Vol. 274, Issue 4, H1121-H1131, April 1998
Reduction in arterial compliance alters carotid baroreflex
control of cardiac output in a model of hypertension
Jeffrey T.
Potts1,
Kelly P.
McKeown2, and
Artin A.
Shoukas2
1 Department of Physiology,
Harry S. Moss Heart Center, University of Texas Southwestern
Medical Center, Dallas, Texas 75235; and
2 Department of Biomedical
Engineering, The Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205
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ABSTRACT |
Baroreflex
regulation of cardiac output is determined by the performance of the
heart as well as the available blood flow returning to the heart (i.e.,
venous return). We hypothesized that a decrease in arterial compliance
(Ca) would affect carotid baroreflex control of cardiac output by altering the slope of the
venous return curve (VR curve). Baroreflex control of systemic arterial
pressure (Pa), central venous
pressure (Pv), heart rate, cardiac output (CO), and peripheral vascular resistance
(R) were determined during bilateral
carotid occlusion (BCO) in spontaneously hypertensive (hypertensive,
HT) and Sprague-Dawley (normotensive, NT) rats.
Ca was determined from the rate of
arterial pressure decay when CO was transiently stopped, and the VR
curve was obtained during graded inflation of a vascular balloon
positioned in the right atrium. The inverse slope of the VR curve was
used as an index of the resistance to venous return (RVR). The baseline
slope of the VR curve was 
50.5 ± 3.3 vs. 35.5 ± 2.6 ml · kg
1 · min1 · mmHg1
in NT vs. HT, respectively (P < 0.05). Control values of Pa (96 ± 5 vs. 124 ± 8 mmHg) and R
[0.43 ± 0.04 vs. 0.80 ± 0.07 peripheral resistance units
(PRU)] were reduced in NT, whereas
Ca (0.062 ± 0010 vs. 0.036 ± 0.003 ml · kg1 · mmHg1)
was elevated in NT vs. HT, respectively
(P < 0.05). Analysis of the pressure
dependence of Ca demonstrated that
Ca was a nonlinear function of
Pa, and the exponential decay
constant for the
Ca-Pa relationship was reduced in HT (0.0055 ± 0.0012 vs. 0.0012 ± 0.0002 min, NT vs. HT, P < 0.05).
Baroreflex activation by BCO significantly increased
Pa
(
Pa, 20 ± 4 vs. 28 ± 3 mmHg) and R
(R, 0.16 ± 0.04 vs. 0.24 ± 0.06 PRU) in NT vs. HT, respectively. However, BCO significantly
decreased CO in NT but not HT (CO, 24 ± 5 vs. 4 ± 6 ml · kg1 · min1,
P < 0.05). In NT, RVR was increased
39 ± 9% during BCO (P < 0.05),
whereas RVR increased 8 ± 3% in HT
(P = NS). From these findings, we
conclude that the difference in baroreflex control of CO is mediated,
in part, by the reduction in Ca,
which minimized the baroreflex-evoked increase in RVR.
blood volume distribution; vascular capacitance; sympathetic
nervous system
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INTRODUCTION |
THE EFFECT OF arterial baroreceptor reflex control of
capacitive vessels on cardiac output (CO) regulation, particularly
reflex control of venous capacitance, is well known (5, 25, 29). However, less attention has been placed on the capacitive properties of
the arterial circulation and CO regulation. Recently, we have shown
that an acute increase in arterial compliance
(Ca) attenuated carotid
baroreflex control of CO and arterial blood pressure
(Pa) (24). The mechanism
mediating the reduction in baroreflex sensitivity appeared to be an
alteration in the slope of the venous return curve (VR curve), namely,
the resistance to venous return, which attenuated the CO response when
the carotid baroreflex was activated. However, the effect of a chronic
reduction in Ca, such as found in
hypertension, on baroreflex control of the CO and
Pa has not been shown
experimentally. Furthermore, it remains unknown whether this mechanism
is valid in a more chronic condition.
Changes in the resistive and capacitive properties of the arterial
circulation have been well documented in hypertension (2, 3, 13, 14,
16, 20, 21, 30, 33, 35, 36). These alterations include rarefaction (3,
13, 14), changes in vessel wall thickness-to-lumen ratio, and a shift
in the ratio of elastin to collagen in blood vessels (20, 35, 36).
Modifications in the mechanical properties of peripheral blood vessels
have also been shown to manifest changes in systemic hemodynamics. Particularly noted is the reported increase in peripheral vascular resistance, the decrease in Ca,
the increase in pulse wave velocity, and the redistribution of stressed
blood volume (14, 16, 18, 20, 21, 30, 34). These changes in circulatory
hemodynamics result in an elevation in arterial input impedance that
negatively affects left ventricular ejection and CO regulation (21).
It has been reported that a redistribution of stressed blood volume
between the peripheral and central circulation improved CO regulation
in a group of hypertensive patients (15, 33). These changes were
attributed to the reduction in total systemic vascular capacitance that
accompanied hypertension. Moreover, alterations in vascular resistance
and capacitance have been reported in both human (15, 33) and animal
models of hypertension (3, 14, 35, 38). Thus baroreflex control of
cardiovascular function may be affected, in part, by alterations in the
mechanical properties of the circulation (i.e., reductions in
Ca and elevations in vascular resistance). Furthermore, these changes may contribute to the redistribution of blood volume between the arterial and venous circulation that has been previously reported (15, 33).
