca2+]i
responses to 0% O2 in the CON
clusters were small at 3 days of age and increased by 11 days of age,
with no further change noted at 18 days. In contrast,
[Ca2+]i
responses of type I cell clusters were significantly smaller in CH than
in CON rats, and there was no age-related increase in the response to
the 0% O2 challenge. Thus chronic
hypoxia blunts the
[Ca2+]i
response as early as 3 days of age and abolishes the normal developmental increase in the
[Ca2+]i
response to hypoxia.
|
|
Elevated extracellular
K+.
Chronic hypoxia abolished the postnatal development of the
[Ca2+]i
response to acute hypoxia. To determine whether this effect was
specific to hypoxia sensing or a nonspecific effect on
Ca2+ influx during depolarization,
the effect of chronic hypoxia on the
[Ca2+]i
responses to other challenges was measured. Elevated extracellular K+ causes depolarization and a
rise in
[Ca2+]i
in type I cells. In all groups studied, the response to 40 mM
K+ was significantly larger than
the
[Ca2+]i
response to 0% O2 (Fig. 1). At 3 days of age, the
[Ca2+]i
responses to 40 mM K+ were 848 ± 87 and 790 ± 70 nM in the CON and CH groups, respectively (not significant). At 11 days of age, the response was statistically significantly less in clusters from CH than in clusters from CON rats:
543 ± 60 and 758 ± 91 nM, respectively
(P = 0.003; Fig. 4). In the 18-day-old group, the
[Ca2+]i
response to elevated extracellular
K+ was reduced by approximately
the same amount in the CH and CON groups (546 ± 94 and 767 ± 129 nM, respectively), but this difference was not statistically
significant (P = 0.052; Fig. 4).
|
Hypercapnia.
Hypercapnic acidosis raises
[Ca2+]i
in type I cells through membrane depolarization and extracellular
Ca2+ entry through voltage-gated
channels (7). The
[Ca2+]i
response to 15% CO2 measured at
11 days showed no difference between the CON and CH groups (Fig.
5). These data show that the type I cell
cluster
[Ca2+]i
response to CO2/acid challenges
was not significantly reduced by chronic hypoxia, contrasting sharply
with the 90% reduction in
[Ca2+]i
response to 0% O2 at this age.
|
Recovery from chronic hypoxia.
To determine whether recovery of the
[Ca2+]i
responses to hypoxia (0 and 1%
O2) occurred, rats raised in
hypoxia until 11 days of age were returned to room air and studied 1 wk
later at 18 days of age (Fig. 3C).
Type I cell clusters from pups allowed to spend 1 wk in room air after
11 days in 12% O2 demonstrated greater
[Ca2+]i
responses to hypoxia than clusters from rats raised in hypoxia for 18 days. By ANOVA, the
[Ca2+]i
responses to 0 and 1% O2 of the
recovery group were intermediate, not statistically different from the
CON or the CH group. Thus the effect of chronic hypoxia on the type I
cell's sensitivity to O2 is at
least partially reversible.
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The major finding of this study is that the normal postnatal increase
in type I cell O2 sensitivity, as
reflected by the
[Ca2+]i
response to graded hypoxia, is abolished by rearing rats in a hypoxic
environment. We previously showed that
[Ca2+]i
responses of carotid chemoreceptor type I cells to hypoxia are weak
just after birth and increase with postnatal age in rabbits (35) and
rats (40) with the same developmental time course as CSN activity (24).
This resetting of carotid chemosensitivity is modulated, at least in
part, by the almost fourfold rise in PaO2
after birth (5), suggesting that type I cell maturation may also be
dependent on postnatal PO2. Our
results demonstrate that in type I cells of rats reared in a low
O2 environment from birth,
sensitivity to hypoxia was significantly reduced, as evidenced by the
remarkably smaller
[Ca2+]i
responses to hypoxic challenges than in type I cells from rats reared
in room air. This novel finding raises the possibility that the level
of PO2 during infancy may regulate
maturation of carotid chemoreceptor sensitivity by regulating the
[Ca2+]i
response to hypoxia of the type I cell. The findings that the type I
cell response to elevated extracellular
K+ remained 75% intact and that
the response to 15% CO2 was not affected by exposure to chronic hypoxia suggest that chronic hypoxia affects a component specific to the
O2 transduction cascade.
