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1 Department of Physiology, The purpose of the present study was to
determine the effect on breathing in the awake state of carotid body
denervation (CBD) over 1-2 wk after denervation. Studies were
completed on adult goats repeatedly before and
1) for 15 days after bilateral CBD (n = 8),
2) for 7 days after unilateral CBD
(n = 5), and
3) for 15 days after sham CBD
(n = 3). Absence of ventilatory
stimulation when NaCN was injected directly into a common carotid
artery confirmed CBD. There was a significant
(P < 0.01) hypoventilation during the breathing of room air after unilateral and bilateral CBD. The
maximum PaCO2 increase (8 Torr for
unilateral and 11 Torr for bilateral) occurred ~4 days after
CBD. This maximum was transient because by 7 (unilateral)
to 15 (bilateral) days after CBD, PaCO2 was only 3-4 Torr above control.
CO2 sensitivity was attenuated from control by 60% on day 4 after
bilateral CBD and by 35% on day 4 after unilateral CBD. This attenuation was transient, because CO2 sensitivity returned to
control temporally similar to the return of
PaCO2 during the breathing of room air.
During mild and moderate treadmill exercise 1-8 days after
bilateral CBD, PaCO2 was unchanged from
its elevated level at rest, but, 10-15 days after CBD,
PaCO2 decreased slightly from rest
during exercise. These data indicate that
1) carotid afferents are an
important determinant of rest and exercise breathing and ventilatory
CO2 sensitivity, and
2) apparent plasticity within the
ventilatory control system eventually provides compensation for chronic
loss of these afferents.
carotid body denervation; breathing; ventilatory carbon dioxide
sensitivity; exercise hyperpnea
HISTORICALLY, there have been different opinions on the
contribution of carotid chemoreceptor afferents to the control of breathing. One view, that their contribution is minor, is
based largely on the observed small decrease in breathing when
chemoreceptor activity is attenuated acutely by hyperoxygenation (7, 9, 12, 32, 38). Another view of a greater role is based largely on
hypoventilation after surgical carotid body denervation (CBD) (1- 5, 16, 19, 27, 30, 34, 38). In most studies, the effects of CBD have been
assessed immediately after CBD in the anesthetized state (25) or weeks
later in the awake state (1-5, 16, 19, 27, 30, 34, 38). However,
Bisgard et al. (2, 3) studied ponies in the awake state 7 and 14 days
after CBD and found that, during the breathing of room air, arterial
PCO2 (PaCO2) was 18 and 10 Torr,
respectively, above pre-CBD values. These findings indicate a greater
effect on breathing over the first few days after CBD than has been
generally accepted. Because of the paucity of data over this time
period (particularly CO2 sensitivity and the exercise hyperpnea), the purpose of the present study was to determine the effect on breathing in the awake state over
the first 2 wk after CBD. We hypothesized hypoventilation at rest and during exercise and attenuated
CO2 sensitivity over the first few
days after bilateral CBD would be followed by a return of ventilatory
control toward pre-CBD status. Furthermore, because there appears to be
redundancy/plasticity within ventilatory control mechanisms (6, 36), we
hypothesized that breathing at rest and
CO2 sensitivity would not be
altered by unilateral CBD.
Four female and four male castrated adult goats (28-55 kg) were
studied repeatedly before and over 15 days after surgical bilateral
CBD. Five castrated male adult goats (28-35 kg) were studied
before and for 7-10 days after surgical unilateral CBD. Finally,
two female and one male adult goats (35-40 kg) were studied over
15 days after sham bilateral CBD. Goats were chosen for study because
this species is commonly used for studies on the awake state. Goats
were housed in an environmental chamber with ambient temperature and
photoperiod adjusted seasonally. They had free access to hay and water
except for periods of study.
An initial surgery was performed for bilateral elevation of the carotid
arteries. Anesthesia was induced by using ketamine (Ketaset; 15 mg/kg
im). After intubation, the goats were mechanically ventilated and
anesthesia was maintained with 1-1.5% halothane in oxygen. Under
sterile conditions, a 5-cm segment of each carotid artery was elevated
subcutaneously. Two weeks were allowed for the goats to recover from
this surgery before pre-CBD studies were begun.
Details on the CBD surgical procedure have also been presented
elsewhere (31). Briefly, with the head rotated to a supine position, a
midline incision was made. Blunt dissection accessed the carotid
arteries, exposing the carotid bifurcation. One centimeter proximal to
the bifurcation and dorsal to the carotid artery, a bundle of small
vessels carrying the carotid sinus nerve was located. The nerve was
dissected free, ligated at two points, and cut between the two points.