Recently, we reported that selectively increasing
Ca attenuated carotid baroreflex
control of CO in anesthetized dogs (24). In these experiments, total
blood volume remained constant. Therefore, the blood volume in the
systemic vascular bed could only shift between arterial and venous
compartments. Because the magnitude of the baroreflex change in total
peripheral resistance was not affected by the increase in
Ca, we hypothesized that
attenuation of the CO response was due, in part, to a greater shift in
blood volume from the central venous circulation into the arterial
circulation. This shift in central blood volume effectively reduced
venous filling pressure and attenuated the CO response via the Starling mechanism. An alternative way to explain the mechanism, which is not in
opposition to the above, is in terms of the VR curve and the resistance
to venous return. It has been theoretically established (7) that
increasing the Ca causes an
increase in the resistance to venous return and consequently a decrease
in venous return (i.e., the flow returning back to the heart from the
periphery). The decrease in venous return, caused by the increase in
resistance to venous return, would then decrease the CO. Although Guyton and co-workers (6, 8, 9) provided the theoretical basis showing
the affect of vascular resistance and compliance on the VR curve in the
1950s, it was never proven experimentally until recently. Greene and
Shoukas (5) provided evidence showing that the slope of the VR curve
remained constant during baroreflex activation because of the opposing
effects of the carotid baroreceptor reflex on peripheral resistance and
vascular compliance. Moreover, Hatanaka et al. (11) used a lumped
four-parameter model of the systemic circulation to determine whether
an acute increase in Ca altered
baroreflex control of CO by changing the slope of the VR curve. When
Ca was acutely increased, they
reported that the baroreflex-evoked change in CO and
Pa was attenuated. This effect was
ascribed to an increase in the resistance to venous return. The
elevation in the resistance to venous return effectively attenuated the
changes in CO without affecting other baroreflex-controlled variables
(i.e., reflex changes in heart rate and peripheral vascular resistance). Taken together, these studies (5, 11, 24) suggest that the
relationship between Ca and
peripheral vascular resistance may be important in
Pa regulation and baroreflex
control of CO.
The purpose of the present study was to determine if a chronic
reduction in Ca, such as found in
experimental models of hypertension, may alter baroreflex control of
CO. We reasoned that if acutely increasing the
Ca increased the resistance to
venous return, the converse may also be true. Furthermore, it was
proposed that it did not matter if the differences of
Ca were acutely instilled or if
they existed chronically. Baroreflex changes in CO were compared
between normotensive Sprague-Dawley (SD) rats and spontaneously hypertensive (SHR) rats characterized by genetically different levels
of Ca and total peripheral
resistance (16, 20). We hypothesized that a reduction in
Ca in SHR would maintain CO during bilateral carotid occlusion (BCO) and thus preserve baroreflex control
of Pa despite the elevation in
basal peripheral vascular resistance. The influence of a chronic
elevation in vascular resistance and a reduction in vascular compliance
on baroreflex control of CO was evaluated by measuring the VR curve in
the presence and absence of BCO. The slope of the VR curve and the
resistance to venous return (1/slope) were used as indexes of the
affect of vascular resistance and compliance on baroreflex control of
CO in normotensive (NT) and hypertensive (HT) rats. A preliminary report of these findings has been previously published (23).
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METHODS |
Surgical procedures.
Fifteen- to twenty-five-week-old SD rats (Charles River) and SHR rats
(Taconic) (431 ± 27 vs. 352 ± 10 g, respectively)
were anesthetized with an intramuscular injection of a mixture of
ketamine (120 mg/kg) and acepromazine (50 µg/kg). Body temperature
was maintained at 37°C by a heated water-perfused surgical
platform. Catheters (PE-50, Intramedic) were inserted into the femoral
artery to record Pa and the
inferior vena cava via the femoral vein to record central venous
pressure (Pv). Both catheters
were advanced ~3 cm in the cephalad direction so that their tips were
in the central circulation. These catheters were connected to pressure transducers (Statham P23 Db and P23 BB) to monitor
Pa and
Pv, respectively. Placement of the
central venous catheter was confirmed at the termination of each
experiment by direct visual inspection. Supplemental anesthesia was
administered when required.
A midline incision was made on the ventral surface of the neck
extending to the sternum. The skin was retracted using silk ties, two
posteriorly and two anteriorly. The overlying fat and connective tissue
from the masseter muscle to the sternum were cleared by blunt
dissection. The sternohyoideus was carefully separated longitudinally
to expose the trachea, and a polyethylene catheter (PE-240, Intramedic)
was inserted. A vascular balloon (4-F Fogarty, Baxter Healthcare, Santa
Ana, CA) was carefully advanced to the junction of the caval veins and
the right atrium by the right external jugular vein. Placement of the
vascular balloon was confirmed by visual inspection at the end of each experiment.
The common carotid arteries were isolated by retracting the
sternohyoideus and sternomastoideus and carefully cauterizing the
omohyoideus. This approach exposed the common carotid artery and the
carotid bifurcation. Ligatures were placed around the cervical
vagosympathetic trunk bilaterally, and the nerves were tied and
transected to eliminate the buffering capacity of the aortic and
cardiopulmonary baroreceptors. Finally, a vascular occluder (2 mm ID,
In Vivo Metrics, Healdsburg, CA) was placed around each common carotid
artery ~1 cm proximal to the carotid bifurcation. Rapid inflation of
the vascular occluders temporarily decreased carotid sinus pressure to
activate the carotid sinus baroreceptor reflex.
