Download Reflex Control of the Systemic Venous Bed

Reflex Control of the Systemic Venous Bed
EFFECTS ON VENOUS TONE OF VASOACTIVE DRUGS, AND OF
BARORECEPTOR AND CHEMORECEPTOR STIMULATION
By Eugene Braunwald, M.D., John Ross, Jr., M.D., Richard L. Kahler, M.D.,
Thomas E. Gaffney, M.D., Allan Goldblatt, M.D., and Dean T. Mason, M.D.
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• Dr. Carl AViggers concludes the introductory chapter to the section on the circulation
of the Handbook of Physiology1 in the following manner: " The present author finds it
difficult to understand why so much current
emphasis is given to mechanisms of blood supply that can be only temporary emergency
mechanisms. My calculations indicate that
the total cardiopulmonary reserve can be
pumped out within five or six seconds after
the onset of strenuous exercise. Thereafter,
augmented cardiac output can be maintained
only by a corresponding increase in venous
retui'n. Despite many earnest efforts to elucidate the sources of additional venous blood
and the mechanisms by which venous return
is augmented, most of the conclusions are
based on inference and extrapolations rather
than on direct experimental evidence. Hence
the study of venopressor mechanisms remains
a promising field for future investigations."
In order to understand the importance of
the venous system in circulatory control, it
has been found helpful to consider the heart
as a pump which is capable, within broad limits, of expeUing blood at the same rate at
which it is received from the venous bed.
Since the postcapillary bed contains approximately 75% of the extrathoracic blood volume, it is clear that even slight changes in
venous compliance can profoundly modify the
distribution of blood between the systemic
and intrathoraeic beds and can thereby alter
the venous return to the heart and the cardiac
output. Thus, generalized systemic venodilatation increases the volume of blood contained
in the venous bed at any given venous presFrom the Cardiology Branch, National Heart Institute, Bethesda Maryland.
Circulation Research. Volume XII, May 190S
sure, and decreases the venous return, cardiac
output, and arterial pressure in a manner
analogous to hemorrhage; generalized venoconstriction has the opposite effect.
For a number of years, it has been appreciated that the venous bed is not a simple
series of elastic tubes, but that the veins are
capable of reacting to a number of humoral
or neurogenic stimuli.3"7 Thus, several investigators have demonstrated that sympathomimetic amines produce a contractile response
of excised vein segments, 8 ' ° while others have
shown that changes in the capacity of isolated
venous segments result from activation of
carotid sinus receptors.10"17 It is the objective
of this report to review the results of a series
of experiments in which the effects of a variety of stimuli on the entire systemic venous
bed of the dog could be determined in a precise manner, and in which the effects of
alterations of venous tone on venous return
could be established quantitatively. In addition, the importance of effects on the venous
system in the mechanism of action of some
antihypertensive drugs will also be considered.
In order to study the entire systemic venous bed of the dog directly, it was necessary
to devise a preparation in which changes in
cardiac activity and in the pulmonary vascular bed would not obscure alterations in
the systemic vascular bed. The basic experimental plan employed was to remove the
heart and lungs from the circulation functionally, by means of extracorporeal circulation, as shown in figure I. 18 Utilizing morphine-chloralose-urethane anesthesia, positive
pressure respiration was maintained through
a cuffed endotracheal tube until extracorporeal circulation was established. After right
thoracotomy and isolation of the femoral ves539
540
BBAUNWALD ET AL.
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FIGURE 1
Diagrammatic representation of the basic extracorporeal circuit employed. Blood
drains by gravity from the superior vend wva (SVC) and inferior vena cava (IVG)
to the oxygenator. The aorta (A0) is cross-clamped above the coronary arteries and
blood accumulation in the right atrium (RA) and left atrium (LA) is prevented by
means of tiuo other drainage tubes. Oxygenated blood is pumped through a rotanneter
(ROT.) into the femoral artery (FA). The level of blood in the oxygenator is sensed
by the detecting electrodes (DET.) which activate a reversible pump connected with
the calibrated reservoir (RES.).
sels, cardiopulmonary bypass was instituted.
Blood was drained from the venae eavae and
atria through large-bore, rigid cannulae into
a rotating disc oxygenator. The blood then
passed to a roller pump through a recording
rotameter, and was returned to the dog
through a cannula in the femoral artery. All
blood entering the right atrium was diverted
into the oxygenator and thus the pulmonary
circuit was not perfused. Except when specifically noted, the S3rstemic perfusion rate
was maintained constant at approximately
100 ml/kg/min throughout each experiment.
