11-182
Effect of Selective Denervation of
Baroreceptors on Pulmonary Ventilation and
Arterial Pressure Lability in Rat
Helder Mauad, Mogens L. Glass, and Benedito H. Machado
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Earlier studies report that sinoaortic baroreceptor denervation (SAD) in rats causes moderate
elevation of mean arterial pressure along with a marked increase of arterial pressure lability
(APL). In this context, we studied the effects of selective aortic denervation (AD) or selective
carotid denervation (CD) on the regulation of blood pressure. In addition, we evaluated the
effects of selective or total baroreceptor denervation on pulmonary ventilation and ventilationrelated changes of arterial pressure. Mean arterial pressure was evaluated by computerassisted techniques, and ventilation was measured by whole body plethysmography on
conscious freely moving rats. With this approach, equal increases of mean arterial pressure
were obtained for rats that had undergone AD, CD, and SAD. The APL was higher in SAD rats
than in selectively denervated rats. CD and AD rats had an elevated APL relative to
sham-operated animals, and its increase was approximately equal for the two selectively
denervated groups. Total as well as selective denervation had relatively small effects on
ventilation and on the general pattern of breathing. In all groups, this pattern consisted of
regular ventilation, periodically interrupted by single deeper breaths. In SAD, AD, and CD
animals, these larger tidal volumes were associated with marked transient reductions of mean
arterial pressure, whereas small decreases of pressure occurred in sham-operated rats. The
results indicate that both groups of baroreceptors must be present to keep mean arterial
pressure at its normal level. Moreover, both receptor groups are equally important in reducing
APL. Ventilation contributes to generation of APL after total or selective baroreceptor removal.
Such ventilation-induced pressure changes are kept at a minimum in baroreceptor-intact rats.
(Hypertension 1992;19[suppl U]:U-182-n-186)
T
he fine regulation of blood pressure in healthy
mammals involves fast-responding aortic and
carotid baroreceptors that provide information to the central nervous system.1 Removal of these
receptors (sinoaortic deafferentation, SAD) causes
moderate elevation of blood pressure2"3 accompanied
by a marked increase of arterial pressure lability
(APL).2~5 The generation of this lability is ascribed
to a complex of factors that have not been completely
evaluated. Earlier studies have not reported on the
effects on APL of selective aortic denervation (AD)
or selective carotid denervation (CD) of the baroreceptors. In the present study, we sought 1) to assess
From the Department of Physiology, School of Medicine of
Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Sao
Paulo, Brazil.
Supported by Fundacao de Amparo a Pesquisa do Estado de
Sao Paulo grants 87/2227-6, 88/2522-0, and 90/0913-2. H.M. was a
recipient of Coordenadoria do Aperfeicpamento do Pessoal do
Ensino Superior fellowship (Brazil).
Address for correspondence: Benedito H. Machado, PhD, Department of Physiology, School of Medicine of Ribeirao Preto,
University of Sao Paulo, 14.049, Ribeirao Preto, Sao Paulo, Brazil.
the effects of selective denervation on mean arterial
pressure and its lability, 2) to evaluate the effects of
such denervation on the pattern of pulmonary ventilation, and 3) to study the involvement of ventilatory
events in the generation of mean APL.
The inclusion of ventilation measurements was
motivated by a study reporting CD- and SADinduced changes in the breathing pattern of infant
rats.6 Moreover, observations by Krieger7 on rats
that had undergone SAD suggested that some
changes in mean arterial pressure could be ventilation related. Consequently, the present study focuses on the influences of both selective baroreceptor denervation and of pulmonary ventilation on
mean arterial pressure and its lability.