The chest was opened using a right lateral thoracotomy at the level of
the second or third intercostal space, and the rat was placed on a
mechanical ventilator. A small retractor was used to separate the ribs
to expose the heart, and the thymus gland was reflected to expose the
ascending aorta. The aorta was carefully dissected free of surrounding
adipose and connective tissues until the region was clear and the aorta
was accessible. An ultrasonic transit-time flow probe (2.0 or 2.5 mm,
Transonic Systems, Ithaca, NY) was positioned around the ascending
aorta, and ultrasound gel (Sonostat, Lewistown, PA) was used to ensure
adequate coupling and signal quality. The thoracotomy was then closed
with 3-0 sutures; however, the pneumothorax was not reduced.
Mechanical ventilation was continued with supplemental oxygen through
the remainder of the experiment, and blood gases were measured to
determine the adequacy of ventilation.
Experimental protocols.
Carotid sinus baroreflex function was first assessed by BCO and
steady-state reflex changes in Pa,
Pv, and CO (~2 min after initiation of common carotid artery occlusion) were recorded. Reflex
changes in peripheral vascular resistance
(R) were calculated as
(PaPv)/CO
and expressed in peripheral resistance units (PRU; mmHg · ml1 · min · kg).
The effect of the intrinsic mechanical properties of the peripheral
circulation on venous return and CO was characterized by measuring the
slope of the VR curve (VR-Pv
relationship). Steady-state changes in
Pa,
Pv, and CO were obtained during
graded inflations of the vascular balloon positioned near the right
atrium. Approximately 15 s were required for the hemodynamic variables
to obtain a steady-state value after each inflation of the balloon.
Sequential inflations of the vascular balloon produced stepwise
reductions in Pa and CO and
simultaneous increases in Pv. The
VR curve was obtained by plotting the steady-state reduction in CO with
the corresponding increase in Pv
over the period of graded right atrial occlusion. Approximately
2-3 min were required to complete a single VR curve. This
procedure was again repeated during BCO. Finally, the stop-flow method
was used to obtain a measure of
Ca. Briefly,
Ca was estimated by rapidly
inflating the vascular balloon and recording the rate of decay of
Pa when CO was zero. To assess the
dependency of Ca on
Pa, we used a series of small
hemorrhage and volume transfusions (±0.5 ml) to alter
steady-state Pa and CO and then
repeated the zero-flow procedure.
Measurement of Ca, venous compliance,
and determination of the pressure dependence of
Ca.
Data obtained during the arterial pressure decay were fit to a
monoexponential decay function describing a two-element windkessel model of the arterial circulation. The equation is of the form
|
(1)
|
where
Pa(t) is arterial
pressure at time t,
Pai is the initial arterial
pressure before balloon inflation,
Pazf is the zero-flow arterial
pressure, and 
is the time constant for the rate of arterial
pressure decay. Arterial resistance is calculated from the equation
|
(2)
|
where
Ra is arterial
resistance
(mmHg · ml1 · min · kg)
and COi is aortic blood flow
before balloon inflation. Finally,
Ca is calculated from the equation
|
(3)
|
where
Ca is expressed in units of
ml · kg1 · mmHg1.
To assess the pressure dependence of
Ca, a series of rapid hemorrhage
and volume transfusions (in ±0.5 ml steps ranging from 3 ml
to +3 ml) was performed, and the stop-flow procedure was repeated. The
data were then fit to a nonlinear exponential function (17) using an
iterative curve-fitting algorithm (Sigma Plot, Jandel Scientific, San
Rafael, CA)
|
(4)
|
where
Ca'(Pa)
represents Ca as a nonlinear
function of Pa,
Ca0 is the
Ca extrapolated to an arterial
pressure of 0 mmHg, and 
is the exponential decay constant for the
Ca-Pa
relationship.
To obtain an estimate of the lumped venous pressure-volume (P-V)
relationship, the steady-state levels of venous pressure were plotted
with the corresponding change in blood volume (±0.5 ml) during the
stop flow. Linear regression analysis computed the slope of the venous
P-V relationship, and venous compliance (Cv) was than estimated.
Data analysis.
All pressure and flow signals were sampled and digitized at 100 Hz
using a Data Translation analog-to-digital convertor (model DT2801A,
Data Translation, Marlboro, MA) and a commercially available data
acquisition package (Global Lab, V3.0, Data Translation). Data were
displayed on line and stored on a 486 personal computer for later
analysis. All signals were also recorded on a four-channel ink recorder
(model 2400, Gould). Least-squares linear regression (Sigma Plot,
Jandel Scientific) of steady-state values for CO and
Pv was computed to obtain the
slope of the VR curve. The inverse slope of the VR curve was used as an
index of the resistance to venous return (RVR) (6, 7). Finally,
extrapolation of the slope to the zero-flow intercept was used to
estimate mean circulatory filling pressure
(Pmcf). Also, least-squares
linear regression (Sigma Plot, Jandel Scientific) of steady-state
values for Pv and the changes in
vascular volume (±0.5 ml) during hemorrhage/infusion was used to
determine the lumped venous compliance. Nonlinear curve-fitting
analyses were also computed to determine the rate constant for arterial
pressure decay () and the exponential decay constant for the
Ca-Pa
relationship () to determine the pressure dependence of
Ca.