Heparin (4 mg/kg) was used as the anticoagulant. The blood volume in the oxygenator
was kept constant at all times by an electronic
sensing device which actuated au auxiliary
pump. In order to maintain the volume of
blood in the oxygenator at a constant value,
the auxiliary pump automatically exchanged
blood between the oxygenator and a separate
blood reservoir. By this technique, any change
in the volume of this second reservoir reflected
an inverse change in the intravascular blood
volume of the animal. The volume of blood
in the reservoir was determined at one-minute
intervals throughout each experiment, providing minute-to-minute measurements of
changes in the animal's intravascular blood
volume. Thus, generalized venoconstriction
would be accompanied by an increase in venous return to the oxygenator. a decrease in
intravascular blood volume, and a reciprocal
increase in the volume of blood in the second
reservoir. In other experiments, in order to
measure venous return more directly, alterations of the intravascular blood volume could
be prevented by modifying the output of the
pump. For example, when venous return to
the reservoir increased, the pump output was
manually increased at a rate sufficient to
maintain the volume of the extracorporeal
circuit constant. The alterations of systemic
perfusion rate were determined and provided
Circulation Research, Volume XII, May 196S
541
REFLEX CONTROL OF SYSTEMIC VENOUS BED
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a direct measurement of the changes in venous return.
In addition, changes in venous distensibility of the entire systemic venous bed could
also be studied in this preparation by modifying the method utilized by Alexander 14-10
in studies on the splanchnic venous system.
Pressures were measured in the superior and
inferior venae cavae during sudden, brief
occlusions of the venous outflow line, while
arterial inflow was maintained constant. During a steady state, venous return to the oxygenator equaled the output of the pump and
it is assumed that blood entered the venous
segment of the circulation at an identical
rate. When, under these circumstances, the
venous outflow is briefly occluded, the pressure in the venous system rises abruptly. The
rate of this pressure elevation is primarily a
function of the initial volume of the venous
bed, its distensibility, and the rate of blood
flow into it; since the latter Avas held constant
throughout any given experiment, the influence of flow rate, as well as of any effects due
to the inertia! and viscous properties of the
vessel walls, was minimized. The steady state
was assured by performing the venous occlusions only after the transient alterations in
venous return accompanying the intervention
under study had been completed and at a
time when arterial pressure was stable.
intravascular blood volume. In four experiments, in which the extracorporeal blood
volume was held constant during infusion of
either catecholamine, it was necessary to increase the output of the pump by an average
of 40% of the control perfusion rate. These
changes in pump output are analogous to the
alterations in cardiac output which would
have occurred had the heart responded passively to the volume of blood returned to it
by the venous s}rstem, and had the intervention under study produced no effect on the
heart itself or on the pulmonary vascular bed.
Analysis of the venous occlusion curves in
five experiments also confirmed the impression that the catecholamines had produced a
profound generalized sjrstemic venoconstriction.
The infusion of trimethaphan (Arfonad)
at an average rate of 26 ptg/kg/min into four
dogs had the opposite effect. The intravascular blood volume increased by an average of
17.3 ml/kg at the expense of the volume of
blood in the oxygenator. Venous occlusion
curves also indicated that the trimethaphan
had resulted in generalized systemic venodilatation. In experiments in which blood volume
was held constant, the infusion of trimethaphan resulted in a decline in venous return
by an average of 30% of the control level.20
CAROTID SINUS REFLEXES
DIRECT EFFECTS OF VASOACTIVE DRUGS
The infusion of norepinephrine at an average rate of 2.4 fig/kg/min, and of epinephrine
at a rate of 1.5 /Ag/kg/min, into seven dogs,
resulted in a prompt and profound shift
of blood from the systemic venous bed into
the oxygenator. The volume of blood displaced
into the oxygenator averaged 19.0 ml/kg. The
large magnitude of the alterations in the systemic vascular volume observed in these experiments suggested that the major changes
in capacity occurred in the postcapillary or
venous bed. The importance of the changes
in the venous return accompanying these
shifts in blood volume is indicated by the
large modifications of the output of the pump
which were necessarj' to obviate alterations in
Circulation Research. Volume XII. May 1963
The chief purpose of studying the effects of
these well-known venoconstrictor and venodilator drugs was to provide a background from
which the effects of a number of circulatory
reflexes on the venous bed could be evaluated.