This procedure was completed on both sides for bilateral CBD but only
on one side for unilateral CBD. For sham CBD, the same procedure was
followed except the ligation and cutting were omitted. The incisions
were closed, and the goat was allowed to recover. Ceftiofur sodium (2 mg/kg) was administered daily as an antibiotic for at least 1 wk after each surgery.
At least one carotid artery was catheterized for 1 wk before and 2 wk
after CBD surgery. In addition, a jugular vein was catheterized on 1 day before and after CBD. For most studies, a mask with attached breathing valve was securely taped to the goat's snout. Breathing was
monitored by connecting the valve to a Tissot spirometer that was
connected to a Grass recorder. Arterial blood pressure was monitored by
connecting the arterial catheter to a Statham transducer, which was
connected to the Grass recorder.
One assessment of the carotid (or peripheral) chemoreflex was made by
determining the ventilatory response to intravenous or intra-arterial
bolus injections of NaCN. While the goat was breathing room air, 100 µg/kg of NaCN were rapidly injected into the catheterized jugular
vein. Breathing was continuously monitored, and the response to NaCN
was expressed as inspired pulmonary ventilation ( A second assessment of the carotid chemoreflex was the ventilatory
response to hypoxia. After the control data were obtained, the inspired
O2 for carotid intact goats was
reduced to 12.5% for 20 min. After CBD, inspired oxygen was lowered to
only 13-14%, thus providing the same arterial
PO2
(PaO2) as during the hypoxia in the
intact condition. Breathing was monitored for at least 5 min before and
continuously during the hypoxic period. Duplicate samples of arterial
blood were withdrawn before and between 5 and 7 and between 18 and 20 min of hypoxia.
To assess ventilatory sensitivity to
CO2, inspired
CO2 was increased in 2.5%
increments at 5-min intervals to a maximum of 7.5% (balance room air).
Breathing was continuously monitored, and duplicate samples of arterial
blood were withdrawn over the last 2 min at each
CO2 level.
To assess the effect of CBD on the exercise hyperpnea, arterial blood
was withdrawn (n = 4) while the goats
were standing on a treadmill and then at 15-, 30-, or 60-s intervals
(n = 16) during 4 min of exercise at
1.8 miles/h (mph) and 5% grade and at 1.8 mph and 15% grade. Because
of concern that instrumentation with a mask and breathing valve may
affect the exercise hyperpnea, the goats were not instrumented other
than with the arterial catheter. As in the past, we assessed the
ventilatory response to exercise by the temporal pattern of
PaCO2.
A Ciba-Corning analyzer (model 278) was used for determination of
arterial blood gases and pH. Corrections were made between the
temperature setting of the analyzer and the goat's measured rectal
temperature.
Linear regression analysis was used to compute ventilatory
responsiveness to CO2. ANOVA for
repeated measures was used to determine whether
Effect of CBD on ventilatory response to hypoxia.
Within the first minute of exposure to 12.5% inspired
O2
(PaO2 ~35 Torr),
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
I) between 10 and 30 s postinfusion
divided by I for the minute preceding
the infusion. Three such injections were made (at 5-min
intervals) 1 day before and 1 or 2 days after CBD or sham CBD. In
addition, 1 day before CBD, 1-2 days after CBD, and 7-15 days
after CBD, we also rapidly injected NaCN (10 or 20 µg/kg) individually into one or both catheterized carotid arteries. The response to these injections was expressed as
I for the first five breaths after the
injection divided by the control I.
Three to five such injections were made each day.
I, breathing frequency (f), tidal
volume (VT), PaO2, and
PaCO2 changed significantly during
hypoxia; whether PaCO2 changed
significantly during exercise; and whether arterial blood gases,
acid-base status, blood pressure, heart rate, and CO2 sensitivity changed over days
before and after surgery. Significant (P < 0.05) ANOVA was followed by the
Newman-Keuls post hoc test. Paired
t-tests were used to assess whether
responses to NaCN injections were significantly altered by CBD.
RESULTS
Top
Abstract
Introduction
Methods
Results
Discussion
References
I increased in carotid
chemoreceptor-intact goats (Figs. 1 and
2). I
increased further in the second minute to ~35% above control. Over
the next few minutes, I decreased
insignificantly (P > 0.05) to only
20% above control, with no consistent changes over the remaining
hypoxic period. The hyperpnea was accompanied by a 3- to
4-Torr decrease (P < 0.05) in
PaCO2
(inset, Figs. 1 and 2), and it was a
result of small but insignificant (P > 0.10) increases in both f and
VT (data not shown).
View larger version (22K):
[in a new window]
Fig. 1.
Inspired pulmonary ventilation ( I) before
and during 20 min of hypoxia before (
) and 1-8 (
) and
10-15 (
) days after bilateral carotid body denervation (CBD).