Statistical analysis.
Baseline values for the cardiovascular variables and the parameters
used to estimate Ca and the
pressure dependence of the Ca-Pa
relationship were tested for differences using an unpaired t-test. Carotid baroreceptor reflex
changes in Pa, CO, and
R were compared using a paired
t-test. Linear correlations were also computed between Ca and these
three variables. The effects of BCO on the slope of the VR curve, RVR,
and Pmcf were also compared using
a paired t-test. For all analyses, a
statistical significance was set at P < 0.05. Group data are presented as means ± SE.
| |
RESULTS |
Baseline hemodynamics and responses to BCO.
A summary of the baseline hemodynamics and the reflex responses to BCO
are presented in Fig. 1 (see also Table
1). In HT rats, baseline mean
Pa and
R were increased and CO was reduced (P < 0.05). However, there was no
significant difference in baseline heart rate (HR) or stroke volume
(SV), although both HR (399 vs. 356 beats/min) and SV (0.58 vs. 0.53 ml/kg) were larger in NT vs. HT rats, respectively. Clamping the common
carotid arteries increased Pa and
R in both strains of rat. However, the
reflex change in CO differed considerably between groups. BCO
consistently decreased CO in NT rats, whereas CO increased or remained
unchanged in HT rats. The reflex HR responses to BCO were similar
between the two strains (P = NS).
However, SV decreased 16% in NT rats, whereas in HT rats, SV decreased
only 4% (NT vs. HT, P < 0.05).
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Fig. 1.
Summary data showing baseline (open bars) and reflex responses to
bilateral carotid occlusion (solid bars) for systemic arterial pressure
(SAP), cardiac output (CO), peripheral vascular resistance (PVR),
peripheral resistance units (PRU), heart rate (HR), and stroke volume
(SV) in normotensive (NT) and hypertensive (HT) rats
(n = 8 for NT and HT).
* Significant difference from baseline
(P < 0.05). ** Significant
difference between NT and HT (P < 0.05).
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Table 1.
Summary of baseline hemodynamics and the effect of bilateral carotid
occlusion in normotensive and spontaneously hypertensive rats
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Correlation analyses were computed to determine the effect of
Ca, as well as the reflex changes
on Pa and
R, on the CO response during BCO (see
Table 2). No significant relationships were
found between CO-Pa
(F = 0.75, r = 0.23, P = 0.40) or between
CO-R (F = 0.66, r = 0.21, P = 0.43). However, there was a
significant correlation between the level of
Ca and the baroreflex change in CO
(F = 8.80, r = 0.72, P = 0.02).
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Table 2.
Correlation analyses between baroreflex changes in cardiac output,
arterial blood pressure, peripheral vascular resistance, and level of
arterial compliance
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Measurement of Ca,
Cv, and determination of the pressure
dependence of Ca.
In a subset of animals (useable data were available from 5 NT and 3 HT
animals from each group), Ca was
estimated from the rate of Pa
decay when CO was temporarily reduced to zero using the stop-flow
method. An original trace illustrating the hemodynamic responses is
shown in Fig. 2. Rapid balloon inflation
reduced CO to zero over 2-3 s, and
Pa fell to a steady-state
zero-flow pressure within 10-15 s.
Ca was calculated using a
monoexponential pressure decay method during the stop-flow procedure.
The variables derived from these analyses are listed in Table
3. Arterial pressure (Pai) and arterial resistance
(Ra) before the
stop-flow procedure were greater in HT rats, whereas the derived rate
constant for arterial pressure decay () as well as the calculated
Ca were reduced
(P < 0.05). Although the zero-flow
arterial pressure (Pazf) tended
to be greater in HT rats, no significant difference was found between
the two rat strains.
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Fig. 2.
Original tracing showing effect of a small, rapid hemorrhage (2
ml) on decay of arterial pressure during stop-flow procedure. Inflation
of right atrial balloon (solid bar) rapidly reduced cardiac output
(flow) to zero, and systemic arterial pressure (SAP) fell
monoexponentially. A single hemorrhage reduced baseline SAP, flow, and
central venous pressure (CVP).
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Results from the nonlinear analysis of the effect of
Pa on
Ca is also shown in Table
3 and Fig. 3.
To generate these data, a series of small volume changes (±0.5 ml)
was used to increase and decrease
Pa.
Ca was then determined using the
stop-flow method. With this approach,
Pa was altered over a wide
pressure range (75-100 mmHg) to determine the pressure dependence
of Ca. Several points can be made
from these data. First, the nonlinear model used to assess the pressure
dependence of Ca was appropriate
(17). This was supported by the uniform distribution of the raw
residuals over the range of Pa
tested (see Fig. 3B,
inset). Furthermore, the magnitude
of the residuals was within ±1 SD from the mean, indicating that
this fit of the data was accurate. Second, there is an inverse
relationship between the level of
Pa and the level of
Ca. Therefore, when
Pa was increased,
Ca was reduced. Moreover, we found
that the effect of Pa on
Ca was variable and that at any
level of Pa,
Ca was reduced in HT. This was
substantiated by a significant difference in the exponential decay
constant () between NT and HT rats (0.0055 vs. 0.0012 min,
respectively; P < 0.05).