Methods
Male Wistar rats (250-300 g) were instrumented
with chronic arterial and venous catheters. To monitor arterial pressure, the abdominal aorta was cannulated via the femoral artery (PE-10 connected to a
PE-50, Clay Adams, Parsippany, NJ.). In addition,
Mauad et al
Selective Denervation of Baroreceptors
11-183
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FIGURE 1. Bar graph shows mean arterial pressure after sinoaortic denervation (SAD), selective
aortic denervation (AD), and carotid denervation (CD). Respective sham-operated groups are
also indicated. *p<0.05 in relation to shamoperated group. Mean values±SEM; see Table 1
for n values.
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the femoral vein was cannulated for drug injection.
SAD and selective CD or AD were performed as
described by Krieger.7 With rats under ether anesthesia, a ventral midline incision followed by muscle
retraction exposed the vagus, superior cervical ganglion, superior laryngeal nerve, and carotid bifurcation. Selective AD involved resection of the superior
cervical ganglion and the superior laryngeal nerve.
Selective CD required stripping of all fibers from the
carotid sinus and subsequent painting with 10%
phenol in ethanol solution to remove all baroreceptor
afferents. Complete SAD required a combination of
both denervation procedures. To assure complete
recovery of rats from anesthesia, a postsurgical period of 24 hours preceded experimentation. The
efficacy of SAD was tested just before study. Rats
were accepted for study if they presented bradycardia
of less than 24 beats per minute in response to an
intravenous phenylephrine injection (3-5 /ig/kg).
Arterial pressures were monitored with a Statham
pressure transducer (P23Db) connected to a fourchannel recorder (model 7754A, Hewlett-Packard
Co., Palo Alto, Calif.). Mean arterial pressure was
obtained from pulse pressure by means of a Bioelectric Amplifier (model 8811 A, Hewlett-Packard) with
an analog-to-digital interface to a Monydata-XT microcomputer. To obtain APL, sampling of individual
pressure points was performed at a frequency of 1 Hz
over a period of 30 minutes.2-3 APL was expressed as
the standard deviation of the mean of all sampling
points. Statistical evaluation of APL requires a special approach as applied by Alper et al2 and Jacob et
al,3 because the standard deviation (the index for
measurement of lability) does not fit a normal distribution, which precludes analysis by parametric statistics unless prior transformation is performed. Accordingly, the data were submitted to logarithmic
transformation before further analysis. The differences between means of standard deviation were
CD
evaluated using the Newman-Keuls test with the level
of significance at/><0.05.
Ventilation was measured by means of whole body
plethysmography using the approach of Malan,8
which is based on monitoring of small pressure
changes within a closed animal chamber. During
inspiration, a gas volume is heated from ambient to
body temperature, which increases total pressure
within the chamber. Conversely, expiration decreases
total pressure. A highly sensitive differential pressure
transducer (Statham PM 979) connected to the recorder was applied for these measurements. For
further details of the method and calculations, see
Malan.8
Experiments were performed on three groups of
animals: those that had undergone SAD (SAD rats),
AD (AD rats), or CD (CD rats). Sham-operated
animals were provided separately for each group.
Results
The mean arterial pressures of SAD, AD, and CD
rats were virtually the same and significantly elevated
when compared with values for sham-operated animals (Figure 1). In SAD rats, APL was three to four
times higher than their sham-operated control group
and was also significantly higher than the CD and AD
groups. Likewise, the lability of the selectively denervated rats was two to three times higher than their
sham-operated control animals; however, there was
no difference between the CD and AD groups (Figure 2).
Table 1 shows data for the ventilatory patterns in
all groups, including controls. The general breathing
pattern (frequency and tidal volume) was the same
for all groups, with the exception of a reduced minute
ventilation that reached significance in SAD rats.
Regardless of group, the breathing pattern consisted
of regular ventilation interrupted by single much
deeper breaths, interposed at intervals of approximately 60-100 seconds (Table 1). In SAD, AD, and
11-184
Supplement II
Hypertension
Vol 19, No 2
February 1992
DENB^VATHD
E
16n
SHAM-OPERATHJ
12-
•
FIGURE 2. Bar graph shows arterial pressure
lability in sinoaortic-denervated (SAD), aorticdenervated (AD), and carotid-denervated (CD)
rats, and in their respective sham-operated
groups. *p<0.05 in relation to sham-operated
group; +p<0.05 in relation to SAD group. Mean
values±SEM; see Table 1 for n values.