Values are means ± SE of 8 awake goats.
I increased significantly during hypoxia
before CBD (P < 0.05) but not
1-8 (P = 0.09) and 10-15
days (P = 0.08) after CBD.
Inset, group mean values of arterial
blood gases measured at the indicated periods. Room-air blood-gas
values in this inset do not correspond
to Table 1 and Figs. 5 and 8 because the data in this
inset are specific to hypoxia studies,
whereas the data in Table 1 and Figs. 5 and 8 are specific to studies
assessing CO2 sensitivity or
exercise. These 3 protocols were not all completed consistently on the
same day in each animal, which contributes to the variation in arterial
PCO2
(PaCO2) values between Table 1 and Figs
5 and 8. PaO2, arterial
PO2. * Statistically
significant difference from control, P < 0.05.
View larger version (18K):
[in a new window]
Fig. 2.
I before and during 20 min of hypoxia
before () and 1-7 days () after unilateral CBD. Values are
means ± SE of 5 awake goats. I
increased significantly (P < 0.01)
during hypoxia both before and after CBD.
Inset, group mean values of arterial
blood gases measured at indicated periods. * Statistically
significant differences from control,
P < 0.05.
I did not change during the first minute
of hypoxia (Figs. 1 and 2). Thereafter, average
I and
PaCO2 followed a pattern during hypoxia
similar to chemoreceptor-intact goats. However, throughout the 15 days after bilateral CBD, there was no statistically significant
(P > 0.05) change during hypoxia in
I and
PaCO2 (Fig. 1) nor in f and
VT (data not shown). After
unilateral CBD, significant (P < 0.01) hyperpnea and hypocapnia were elicited by hypoxia (Fig. 2), but neither f nor VT changed
significantly (P > 0.10) during hypoxia.
Effect of CBD on ventilatory response to venous NaCN. The ventilatory ratio for the intravenous response to NaCN was reduced significantly (P < 0.01) from 2.81 ± 0.26 to 1.56 ± 0.20 1-2 days after bilateral CBD (Fig. 3). In contrast, this ratio was not significantly reduced (P > 0.05) 1-2 days after unilateral CBD (2.80 ± 0.33 vs 2.60 ± 0.30). For the three sham CBD goats, the average ventilatory ratio was 3.10 and 3.27 before and after surgery respectively.
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Effect of CBD on ventilatory response to carotid artery NaCN.
In intact goats, a 10 µg/kg bolus injection of NaCN into a carotid
artery elicited a hyperpnea within the first breath after the
injection, and the hyperpnea continued for three to five breaths. I over these five breaths was usually
about twice that of control. However, in both the bilateral and the
unilateral CBD goats, there was no significant
(P > 0.10) hyperpnea when NaCN was
injected into a carotid artery where the sinus nerve had been cut (Fig. 4). This lack of response was observed
1-2 and 7-15 days after CBD. In contrast, in the unilateral
CBD goats, injection of NaCN into the carotid artery contralateral to
the denervated side elicited a ventilatory ratio of 1.76 ± 0.12. Finally, the ventilatory ratio for arterial NaCN injection was 1.90 and
1.83 before and after sham CBD, respectively (Fig. 4).
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Effect of CBD during the breathing of room air. There was a significant (P < 0.01) hypoventilation during the breathing of room air over 15 days after bilateral CBD (Fig. 5). In a majority of goats, the hypopnea and hypercapnia were progressive over the first 4-7 days after CBD (Fig. 6). The maximum hypercapnia of 11 Torr above control occurred ~4 days after CBD (Fig. 5). However, beginning about 7 days after CBD, PaCO2 began to return toward control, and, 15 days after CBD, PaCO2 was only increased above control by 3.5 Torr.
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3 concentration (~3.5
meq/l) and in an insignificant decrease in arterial pH (Table
1). In the bilateral CBD
goats, the hypoventilation also significantly
(P < 0.05) reduced
PaO2 from 99 ± 3.8 to 85.7 ± 3.2 Torr (Table 1).
|
Effect of CBD on ventilatory sensitivity to
CO2.
There was a significant attenuation of ventilatory sensitivity to
CO2 [ratio of change in
I to change in
PaCO2
(
I/PaCO2)] for several days after bilateral CBD (Fig.
7). For some goats, this attenuation was
progressive over the first 4-7 days after CBD (Fig. 6). The nadir
for the group in CO2 sensitivity
occurred 4 days after CBD when it was reduced 60% below control (1.55 ± 0.1 vs. 0.65 ± 0.05 l · min1 · Torr1).
