The Effect of Sympathetic Denervation on
Cerebral CO2 Sensitivity
BY H. L. STONE, PH.D.,* M. E. RAICHLE, M.D.,f
AND M. HERNANDEZ, PH.D.J
Abstract:
The Effect of
Sympathetic
Denervation
on Cerebral C
Sensitivitv
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• The responsiveness of cerebral blood flow to changes in arterial carbon dioxide tension was
determined in six monkeys following bilateral superior cervical ganglionectomy. Experiments
were conducted 10 to 14 days following the removal of both ganglions using phencyclidine
hydrochloride as the anesthetic agent. Following the initial acute experiments, the animals were
placed in a sealed environmental chamber for five days at an inspired carbon dioxide level of
6%. The responsiveness to carbon dioxide was repeated following the chronic exposure to carbon dioxide. The animal was killed immediately and the brain removed. The major vessels of
the circle of Willis were examined histochemically for the presence of sympathetic nerve fibers.
The results of the study demonstrated that: (1) autoregulation was still present, (2) acute exposure to increased levels of carbon dioxide increased flow, and (3) some adaptation of flow occurred following a chronic exposure to 6% carbon dioxide. The carbon dioxide sensitivity of this
group of animals was found to be 0.37 cm per second mm Hg' 1 as compared to a value of 0.94
cm per second mm Hg"1 for normal animals. The difference in these two values was significant.
It is concluded that the sympathetic nervous system is necessary for the normal responsiveness
to changes in arterial carbon dioxide.
Additional Key Words
autonomic nervous system
cerebrospinal fluid
superior cervical ganglion
chronic carbon dioxide
autoregulation
hydrogen ion
bicarbonate
the cerebrospinal fluid hydrogen ion concentration
and an increase in bicarbonate levels.
The rich innervation of the cerebral vessels with
adrenergic nerve fibers4 led us to question the role
played by these nerves in the response of the cerebral
vessels to carbon dioxide and adaptation to chronic
carbon dioxide exposure. The results of this study indicate that the sympathetic nerves are necessary for
the normal responsiveness of the cerebral vessels to
carbon dioxide. Removal of the superior cervical
ganglion in the monkey reduced the carbon dioxide
sensitivity when compared to a group of normal
animals. Exposure to a chronic carbon dioxide environment led to some adaptation of the carbon dioxide response but the sensitivity did not change a great
deal.
• The responsiveness of the cerebral vessels to
changes in inspired carbon dioxide has been well
documented.1 Reivich2 found a relatively linear
relationship between the change in the arterial level of
carbon dioxide and cerebral blood flow over a range of
arterial carbon dioxide levels from about 30 to 90 mm
Hg. The change in cerebral blood flow per change in
arterial carbon dioxide in this range was found to be
about one. In a previous work,3 we have demonstrated
that the carbon dioxide responsiveness of the cerebral
vascular bed in the monkey was nearly the same as
shown by Reivich over this range of values, and
further that upon chronic exposure to elevated carbon
dioxide levels, an adaptation of the flow would occur.
Cerebral flow decreased at all levels of inspired carbon
dioxide tested following chronic exposure to an environment containing 6% carbon dioxide. The adaptation was found to be associated with normalization of
Methods
*Marine Biomedical Institute, University of Texas Medical Branch
at Galveston, 200 University Boulevard, Galveston, Texas 77550.
tDivision of Neurology, Washington University School of
Medicine, 510 South Kingshighway, St. Louis, Missouri 63110.
JUSAF School of Aerospace Medicine, Brooks Air Force
Base, San Antonio, Texas 78235.
This work was supported in part by NASA NGR 48-088-002.
Portions of this study were presented at the Sixth International
Cerebral Blood Flow Symposium in Philadelphia, Pennsylvania,
June 6 to 9, 1973.
The experiments were conducted on six adult monkeys
(Macaca mulatto) weighing 4 to 6 kg. The animals were
anesthetized with phencyclidine hydrochloride (0.5 mg per
kilogram) and maintained on halothane and oxygen for
sterile surgery. Incisions were made bilaterally from the
angle of the mandible down the neck to approximately the
midcervical region. The superior cervical ganglion was
isolated and removed on each side. Careful inspection was
made at this time to ensure that all of the ganglion was
removed. The external carotid was dissected and ligated on
Stroke, Vol. 5, January-February 1974
13
STONI, RAICHLE, HIRNANDIZ
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both sides of the neck. The left common carotid was dissected in the cervical region and a Dopplerflowprobe placed
around it and anchored in place. At this juncture, a careful
inspection was made of the artery between the flow probe
implantation and the base of the cranium to ensure that all
branches had been tied. The lead wires from the flow probe
were passed ventrally under the skin and buried for future
use.