8-
4-
T
CD
AD
SAD
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CD rats, these larger tidal volumes were accompanied by transient (no more than 5-seconds duration),
abrupt reductions of mean arterial pressure (Figure
3). The degree of such breathing-correlated falls of
pressure was the same in all denervated groups,
whereas a much smaller reduction occurred in their
respective sham-operated control groups.
Discussion
The increase of mean arterial pressure in the SAD
group was consistent with earlier data.1-5 Denervation of baroreceptors activates the sympathetic system, which in turn, results in an elevated mean
arterial pressure. The pressure may return toward
normal levels after a period of several days, even if
the sympathetic activity remains higher than normal.1
Likewise, studies on dogs9 and rats 410 document that
the mean arterial pressure of SAD animals is not at
a hypertensive level when recordings are performed
on a 24-hour basis. An improved regulation of the
level of mean arterial pressure in SAD animals may
result from an increased role of cardiopulmonary low
pressure baroreceptors that, however, are unable to
exert the precise moment-to-moment adjustments
typical of the arterial baroreceptors.11 Consequently,
an increased pressure lability remains even after
prolonged periods.
Selective denervation of aortic or carotid baroreceptors produced an increase of mean arterial pressure of the same magnitude as in SAD rats. This
indicates that the presence of both sets of baroreceptors is necessary to keep mean arterial pressure at
normal levels. Our study used computer-assisted
evaluation of mean arterial pressure changes. Earlier
work did not apply this technique to assess the effects
of selective denervation in rats, so it is difficult to
make comparisons with reports on different mammalian species.12
In contrast to the uniform effect of SAD, CD, and
AD on mean arterial pressure, selective denervation
had a significantly smaller effect in relation to APL.
These results indicate that the two sets of barorecep-
TABLE 1. Recorded Ventilatory Variables in Rats With Sinoaortic Denervation, Aortic Denervation,
and Carotid Denervation
Groups
(min ')
VT
(ml • kg"')
V,
(ml • kg"1 • min"')
INTEV
(sec)
V EV
(ml kg-')
SO (/i=6)
119+8
6.9±0.8
787±50
71 ± 8
22.9 ±0.8
S A D ( n = 10)
114±6
5.4±0.4
617+48*
89±13
19.8±1.7
SO (n=6)
107±5
4.9±0.3
524±15
92+11
18.5±1.5
AD (n=9)
102±4
4.6±0.4
465 ±35
97±9
14.8+1.0
SO (/i=6)
113±5
4.9±0.5
568±77
80±6
15.5±1.1
CD (TI = 1 3 )
108±4
4.3±0.2
467±32
100±ll
15.5±0.8
Values are mean+SEM. fR) respiratory frequency; V T , tidal volume; Vi, minute ventilation; INTEV, interval between
large inspiratory event; VEV> volume of large inspiration; SO, sham-operated control; SAD, sinoaortic-denervated
group; AD, aortic-denervated group; CD, carotid-denervated group.
V<0.05, Student's t test.
Mauad el al
8AD
AD
Selective Denervation of Baroreceptors
11-185
CD
-5
FIGURE 3. Bar graph shows decreases of arterial pressure induced by large breaths in sinoaortic-denervated (SAD), aortic-denervated (AD),
and carotid-dencrvated (CD) rats and their respective sham-operated groups. *p<0.05 in relation to sham-operated group. Mean values ±SEM;
see Table 1 for n values.
-10
-15
a.
-20
J
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tors are equally important in stabilizing arterial pressure. In the absence of one set of receptors, the
remaining set was partially able to limit pressure
lability.