About 7 days after CBD, the
I/PaCO2
returned toward control, and 15 days after CBD it did not differ from
control (Fig. 7).
|
I/PaCO2
also decreased from a control of 1.15 ± 0.20 to a nadir of
0.75 ± 0.08 l · min1 · Torr1
2 days after CBD (Fig. 7). This decrease was not statistically significant.
Ventilatory CO2 sensitivity did
not change from control after sham CBD surgery.
Effect of bilateral CBD on exercise PaCO2. Before CBD, PaCO2 did not change significantly (P > 0.10) from rest during mild (1.8 mph and 5% grade) and moderate (1.8 mph and 15% grade) treadmill exercise (Fig. 8) Over about the first 7 days after CBD, PaCO2 increased from rest during exercise in some goats (Fig. 9) and decreased from rest in other goats. As a group, over this period, PaCO2 was ~10 Torr above pre-CBD at rest and during exercise, and PaCO2 did not change from rest to exercise (Fig. 8). Between 10 and 15 days after CBD, PaCO2 was increased from pre-CBD by 5 Torr at rest and 3 Torr during exercise. This 2-Torr difference between rest and exercise was statistically significant (P < 0.05).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The major finding in this study is that CBD results in transient rest and exercise hypoventilation and attenuated CO2 sensitivity over 7-15 days after CBD.
NaCN and hypoxic chemoreception after CBD.
Ventilatory responses to intravenous NaCN and to inhalation of low- or
high-O2 gas mixtures have been the
traditional means of assessing peripheral chemoreception. Accordingly,
all eight bilateral CBD goats of this study had attenuated peripheral
chemoreception after CBD (Fig. 1 and 3). However, there was
considerable variation among goats in this attenuation, and, in seven
of these goats, I responses to
intravenous NaCN were not eliminated by CBD. These CBD goats had
insignificant ventilatory stimulation when NaCN was injected directly
into the carotid arteries at any time up to 15 days after CBD (Fig. 4);
thus the residual peripheral chemoreception was not due to incomplete
CBD or regeneration of responsiveness in the carotid region. This
residual response could be due to
O2-sensing mechanisms recently
shown to exist within several areas of the brain (23, 24). Indeed, with
a 20 µg/kg injection of NaCN into a carotid artery, we often observed
a behavioral response, which suggests a NaCN effect within the
brain. However, in the CBD goats this response did not
elicit a hyperpnea. We therefore believe it likely that aortic
chemoreceptors mediated this residual response, which has been shown to
explain a residual response in CBD ponies (2). In any event, there is
redundancy in hypoxic and NaCN-sensing mechanisms even after bilateral
CBD. Moreover, there is redundancy in carotid chemoreception because unilateral CBD did not significantly alter
I responses to intravenous NaCN
injections.
Carotid chemoreceptor contribution to breathing at rest. As pointed out by Comroe and Schmidt in 1938 (7) and Perkins in 1968 (32), there have been different views on the contribution of peripheral chemoreceptors to breathing at rest. One view is based largely on the finding that, when carotid chemoreceptor activity is transiently attenuated in awake humans or dogs by a few breaths of 100% O2, breathing decreases only ~10% (7, 9, 12, 38). If the hyperoxia is sustained for several minutes, the reduced capacity of hemoglobin to buffer H+, coupled with a slight reduction in cerebral blood flow, results in a slight increase in brain H+ concentration. This acidosis increases intracranial chemoreceptor activity, which offsets the reduction in carotid chemoreception resulting in a restoration of breathing to near normal. These data support the view that carotid chemoreceptors provide only a small portion of the total drive to breathing at rest in the awake state. Or, as stated by Comroe and Schmidt (7) in 1938, the "Carotid body reflexes constitute an accessory mechanism; . . . the control of breathing under ordinary conditions is accomplished entirely by the direct effects of chemical stimuli (mainly CO2) upon the cells of the center." And more recently, in 1997, Donnelly stated that the carotid bodies' "primary mission in life is to detect and respond to hypoxia" (11).
Others have studied the contribution of carotid afferents by altering PO2 and/or PCO2 of blood perfusing the carotid region. Smith et al. (35) found that in awake dogs unilateral perfusion of an isolated carotid artery with hyperoxic (PO2 >500 Torr) or hypocapnic (
7.2 Torr) blood reduced I by
~30%. Fitzgerald et al. (15) found in anesthetized dogs that
bilateral carotid perfusion with hyperoxic
(PO2 >500 Torr) and hypocapnic
(PCO2 <10 Torr) blood reduced I ~24%. Accordingly, these data seem
to suggest a greater contribution of the carotid chemoreceptors to
breathing at rest than indicated by the
high-O2 breathing studies.