After a two-week recovery period, the animals were
used in the following experimental protocol. Anesthesia was
accomplished with phencyclidine hydrochloride and the
animal was placed in a supine position. An endotracheal
tube was positioned. The wires from the Dopplerflowprobe
were exposed and connected to appropriate electronics to
record the velocity of blood flow in the carotid artery.5 The
left femoral artery and vein were exposed and cannulated.
The arterial catheter was attached to a Statham P23Db
pressure transducer zeroed to the midchest level of the
animal to measure arterial pressure. The endotracheal tube
was connected to a Harvard respirator with the frequency
and tidal volume adjusted for each animal. Arterial blood
samples were taken before and after the animal was placed
on the respirator to ensure that arterial blood gases were
very near the spontaneous breathing values. Arterial blood
gases were measured on an Instrument Laboratories Model
313 blood gas analyzer, and cerebrospinal fluid values were
determined using a Radiometer gas analyzer.
Cerebral blood flow autoregulation was determined by
changing mean arterial pressure. Pressure was lowered by
the withdrawal of blood very rapidly from the femoral vein
catheter and increased by the infusion of metaraminol.
Arterial pressure and the Doppler flow signal were recorded
on magnetic tape and an X-Y plotter as well as an oscillographic recorder. After obtaining an autoregulatory
curve with the animal breathing room air, the respirator intake was successively connected to a cylinder containing 6%,
9% and 12% carbon dioxide in air. At each level another
autoregulatory curve was obtained. The animal was respired
on each mixture for ten minutes before an arterial blood
sample was taken and the autoregulatory curve determined.
Upon completion of the experiment, a 1-cc sample of
cerebrospinal fluid was obtained from each animal and the
wires from the flow probe were placed beneath the skin
again.
The animals were placed immediately in a sealed environmental chamber for five days. The inspired carbon
dioxide partial pressure was maintained at 42 mm Hg and
the alveolar oxygen pressure was maintained at 100 mm Hg.
At the end of the five-day period, the experimental protocol
given earlier for the acute phase of the study was repeated.
The animals were removed from the chamber breathing
from a bottle containing 6% carbon dioxide and were maintained on this mixture when connected to the respirator. At
the end of this portion of the experiment, a second
cerebrospinal fluid sample was taken and the animal immediately killed. The brain was removed and the major
vessels composing the circle of Willis were taken for the examination of the adventitial layer for the presence or
absence of sympathetic nerve fibers. A histochemical
technique' was used for this purpose.
The data analysis was accomplished from the magnetic
tape record through the use of an analog computer.
Statistical analysis was accomplished on the carbon dioxide
14
sensitivity data using an unpaired t-test for small sample
sizes.
Results
The carotid flow response to changes in mean arterial
pressure and inspired carbon dioxide levels for a
representative animal used in this study can be seen in
figure 1. When the animal was respired on room air
(RA), there was a small change in flow as mean
arterial pressure was changing over a large range. As
the inspired level of carbon dioxide was increased, the
resting flow increased. This can be noticed by following the change in flow at a pressure of 100 or 120 mm
Hg. At each successive level of inspired carbon dioxide, flow changed more with changes in arterial
pressure. At 12% inspired carbon dioxide, flow was
almost a linear function of arterial pressure.
The average response of all six animals used in
the study to change in mean arterial pressure and inspired carbon dioxide can be seen in figure 2. The
average response of the animals demonstrates the
same as that shown for the individual animals.
Constancy of flow was found to be almost lost at the
highest level of inspired carbon dioxide (12%) in each
experiment in what would be termed the physiological
pressure range. At 100 mm Hg mean arterial pressure,
the flow with the animal breathing room air averaged
25 ± 2 cm per second and while breathing 12% carbon
dioxide averaged 38 ± 4 cm per second. More
variability in the response was noted in the animals being respired on 12% carbon dioxide. The changes in
arterial carbon dioxide partial pressure with the
various gas mixtures can be found in table 1. The
average arterial carbon dioxide tension was 41.2 ± 1.9
mm Hg breathing room air, which increased to
12% CO,
ooi20
MAP (
BO
200
220
2«O
noum
Carotid blood flow velocity plotted against changes in mean arterial
pressure in a representative animal. The blood flow response to
respiring on room air(RA) and the various carbon dioxide levels are
shown on the right of the figure, adjacent to the data for that particular level. The curves were taken from the magnetic tape record
and represent the actual mean data.
