Download Role of Cardiac, Pulmonary, and Carotid

Role of Cardiac, Pulmonary, and Carotid
Mechanoreceptors in the Control of Hind-Limb and
Renal Circulation in Dogs
By Giuseppe Mancia, John T. Shepherd, and David E. Donald
ABSTRACT
Reflex control of hind-limb and renal resistance vessels by cardiac and pulmonary
receptors was studied by interrupting afferent vagal nerve traffic when only the heart or
only the lungs were in situ in anesthetized dogs with sinoaortic denervation. During
normocapnia, interruption of cardiac and of pulmonary vagal traffic decreased hind-limb
blood flow (constant-pressure perfusion) by 23% and 21%, respectively. Corresponding
decreases in renal blood flow were 23% and 33%. Hypercapnia augmented the decreases in
renal blood flow due to the vagal block. Thus, the inhibitions exerted by the heart and
lung receptors on these two beds were similar during normocapnia but were greater on the
renal vessels during hypercapnia. In closed-chest dogs with their aortic nerves sectioned
and their carotid sinus pressure controlled, combined withdrawal of carotid and
cardiopulmonary inhibition decreased hind-limb and renal blood flow by about 80% and
40%, respectively, during both normovolemia and hypervolemia. Interruption of cardiopulmonary inhibition was responsible for 17% and 31% of the decrease in hind-limb blood
flow at normal and increased blood volumes, respectively; values for the decreases in renal
blood flow were 50% and 65%. Thus, cardiopulmonary receptors oppose the vasoconstriction due to carotid sinus hypotension more effectively in the kidney than they do in the
hind limb.
• In recent years, the control of muscle and renal
circulations by different reflexogenic areas has
received much attention. In cats (1-4) and dogs (5,
6), a change in carotid mechanoreceptor activity
has a greater effect on muscle resistance vessels
than it does on renal resistance vessels. When
inhibitory traffic from the cardiopulmonary receptors is interrupted by vagal cooling (3) or decreased
by hemorrhage (4, 5, 7) in cats (3, 4), rabbits (7), or
dogs (5), the constriction of renal resistance vessels is greater than that of muscle resistance vessels. Direct comparisons of carotid and cardiopulmonary inhibitory influences in cats have shown
that carotid occlusion consistently leads to more
pronounced hind-limb responses than does vagal
cooling; the opposite occurs for the renal responses
(3). A major functional role has been ascribed to cardiac receptors by Oberg and White (3, 4), who have
found that, in cats, the renal and the hind-limb responses to vagal cooling or hemorrhage are greatly
decreased after section of the cardiac nerves. However, Ott et al. (8, 9) have shown in rabbits that the
From the Mayo Clinic and Mayo Foundation, Rochester,
Minnesota 55901.
This investigation was supported in part by U. S. Public
Health Service Grants HL-5883 and HL-6143 and by International Research Fellowship Grant F05 TW 1962 from the
National Institutes of Health.
Dr. Mancia is a Postgraduate Fellow of the U. S. Public
Health Service on leave from the University of Milan, Italy.
Received November 11, 1974. Accepted for publication May
13, 1975.
200
lung depressor reflex is responsible for opposing
the increase in renal and hind-limb vascular resistance caused by the action of carbon dioxide at the
vasomotor center.
These studies suggest that it is important (1) to
compare, in the same species, the separate roles of
the receptors in the heart and the lungs in the
inhibitory control of hind-limb and kidney vessels
during normocapnia and hypercapnia and (2) to
extend the comparison of carotid and cardiopulmonary inhibitory influences by utilizing the full
range of activity of the former and increasing the
activity of the latter by augmenting the blood
volume.
Methods
Twenty-nine dogs were anesthetized with sodium
thiopental (15 mg/kg, iv) and chloralose (80 mg/kg
initially and 10 mg/kg hourly, iv), paralyzed with gallamine triethiodide (3 mg/kg hourly, iv), and mechanically
ventilated. Heparin was given prior to cannulation of
blood vessels (2.5 mg/kg initially and 1 mg/kg hourly, iv).
The vagal efferent cardiac nerves were blocked with
atropine (0.2 mg/kg hourly, iv). Both the right and left
aortic nerves and cervical sympathetic nerve trunks were
divided (10). Section of the cervical aortic nerves results
in acute loss of the chemoreflex and the baroreflex from
the aortic arch and the major intrathoracic arteries
(10-15). Further proof of acute loss of the aortic baroreflex was afforded in the present study by the failure of
vagal blockade to elicit an increase in systemic vascular
resistance after removal of the heart and lungs.