Data from CBD studies also suggest an important role of these
chemoreceptors in breathing at rest. For example, in anesthetized cats
in which carotid chemoreceptors had been blocked chemically, bilateral CBD transiently reduced I by
~30% (25). From these data, Katsaros (25) concluded "that carotid
sinus nerves conduct an important respiratory drive which is
independent of chemical and pressure stimuli." Supporting
this conclusion are most studies that have found hypoventilation in
the awake state after CBD in goats, dogs, ponies, rabbits, cats, and
humans (2-5, 16, 19, 21, 27, 30, 34, 37). Most of
these data were obtained at least 2 wk after CBD, when the
hypercapnia at rest ranged between 3 and 12 Torr above pre-CBD.
However, Bisgard et al. (2, 3) found that, in ponies 1 wk after
CBD PaCO2 was 18 Torr above pre-CBD, but 1 wk later and thereafter, PaCO2 was
<10 Torr above control. This latter study suggested time-dependent
changes in breathing at rest after CBD; thus, in the present
study, we focused on the changes that occurred over the first
1-2 wk after CBD.
We have confirmed the previous finding of time-dependent changes in
breathing at rest after CBD. In a majority of both unilateral and
bilateral CBD goats, PaCO2 did not reach
a maximum until the fourth to seventh day after surgery (Figs. 5, 6,
and 9). The maximum values were sustained for a few days, after which
PaCO2 decreased such that by 7 (unilateral) and 15 (bilateral) days after surgery PaCO2 was within 3 Torr of pre-CBD. Most
previous studies on chronic CBD thus did not obtain data during the
period of maximal effects, and therefore these studies underestimated
the contribution of the carotid chemoreceptors to breathing at rest.
Our data do indeed confirm that carotid chemoreceptors provide an
important contribution to ventilatory control mechanisms. These data
support the conclusions of Katsaros (25) and Smith et al. (35) and our
previous conclusion "that the carotid chemoreceptors may influence
breathing through tonic facilitation of medullary centers" (31).
Carotid chemoreceptor contribution to CO2
sensitivity.
There have also been differing opinions on the role of the carotid
chemoreceptor in ventilatory sensitivity to
CO2 (see Ref. 10 for review).
There seems little doubt that carotid chemoreceptor activity and
I increase with hypercapnia and decrease
with hypocapnia. Several studies have shown, however, that the increase
in I with hypercapnia remains after
CBD and that CO2 sensitivity is reduced only 10-40% when measured weeks after CBD (1, 20, 25).
Data from several other studies in which different techniques were used
to separate peripheral and central chemoreception in intact animals
also suggest a modest but definite contribution of carotid
chemoreception to CO2 sensitivity
(1, 10, 32). Mitchell (28) thus proposed a "unified control
theory" whereby the ventilatory response at any stage of respiratory
and metabolic disorders is the algebraic sum of inputs from peripheral
and central H+ chemoreceptors.
1 · Torr1).
However, as with the hypercapnia during the breathing of room air, the
CO2 attenuation was not sustained,
and, by 15 days post-CBD, CO2
sensitivity did not differ from pre-CBD (Figs. 6 and 7). The attenuated
CO2 sensitivity was less in
magnitude and duration in the unilateral compared with the bilateral
CBD goats. Accordingly, these data indicate that carotid afferent
activity has a major influence on ventilatory
CO2 sensitivity that temporally
corresponds with PaCO2 during the
breathing of room air.
Carotid chemoreceptor contribution to the exercise hyperpnea. The mechanism underlying the exercise hyperpnea remains controversial (26). Moreover, there has been a controversy over the role of the carotid chemoreceptors in this hyperpnea (7, 21, 30, 37). However, recent findings suggest that these chemoreceptors do not provide the primary stimulus for the hyperpnea and that their role is to "fine tune" alveolar ventilation to minimize during exercise the deviation of PaCO2 and PaO2 from resting levels (17, 30). The data from the present study are in agreement with this view. Bilateral CBD did not have an effect on the primary exercise ventilatory stimulus, as indicated by the finding that exercise PaCO2 did not significantly change from rest either before or the first week after CBD. In other words, metabolic rate and alveolar ventilation changed from rest proportionally the same during exercise both before and after CBD. There was, however, considerable variation among goats, because some were slightly hypercapnic (Fig. 8), whereas others were hypocapnic during exercise. During the second week after CBD, exercise PaCO2 decreased significantly from rest. Accentuated hypocapnia during exercise has previously been observed after CBD (30), which supports the concept that intact chemoreceptors fine tune alveolar ventilation in addition to their role of tonic facilitation of medullary centers.