Attention was first directed to the well-known
carotid sinus reflex. The basic preparation
shown in figure 1 was modified in a manner
so as to permit study of the effects of altering
the pressure acting on the carotid sinuses on
the systemic arterial and venous beds.20 The
carotid artery bifurcations were completely
isolated in the manner described by He j 'mans
and Bouckaert.21 The common carotid arteries
were cannulated proximal to their bifurcations, and the external carotid arteries were
cannulated distally. Care was taken to avoid
542
BKAUNWALD ET AL.
MIC FLOW
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zooo
isoo
•cot
H
CAROTID
MEAN
L
CAROTID MEAN
A BU30C «J
H
FIGURE 2
Recordings, from above, of pressures in the superior vena cava (S.V.C.), inferior vena
cava (I.V.C.), aorta. Systemic flow and mean pressures in the right (R.) and left
(L.) isolated carotid, sinuses. Venous occlusion curves inscribed at a loto (left) and
at an elevated (right) pressure. The graph at the bottom indicates the time course and
the magnitude of the reflex increment in intravascular blood volume which resulted
from carotid sinus hypertension. (Reproduced by permission from Ross, J., Jr.,
Frahm, C. J., and Braunivald, E.: Influence of carotid baroreceptors and vasoactive
drugs on systemic vascular volume and venous distensibility. Circulation Research
9: 75,1961.)
denervation of the carotid bodies, the carotid
sinuses and their nerves. Perfusion of the
sinuses was carried out by the arterial pump,
and variations in perfusion pressures were
achieved b}' modifying the resistance of the
outflow line from the sinuses with a screwclamp. Bilateral cervical vagotomy was performed in these animals in order to minimize
the buffering effects of the aortic pressure receptors.
When carotid sinus pressure was suddenly
elevated while the systemic perfusion rate was
held constant, systemic vascular resistance
fell by an average of 40%, venous return declined, and the dag's systemic blood volume
increased. The increases averaged 12.9 ml/kg,
and the venous occlusion curves confirmed the
impression that venodilatation had taken
place, in a manner similar to that which was
observed during the infusion of trimethaphan
(fig. 2). In contrast, when carotid sinus pressure was suddenly reduced, systemic vascular
resistance increased by an average of 41% of
the control values, venous return suddenly
increased, and blood shifted from the dog into
the extracorporeal circuit. When the pump
Cirndation Research, Volume XII, May 196S
KEFLEX CONTBOL OF SYSTEMIC VENOUS BED
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output was changed in order to measure this
augmented venous return, it was found to
have increased by 27% of the control levels.
Analysis of the venous occlusion curves also
confirmed the impression that lowering of the
carotid sinus pressure had resulted in generalized reflex venoconstriction, quite similar to
that which occurred after norepinephrine infusion.
As a result of these studies, the baroreeeptor mechanism may be considered to assume
a broader integrative role in circulatory regulation. It appears that the well-known
homeostatic role of these receptors may be
extended to include the reflex control of the
entire systemic venous bed. Thus, when hypotension activates the baroreceptor mechanism,
or when a sympathoadrenal discharge is initiated by exercise, anxiety, or other stimuli, in
addition to arteriolar constriction, tachycardia, and augmented myoeardial contractility,
reflex venoconstriction also takes place and
results in an augmentation of venous return
to the heart and an increase in the cardiac
output.
REFLEXES ORIGINATING FROM
INTRACARDIAC BARORECEPTORS
The presence of baroreceptors in the walls
of the cardiac chambers and the pulmonary
vascular bed is now well established, and their
function in the reflex control of the circulation has been the subject of a number of
investigations.11' 22~27 Action potentials have
been recorded from afferent fibers originating
in the heart and lungs, 22 ' 23 and elevation of
pressures within the ventricular chambers24"27
and pulmonary vascular bed 25 ' 2S| "" has resulted in bradycardia,24"28 a decline in systemic arterial pressure,25"27 and in changes in
ventilation.25'26>28>29
In order to study the effects of stimulating
the cardiac baroreceptors on the venous bed,
the basic preparation shown in figure 1 was
again modified.30 Blood was circulated
through the heart by utilizing a separate circuit, entirely separated from the pump-oxygenator system. Oxygenated blood drained
from a reservoir through a cannulated pulCirculation Research, Volume XII. Mw 1SGS
543
nionary vein and into the left side of the
heart. In addition to the drainage cannula
placed in the right ventricle, a tube was inserted into a segmental pulmonary artery to
assure complete emptying of the right heart
and pulmonary artery; the blood from these
two drainage tubes was collected in an accessory reservoir. Circulation through the lungs
was prevented by mass ligation of each hiluni.