Thermodes were applied to the vagal nerves and perCirculation Research. Vol. 37, August 1975
REFLEX CONTROL OF MUSCLE AND RENAL FLOW
fused with cold alcohol until a temperature of -1°C was
registered at the surface of the nerve; the block was
reversed by perfusion with water at 37CC. The effectiveness of the block was demonstrated by the absence of
vascular changes when the vagi were severed caudal to
the thermodes.
Measurements.—Aortic blood pressure and, in openchest dogs, right and left atrial pressures were measured
through catheters connected with strain-gauge transducers (Statham P23De). Mean blood pressure was obtained
by electronic damping of the pulsatile signal. Respiratory
pressures were measured with a strain-gauge transducer
(Statham PM5d) connected to a side arm of the cuffed
tracheal tube. The left kidney and either the left or both
hind limbs were perfused at a constant nonpulsatile
pressure of 120 mm Hg with oxygenated blood obtained
from an extracorporeal circuit or the brachial artery.
Because the perfusion pressure was constant, the
changes in blood flow reflected changes in vascular
resistance.
The abdominal aorta was cannulated in a cephalad
direction distal to the origin of the left renal artery and in
a caudad direction central to the origins of the external
iliac arteries and perfused from the common outlet of the
servocontrolled blood-flow pump. Heat exchangers
maintained the blood temperature at 37°C. To eliminate
other sources of blood to the hind limbs and the left
kidney, the lumbar arteries originating along the exposed aortic segment, the deep circumflex iliac and
inferior mesenteric arteries, the terminal aorta, and the
aorta above the origin of the left renal artery were
ligated.
Blood flows were measured with cannulating electromagnetic flow probes (Carolina Medical Electronics).
Zero-flow signals were recorded while both circulations
were maintained through bypass lines. The flow probes
were calibrated at the end of the experiment using the
dog's own blood and a pump-reservoir system.
Separate Roles of Cardiac and Pulmonary Receptors.—
To allow full manifestation of the vasomotor inhibition
from the heart and lung receptors, the carotid baroreceptors and chemoreceptors were denervated by stripping
the common carotid, internal carotid, and occipital arteries. After this procedure, occlusion of the common
carotid arteries did not result in an increase in arterial
blood pressure. The vagi were cut at the diaphragm.
The response of resistance vessels of both hind limbs
and the left kidney to interruption of afferent vagal nerve
traffic was studied when only the heart was left in situ
(the lungs having been removed) and when only the
lungs were left in situ (the heart having been removed).
Studies were made during systemic normocapnia and
hypercapnia. The details of these preparations have been
described previously (15). Ventilation of the extracorporeal oxygenator with 100% O2 maintained the arterial
oxygen tension (Po2) of the experimental dog above 300
mm Hg, the arterial carbon dioxide tension (Pco2)
between 30 and 40 mm Hg, and the pH between 7.30 and
7.40. To produce hypercapnia, the oxygenator was ventilated with 90% O2-10% CO2. In this situation, the Po2
remained above 300 mm Hg while the Pco2 increased
above 70 mm Hg and the pH decreased below 7.15. Five
to ten minutes were required to produce and to reverse
these changes.
Comparison of Cardiopulmonary and Carotid RecepCirculation Research, Vol. 37, August 1975
201
tors.—The responses of left renal and left hind-limb
resistance vessels to withdrawal of inhibitory traffic from
the cardiopulmonary region were compared, in closedchest dogs, with the responses to withdrawal of the
inhibitory traffic from the carotid sinuses. The carotid
sinuses were vascularly isolated and perfused according
to a previously described technique (13, 16) and set at an
intrasinus pressure of 220 mm Hg to provide maximal
inhibition from these receptor sites (17-19). The intrasinus pressure then was decreased rapidly to 40 mm
Hg, at which pressure the carotid baroreceptor inhibition
is minimal or absent (17-19). Both vagal nerves then
were cold blocked. This sequence was followed because
previous studies (13) have shown that the inhibition from
the cardiopulmonary receptors is maximally evident in
the absence of the inhibition from the carotid mechanoreceptors.