Mean arterial pressure was the same in all three
denervated groups, whereas APL was distinctly
higher in SAD rats than in selectively denervated
rats. This suggests a dissociation between lability and
mean arterial pressure, which is consistent with Jacob et al,3 who reported that sustained increases of
arterial pressure did not affect lability and concluded
that APL is not pressure dependent.
The present data on respiratory frequency, tidal
volume, and minute ventilation in normal rats are in
complete agreement with the literature.13 The relatively small effect of denervation on the ventilatory
pattern after SAD or selective denervation in adult
rats gains interest in relation to a recent study by
Hofer,6 who investigated CD and SAD in 8- to
10-day-old rats. In that study, both denervations
caused abnormal and irregular ventilation characterized by frequent end-expiratory pauses.
In normal as well as in SAD rats, the ventilatory
pattern consisted of prolonged (60-100-second) periods of continuous breathing, interrupted by recurring single breaths of an increased volume. These
deep breaths caused small transient reductions of
arterial pressure in normal rats, whereas SAD animals presented large and abrupt transient falls of
mean arterial pressure. Selective denervations also
produced large pressure reductions associated with
deep breathing. These ventilation-related effects on
pressure were of the same magnitude in AD, CD,
and SAD animals. Consequently, partial or complete
removal of arterial baroreceptors produced the same
degree of ventilation-induced imbalance of arterial
pressure regulation, which reflects a lack of momentto-moment buffering of mean arterial pressure.1
Simultaneous ventilatory and circulatory events
may originate from central mechanisms. Working on
anesthetized, artificially ventilated rats, Cox and
Brody14 reported decreases of arterial pressure after
microinjection of lidocaine into the ventrolateral
portion of the rostral medulla, an essential region for
vasomotor tone and regulation of arterial pressure.
The magnitude of these depressor events was augmented when tidal volume was increased. Their
results indicate an interaction between pulmonary
and chest wall afferent information to the central
nervous system and regulation of arterial pressure.
For a possible anatomic basis of such cardiorespiratory interactions, see Richter and Spyer.15
In conclusion, SAD, CD, and AD produced equal
increases of mean arterial pressure, whereas the
accompanying increases of APL were larger in SAD
rats than in CD and AD animals. Moreover, selectively denervated rats presented a higher degree of
APL than sham-operated rats. The results suggest an
equal role of aortic and carotid baroreceptors in
reducing APL. Large tidal volumes were associated
with marked transient decreases of mean arterial
pressure in all denervated groups, indicating that
ventilation contributes to the generation of APL in
the absence of an adequate baroreceptor control.
References
1. Jacob HJ, Barres CP, Machado BH, Brody MJ: Studies on
neural and humoral contributions to arterial pressure lability.
Am J Med Sd 1988;295:341-345
2. Alper RH, Jacob HJ, Brody MJ: Regulation of arterial pressure lability in rats with chronic sinoaortic deafferentation. Am
JPhyswl 1987;253.H466-H474
3. Jacob HJ, Alper RH, Brody MJ: Lability of arterial pressure
after baroreceptor denervation is not pressure dependent.
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4. Buchholz RA, Hubbard JW, Nathan MA: Comparison of 1
hour and 24 hour blood pressure recordings in central or
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Supplement D
Hypertension
Vol 19, No 2 February 1992
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9. Cowley AW Jr, Liard JF, Guyton AC: Role of the baroreceptor reflex in daily control of arterial blood pressure and other
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pp 587-621
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medulla. Am J Physiol 1989;257:R626-R634
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AD, Spyer KM (eds): Central Regulation of Autonomic Functions. New York, Oxford University Press, Inc, 1990, pp
189-207
KEY WORDS • baroreceptors •
ventilation • respiratory function
sinoaortic denervation
•
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Effect of selective denervation of baroreceptors on pulmonary ventilation and arterial
pressure lability in rat.
H Mauad, M L Glass and B H Machado
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Hypertension. 1992;19:II182
doi: 10.1161/01.HYP.19.2_Suppl.II182
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1992 American Heart Association, Inc. All rights reserved.
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