Furthermore, the predicted level of
Ca at
Pa values of 0 mmHg
[Ca(0)] and 250 mmHg
[Ca(250)] also
approached significance [Ca(0),
T = 2.4, P = 0.09;
Ca(250),
T = 2.2, P = 0.08]. Therefore, there was
a quantitative difference in the
Ca-Pa
relationship between NT and HT rats. These findings suggest that the
difference in Ca between NT and HT
was not due exclusively to the level of Pa.
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Fig. 3.
Representative examples of influence of arterial pressure
(Pa) on arterial compliance
(Ca). Hemorrhage and volume
transfusion (±0.5 ml) were used to rapidly change stressed blood
volume and Pa over a wide pressure
range (50-175 mmHg). Ca was
assessed at each level of Pa for
normotensive ( ) and hypertensive ( ) animals using stop-flow
procedure. A: data fit to nonlinear
equation (solid line) that describes relationship between
Pa and
Ca (see
METHODS for details). Illustrated is a
representative example from a normotensive
(left) and hypertensive animal
(right).
B: individual data from 5 normotensive
and 3 hypertensive animals were combined.
Inset: raw residuals between predicted
and observed values from fit.
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Steady-state levels of venous pressure were plotted with the
corresponding change in blood volume during the stop-flow procedure to
determine the lumped venous pressure-volume (P-V) relationship. Data
obtained from 5 NT and 3 HT rats are illustrated in Fig. 4. The derived slope of the venous P-V
relationship for NT and HT rats was 1.54 and 1.06 ml / mmHg, respectively. The correlation coefficients
(r2) for the
goodness of fit were 0.8934 and 0.8631 for NT and HT rats,
respectively. From the slope, we estimated that
Cv was reduced by 20% reduction
in HT rats (3.6 vs. 3.0 ml · kg1 · mmHg1,
NT vs. HT).
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Fig. 4.
Whole body venous pressure-volume relationship, an estimate of lumped
venous compliance. Steady-state changes in venous pressure are plotted
against changes in blood volume (±0.5 ml) in normotensive () and
hypertensive () rats. Solid lines represent linear regression
between changes in blood volume and changes in venous pressure. Slope
was 20% greater in normotensive vs. hypertensive rats.
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Effect of BCO on VR curve.
An example of the hemodynamic responses to graded right atrial
occlusion obtained from one NT and one HT rat are illustrated in Figs.
5 and 6,
respectively. Baseline Pa was
lower (110 vs. 150 mmHg) and CO higher (275 vs. 225 ml · kg1 · min1)
in NT vs. HT. Baseline central venous pressure (3.0 vs. 2.5 mmHg) was
similar in NT and HT rats. During control, graded balloon inflation
reduced systemic Pa and CO and
increased Pv. BCO (shown by the
stippled bars) reduced CO 20% in NT (275 to 250 ml · kg1 · min1,
P < 0.05). In comparison, CO
decreased 4% in HT (225 to 215 ml · kg1 · min1,
P = NS).
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Fig. 5.
Original tracing showing cardiovascular responses elicited by graded
reductions of venous return in absence
(left) and presence
(right) of bilateral carotid
occlusion (BCO) in a normotensive Sprague-Dawley rat. Shaded
bar indicates period of BCO. Note that pressor response during
BCO is accompanied by a fall in cardiac output. SAP, systemic arterial
pressure; CVP, central venous pressure; flow, cardiac output measured
from ascending aorta.
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Fig. 6.
Original tracing showing cardiovascular responses elicited by graded
reductions of venous return in absence
(left) and presence
(right) of BCO in a spontaneously
hypertensive rat. Shaded bar indicates duration of BCO. Note that
cardiac output is maintained during BCO. Definitions are as in Fig.
5.
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Figure 7 illustrates the VR curve
constructed from the data presented in Figs. 5 and 6. Graded balloon
inflation was well tolerated by all animals, and the hemodynamic
responses were very reproducible. The relationship between VR and
Pv was essentially linear over a
wide range of CO and Pv values.
The coefficients of determination
(r2) for the VR
curves obtained from least-squares linear regression ranged between
0.9360 and 0.9992, and an average value of 0.9839 ± 0.0173 was
obtained. Although baseline CO was similar in these two rats, the slope
of the VR curve was steeper in NT rats (58.1 ml · kg1 · min1 · mmHg1)
than in HT rats (39.2
ml · kg1 · min1 · mmHg1).
A summary of the baseline hemodynamics and the effect of BCO on
parameters used to describe the VR curve are presented in Table 4. BCO decreased the slope of the VR curve
28% in NT rats compared with 7% in HT rats
(t = 3.3,
P = 0.009). The reduction in slope corresponded to 39% increase in RVR in NT rats compared with 8% in HT
rats (t = 3.0, P = 0.018). This difference in
baroreflex control of the VR curve and CO occurred despite similar
reflex changes in Pa, HR, and
R (see Table 1). The zero-flow
pressure intercept of the VR curve, used as an index of
Pmcf, was similar between NT and
HT animals (t = 0.14, P = 0.89). BCO did not affect Pmcf
(P = NS).
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Fig. 7.
Example of venous return curve from a normotensive
(A) and hypertensive
(B) rat during control () and BCO
(). Venous return curves were obtained from data in Figs. 5 and 6.