The observations were made during normovolemia
and after the firing of receptors in the cardiopulmonary
region had been augmented by increasing the blood
volume (20, 21). A low-molecular weight dextran solution (isotonic with plasma) at 37°C was infused into a
femoral vein over a period of 3 minutes. The increases in
blood volume were estimated at 15% and 30%, assuming
the total blood volume to be 90 ml/kg body weight (22).
The dogs were ventilated with O2 at 12 cycles/min and
peak inspiratory pressures of 10-12 cm H2O; this procedure maintained the arterial Po2, Pco2, and pH above
300 mm Hg, between 30 and 40 mm Hg, and between
7.30 and 7.40, respectively.
To stimulate the sympathetic nerves to the left hind
limb, the left paravertebral sympathetic chain was cut
above the level of L4 and the caudal stump was stimulated electrically with 5-msec pulses of supramaximal
intensities (> 10 v) and frequencies of 1-14 cycles/sec.
To stimulate the sympathetic nerves to the left kidney
(23, 24), the left splanchnic nerve was cut at its entrance
into the abdomen, and the caudal stump was stimulated
electrically as described for the lumbar chain. The delay
time of 60 seconds or longer in the perfusion circuit
ensured that the measured response was not due to the
release of catecholamines from the adrenal glands.
Protocol and Data Analysis.—In the first part of the
experiments with only the heart or only the lungs in situ,
cold block of the cervical vagal nerves was performed
during normocapnia; in the later part, multiple paired
vagal blockades were performed during normocapnia and
hypercapnia. In the experiments in which inhibition
from the cardiopulmonary region and the carotid sinus
region was compared, the observations were made in
sequence during normovolemia and 15% and 30% hypervolemia. The responses to the various experimental
procedures were measured as soon as steady values were
obtained. The observations in each dog were summed to
obtain the mean ± SE for the group. The statistical
significance of the difference in the means was evaluated
by Student's (-test. The level of significance was taken
as P = 0.05.
Results
Separate Responses of Cardiac and Pulmonary
Receptors.—In these experiments, the carotid
baroreceptors were denervated 3-4 hours before
the observations began. By this time the marked
202
MANCIA, SHEPHERD. DONALD
vasoconstriction of the hind-limb vessels that followed the denervation had disappeared, and blood
flow approximated predenervation values.
Cardiac Receptors.—The experiments with only
the heart in situ were performed in eight dogs. The
cardiac output was 90 ± 3 (SE) ml/min kg"1 body
weight; the left and right atrial pressures were 6.6
± 0.3 and 0.9 ± 0.2 mm Hg, respectively. Vagal
cold block caused a significant increase in mean
aortic blood pressure and significant decreases in
hind-limb and renal blood flows (Fig. 1, Table 1).
The changes were sustained throughout the period
of cold block (2-3 minutes). The mean percent
decrease in hind-limb blood flow in the eight dogs
was not significantly different from that in kidney
blood flow (Table 1).
Pulmonary Receptors.—The experiments with
only the lungs in situ were performed in eight dogs
in which the input to the aorta was 88 ± 3 (SE)
ml/min kg" 1 and the tidal volume was 20 ml/kg;
the inspiratory and expiratory pressures were 12.5
± 0.5 and 2.5 ± 0.2 cm H2O, respectively. Vagal
cold block caused a sustained increase in mean
aortic blood pressure and sustained decreases in
hind-limb and renal blood flows (Fig. 1, Table 1).
The mean percent decrease in hind-limb blood flow
in the eight dogs was not significantly different
Heart
In Situ (8 Dogs)
• 40
IO
O
"40
Vif If "^ l»
fl
Longs In Situ (8 Dogs)
-BO h
• Mean Aortic Pressure
• Hind Limb Blood Flow
a ftenol Blood Flow
FIGURE 1
Data presented in Figures 1-4 were obtained in open-chest dogs
with their carotid sinuses denervated, their aortic nerves cut,
their vagi divided at the diaphragm, and both hind limbs and
the left kidney perfused at a constant pressure of 120 mm Hg.
This figure shows the vascular responses to bilateral cervical
vagal cold block in eight dogs with only the heart in situ (top)
and in eight dogs with only lungs in situ (bottom). The mean (±
SD) percent change from the control value for each dog is shown;
n = number of vagal blocks performed in each dog.
from that in renal blood flow (Table 1). The mean
decreases in hind-limb and renal blood flows during vagal cold block were not significantly different
from those with only the heart in situ.