Alterations in pressure in the left side of the
heart could be induced by varying the inflow
from the reservoir while the ascending aorta
was kept clamped. When the inflow of blood
into the heart was increased, left heart pressures rose, since the only egress of blood was
through the coronary bed. Pressure in the
right side of the heart could be modified by
varying the resistance in the right ventricular
and pulmonary arterial drainage lines, since
clamping of the lines resulted in a "damming
u p " of blood in the right side of the heart.
In all 10 dogs studied, elevation of intracardiac pressures resulted in a decline of the
extracorporeal volume and, therefore, an augmentation of intravaseular blood volume,
which averaged 120 ml (fig. 3). In six of
these animals, the pressures were raised in
the right side of the heart, the left atrium and
the left ventricle, and in four dogs the pressure elevation was confined to the left side
of the heart, while right heart pressures were
not altered. The increments of intravaseular
volume observed in these two groups of experiments were similar. When intraeardiac
pressures were elevated in these experiments,
the pump output had to be diminished by an
average of 25.3% of the control values in
order to maintain the intravaseular blood
volume constant, i.e., an increase in the intraeardiac pressure resulted in a reflex venodilatation which diminished venous return by
approximately one-fourth of the control level.
In the course of these experiments, it was
observed that an increase in left ventricular
systolic pressure alone, or combined with an
elevation of left ventricular diastolic pressure
and left atrial pressure, resulted in a reflex
decline of systemic vascular resistance. How-
544
BEAUNWALD ET AL.
A.
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rr.l
50
CONTROL
9MIN.
6 MIN
B.
A
BLOOD VOLUME
__,
00 i 0
0-
Control
5
Minutes
FIGURE 3
(A.) Recordings, from above downtoard, of "pressure in the aorta (Ao.), systemic
In
flow (8.F.), pressures in the left ventricle (L.V.), and right ventricle (R.V.).
the panel on the left, ventricular pressure was elevated. Six minutes later, R.V.
pressure ivas also elevated (center panel). In the panel on the right, ventricular
pressures were lowered.
(B.) The alterations in systemic vascular volume which occurred simultaneously are
depicted. The vertical arrows indicate the points in time at which left and right
ventricular pressures were elevated.
ever, there was little change in systemic resistance when only right heart pressures were
altered.30
The reflex effects of the stimulation of intracardiac baroreceptors may be of importance in a variety of physiological and pathological circumstances. It would seem likely
that they operate in conjunction with the sino-
aortic mechanism in the regulation of both
arteriolar and venous tone and therefore of
arterial pressure and cardiac output. In addition, when intracardiac pressures alone are
elevated, as in the presence of congestive
heart failure or valvular stenosis, the resulting arteriolar and venous dilatation could
serve to decrease the hemodynamic burden
Circulation
rch,
Volume XII.
May 196S
545
KEFLEX CONTROL OF SYSTEMIC VENOUS BED
imposed on the heart by diminishing systemic
pressure and by decreasing venous return.
EFFECTS OF HYPOXIA
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In view of the profound circulatory changes
whicli occur during hypoxia, it was of interest
to determine whether this stimulus also alters
venous tone. In the experiments described
thus far, the gas mixture in the oxygenator
consisted of 98% O2 and 2% CO2. In order
to study the effects of hypoxia, this mixture
was suddenly changed to 10% 0 2 , 2% CO2,
and 88% N2. This resulted in a decline of
arterial O2 saturation from an average value
of 97.4% during the control period to an
average value of 50.1% during the experimental period.31
Hypoxia resulted in an increase in venous
return and a consequent decline in systemic
blood volume in all 11 dogs with intact chemoreceptors studied. The decrease in blood
volume averaged 16.0 ml per kg in the seven
"intact" dogs (including two animals which
had received succinylcholine and one animal
in which the phrenic nerves had been sectioned—fig. 4). In four dogs in which bilateral adrenaleetomy and splenectomy had been
performed, the blood volume decreased by an
average of 10.9 ml per kg. In order to maintain the volume of the extraeorporeal circuit
and therefore of the intravascular compartment constant, it was necessary to increase
the output of the pump by an average of 20%
of control values in dogs with intact chemoreceptors during the period of hypoxia. Hypoxia did not result in any change in venous
return or in intravascular blood volume in
the six dogs which had been subjected previously to denervation of the carotid and
aortic chemoreceptors.