Stroke, Vol. 5, January-Ftbrvary 1974
SYMPATHETIC DENERVATION
CBFV
(cm/sec)
60r
CBFV
(cm/sec)
50
50
40-
40
30
30
ao
20
10
10
60 r
T
T
12% C0 2
9% COj
6% C02
20
40
60
80
100
MAP
120 140
(mmHg)
160
180
20
FIGURE 2
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Average carotid blood flow velocity
pressure obtained from six monkeys.
figure are the same as given in figure
represent one standard error of the
40
60
80
100
120 140
M A P (mmHg)
FIGURE 3
160
180
Average carotid blood flow velocity plotted against mean arterial
pressure for the same group of animals as used in figure 2. These
curves were obtained following chronic exposure to 6% carbon dioxide for five davs. The symbols at the right of the figure are the same
as used in figure I. The bars through the points represent one standard error of the mean.
plotted against mean arterial
The symbols at the right of the
I. The bars through the points
mean.
69.6 ± 2.2 mm Hg while breathing 12% carbon dioxide.
Following the chronic exposure to 6% inspired
carbon dioxide for five days, the above experiments
were repeated. The average response of flow to change
in mean arterial pressure can be seen in figure 3. Each
animal in this group showed the same response as the
average depicts. The main noticeable feature was the
presence of a range of pressure over which flow
remained fairly constant while breathing 12% carbon
dioxide. Some adaptation of the flow response had occurred in this group of animals. The difference
between the acute and chronic exposure to levels of
carbon dioxide in this group of animals can be seen
better in figure 4. With the chronic exposure to carbon
dioxide, the 6% CO 2 curve appeared as the room air
curve before the chronic exposure. This same trend
was true for the remaining levels of carbon dioxide
studied. A comparison between the cerebrospinal fluid
values for pH and bicarbonate before and after the
chronic exposure can be found in table 1. The increase
in bicarbonate from 22 mEq per liter to 32 mEq per
liter was significant (P < 0.02). It should be noted that
there was not any change in the cerebrospinal fluid pH
value.
The histochemical examination of the major
cerebral vessels revealed that in most of the animals
very few sympathetic fibers could be found when compared to normal animals. It should be emphasized that
in only two of the six animals used in this study was
there a complete lack of any sympathetic fibers. In the
remaining animals very little innervation by the sympathetic system could be found; when it was observed,
it consisted of thin-appearing fibers running in the
adventitia with no varicosities along the length of the
fiber. We have termed this latter appearance as dener-
TABLE 1
Average Arterial Blood Values for Pco2 During Exposure to Various Inspired Carbon Dioxide Levels in
Six Monkeys
Room afr
Arterial blood (mm Hg)
Acute
41.2 ± 1 . 9
Chronic
CSF - pH
Acute
7.31 ±0.01
Chronic
CSF - HCO3- (mEq/liter)
Acute
22.0 ± 1 . 0
Chronic
-
6% CO,
9% CO,
12% CO:
46.7 ± 3.6
53.7 ± 2.1
57.4 ± 1.6
60.7 ± 1.8
69.6 ± 2.2
73.4 ± 3.1
7.30 ± 0.01
32.0
± 1.0
Values are given with the standard error of the mean. The chronic values represent an exposure to 6%
carbon dioxide for five days. The average cerebrospinal fluid (CSF) values are for pH and HCO3~ before and after the chronic exposure.
Stroke, Vol. 5, January-February
1974
15
STONE, RAICHLE, HERNANDEZ
CBFV
(cm/sec)
60r
50
40
30
20
10
20
40
60
80
100
120 140
M A P (mmHg)
160
180
FIGURE 4
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Average carotid blood flow velocity plotted against mean arterial
pressure in all six monkeys. The heavy dark lines represent the
average control data obtained in the animal as given in figure 2. The
lower dark curve represents the room air (RAj control while the
other heavy curves are the 6%, 9%, and 12% carbon dioxide exposures. The symbols at the right of the figure are the same as
shown in figure 3.
vation also. In comparison with other experimental
animals, this would seem to be valid.