In all eight dogs with only the lungs in situ, vagal
block also was performed with the tidal volume set
at 10 and at 40 ml/kg—that is, at half and at twice
the control tidal volume. The increase in ventilation from 10 to 40 ml/kg decreased the aortic blood
pressure and increased the hind-limb and renal
blood flows; with vagal block, similar pressures and
flows were recorded at each tidal volume (Fig.
2). Thus, the increase in tidal volume resulted in a
greater inhibition of the vasomotor center by the
vagal afferents from the lung receptors. The percent decrease from control blood flow in the hind
limb during vagal block was not significantly
different from the percent decrease in renal blood
flow at any of the tidal volumes studied.
Two additional types of observations were made
in four of these eight dogs. First, vagal block was
performed with the ventilation suspended and the
lungs collapsed at atmospheric pressure. In this
condition, no response to vagal block was observed
in one dog, but the three other dogs showed
increases in aortic blood pressure and decreases in
hind-limb and renal blood flows that were only
slightly less than those observed when the lungs
were ventilated with the smallest tidal volume
(10 ml/kg). Second, the lungs were removed; this
procedure increased the aortic blood pressure and
decreased the hind-limb and renal blood flows to
values similar to those observed with vagal block
before lung removal. In no instance after lung
removal did vagal block have any effect on the
aortic blood pressure or the hind-limb and renal
blood flows.
Hypercapnia.—The data are summarized in Figure 3. In the experiments with only the heart in
situ, left and right atrial pressures were not significantly changed by hypercapnia. In the experiments
with only the lungs in situ (tidal volume 40 ml/kg),
the ventilatory pressures were identical during
normocapnia and hypercapnia. In both preparations, hypercapnia caused a significant decrease in
base-line aortic blood pressure but did not augment the increase caused by vagal block.
In both experimental preparations, hypercapnia
failed to exert a significant effect on the base-line
hind-limb blood flow; moreover, it did not significantly modify the decrease in hind-limb blood flow
caused by vagal block. In contrast, in both preparations, hypercapnia caused a considerable increase
in base-line renal blood flow. With vagal block, the
Circulation Research, Vol. 37, August 1975
203
REFLEX CONTROL OF MUSCLE AND RENAL FLOW
TABLE 1
Vascular Responses to BilateralCervical Vagal Cold Blockwith Only the Heart or Only the Lungs In
Situ
Only heart in situ
Initial
Mean aortic blood pressure (mm Hg)
Hind-limb blood flow (ml/min)
Renal blood flow (ml/min)
123 ± 12
104 ± 10
125 ± 15*
Only lungs in situ
Change
Initial
Change
+ 25 ± 3
-24 ± 4
-29 ± 6
130 ± 6
114 ±11
101 ± 9t
+ 19 ± 5
-24 ± 6
-33 ± 6
All values are means ± SE for observations in eight (in each group) extracorporeally oxygenated,
sinoaortic denervated dogs with their vagi divided at the diaphragm and their hind limbs and left
kidneys perfused at a constant pressure of 120 mm Hg.
* Equivalent to 3.5 ± 0.4 ml/min g~' kidney tissue.
t Equivalent to 3.2 ± 0.5 ml/min g"1 kidney tissue.
decrease in renal blood flow was greater during
hypercapnia; this response was greater in the
heart-only preparation ( + 162%) than it was in the
lungs-only preparation (+38%). The greater response to vagal block during hypercapnia in the
heart-only preparation was significant. That the
renal vasodilatory response to hypercapnia was
dependent on intact vagal afferents was demonstrated by inducing hypercapnia in sequence before, during, and immediately after vagal cold
block in six dogs with only the heart in situ (Fig. 4).
Before vagal block, renal blood flow was greater
during hypercapnia than it was during normocapnia. In contrast, when hypercapnia was
induced during vagal block, renal blood flow either
did not change or decreased below the normocapnic
MEAN AORTIC
PRESSURE
mm Hg
HIND LIMB
BLOOD FLOW
ml/min
RENAL
BLOOD FLOW
values. After the vagal block had been ended, the
renal blood flow returned to or close to the level
seen in the initial hypercapnic state.