Methodological issues.
In studies of developing mammals, in which
[Ca2+]i
responses are low, it is important to ensure that differences between
age groups are due to maturation rather than technical factors that affect cells from immature and mature rats differently. In our previous
study on postnatal development of rat type I cell function, we used the
same cell preparation methods to demonstrate that there were no
age-related differences in
[Ca2+]i
responses to the Ca2+ ionophore
ionomycin from full-term fetal to 21-day-old animals (40). This
suggests that cells from immature and mature rats load and deesterify
fura 2 in a similar manner. Similarly, the CON and CH groups exhibited
large
[Ca2+]i
responses to 40 mM K+ at all ages
(Fig. 4). Finally, the viability of each cell was tested before study
with PI. These results indicate that, under the conditions of study,
observed differences were not due to age-related differences in the
ability to measure or mobilize large
[Ca2+]i
or to poor health of the cells.
Effects of chronic hypoxia on type I cell
[Ca2+]i
responses.
There is controversy concerning the possible effects of chronic hypoxia
on development of carotid chemosensitivity at the O2-sensing, type I cell level.
Using whole cell patch-clamp recording, Hempleman (17, 18) found
reduced K+ and increased
Ca2+ current density in type I
cells from rats exposed to chronic hypoxia (80 mmHg inspired
PO2) during gestation and 5-8 days after birth and suggested that excitability may be increased by
chronic hypoxia. Stea et al. (34) reported increased electrical excitability and Ca2+ mobilization
in type I cells made chronically hypoxic in vitro. However, rats in the
study of Stea et al. were raised in normoxia 5-12 days before cell
harvesting, and, therefore, their model examines the effect of in vitro
chronic hypoxia on cells from rats that matured under normoxic
conditions. Peers et al. (31) studied 9- to 12-day-old rats born and
reared in a 10% O2 environment and found no specific adaptive changes in the properties of type I cell
Ca2+ channels. More importantly,
Wyatt et al. (42), reported that type I cells from normoxic 9- to
14-day-old rats depolarized in response to hypoxia, whereas same-age
rats born and reared in 10% O2
failed to depolarize when exposed to acute hypoxia. These findings
indicated that, whatever the properties of individual ion channels or
electrical excitability of the cell, type I cells from chronically
hypoxic rats did not depolarize in response to acute hypoxia. However,
inasmuch as the source of intracellular Ca2+ and the role of intracellular
Ca2+ stores remain controversial
(29), whether chronic hypoxia affected the ability of the type I cell
to mount a
[Ca2+]i
response to hypoxia was unknown. The results of our hypoxia challenges
are most consistent with the findings of Wyatt et al. that the cells
fail to depolarize, demonstrating a marked blunting of the type I cell
[Ca2+]i
response to acute hypoxia in the CH group.
Recovery from chronic hypoxia. The time course of recovery found in this study may provide further insight into the question of developmental plasticity of type I cell O2 sensitivity maturation. Type I cells from rats reared until 18 days of age in chronic hypoxia showed no sensitivity to acute hypoxia. However, when rats were reared until 11 days of age in chronic hypoxia and then returned to room air, the type I cell sensitivity to hypoxia at 18 days, as measured by the [Ca2+]i response to graded hypoxia (Fig. 3C), had partially recovered. This time course, reaching ~60% of the mature response ~1 wk after return to room air, is similar to that previously reported for type I cell O2 sensitivity maturation after birth (40). These findings strongly suggest that the development of type I cell O2 sensitivity is modulated by PO2 and is, at least to some degree, independent of gestational or postnatal age. In other words, it appears that in the CH group at 11 days of age, once the chronic hypoxia was corrected by returning the litter to room air, the normal maturation increase in type I cell O2 sensitivity was triggered and/or disinhibited. However, Eden and Hanson (12) suggested that rats may eventually reset their peripheral chemoreceptor sensitivity to O2, despite chronic hypoxia (13-15%), on the basis of the finding that CSN recordings from chronically hypoxic 5- to 10-wk-old rats were not different from controls (12). These findings raise several questions with respect to the time course of full recovery, developmental time windows within which full recovery is possible, and the relationship between effects of chronic hypoxia and developmental stage, among others, which require further study.