BCO decreased slope of venous return curve 25% in normotensive rat vs.
5% reduction in hypertensive rat. Note steeper slope of venous return
curves in normotensive rat.
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DISCUSSION |
The purpose of this study was to determine whether genetic alterations
in resistive and capacitive properties of the arterial circulation
altered carotid baroreflex control of CO. We used the SHR as a model to
study these effects because these animals are characterized by
reductions in vascular compliance and elevations in vascular
resistance. In the present study, the level of
Ca was significantly reduced in
SHR. The reduction in Ca was due, in part, to a decrease in the mechanical distensibility of the arterial
compartment as indicated by the difference in the
Ca-Pa relationship (see Fig. 3). BCO produced vastly different changes in the
slope of the VR curve in NT vs. HT rats. In NT, BCO significantly decreased the slope, increased RVR, and decreased CO 11%. In contrast, BCO did not alter the slope of the VR curve, RVR, or CO in HT rats.
Changes in SV, calculated from the CO and HR responses, also differed
between strains. SV decreased 16% in NT compared with only a 4%
reduction in HT rats. Taken together, these findings support the
hypothesis that changes in vascular resistance and compliance can alter
baroreflex control of VR and CO in NT and HT, despite no
apparent difference in the pumping ability of the heart.
Baseline levels of CO and the slope of the VR curve were significantly
reduced in HT compared with NT animals. The reason behind this finding
is not readily apparent. Our finding is in agreement with Levy et al.
(16), who reported that baseline CO was reduced in SHR compared with NT
control rats. However, the level of CO in their study was lower than
the CO reported in our study. This difference may have been because of
the depressive actions of pentobarbital sodium that was used in the
study of Levy et al. (16). A reduction in baseline CO is also supported by Pfeffer et al. (22), who investigated the effect of aging on cardiac
function in different strains of NT and HT rats. However, they reported
that the peak pumping ability of the left ventricle (assessed by rapid
infusion of Tyrode solution) did not differ between strains and was
only decreased in SHR at 52 wk of age. These data suggest that the
pumping ability of the left ventricle was not compromised in SHR of
15-25 wk of age. Therefore, myocardial dysfunction cannot explain
the differences in CO between NT and HT rats in the present study.
In addition to the heart itself, the volume of blood returning to the
heart (i.e., venous return) plays an important role in determining
steady-state CO. Guyton and co-workers (6, 8, 9) developed the concept
of using venous return and cardiac function curves to determine the
relative contribution of peripheral and cardiac factors that determine
steady-state CO. They considered the inverse slope of the VR curve a
measure of the resistance to venous return and have reported that for
any given pressure gradient venous return is inversely proportional to
the quantitative value of its slope. The inverse slope of the VR curve
represents the algebraic sum of all the peripheral resistances weighted
proportionally to the compliance of individual circulatory beds (6).
Moreover, it has been demonstrated that reflex changes in total
peripheral resistance and peripheral vascular compliance (arterial and
venous) exert opposing affects on the slope of the VR curve (5, 11). These studies demonstrated that an increase in peripheral vascular resistance reduced venous return, whereas a decrease in vascular compliance increased venous return and steady-state CO in the absence
of changes in cardiac function.
In the present study, the baseline level of peripheral vascular
resistance and total systemic Ca
were significantly different between the two rat strains. Peripheral
vascular resistance in HT rats was approximately twice as large as the
measured level in NT rats. This finding is supported by a number of
previous studies (1, 3, 14, 20, 21, 26). If left ventricular afterload
was a critical factor in determining venous return and CO, then the
significant elevation in baseline vascular resistance should have a
negative influence on the heart (and on venous return). However,
despite the elevation in baseline resistance in HT animals, venous
return and CO were affected to a lesser degree during BCO. Our model
suggests that this effect is due, in part, to the reduction in
Ca in HT that favored venous
return.
Of particular interest to the present study, the level of
Ca was also significantly reduced
in SHR. From the correlation analyses (see Table 2), we can estimate
that the difference in Ca may account for ~50% of the CO response elicited by BCO. A significant reduction in Ca in SHR is in
general agreement with the findings of Samar and Coleman (27). In their
study, Ca was determined by
measuring the change in Pa
produced by small, rapid changes in arterial blood volume when blood
flow through the arterial circuit was zero. However, because this
approach was different from the modeling approach used in our study, it
is not possible to determine whether the difference in
Ca reported by Samar and Coleman
(27) was because of a change in the distensibility of arterial blood
vessels, or whether it occurred passively as a result of the elevated
Pa in SHR.
To determine the passive effect of
Pa on total systemic
Ca, we repeatedly measured
Ca while varying the level of
Pa over 100 mmHg (see Fig. 3 and
Table 3). Several important features should be gleaned from these data:
1) the relationship between
Pa and total systemic
Ca is nonlinear in both NT and HT
rats; 2) at any level of
Pa, the total systemic
Ca was found to be lower in HT rats; and 3) because the exponential
decay constant for the
Ca-Pa relationship was significantly reduced in HT rats, it follows that for
a given increase in Pa the
accompanying increase in stressed arterial blood volume must also be
reduced in HT rats. Therefore, our findings show that the arterial
compartment in HT animals was ~60% less compliant than their NT
counterpart. Furthermore, we have shown that the reduction in
Ca appears to be independent of
the higher blood pressure in HT rats.