To assess the effect of the local increase in
arterial Pco2 on the responses of the kidney and the
hind limb, the effects of hypercapnia were compared before and after sympathetic denervation of
each area by bilateral splanchnicotomy and by
removal of the left lumbar paravertebral sympathetic chain. In both the heart-only (eight dogs)
and the lungs-only (six dogs) preparations, hypercapnia increased the blood flow in the sympathectomized kidney to a degree (+41%) similar to that
observed before denervation (+33%). In the hind
MEAN AORTIC
PRESSURE
mmHg
180 r
HIND LIMB
BLOOD FLOW
ml/min
180 r
RENAL
BLOOD FLOW
ml/min
180 r
ml/min
120
T
g'Block
O Normocapnic
A Hyporcapnto
130
90
Heart
60
Lungs
FIGURE 3
90 L.
Tidal Volume
(ml/ta): 10 20
50
40
u
10 20
40
10
20
40
FIGURE 2
Mean ( ± SE) vascular responses to bilateral cervical vagal cold
block at respiratory tidal volumes of 10, 20, and 40 ml/kg in
eight dogs with only their lungs in situ. Respective mean ( ± SE)
inspiratory pressures were 6.0 ± 0.4, 12.0 ± 0.5, and 32.0 ±1.6
cm H2O; corresponding expiratory pressures were 2.0 ± 0.2, 2.5
± 0.2, and 4.0 ± 0.3 cm H2O.
Circulation Research, Vol. 37, August 1975
Mean (± SE) vascular responses to bilateral cervical vagal cold
block during normocapnia and hypercapnia in eight dogs with
only their hearts in situ (left side of each section) and in eight
dogs with only their lungs in situ and ventilated with a
respiratory tidal volume of 40 ml/kg (right side of each section).
With only the heart in situ, arterial Pco2 was 34 ± 1 mm Hg and
pH was 7.30 ± 0.02 during normocapnia; corresponding values
during hypercapnia were 75 ± 1 mm Hg and 7.08 ± 0.01. With
only the lungs in situ, arterial Pco2 was 32 ± 2 mm Hg and pH
was 7.38 ± 0.02 during normocapnia and 70 ± 1 mm Hg and 7.11
± 0.01 during hypercapnia.
204
MANCIA. SHEPHERD. DONALD
O 150
100% = 117 ± 15 ml/min
O
o
100
o
o
.J
u.
Q
O
O
50
-J
QQ
Vagal Block
-J
UJ
(fc
I
I
I
I
31
31
73
73
7.4
7.4
7.1
7.1
Arterial:
75
pH
7.1
FIGURE 4
Effect of hypercapnia on renal blood flow before, during, and
after bilateral cervical vagal cold block in six dogs with only
their hearts in situ. The kidney was perfused first with hypercapnic blood; then it was perfused with normocapnic blood, and
finally the cervical vagi were cold blocked. During the block, the
perfusing blood was again made hypercapnic, and then the
vagal block was relieved. Renal blood flow is shown as the
percent change from the value recorded during normocapnia
with the vagi unblocked. Hypercapnia caused an increase in
renal blood flow in all dogs with the vagi unblocked but no
change (three dogs) or a decrease in flow (three dogs) when the
vagi were blocked.
limbs, hypercapnia did not induce a significant
increase in blood flow before (+2%) or after (-3%)
denervation. The capability of the hind-limb vessels to dilate was shown by the increase in blood
flow induced by a close intra-arterial injection of 10
fig of isoproterenol hydrochloride.
Comparison of Carotid and Cardiopulmonary
Receptors.—In 13 dogs, withdrawal of inhibitory
traffic from the carotid sinus and the cardiopulmonary receptors each resulted in a decrease in kidney
and hind-limb blood flows (Fig. 5, left). At all
blood volumes, the decrease in renal blood flow
caused by vagal block was equal to or greater than
that due to the reduction in sinus pressure. In
contrast, in the hind limb, the decrease in flow due
to vagal block was always substantially less than
that resulting from carotid sinus hypotension.