These observations indicate that, in the
absence of any direct effect upon the heart
itself, hypoxia would increase the cardiac output as a result of venoconstriction and the
resultant increase in venous return. Since the
augmentation of venous return induced by
hypoxia was completely eliminated by interruption of the chemoreceptor reflex arc, it is
concluded that it resulted from stimulation
Circulation Research. Volume XII. May 196S
DECREASE
IN
INTRAVASCULAR
BLOOD VOLUME
DURING HYPOXIA
ML./KG.
•
•
NORMAL
ADRENALECTOMY
AND SPLENECTOMY
FIGURE 4
Decrease in intravascular blood volume during
systemic hypoxia. The circles represent observations carried out on dogs with adrenal glands and
spleen intact, while the squares represent observations carried out following bilateral adrenaleetomy
and splenectomy. The upper horizontal line represents the mean value in the "normal" dogs, while
the lower horizontal line represents the mean value
in the adrenalectomized-splenectomized
dogs.
of the carotid and/or the aortic chemoreceptors. Bilateral adrenaleetomy and splenectonvy
tended to diminish the decrease in blood volume that occurred during hypoxia, although
there was considerable overlap among the
values observed in these animals with those
obtained in the " i n t a c t " dogs. These findings
suggest that the release of eatecholamines
from the adrenal medulla and/or the contraction of the spleen, play a significant but not
a major role in the displacement of blood
from the systemic vascular bed during hypoxia. The observation that the decrease in
systemic blood volume induced by hypoxia
was not diminished by section of the phrenic
nerves or by skeletal muscle paralysis, indicates that in these open-chest dogs increased
activity of the thoracic pump induced by hy-
546
BRAUNWALD ET AL.
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FIGURE 5
Decrease in intravascular blood volume during
hypercapnia induced with 6% COS. The circles
represent observations carried out on dogs with
adrenal glands and spleen intact, while the squares
represent observations carried out folloiving bilateral adrenalectomy and splenectomy.
poxia was not responsible for the augmentation of venous return.
EFFECTS OF HYPERCAPNIA
Hj'percapnia was produced by changing
the gas mixture in the oxygenator from 98%
O2 and 2% CO2 to 94% O2 and 6% CO2. In
tins manner, the pCO2 of the blood pumped
into the arterial system was elevated. During
the control period, the arterial blood CO2
content ranged from 17.4 to 30.2 vol % with
an average value of 23.6 vol %. At the termination of the period during which 6 % CO2
was employed in the gas mixture, the CO2
content ranged from 24.0 to 37.0, with an
average value of 31.8 vol %. Although pCO r
was not determined directly in these experiments, the elevation in arterial CO2 content
substantiates the view that PCO2 actually
rose. An increase in venous return, and consequently a decline in intravascular blood
volume, occurred in all of the dogs studied.
This decrease ranged from 5.0 to 12.6 ml/kg,
with an average value of 9.5 ml/kg in nine
dogs (including one animal which had received succinylcholine—fig. 5). In order to
maintain the volume of the extracorporeal
circuit and therefore of the intravascular
compartment constant during the period of
C0 2 administration, it was necessary to increase the output of the pump by 22% and
28% of the control values in the two dogs
with intact cliemoreceptors studied in this
manner. In two additional dogs, which had
undergone adrenalectomy and splenectomy
prior to study, the blood volume decreased
by 8.8 and 13.8 ml/kg. In contrast to the
results observed with hypoxia, denervation of
the cliemoreceptors did not modify the alterations of venous return or of intravascular
blood volume induced by CO 2 ; in the two animals in which the carotid and aortic chemoreceptors had been denervated, the venous
return increased, and the intravascular blood
volume decreased by 11.0 and 12.9 ml/kg,
respectively.
In spite of the observation that CO has
a direct dilating effect on veins, the present
results indicate that in the whole animal this
stimulus induces venoconstriction. The data
obtained are compatible with the view that
the chemoreceptor reflex arc is of little, if
any, importance in mediating this CO2-induced venoconstriction. It appears likely that
it occurs as a result of the direct action of
CO2 on the central nervous system. The
adrenal glands and spleen did not appear to
play au important role in increasing venous
return.