Several different approaches have been developed to estimate total
Ca (31, 37). We chose a nonlinear
equation to fit these data over the wide range in
Pa values because a linear fit was not acceptable. This is contrary to the reported findings from Samar
and Coleman (27). They reported that over a smaller pressure range
(7-40 mmHg), the pressure-volume relationship of the arterial compartment was essentially linear. It is reasonable to assume that
larger changes in Pa are required
to exhibit the nonlinear behavior on the
Pa-volume relationship. It is
known that Ca is a nonlinear
exponential function of Pa (17).
With the use of a nonlinear model to assess the pressure dependence of
Ca, it was concluded that over a
wide range of Pa (50-180
mmHg), the compliance of the arterial bed was reduced in SHR.
In addition to a reduction in Ca,
a decrease in the capacitive properties of the venous compartment has
also been reported in hypertension. Greenburg and Bohr (4) found that
the distensibility of portal vein strips in SHR was reduced when
compared with normotensive controls. Simon (30) compared the upper body
and lower body venous pressure-volume relationship in SHR and NT
controls. In SHR, they reported that the venous pressure-volume
relationship was shifted down toward the pressure axis showing that the
slope of the pressure-volume relationship was reduced in hypertension. However, it was not possible to discern whether these changes in
pressure-volume relationship were because of alterations in venous
compliance, unstressed venous volume, or both. Samar and Coleman (27)
used the relationship between Pmcf
and blood volume to evaluate whole body venous compliance and
unstressed volume. They also reported a shift in the
Pmcf-blood volume curve toward the
pressure axis in SHR. This shift was similar to the pressure-volume shift reported by Simon (30). However, within a range of
Pmcf (4-12 mmHg), they found
no difference in whole body venous compliance. Therefore, they
explained the shift in the pressure-volume curve by a decrease in
unstressed volume in SHR.
We also found a difference in the venous pressure-volume relationship
between NT and HT animals when vascular volume was changed (see Fig.
4). The values for lumped venous compliance are in general agreement
with those reported by Samar and Coleman (27). Although this approach
constitutes a rough estimate of venous compliance, the effect of a
change in the unstressed venous volume cannot be directly determined.
Furthermore, the contribution that this reduction in
Cv may have exerted on the slope
of the VR curve was not directly assessed in the present study.
However, because the resistance to venous return is given by the
product of
[Ca/(Ca + Cv)] · R,
it follows that a decrease in Cv
would increase the [Ca/Ca + Cv] ratio and increase the
RVR. Therefore, our model predicts that a reduction in
Cv would negatively affect venous return and CO during BCO.
Proposed mechanism.
The aorta and large arteries serve not only as conduit vessels but also
as a blood storage compartment. Furthermore, the elastic properties of
blood vessels, and the higher intravascular pressure in arteries,
enable large arteries to accumulate and store a considerable blood
volume (Va). Because of the
nonlinearity of the Pa-volume relationship (17), the magnitude of
Va will depend on the pressure in
the compartment (Pa), the
compliance of the arterial compartment (Va/Pa),
and the arterial unstressed volume. Therefore, any increase or decrease
in Pa must be associated with a
concomitant increase or decrease in blood volume in the arterial
compartment. We have proposed a lumped-parameter model of the
circulation to illustrate the potential impact that a reduction in
Ca may have on the mobilization of
blood volume (see Fig. 8). Distributed models may be more accurate in predicting the changes in pressure, flow, and the redistribution of blood volume between specific vascular
beds, but there exists a problem. In most instances, we do not know the
absolute parameter values or even the relative changes in these
parameters. Therefore, although the structure of a distributed model
may be more appropriate, the parameter values cannot be experimentally
confirmed. Thus the principal reason for the popularity of
lumped-parameter models is that one can determine the parameter values
and then use them to predict the gross hemodynamic features of the
circulation (8, 11, 24, 28, 29).
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Fig. 8.
Theoretical model of circulation to explain how a decrease in
Ca may alter distribution of blood
volume between arterial and venous compartments. Model consists of an
arterial compartment, a venous compartment, a variable peripheral
resistor (R), a volume reservoir,
and a fixed-rate flow pump. Cross-sectional area of each compartment
represents vascular compliance, and height of fluid column represents
hydrostatic pressure in each compartment. Constriction between arterial
and venous compartments represents peripheral vascular resistance. Note
that this constriction is larger in hypertensive model. Venous pressure
(Pv) and flow rate are fixed.
A: normotensive model.
B: changes in model used to reflect
systemic hypertension. Note that, at a given flow rate, pressure in
arterial compartment (Pa) will
be greater in hypertensive animal because of larger
R. To determine effect of a decrease
in Ca on blood volume,
R was increased same amount in both
models. At a constant flow rate, this resulted in same increase in
Pa in both models. However, there
was a larger increase in arterial volume (solid area) in normotensive
vs. hypertensive model. This was accompanied by a larger corresponding
decrease in volume reservoir (Vol) in normotensive model. Predicted
outcomes from model (baseline and steady-state changes) are summarized
in box. See DISCUSSION for a detailed
description of predicted responses from model.