Carotid afferent tonic facilitation of medullary centers. Katsaros (25) speculated that the function of a nonspecific, tonic carotid "drive seems to consist mainly in keeping the threshold of the respiratory centers at a low level, so that they can respond more efficiently to the adequate respiratory stimuli, CO2 and H+." In other words, for a period after CBD, CO2/H+ chemoreception per se is probably minimally affected, but the capability of the medullary centers to respond to chemoreceptor input is greatly attenuated.Similarly attenuated are the responses to all stimuli that determine breathing at rest and during exercise. Accordingly, the carotid afferents are not an "accessory mechanism" (7) "primarily responding to low O2" (11), but they provide an important, major input that determines normal ventilatory responsiveness.
The mechanism by which carotid tonic facilitation influences the gain or threshold of medullary centers is speculative. One possibility is suggested by the findings of Hoop et al. (22), who found that CBD in anesthetized dogs decreased glutamate turnover in the medulla during normoxia and increased GABA turnover, particularly during hypoxia. Because neuronal membrane conductances are determined by the balance between glutamate facilitation and GABA inhibition, the net effect of CBD is to reduce neuronal excitability. There also could be a comparable shift in the balance between the density of glutamate and GABA receptors. Such changes in neurotransmitter turnover and/or receptor density would seemingly be time dependent, which could account for the finding that the greatest effect on breathing of CBD is not immediate. Furthermore, the recovery toward normal breathing at rest and CO2 sensitivity was also gradual over days suggesting a time-dependent metabolic or ultrastructural change in medullary neurons. These changes might be inherent to the neurons, or they might result from increased tonic facilitation from other sources, such as the retrotrapezoid nucleus, which appears to serve a tonic facilitatory function in respiratory control similar to carotid afferents (18, 29). Whatever the mechanism, the return of normal function demonstrates a high degree of plasticity in respiratory control mechanisms. Notable is that after bilateral CBD there was considerable intergoat variation in peripheral chemoresponsiveness, but the effect of CBD on breathing at rest and CO2 sensitivity was remarkably consistent over all goats. Moreover, unilateral CBD did not alter peripheral chemoresponsiveness, but it did cause hypoventilation during the breathing of room air and attenuated CO2 sensitivity. These findings suggest a mechanistic distinction between carotid/peripheral chemoresponsiveness and carotid tonic facilitation of medullary centers.Clinical relevance. The data from the present study are relevant to the clinical applicability of carotid body autotransplants in Parkinson's disease. Recently, in a rat model of hemi-Parkinson's disease, Espejo et al. (13) found that autotransplants of carotid body cell aggregates into the rat's substantia nigra nearly abolished motor asymmetries and deficits of sensomotor orientation. These behavioral effects were observed within days after transplants; they were sustained for at least 3 mo, and they were associated with dopamine secretion by the implanted glomus cells. Accordingly, it was concluded that these findings "should stimulate research on the clinical applicability of carotid body autotransplants in Parkinson's diseases." The relevance of the data in the present study is that with such autotransplants there would be only small and transient effects on the control of breathing when one carotid body is eliminated from its normal function.
Redundancy and/or plasticity, as presently demonstrated, is probably a general characteristic of the central nervous system, and, as such, it may underlie recovery from temporary dysfunctions caused by head trauma and other injuries. Careful investigation and documentation of redundancy/plasticity and insights into mechanisms should be useful in the management of neurologically impaired patients.Summary. CBD results for a few days in hypoventilation at rest and during exercise and attenuated ventilatory sensitivity to CO2. These data are consistent with the concept that carotid afferents tonically facilitate medullary respiratory neurons to influence their responsiveness to other stimuli (CO2, exercise, etc.). The hypoventilation and attenuated CO2 sensitivity are transient; thus chronic loss of carotid afferent facilitation appears to be compensated, which emphasizes the plasticity within the ventilatory control system.
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ACKNOWLEDGEMENTS |
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We are grateful for the aid provided by Sue Raschka in preparation of this manuscript.
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FOOTNOTES |
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This research was supported by National Heart, Lung, and Blood Institute Grant HL-25739 and by the Department of Veterans Affairs.
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: H. V. Forster, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226.
Received 17 February 1998; accepted in final form 25 May 1998.
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REFERENCES |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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1.
Berger, A. J.,
R. E. Dutton,
and
J. A. Krasney.
Respiratory recovery from CO2 breathing in intact and chemodenervated awake dogs.
J. Appl. Physiol.
35:
35-41,
1973
2.
Bisgard, G. E.,
D. D. Buss,
H. V. Forster,
J. A. Orr,
B. Rasmussen,
and
C. A. Rawlings.
Hypoventilation in ponies after carotid body denervation.
J. Appl. Physiol.
40:
184-190,
1976
3.
Bisgard, G. E.,
H. V. Forster,
and
J. P. Klein.
Recovery of peripheral chemoreceptor function after denervation in ponies.