Conclusions. Chronic hypoxia from birth in vivo up to 18 days of age abolishes the normal postnatal maturation of O2 sensing by carotid chemoreceptor type I cells. The mechanism is unknown, but the effects of chronic hypoxia appear to be at least partially reversible. We speculate that the normal rise in PaO2 at birth is required to promote expression of critically important components in the O2 transduction cascade.
![]() |
ACKNOWLEDGEMENTS |
---|
This work was supported by National Heart, Lung, and Blood Institute Grants K08-HL-03791 (L. M. Sterni) and R01-HL-54621 (J. L. Carroll). We also thank the Mount Washington Pediatric Hospital Foundation (Baltimore, MD) for their generous support.
![]() |
FOOTNOTES |
---|
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: L. M. Sterni, The Johns Hopkins Children's Center, Park 316, 600 North Wolfe St., Baltimore, MD 21287-2533 (E-mail: lsterni{at}welchlink.welch.jhu.edu).
Received 2 October 1998; accepted in final form 13 April 1999.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Beitner-Johnson, D.,
J. Leibold,
and
D. E. Millhorn.
Hypoxia regulates the cAMP- and Ca2+/calmodulin-signaling systems in PC12 cells.
Biochem. Biophys. Res. Commun.
242:
61-66,
1998[Medline].
2.
Benot, A. R.,
and
J. Lopez-Barneo.
Feedback inhibition of Ca2+ currents by dopamine in glomus cells of the carotid body.
Eur. J. Neurosci.
2:
809-812,
1990[Medline].
3.
Bisgard, G. E.
Increase in carotid body sensitivity during sustained hypoxia.
Biol. Signals
4:
292-297,
1995[Medline].
4.
Blanco, C. E.,
G. S. Dawes,
M. A. Hanson,
and
H. B. McCooke.
The response to hypoxia of arterial chemoreceptors in fetal sheep and new-born lambs.
J. Physiol. (Lond.)
351:
25-37,
1984[Abstract].
5.
Blanco, C. E.,
M. A. Hanson,
and
H. B. McCooke.
Effects on carotid chemoreceptor resetting of pulmonary ventilation in the fetal lamb in utero.
J. Dev. Physiol.
10:
167-174,
1988[Medline].
6.
Buckler, K. J.,
and
R. D. Vaughan-Jones.
Effects of acidic stimuli on intracellular calcium in isolated type I cells of the neonatal rat carotid body.
Pflügers Arch.
425:
22-27,
1993[Medline].
7.
Buckler, K. J.,
and
R. D. Vaughan-Jones.
Effects of hypercapnia on membrane potential and intracellular calcium in rat carotid body type I cells.
J. Physiol. (Lond.)
478:
157-171,
1994[Abstract].
8.
Bureau, M. A.,
J. Lamarche,
P. Foulon,
and
D. Dalle.
Postnatal maturation of respiration in intact and carotid body-chemodenervated lambs.
J. Appl. Physiol.
59:
869-874,
1985
9.
Carroll, J. L.,
O. S. Bamford,
and
R. S. Fitzgerald.
Postnatal maturation of carotid chemoreceptor responses to O2 and CO2 in the cat.
J. Appl. Physiol.
75:
2383-2391,
1993[Abstract].
10.
Cote, A.,
H. Porras,
and
B. Meehan.
Age-dependent vulnerability to carotid chemodenervation in piglets.
J. Appl. Physiol.
80:
323-331,
1996
11.
Donnelly, D. F.,
and
G. G. Haddad.
Prolonged apnea and impaired survival in piglets after sinus and aortic nerve section.
J. Appl. Physiol.
68:
1048-1052,
1990
12.
Eden, G. J.,
and
M. A. Hanson.
Effects of chronic hypoxia from birth on the ventilatory response to acute hypoxia in the newborn rat.