This difference in the reflex control of kidney and
hind-limb resistance vessels was more evident from
the relative contributions of the carotid and the
cardiopulmonary reflexes to the decrease in renal
and hind-limb blood flows recorded during interruption of inhibitory traffic from both receptor
regions (Fig. 5, right). Combined withdrawal of
carotid sinus and cardiopulmonary inhibitory traffic decreased hind-limb blood flow by 88% during
normovolemia and by 77% and 83%, respectively,
during 15% and 30% hypervolemia. Corresponding
decreases in renal blood flow were 42%, 39%, and
40%. Interruption of cardiopulmonary inhibitory
traffic was responsible for 17%, 33%, and 32% of the
reflexly induced changes in hind-limb blood flow
and for 50%, 62%, and 68% of the changes in renal
blood flow.
At the end of the experiment, both vagus nerves
were cut. A decrease in sinus pressure from 220 to
40 mm Hg caused the same decreases in renal and
hind-limb blood flows as those noted with vagal
cold block and decreased sinus pressure.
Direct Stimulation of Sympathetic Nerves.—In
12 of the 13 dogs, electrical stimulation of the
sympathetic nerves to the hind limb and the
kidney was performed after bilateral cervical vagotomy. This stimulation caused an immediate
HIND LIMB
BO
Carotid
50
Pressure
Change
Vagal Block
£
s
i
RENAL
o
i 190
<o too
Q
O
O 150
o
Q.
<O
£ 50
Normovolemia
15%
30%
Hypervolemia
FIGURE S
Changes (mean ± SE) in hind-limb (top) and renal (bottom)
blood flow in response to a decrease in carotid sinus pressure
from 220 to 40 mm Hg and then to bilateral cervical vagal cold
block at the sinus pressure of 40 mm Hg in 13 closed-chest dogs
with their aortic nerves cut, their carotid sinuses vascularly
isolated and maintained at a desired constant nonpulsatile
pressure, and their left hind limb and their left kidney perfused
at a constant pressure of 120 mm Hg. The observations were
made in sequence during normovolemia and during 15% and
30% increases in blood volume. The bar graphs show the mean
decrease in blood flow with the decrease in carotid sinus
pressure and with vagal block as a percent (± SE) of the mean
decrease in blood flow caused by the combined procedures
(maximum) during normovolemia and 15% and 30% hypervolemia.
Circulation Research, Vol. 37, August 1975
REFLEX CONTROL OF MUSCLE AND RENAL FLOW
o
u.
Hind Limb
80 -
Q
O
O
-j
tn
.c
UJ
40
Control Flow
68 ± 7 ml/min
170 ± 15 ml/min
Uj
Q:
o
Q
0
I
I
4
8
12
CYCLES / SECOND
FIGURE 6
Mean (± SE) decrease in blood flow in the left hind limb and the
left kidney in response to electrical stimulation at different
frequencies of the decentralized left parauertebral chain at L4
and of the left splanchnic nerue in 12 of the 13 dogs shown in
Figure 5. The decreases in flow are shown as percents relative to
control flows.
and sustained decrease in the hind-limb and renal
blood flows. With frequencies of stimulation
greater than 8 cycles/sec, the percent decreases in
hind-limb and renal blood flows were similar
(80-90%) (Fig. 6). In contrast, at frequencies less
than 6 cycles/sec, the percent decrease in hindlimb blood flow was much greater than that in
renal blood flow.
Discussion
Separate Roles of Cardiac and Pulmonary Receptors.—The present study indicates that vagally
innervated receptors in the heart and the lungs
exert a tonic inhibition on the sympathetic outflow
to the hind-limb and kidney resistance vessels. The
similar mean decreases in blood flow of 23% and
21%, respectively, when cardiac or pulmonary
vagal nerve traffic was interrupted imply a similar
role for the heart and the lung receptors in the tonic
control of the hind-limb circulation; this situation
also applies for the renal circulation (mean flow
decreases of 23% and 33%, respectively).
The tonic vasomotor inhibition exerted on both
the hind-limb and the kidney resistance vessels by
the pulmonary afferents was related to the ventilatory volumes and pressures and was also present
during apnea when the lungs were collapsed at
atmospheric pressure. These findings are in agreement with the observations of others (8, 9, 25-27)
that inflation of the lungs has a reflex depressor
influence on the systemic circulation and that this
Circulation Research, Vol. 37, August 1975
205
reflex has a low threshold (26). They are difficult to
reconcile with the findings of Hainsworth (14), who
observed that systemic vasodilation occurred only
on hyperinflation; lung inflations at a moderate
pressure caused a small vasoconstriction, if anything. Hainsworth (14) suggested that abnormal
perfusion of the lungs, as used in other studies,
might alter the lung compliance and cause overdistention at smaller inflation pressures. However,
this mechanism cannot explain the presence of a
tonic vasomotor inhibition during apnea with the
lungs collapsed at atmospheric pressure.