The responsiveness of the cerebral vasculature to
change in arterial carbon dioxide levels was determined by taking the flow at 100 mm Hg mean arterial
pressure and plotting this versus the change in arterial
carbon dioxide. The results of this can be observed in
figure 5. The curve labeled control was obtained from
a group of normal animals, 2 while the denervated
curve represents the results from the current group of
experimental animals. It can be readily observed that
cerebral blood flow increased less with an equivalent
increase in arterial carbon dioxide in the denervated
group as compared to the control group. The slope of
these two curves can be termed the sensitivity of
cerebral blood flow to carbon dioxide. The slope of the
control curve was 0.94 cm per second mm Hg"1 while
that from the denervated group was 0.37 cm per
second mm Hg' 1 . The difference between the slope of
these two curves was found to be significantly different
(P < 0.05). The cerebral bed in the denervated group
was less sensitive to arterial carbon dioxide levels than
the cerebral bed of the control group.
Discussion
The major question posed in this study was the role of
the sympathetic nervous system in the cerebral
vascular response to carbon dioxide. Referral to figure
5 clearly demonstrates that the carbon dioxide sensitivity is reduced in the absence of the sympathetic innervation. However, there was still a response to
changes in carbon dioxide. How can this be reconciled
with the other factors known to affect cerebral flow?
Prior to a discussion of the results of this study
16
10
Increase in Arterial
Pco 2 (mmHg)
FIGURE 5
The average increase from resting level of mean carotid blood flow
velocity plotted against the average increase in arterial carbon dioxide partial pressure obtained in a group of normal animals (control)
and the bilaterally denervated group. The slope of the two curves
will be the carbon dioxide sensitivity of the two groups of animals.
one must be sure that the technique used to measure
cerebral flow is valid and measures very little extracranial flow, if any at all. In several animals,
cerebral angiograms were performed to ascertain the
route of any extracranial flow. It was found that the
contrast material visualized the ophthalmic artery
which comprised less than 10% of the estimated total
flow. Acrylic casts have been made in several animals
to anatomically determine the extent of any extracranial contamination. The casts demonstrated the
same results as that found with the angiograms. We
have diligently searched for extracranial flow beyond
the site of our flow probe implantation and have not
been able to find any except a small perforating
branch from the internal carotid in some animals.
Another validation for this inflow technique is the very
close similarity with other data collected using a
different technique.1 Extracranial contamination
would have made the difference extreme because the
extracranial bed does not respond as does the intracranial bed to carbon dioxide. In other experiments
in the monkey7 we compared the response of a carotid
artery approach for measuring cerebral flow to an intracranial flow probe around the middle cerebral
artery. In these animals, we could not find any
difference in the direction of the response to several
stimuli when a comparison was made between the two
probes. For these reasons, the method used in the
current study does measure primarily cerebral blood
flow. Another potential problem area encompasses the
Stroke, Vol. 5, January-February 1974
SYMPATHETIC DENERVATION
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tissue encapsulation of the flow probe in the animal.
How would this affect the results? In many animals we
have found that the tissue encapsulation process is just
about complete in 10 to 14 days. This means that the
fibrotic tissue reaction to the flow probe has reached a
maximum level and will remain stable for the
remainder of the experimental period. Any change in
the cross-sectional area of the vessel will be reflected
in a change in the measured velocity up until this time.
We have not experienced any additional change in
measured velocity or cross-sectional area as determined from angiograms after approximately ten days
and usually not after seven days. Therefore, the
change in the responsiveness of the cerebral vessels
reflects a real change from the resting measurement at
the time of the experiment.
The data obtained in this study clearly indicate
that autoregulation of cerebral flow remains intact but
that the responsiveness of the vessels to carbon dioxide
is reduced. Others have demonstrated similar results8
concerning the intact nature of the autoregulatory
response following denervation in the monkey.
Stimulation of cervical sympathetic nerves has been
demonstrated to produce a vasoconstriction in several
experiments. 9 ' 10 In the latter series of experiments10
the sensitivity to changes in carbon dioxide following
acute denervation was determined and found to increase at arterial carbon dioxide levels greater than 45
mm Hg, which is in contrast to the data presented in
this paper. This difference may be explained by the
lingering presence of norepinephrine in the vessel walls
following the acute sympathectomy. Edvinsson and
co-workers11 have shown that within the first six hours
following sympathectomy, there was no measureable
change in the cerebral blood volume of mice, implying
that the quantity of norepinephrine present in the
vessel walls was not changing greatly. A small increase in flow has been observed with acute sympathectomy,8 implying possible release of some small
amount of neurogenic tone. A reduction in the amount
of norepinephrine at smooth muscle receptor ter-
HYPOTHALAMUS -
t
CRANIAL
- SYMPATHETIC NERVES
± VESSEL
RADIUS
FIGURE 6
Schematic representation of a proposed local control mechanism
for cerebral blood flow regulation. The scheme encompasses the
data obtained in this study. Explanation is given in the text.