J. Physiol. (Lond.)
392:
11-19,
1987[Abstract].
13.
Gonzalez, C.,
L. Almaraz,
A. Obeso,
and
R. Rigual.
Carotid body chemoreceptors: from natural stimuli to sensory discharges.
Physiol. Rev.
74:
829-898,
1994
14.
Grynkiewicz, G.,
M. Poenie,
and
R. Y. Tsien.
A new generation of Ca2+ indicators with greatly improved fluorescence properties.
J. Biol. Chem.
260:
3440-3450,
1985[Abstract].
15.
Hanson, M. A.
Role of chemoreceptors in effects of chronic hypoxia.
Comp. Biochem. Physiol. A. Mol. Integr. Physiol.
119:
695-703,
1998.[Medline]
16.
Hanson, M. A.,
P. Kumar,
and
B. A. Williams.
The effect of chronic hypoxia upon the development of respiratory chemoreflexes in the newborn kitten.
J. Physiol. (Lond.)
411:
563-574,
1989[Abstract].
17.
Hempleman, S. C.
Sodium and potassium current in neonatal rat carotid body cells following chronic in vivo hypoxia.
Brain Res.
699:
42-50,
1995[Medline].
18.
Hempleman, S. C.
Increased calcium current in carotid body glomus cells following in vivo acclimatization to chronic hypoxia.
J. Neurophysiol.
76:
1880-1886,
1996
19.
Hertzberg, T.,
S. Hellstrom,
H. Holgert,
H. Lagercrantz,
and
J. M. Pequignot.
Ventilatory response to hyperoxia in newborn rats born in hypoxiapossible relationship to carotid body dopamine.
J. Physiol. (Lond.)
456:
645-654,
1992[Abstract].
20.
Hertzberg, T.,
S. Hellstrom,
H. Lagercrantz,
and
J. M. Pequignot.
Development of the arterial chemoreflex and turnover of carotid body catecholamines in the newborn rat.
J. Physiol. (Lond.)
425:
211-225,
1990[Abstract].
21.
Hofer, M. A.
Lethal respiratory disturbance in neonatal rats after arterial chemoreceptor denervation.
Life Sci.
34:
489-496,
1984[Medline].
22.
Jackson, A.,
and
C. Nurse.
Dopaminergic properties of cultured rat carotid body chemoreceptors grown in normoxic and hypoxic environments.
J. Neurochem.
69:
645-654,
1997[Medline].
23.
Katz-Salamon, M.,
M. Eriksson,
and
B. Jonsson.
Development of peripheral chemoreceptor function in infants with chronic lung disease and initially lacking hyperoxic response.
Arch. Dis. Child. Fetal Neonatal Ed.
75:
F4-F9,
1996[Abstract].
24.
Kholwadwala, D.,
and
D. F. Donnelly.
Maturation of carotid chemoreceptor sensitivity to hypoxia: in vitro studies in the newborn rat.
J. Physiol. (Lond.)
453:
461-473,
1992[Abstract].
25.
Landauer, R. C.,
D. R. Pepper,
and
P. Kumar.
Effect of chronic hypoxaemia from birth upon chemosensitivity in the adult rat carotid body in vitro.
J. Physiol. (Lond.)
485:
543-550,
1995[Abstract].
26.
Lledo, P. M.,
P. Legendre,
J. Zhang,
J. M. Israel,
and
J. D. Vincent.
Effects of dopamine on voltage-dependent potassium currents in identified rat lactotroph cells.
Neuroendocrinology
52:
545-555,
1990[Medline].
27.
Marchal, F.,
A. Bairam,
P. Haouzi,
J. P. Crance,
C. Di Giulio,
P. Vert,
and
S. Lahiri.
Carotid chemoreceptor response to natural stimuli in the newborn kitten.
Respir. Physiol.
87:
183-193,
1992[Medline].
28.
McGregor, K. H.,
J. Gil,
and
S. Lahiri.
A morphometric study of the carotid body in chronically hypoxic rats.
J. Appl. Physiol.
57:
1430-1438,
1984
29.