During normocapnia there were similar decreases in blood flow to the hind limbs and the
kidney (absolute values as well as percents of
control) when the vagi were cooled with only the
heart and with only the lungs in situ. This finding
suggests that neither of these beds is preferentially
involved in the tonic inhibition exerted by vagal
afferents from the heart or the lungs. It should be
pointed out that this conclusion may not apply to
all receptors in these regions. For example, in the
cat, electrical stimulation of the right cardiac
nerve, a procedure that activates afferent fibers
that are not normally active, causes greater effects
on the renal circulation than it does on the hindlimb circulation (4).
During hypercapnia, the inhibition exerted by
cardiac and by pulmonary vagal afferents on the
kidney vessels became greater. This finding agrees
with those of previous studies in the rabbit in
which hypercapnia augmented the vasodepressor
reflexes from the aortic arch and the lungs, with a
greater effect on the renal bed than on the muscle
vascular bed (8, 9). The present study demonstrates that the cardiac reflexes behave in a similar
fashion. Thus, it seems that this phenomenon is a
general property of reflexes that tonically inhibit
the vasomotor center. In the present study, the
effect of hypercapnia on the renal circulation was
due to an interplay among the local dilatatory
action of CO2, its excitatory action on the vasomotor center, and a more effective inhibition of this
center by the cardiopulmonary receptors. Locally,
the increase in CO2 caused vasodilation, as shown
by the experiments with the kidney denervated.
This dilation was opposed by the simultaneous
excitation of the central neurons so that in the
absence of reflex inhibition of the vasomotor center
by the cardiopulmonary receptors there was no
change or a decrease in renal blood flow with
hypercapnia. With the vagi intact, renal blood flow
was increased during hypercapnia. Thus, an increase in CO2 augmented, in an as yet unexplained
206
way, the inhibition of the vasomotor center normally effected by the vagal afferents; counteracting
the central effects of C0 2 permitted dilation of the
renal vessels.
Regarding possible mechanisms by which the
hypercapnia increased the inhibition exerted by
the vagal afferents, there was no obvious mechanical cause for increased discharge from the receptors; hypercapnia did not change the ventilatory
pressures with only the lungs in situ or the atrial
pressures with only the heart in situ. It could be
argued that C0 2 increases the activity of the
cardiopulmonary receptors. However, it is known
that C0 2 decreases the activity of slowly adapting
pulmonary stretch receptors (28), and Coleridge et
al. (29) have found that ventilation with C0 2 does
not increase activity in ventricular fibers characterized by an irregular, sparse discharge. The
spontaneous activity of most avian cardiac receptors is negatively correlated with arterial Pco2 (30).
Thus, it seems most likely that CO2 acts centrally
to accentuate the inhibitory control of the renal
vessels by the vagal afferents.
In contrast to the response of the renal resistance vessels, CO2 had little effect on the central
vasomotor neurons controlling the hind-limb circulation or locally on the limb resistance vessels.
Also, during hypercapnia there was no evidence of
an increased inhibition of the central neurons controlling the hind-limb vessels. These differences
between the hind limb and the kidney in regard to
hypercapnia are still unexplained.