Stroke, Vol. 5, January-February 1974
minals would imply that a greater dilation might occur when a stimulus was applied that would normally
interfere with the action of norepinephrine. The
difficulty with acute denervation was circumvented in
the present study by using chronic denervation.
Ten days were used as the period between denervation and the initial experiment. The ability to show
some adaptation to chronic carbon dioxide exposure
might indicate a dual effect of carbon dioxide or
hydrogen ion. This could be directly on the vascular
smooth muscle of the cerebral vessels.
To explain the results obtained in this study a
scheme for the local control of cerebral blood flow is
proposed as shown in figure 6. Assuming adequate
mean arterial pressure, the flow (Q) to any area of the
brain will be determined by the radius of the vessels in
the vicinity. The vessel radius will be acted upon by endogenous change in norepinephrine level from sympathetic nerves and by an inherent ability to make
small changes in radius in response to changes in mean
arterial pressure.12 The local level of norepinephrine
will depend on the degree of activation of the sympathetic nerves in the locality which in turn will be
dependent on some area of the brain stem.13"16 The
assumption is made that there is some tonic level of
sympathetic activity to the cerebral vessels. Some
evidence for this has been obtained in previous
studies.9-16 With unilateral superior cervical sympathectomy, it was shown that the denervated cerebral
vasculature received more flow than the opposite innervated vessels. A local factor that will modulate the
radius of the vessel could be the extracellular fluid
hydrogen ion concentration (BECF-H+) as
demonstrated by Wahl and co-workers.17 As the
hydrogen ion concentration increases, it blocks the
release of norepinephrine (minus sign in fig. 6) and
thus the radius would increase to some new level.18 If
the hydrogen ion decreases in the extracellular fluid,
then the radius would tend to decrease since more
norepinephrine would be present (plus sign in fig. 6).
Carbon dioxide as used in this study would act
through this proposed mechanism by adding to the extracellular fluid hydrogen ion concentration. Brain
metabolism also would change the extracellular fluid
hydrogen ion concentration locally.
The carbon dioxide responsiveness would be
dependent on the hydrogen ion concentration or
something directly related to it such as the number of
smooth muscle receptors for norepinephrine or the
liberation of calcium inside the smooth muscle cell.19
This might explain a dual effect of carbon dioxide as
seen in this study. It would appear that the dominant
effect involves an interaction with the sympathetic nervous system with a secondary direct effect on the
vessels themselves. As suggested by the work of
Stromberg,20 the contribution of various segments of
the cerebral vasculature may change as the
17
STONE, RAICHLE, HERNANDEZ
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physiological condition changes. The role of the
hypothalamic centers in this relationship cannot be
separated since they are part of the system under investigation. Direct stimulation of areas of the
hypothalamus has been shown to affect cerebral flow,
but how this would affect carbon dioxide responsiveness directly is not known at the present time.
In summary, the sympathetic nervous system is
directly involved in determining the cerebral vascular
responsiveness to carbon dioxide. Any change in the
system should affect this responsiveness as shown with
cervical sympathectomy. Response to alteration in
mean arterial pressure did not change. We could not
determine if any change in resting flow had occurred
in comparison with a group of control animals. Loss
of carbon dioxide sensitivity would appear to be
related to the loss of some brain center's effect on
sympathetic tone in the cerebral vessels or the
quantity of norepinephrine present in the wall of the
cerebral vessels.
Acknowledgments
Part of this work was accomplished at the LJSAF School of
Aerospace Medicine with the assistance of Major William
Sears and CMSgt Ken Johnson. The authors wish to express
their appreciation for the use of the sealed environmental
chamber and the assistance rendered by the above individuals.
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Sfroke, Vol. 5, January-February 1974
The Effect of Sympathetic Denervation on Cerebral CO2 Sensitivity
H. L. STONE, M. E. RAICHLE and M. HERNANDEZ
Stroke. 1974;5:13-18
doi: 10.1161/01.STR.5.1.13
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