Mokashi, A.,
A. Roy,
C. Rozanov,
S. Osanai,
B. T. Storey,
and
S. Lahiri.
High PCO does not alter pHi, but raises [Ca2+]i in cultured rat carotid body glomus cells in the absence and presence of CdCl2.
Brain Res.
803:
194-197,
1998[Medline].
30.
Nurse, C. A.,
and
C. Vollmer.
Effects of hypoxia on cultured chemoreceptors of the rat carotid body: DNA synthesis and mitotic activity in glomus cells.
Adv. Exp. Med. Biol.
337:
79-84,
1993[Medline].
31.
Peers, C.,
E. Carpenter,
C. J. Hatton,
C. N. Wyatt,
and
D. Bee.
Ca2+ channel currents in type I carotid body cells of normoxic and chronically hypoxic neonatal rats.
Brain Res.
739:
251-257,
1996[Medline].
32.
Pequignot, J. M.,
Y. Dalmaz,
J. Claustre,
J. M. Cottet-Emard,
N. Borghini,
and
L. Peyrin.
Preganglionic sympathetic fibres modulate dopamine turnover in rat carotid body during long-term hypoxia.
J. Auton. Nerv. Syst.
32:
243-249,
1991[Medline].
33.
Sladek, M.,
R. A. Parker,
J. B. Grogaard,
and
H. W. Sundell.
Long-lasting effect of prolonged hypoxemia after birth on the immediate ventilatory response to changes in arterial partial pressure of oxygen in young lambs.
Pediatr. Res.
34:
821-828,
1993[Abstract].
34.
Stea, A.,
A. Jackson,
L. MacIntyre,
and
C. A. Nurse.
Long-term modulation of inward currents in O2 chemoreceptors by chronic hypoxia and cyclic AMP in vitro.
J. Neurosci.
15:
2192-2202,
1995[Abstract].
35.
Sterni, L. M.,
O. S. Bamford,
S. M. Tomares,
M. H. Montrose,
and
J. L. Carroll.
Developmental changes in intracellular Ca2+ response of carotid chemoreceptor cells to hypoxia.
Am. J. Physiol.
268 (Lung Cell. Mol. Physiol. 12):
L801-L808,
1995
36.
Tatsumi, K.,
C. K. Pickett,
and
J. V. Weil.
Attenuated carotid body hypoxic sensitivity after prolonged hypoxic exposure.
J. Appl. Physiol.
70:
748-755,
1991
37.
Vizek, M.,
C. K. Pickett,
and
J. V. Weil.
Increased carotid body hypoxic sensitivity during acclimatization to hypobaric hypoxia.
J. Appl. Physiol.
63:
2403-2410,
1987
38.
Wang, J.,
M. Juhaszova,
L. J. Rubin,
and
X. J. Yuan.
Hypoxia inhibits gene expression of voltage-gated K+ channel -subunits in pulmonary artery smooth muscle cells.
J. Clin. Invest.
100:
2347-2353,
1997
39.
Wang, Z. Z.,
B. Dinger,
S. J. Fidone,
and
L. J. Stensaas.
Changes in tyrosine hydroxylase and substance P immunoreactivity in the cat carotid body following chronic hypoxia and denervation.
Neuroscience
83:
1273-1281,
1998[Medline].
40.
Wasicko, M. J.,
L. M. Sterni,
O. Bamford,
M. H. Montrose,
and
J. L. Carroll.
Resetting and postnatal maturation of oxygen chemosensitivity in rat carotid chemoreceptor cells.
J. Physiol. (Lond.)
514:
493-503,
1999
41.
Whipp, B. J.,
and
S. A. Ward.
Physiologic changes following bilateral carotid-body resection in patients with chronic obstructive pulmonary disease.
Chest
101:
656-661,
1992[Abstract].
42.
Wyatt, C. N.,
C. Wright,
D. Bee,
and
C. Peers.
O2-sensitive K+ currents in carotid body chemoreceptor cells from normoxic and chronically hypoxic rats and their roles in hypoxic chemotransduction.
Proc. Natl. Acad. Sci. USA
92:
295-299,
1995[Abstract].