In the dogs with intact cliemoreceptors,
adrenal glands and spleen, the changes in
mean aortic pressure during hypercapnea
ranged from 0 to —27%, with a decline
which averaged 9.8% of control values. In
the three dogs previously subjected to adrenalectomy and splenectomy, the mean aortic
pressure fell by an average of 21.0% of
control values. The observation that a decrease in systemic vascular resistance occurred when hypercapnea was induced in
the animals with intact chemoreceptors as
well as in those in which the ehemoreceptors
had been denervated, indicates that CO2 results in arteriolar dilatation, presumably because the local dilator effect predominates
Circulation Research, Volume XII. May 19CS
REFLEX CONTROL OF SYSTEMIC VENOUS BED
over any possible arteriolar constriction mediated either through a reflex or through the
central nervous system. In intact man, hypercapnca has been shown to result in an elevation of systemic arterial pressure, but this
effect is accompanied by an elevation of
cardiac output.
RESERPINE AND GUANETHIDINE ON
REFLEX VENOCONSTRICTION
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The concept that some antihypertensive
drugs act, at least in part, on the venous
S3'Stem is not new. A number of "clinical
studies indicated that following the administration of ganglionic blocking agents to
many hypertensive patients, cardiac output
and arterial pressure declined in parallel
fashion, i.e., there was relatively little change
in the calculated systemic vascular resistance.
32-36 RP^G j a jj j n c a r d i a c output was attributed
to a decreased venous return and to failure
of operation of the normal reflex venoconstrictor mechanism, particularly in the upright position. Support for this concept was
obtained from the observation that the socalled "central blood volume" decreased in
hypertensive patients who received ganglionic blocking agents,32 and from the finding
of Restall and Smirk that immersion into a
pool of water counteracted the hypotensive
action of these drugs. 37 The experimental
studies of Freis and collaborators,38 and of
Trapold,39 showed that venous return was
decreased by ganglionic blocking agents. A
number of workers have also shown that reflex elevations of venous pressure in a segment of hitman forearm vein can be prevented
by ganglionic blocking agents.40"*2
With this background of information, it
was of considerable interest to determine
whether some of the newer antihypertensive
drugs, such as reserpine and guanethidine,
affect reflex venoconstriction. The technique
described by Bartelstone for the demonstration of reflex venoconstriction, was employed
in these particular studies.1" In anesthetized,
open-chest dogs, the simultaneous occlusion
of the thoracic aorta distal to the left subclavian artery, and of the inferior vena cava
Circviation Re.ch.
Volume XII,
May 196S
547
just below the right atrium, resulted in isolation of the circulatory bed below the clamps,
while the circulation in the upper segment
was maintained. Bartelstone has shown quite
clearly, and in the course of these experiments
we have confirmed,43 that in this preparation,
the arterial and venous beds in the lower
segment of the animal are functionally separated. Venoconstriction occurring during major vessel occlusion can be recognized by an
abrupt rise in vena caval pressure which
is associated with the distension of the "vena
cava as the volume of blood contained by the
smaller veins and venules is diminished during venoconstriction. After the major vessels
were occluded, tests to determine the presence of reflex venoconstriction were carried
out repeatedly in each experiment by occluding both common carotid arteries for 45
seconds, or by electrically stimulating the
central end of the cut right vagus nerve for
30 seconds.
Reflex venoconstriction was blocked in each
of five dogs by the intravenous administration
of 0.5 mg/kg of reserpine. Treatment of 10
dogs with intravenous guanethidine, in doses
ranging from 1 to 10 mg/kg, also abolished,
or markedly reduced, reflex venoconstriction.
Reserpine eliminated reflex venoconstriction
secondary to carotid occlusion and central
vagal stimulation within 90 minutes after
its intravenous administration, at a time when
the heart rate response to cardioaccelerator
nerve stimulation was only reduced. This
difference in the degree of blockade of the
venoconstriction and of cardiac acceleration
suggests that different dose-response relationships may exist for these two responses.
The venopressor response to carotid occlusion and central vagal. stimulation was
blocked by guanethidine within the first five
minutes after injection during the initial
arterial pressor response.44 The time of onset
of this blockade fits well with the observations
of McCubbin et al. that during stimulation
of the lumbar sympathetic chain the arteriolar constrictor response in the leg is blocked
within five minutes after a guanethidine injec-
548
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tion.45 The observation that an infusion of
norepinephrine did not restore the venopressor responses to carotid occlusion or central
vagal stimulation at a time when these responses were blocked by reserpine OR guanethidine is consistent with the observation of
McCubbin et al.,45 who reported that the
infusion of norepinephrine did not restore
the arteriolar constrictor response to sympathetic nerve stimulation in dogs treated with
guanethidine. It is also consonant with other
observations in this laboratory 46 that the
antiadrenergic effect of guanethidine is not
dependent upon depletion of the tissue norepinephrine stores. An infusion of norepinephrine also failed to restore reflex venoconstriction which had been abolished by
reserpine. This observation was of interest in
view of the report by Burn and Rand*7 that
the abolition of the arteriolar constrictor
response to direct sympathetic nerve stimulation in the reserpine-pretreated animal
could be reversed by the administration of
norepinephrine. However, it correlates with
our finding that a norepinephrine infusion
did not restore the response of the reserpiriized' animal's heart to stimulation of the
right cardioaccelerator nerve.46
All of the observations presented thus far
were carried out on open-chest, anesthetized
dogs. These experimental conditions undoubtedly diminish the reactivity of the preparation, and it appears likely that they decrease
the magnitude of the reflex venous responses.