J. Appl. Physiol.
49:
964-970,
1980
4.
Bouverot, P.,
V. Candas,
and
J. P. Libert.
Role of the arterial chemoreceptors in ventilatory adaptation to hypoxia of awake dogs and rabbits.
Respir. Physiol.
17:
209-219,
1973[Medline].
5.
Brown, D. R.,
H. V. Forster,
A. S. Greene,
and
T. F. Lowry.
Breathing periodicity in intact and carotid body-denervated ponies during normoxia and chronic hypoxia.
J. Appl. Physiol.
74:
1073-1082,
1993
6.
Busch, G. E.,
M. A. Bisgard,
H. V. Forster,
and
J. E. Mesina.
The effects of unilateral carotid body excision on ventilatory control in goats.
Respir. Physiol.
54:
353-361,
1983[Medline].
7.
Comroe, J. H., Jr.,
and
C. F. Schmidt.
The part played by reflexes from the carotid body in the chemical regulation of respiration in the dog.
Am. J. Physiol.
121:
75-97,
1938.
8.
Davenport, H. W.,
G. Brewer,
A. H. Chambers,
and
S. Goldschmidt.
The respiratory responses to anoxemia of unanesthetized dogs with chronically denervated aortic and carotid chemoreceptors and their causes.
Am. J. Physiol.
148:
406-416,
1947.
9.
Dejours, P.
Control of respiration by arterial chemoreceptors.
Ann. NY Acad. Sci.
109:
682-695,
1963.
10.
Dempsey, J. A.,
and
H. V. Forster.
Mediation of ventilatory adaptations.
Physiol. Rev.
62:
262-346,
1982
11.
Donnelly, D. F.
Are oxygen dependent K+ channels essential for carotid chemo-transduction?
Respir. Physiol.
110:
211-218,
1997[Medline].
12.
Dripps, R. D.,
and
J. H. Comroe, Jr.
The effect of the inhalation of high and low oxygen concentrations on respiration, pulse rate, ballistocardiogram and arterial oxygen saturation (oximeter) of normal individuals.
Am. J. Physiol.
149:
277-291,
1947.
13.
Espejo, E. F.,
R. J. Montoro,
J. A. Armengol,
and
J. Lopez-Barneo.
Cellular and functional recovery of Parkinsonian rats after intrastriatal transplantation of carotid body cell aggregates.
Neuron
20:
197-206,
1998[Medline].
14.
Fencl, V.,
T. B. Miller,
and
J. R. Pappenheimer.
Studies on the respiratory response to disturbances of acid-base balance, with deductions concerning ionic composition of cerebral interstitial fluid.
Am. J. Physiol.
210:
459-472,
1966.
15.
Fitzgerald, R. S.,
R. W. B. Penman,
J. F. Perkins, Jr.,
and
J. T. Zajtchuk.
Ventilatory response to transient perfusion of carotid chemoreceptors.
Am. J. Physiol.
207:
1305-1313,
1964.
16.
Forster, H. V.,
G. E. Bisgard,
and
J. P. Klein.
Effect of peripheral chemoreceptor denervation on acclimatization of goats during hypoxia.
J. Appl. Physiol.
50:
392-398,
1981
17.
Forster, H. V.,
M. B. Dunning,
T. F. Lowry,
B. K. Erickson,
M. A. Forster,
L. G. Pan,
A. G. Brice,
and
R. M. Effros.
Effect of asthma and ventilatory loading on PaCO2 during exercise in humans.
J. Appl. Physiol.
75:
1385-1394,
1993
18.
Forster, H. V.,
P. J. Ohtake,
L. G. Pan,
and
T. F. Lowry.
Effect on breathing of surface ventrolateral medullary cooling in awake, anesthetized and asleep goats.
Respir. Physiol.
110:
187-197,
1997[Medline].
19.
Gautier, H.,
and
M. Bonora.
Effect of carotid body denervation on respiratory pattern of awake cats.
J. Appl. Physiol.
46:
1127-1131,
1979
20.
Gemmill, C. L.,
and
D. L. Reeves.
The effect of anoxemia in normal dogs before and after denervation of the carotid sinuses.
Am. J. Physiol.
105:
487-495,
1933.
21.
Honda, Y.,
S. Myojo,
S. Hasegawa,
T. Hawegawa,
and
J. W. Severinghaus.
Decreased exercise hyperpnea in patients with bilateral carotid chemoreceptor resection.
J. Appl. Physiol.
46:
908-912,
1979
22.
Hoop, B.,
M.-R. Masjedi,
V. E. Shih,
and
H. Kazemi.
Brain glutamate metabolism during hypoxia and peripheral chemodenervation.