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|
The lumped-parameter model presented here is a representation of the
peripheral circulation consisting of an arterial compartment, a venous
compartment, and a variable peripheral resistor. For our discussion
concerning the importance of Ca on
CO regulation, we have replaced the heart with a fixed-rate flow pump
and have included a venous volume reservoir. This model has been
extensively used by Shoukas and Sagawa (29) to demonstrate the
importance of carotid baroreflex control of venous capacitance in CO
regulation. A modification of the Shoukas-Sagawa model illustrates how
this model has been adapted to reflect the hemodynamic changes reported in hypertension. Several features of this model should be noted. First,
the cross-sectional area of each compartment reflects the compliance of
that compartment, in so much as a change in pressure is accompanied by
a change in stressed volume. The cross-sectional area in the
hypertensive model has been reduced 50% to reflect the decrease in
Ca (16, 21, 26, 27). Second,
constriction of the tube between the arterial and venous compartments
represents the peripheral vascular resistance. Note that in the
hypertensive model this constriction is larger than in the normotensive
model. This has been done to reflect the elevation in vascular
resistance found in SHR (21). Third, the height of each fluid column
indicates the blood pressure in each compartment. Finally, we have set
the flow rate and venous pressure at a fixed level so that we can clearly demonstrate how a reduction in
Ca would affect arterial and
venous volumes. Thus, at any given flow rate, the
Pa in the hypertensive model will
be elevated.
To determine the effect of a decrease in
Ca on venous return, we increased
vascular resistance equal amounts in both models. Under this condition,
the increase in Pa must be
proportional to the increase in R. Our
data indicated that the baroreflex-induced increase in vascular
resistance was similar in the two rat strains (37 vs. 28%, NT vs. HT,
respectively). Therefore, when R was
increased to the same degree in both the NT and HT model, our model
predicted that Pa would increase a
similar amount (20 vs. 23%, respectively). However, despite similar
increases in pressure, a greater fall in reservoir volume was predicted
in the NT model. This volume was pumped out of the venous reservoir and
into the arterial compartment by the fixed-rate pump to generate the
increase in Pa. The magnitude of
this volume shift was dependent on the pressure-volume relationship (i.e., compliance) of the arterial compartment. The decrease in venous
volume in this model is analogous to a decrease in central blood volume
in an intact animal. If central blood volume is reduced, this can lead
to a decrease in end-diastolic volume and SV and a shift down the
Starling curve. Thus, in the present study, the decrease in SV in NT
during BCO may have resulted from a greater increase in arterial volume
due to the larger Ca. This may
explain the difference in CO regulation found in this study and
reported elsewhere (7, 11, 12, 19, 32).
Limitations.
Because the outflow tract of the left ventricle was not occluded during
the stop-flow procedure and the heart continued to beat, the decay rate
of the downstream Pa was
lengthened, and this would lead to an overestimation of
Ca. This would certainly pose a
problem if there was a difference in the cardiopulmonary blood volume
between NT and HT rats. However, it is not known whether such a
difference exists. It has been reported that cardiopulmonary blood
volume is larger in essential and renovascular HT patients compared
with aged-matched NT controls (15, 33). If this were also the case in
HT rats, then a larger blood volume would have been pumped into the
arterial circulation during the stop-flow procedure. This larger blood
volume would have increased the time constant for
Pa decay and resulted in a larger
Ca in the HT animals (because
Ca was calculated as
/Ra).
Therefore, because we reported that
Ca was reduced 50% in HT rats in
the absence of clamping the ascending aorta, it is likely that the
actual difference in total systemic
Ca between NT and HT animals was
larger than the 50% difference reported in the present study.
Lack of complete vascular isolation of the carotid sinuses may have
resulted in further deactivation of the carotid baroreceptor reflex
during graded occlusion of the right atrium. However, it is unlikely
that this altered our results or our interruption of these experiments
for the following two reasons. First, BCO decreases sinus pressure
close to, or below, the threshold pressure for the baroreflex.
Furthermore, carotid sinus pressure must follow the progressive
reduction in Pa during the balloon
inflation procedure. Therefore, carotid sinus pressure should remain
well below the minimal threshold pressure required to activate the
reflex when the VR curve was measured during BCO. Second, we have
repeated these experiments in rats after vascular isolation and
constant perfusion of the carotid sinus regions. We found that the
slope of the VR curve in a normotensive rat was decreased to a similar degree when the carotid sinus regions were isolated and perfused at
constant pressure as when the baroreflex was activated by BCO (Potts
and Shoukas, unpublished observations).
In summary, hypertension is known to alter CO regulation by decreasing
myocardial function and increasing the resistive properties of the
peripheral circulation. In addition to these factors, the present study
demonstrated that a reduction in
Ca decreased the resistance to
venous return in an experimental model of hypertension. It is proposed
that the difference in Ca may have
contributed to the difference in CO regulation by shifting the volume
of blood between the arterial and venous circulation. A theoretical
model has been proposed to predict how a reduction in
Ca may alter the distribution of
blood volume.
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ACKNOWLEDGEMENTS |
This work was supported by National Heart, Lung, and Blood
Institute (NHLBI) Grant HL-19039. J. T. Potts was supported by NHLBI
Postdoctoral Training Grant T32-HL-07581.
| |
FOOTNOTES |
Address for reprint requests: A. A. Shoukas, Dept. of Biomedical
Engineering, Johns Hopkins University School of Medicine, 720 Rutland
Ave., Baltimore, MD 21205.
Received 11 March 1997; accepted in final form 18 December 1997.
| |
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Abstract
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