Accordingly, it was considered of great interest to extend some of these studies to intact
man.48 The method employed for the estimation of venous tone in the veins of the forearm
resembled that utilized by Gauer and Thron49
and represents a modification of the technique
recently described by Sharpey-Schafer.50 The
latter investigator utilizes a water-filled plethysmograph to record the rate at which
blood accumulates in the venous system of
the forearm during sudden venous occlusion.
In addition, venous pressure in one of the
veins is measured simultaneously and venous
tone is calculated as the increment in venous
BRATJNWALD ET AL.
pressure divided by the increment in volume.
Our modification of this technique consisted
of the substitution of a Whitney mercuryfilled rubber tube strain gauge plethysmograph 51 for the more cumbersome water
plethysmograph.
By means of this method, it was shown in
eight normal young adult subjects that the
oral daily administration of 25 to 50 nig
of guanethidine for three to five weeks abolished the reflex venous constriction which
occurred when the opposite hand was placed
into ice water or during leg exercise. Following discontinuation of the drug, the reflex
venoconstriction to these stimuli returned.
Similar results were obtained in four subjects
treated with 0.5 mg of reserpine. In view of
these findings, the likelihood that blockade of
reflex venoconstriction is of importance in the
antihypertensive action of reserpine and
guanethidine must be considered.
Summary
In a series of investigations on the control
of venous tone, it was shown in anesthetized,
open-chest dogs on cardiopulmonary bypass
that venoconstriction occurs during the infusions of norepinephrine and epinephrine,
while trimethaphan results in venodilatation.
Lowering the pressure acting on the carotid
baroreceptors and on the receptors within the
left atrium and left ventricle results in reflex
venoconstriction, while stimulation of these
receptors relaxes the veins. Hypoxia produces
venoconstriction as a result of stimulation
of the carotid chemoreceptors, but the venoconstriction which results from hypercapnia
evidently is primarily central in origin. Reflex
venoconstriction to carotid occlusion and central vagal stimulation can be blocked by the
administration of guanethidine and reserpine.
In intact, unanesthetized human subjects, to
whom these drugs were administered orally
in doses which are commonly utilized in clinical practice, reflex venoconstriction of the
forearm veins was blocked. These investigations emphasize that the systemic venous bed
reacts vigorously to neural and humoral stimuli, and that these reactions profoundly alter
Circulation Research. Volume XII, May 19S3
REFLEX CONTROL OF SYSTEMIC VENOUS BED
549
the cardiac output. In this manner, by exerting control of the rate at which the blood is
delivered into the systemic arterial bed. the
venous side of the circulation plays AN important role in the control of the arterial
pressure as well.
system in prcssor reflexes. Circulation Research
2: 405, 1954.
15. SALZMAN, E. W.: Reflex peripheral venoconstriction induced by carotid occlusion. Circulation Research 5: 149, 1957.
16. SARNOFF, S. J.: Some physiologic considerations
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Pulmonary Circulation, edited by W. R. Adams
and I. Veith. New York, Grune &• Stratton,
1959, pp. 273-282.
17. BARTELSTONE, H. J.: Role of the veins in venous
return. Circulation Research 8: 1059, 1960.
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Circulation Research, Volume XII, May 196S
551
REFLEX CONTROL OF SYSTEMIC VENOUS BED
Discussion
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Dr. Edward D. Freis, Washington, D. C.:
Some years ago, Dr. John Rose and 1 carried
out a similar type of experiment in dogs;
we replaced the left ventricle with a pump,
the output of which could be kept constant
at any given level. Under those circumstances,
we found the administration of norepinephrine increased the volume of the reservoir
which was receiving the drainage of blood
from the left atrium by an amount which
was comparable to the quantities Dr. Braunwald found after similar stimulation. The
transfer of blood from the dog to the reservoir
was so large in volume that it seemed inconceivable to us that it could be due to anything other than the constriction of the systemic venous system. We also observed that
ganglion blocking drugs had the opposite
effect; that is, there was a transfer of blood
from the reservoir to the animal in a similarly large amount. In those experiments, we
did not control possible changes in pulmonary
vascular capacity since we had replaced only
the left ventricle with a pump. Dr. Braunwald has used complete heart-lung replacement so that the observed changes in vascular
capacity must have occurred on the systemic
side of the circulation.