J. Appl. Physiol.
69:
147-154,
1990
23.
Horn, E. M.,
and
T. G. Waldrop.
Oxygen-sensing neurons in the caudal hypothalamus and their role in cardiorespiratory control.
Respir. Physiol.
110:
219-228,
1997[Medline].
24.
Jiang, C.,
and
G. G. Haddad.
A direct mechanism for sensing low oxygen levels by central neurons.
Proc. Natl. Acad. Sci. USA
91:
7198-7201,
1994
25.
Katsaros, B.
Evidence for the existence of a respiratory drive of unknown origin conducted in the carotid sinus nerves.
In: Arterial Chemoreceptors, edited by R. W. Torrance. Oxford, UK: Blackwell Scientific, 1968, p. 357-372.
26.
Kaufman, M. P.,
and
H. V. Forster.
Reflexes controlling circulatory, ventilatory, and airway responses to exercise.
In: Handbook of Physiology. Exercise: Regulation and Integration of Multiple Systems. Bethesda, MD: Am. Physiol. Soc., 1996, sect. 12, pt. II, chapt. 10, p. 381-447.
27.
Lahiri, S.,
N. H. Edelman,
N. S. Cherniack,
and
A. P. Fishman.
Role of carotid chemoreflex in respiratory acclimatization to hypoxemia in goat and sheep.
Respir. Physiol.
46:
367-382,
1981[Medline].
28.
Mitchell, R. A.
Cerebrospinal fluid and the regulation of respiration.
In: Advances in Respiratory Physiology, edited by C. G. Caro. Baltimore, MD: Williams & Wilkins, 1966, p. 1-47.
29.
Nattie, E. E.,
J. W. Mills,
L. C. Ou,
and
W. M. St. John.
Kainic acid on the rostral ventrolateral medulla inhibits phrenic output and CO2 sensitivity.
J. Appl. Physiol.
65:
1525-1534,
1988
30.
Pan, L. G.,
H. V. Forster,
G. E. Bisgard,
R. P. Kaminski,
S. M. Dorsey,
and
M. A. Busch.
Hyperventilation in ponies at the onset of and during steady-state exercise.
J. Appl. Physiol.
54:
1394-1402,
1983
31.
Pan, L. G.,
H. V. Forster,
P. J. Ohtake,
T. F. Lowry,
M. J. Korducki,
and
A. L. Forster.
Effect of carotid chemoreceptor denervation on breathing during ventrolateral medullary cooling in goats.
J. Appl. Physiol.
79:
1120-1128,
1995
32.
Perkins, J. F.
The contribution of the peripheral respiratory chemoreceptors to pulmonary ventilation
a historical and experimental aproach.
In: Arterial Chemoreceptors, edited by R. W. Torrance. Oxford, UK: Blackwell Scientific, 1968, p. 335-356.
33.
Schlaefke, M. E.,
J. F. Kelle,
and
H. H. Loeschcke.
Elimination of central chemosensitivity by coagulation of a bilateral area on the ventral medullary surface in awake cats.
Pflügers Arch.
378:
231-234,
1979[Medline].
34.
Smith, C. A.,
G. E. Bisgard,
A. M. Nielsen,
L. Daristotle,
N. A. Kressin,
H. V. Forster,
and
J. A. Dempsey.
Carotid bodies are required for ventilatory acclimatization to chronic hypoxia.
J. Appl. Physiol.
60:
1003-1010,
1986
35.
Smith, C. A.,
K. W. Saupe,
K. S. Henderson,
and
J. A. Dempsey.
Ventilatory effects of specific carotid body hypocapnia in dogs during wakfulness and sleep.
J. Appl. Physiol.
79:
689-699,
1995
36.
Tenney, S. M.,
and
J. G. Brooks III.
Carotid bodies, stimulus interaction, and ventilatory control in unanesthetized goats.
Respir. Physiol.
1:
211-224,
1966[Medline].
37.
Wasserman, K.,
B. J. Whipp,
S. N. Kozal,
and
M. G. Cleary.
Effect of carotid body resection in ventilatory and acid-base control during exercise.
J. Appl. Physiol.
39:
354-358,
1975
38.
Watt, J. G.,
P. R. Dumke,
and
J. H. Comroe, Jr.
Effects of inhalation of 100 per cent and 14 per cent oxygen upon respiration of unanesthetized dogs before and after chemoreceptor denervation.
Am. J. Physiol.
138:
610-617,
1942.
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, group mean responses; all other symbols,
responses of individual goats. Effects of CBD were assessed 1-2
days after surgery. Bilateral but not unilateral or sham CBD
significantly (P < 0.01) attenuated
the response.