Roles of Cardiopulmonary and Carotid Receptors.—Previous studies have shown that the cardiopulmonary receptors exert an inhibition on the
vasomotor center that principally serves to oppose
the vasoconstriction due to withdrawal of the
inhibition exerted by the carotid baroreceptors
(13). The present experiments show that this
mechanism operates more effectively in the kidney
than it does in the hind limb. This difference is
partly due to the fact that withdrawal of carotid
sinus inhibition with the vagal nerves intact results
in such marked vasoconstriction in the hind limb
(a reduction in blood flow of 73% compared with
90% during supramaximal direct nerve stimulation) that, of necessity, the vascular response to
subsequent interruption of cardiopulmonary inhibition is small. These findings demonstrate the
very limited ability of the cardiopulmonary receptors to modify the vasoconstriction in the hind limb
due to the withdrawal of carotid inhibition. Withdrawal of carotid sinus inhibition with the vagal
nerves intact resulted in a decrease in renal blood
MANCIA. SHEPHERD. DONALD
flow of 21% or less, but direct renal nerve stimulation reduced blood flew by 88%. However, of the
average reduction of 40% in renal blood flow caused
by combined withdrawal of carotid and cardiopulmonary vasomotor inhibition, half was due to
interruption of cardiopulmonary inhibition during
normovolemia; more than 60% was due to interruption of cardiopulmonary inhibition during hypervolemia. These findings are in accord with previous
studies which have shown (1) that withdrawal of
carotid baroreceptor restraint normally is followed
by considerably lower firing rates in renal than in
skeletal muscle vasoconstrictor fibers (2, 31) and
(2) that for any given reduction in muscle flow
resistance the concomitant reduction in renal flow
resistance is decidedly more pronounced when the
ventricular receptors are stimulated than it is on
carotid baroreceptor activation, i.e., the afferent
impulse traffic from the ventricular receptors
seems to be preferentially oriented toward those
central neuron pools that control the vasoconstrictor fiber discharge to the kidney (32).
Although direct supramaximal sympathetic
nerve stimulation reduced both renal and hindlimb blood flow by 90%, combined withdrawal of
carotid and cardiopulmonary inhibition reduced
blood flow in the kidney only by 42% compared
with 88% in the hind limb. The stimulus-response
curves show that at frequencies less than 6 cycles/
sec there was less vasoconstriction in the kidney
than there was in the hind limb. The reduced
neuroeffector sensitivity of the kidney thus partly
explains the lesser vasoconstriction observed in this
organ compared with that seen in the hind limb
following withdrawal of baroreceptor inhibition.
The experiments provide no explanation for the
different shapes of the hind-limb and renal stimulus-response curves. It is possible that the pronounced autoregulation exhibited by the renal
vasculature is involved. Kendrick and Matson (33)
have suggested that about half of the renal response to carotid occlusion during constant-flow
perfusion is due to the local myogenic response to
the rise in perfusion pressure and about half to the
action of the vasoconstrictor nerves. They did not,
however, offer a similar analysis of the response
during constant-pressure perfusion. A second point
is that the control levels of blood flow in the kidney
are near maximal, although those in the hind limb
are less than 10% of flows during exercise. Comparison of the response curves to electrical stimulation
of the lumbar chain during rest (blood flow 55
ml/min) and simulated exercise (blood flow 257
ml/min) in anesthetized dogs has shown that the
Circulation Research, Vol. 37, August 1975
207
REFLEX CONTROL OF MUSCLE AND RENAL FLOW
exercise curve is displaced to the right of the resting
curve (34) in a manner similar to the displacement
of the renal response curve to the right of the
hind-limb curve observed in the present experiments.
The present findings have certain implications
regarding the reflex control of renal circulation in
abnormal circumstances. For example, during
hemorrhage, when the systemic arterial blood pressure and the central venous pressure decrease,
input from the carotid and the cardiopulmonary
receptors would be diminished, resulting in a
strong constriction of the renal and muscle vascular
beds. However, in cardiac failure accompanied by a
decrease in arterial blood pressure and an increase
in central venous pressure, the decrease in carotid
sinus pressure would act to constrict the renal
vessels, but this change would be opposed by the
simultaneous increase in activity of the cardiopulmonary receptors, thus serving to maintain renal
blood flow. It has been observed that, in experimental cardiogenic shock, in which left atrial
pressure is increased, renal blood flow decreases
less than it does in hemorrhagic shock, in which left
atrial pressure is decreased (35, 36).
The preservation of renal blood flow during
hypercapnia through the mechanism suggested by
these experiments would be of obvious benefit in
contributing to the restoration of acid-base balance
in respiratory acidosis.
7. CHALMERS JP, KORNER PI, WHITE SW: Effects of haemor-
rhage on the distribution of the peripheral blood flow in
the rabbit. J Physiol (Lond) 192:561-574, 1967
8. OTT NT, LORENZ RR, SHEPHERD JT: Modification of lung-
9.
10.
11.
12.
13. MANCIAG, DONALD DE, SHEPHERD JT: Inhibition of adrener-
14.
15.
16.
17.
18.
Acknowledgment
The authors wish to thank Mr. R. R. Lorenz and Mr. G. F.
Burton for technical assistance and Ms. Joan Troxell and Ms.
Jan Applequist for typing the manuscript.
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