In connection with the effects of guanethidine on catecholamine stores in man, Dr.
Jay Cohn, in our laboratory, was unable to
find any inhibition of the tyramine pressor
response either after acute intravenous or
continuous oral administration of guanethidine in hypertensive patients. Maintenance of
the tyramine response was observed despite
significant orthostatic hypotension and inhibition of the Valsalva overshoot following
guanethidine.
Dr. J. Edwin Wood, Augusta, ' Georgia:
Dr. Braunwald, we have obtained information
which suggests that the collection of carbon
dioxide in exercising tissues acts as a stimulus for an afferent impulse to the central
nervous system subsequently resulting in a
sympathetic efferent discharge which in turn
Circulation Research, Volume XII, May 196S
causes venocoustriction. In essence, the evidence was accentuation of forearm venoeonstrictor responses to exercise of the legs
following pretreatment of the patient with
acetazolamide (Diamox). Do you have any
evidence to suggest that this is true of your
animals?
Dr. Leroy J. Hirsh, Chicago: Concerning
your experiments in which hypoxia was induced, did this hypoxia induce a change in
heart rate and cardiac output? Recently,
Mary Scott and de Burgh Daly published a
paper in which they perfused the carotid
chemoreceptors with hypoxic blood and observed that an increase or decrease in heart
rate occurred which depended upon initial
heart rate. When the initial rate was low,
perf usion of hypoxic blood caused an increase
in heart rate and when the initial rate was
high, the hypoxia caused a bradycardia. Dr.
Braunwald commented that although he was
not measuring heart rate, it did appear that
there were changes.
Dr. Eugene Braunwald, Bethesda, Maryland: The results, which Dr. Freis mentioned,
of tyramine injections in patients who have
been treated with guanethidine are extremelj'
interesting. His results are in accordance with
our observations in experimental animals,
which indicate that after the tissue norepinephrine stores have been markedly reduced,
but not depleted, by the administration
of reserpine, the effect of tyramine persists
unchanged. Now, I do not know of any data
in man which indicate the extent of the
depletion of norepinephrine in the tissues
of patients receiving the usual clinical doses
of this drug. However, Dr. Chidsey, Dr.
Morrow, and I have measured the norepinephrine content of the atrial appendages of
patients receiving ordinary clinical doses of
reserpine. Our values in patients not on reserpine averaged 1.82 /±g per g, while the values
in five patients receiving reserpine for six
weeks ranged between 0.04 to 0.34 /xg per
g. These data indicate that reserpine, in dosages commonly employed clinically, results in
552
BRAUNWALD ET AL.
marked reduction of myocardial norepinephthe reflex changes in heart rate during hyrine content.
poxia were variable but that a decrease in
In reply to Dr. Wood, we have no data
heai't rate occurred most commonly. These
to bear on your question as to whether COo
data on heart rate have been published in
in the peripheral tissues acts as a stimulant
extenso.1
for venoconstriction. Our experiments, howReference
ever, permit us to conclude that the chemo1. KAHLES, R. L., GOLDBLATT, A., AND BRAUNWALD,
receptors are not an essential link in the
E . : T l i e e f f e c t s o f a c u t e *rv<>™ °" t h e
. , - , . , ,
. .
systemic venous and arterial systems and on
COo-induced venoconstriction.
systemicvenousandarterialsystemsandonmyocarclhil
c o n t r a c t i l e force. J . Clin. I n v e s t .
In reply to Dr. Hirsh, T would agree that
41: 1553, 1962.
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Circulation Ret
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Reflex Control of the Systemic Venous Bed: Effects on
Venous of Vasoactive Drugs, and of Baroreceptor and
Chemoreceptor Stimulation
EUGENE BRAUNWALD, JOHN ROSS, Jr., RICHARD L.
KAHLER, THOMAS E. GAFFNEY, ALLAN GOLDBLATT
and DEAN T. MASON
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Circ Res. 1963;12:539-552
doi: 10.1161/01.RES.12.5.539
Circulation Research is published by the American Heart Association,
7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1963 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7330. Online ISSN: 1524-4571
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