1078
Contribution of Regional Vascular Responses
to Whole Body Autoregulation in Conscious
Areflexic Rats
Carmen Hinojosa-Laborde, Bruce H. Frohlich, and Allen W. Cowley Jr.
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We designed studies to evaluate the autoregulation response during volume expansion in three
major circulation regions (intestine, kidney, and hind limb) during simultaneous determination of whole body autoregulation in conscious areflexic rats. Cardiac output was measured with
chronically implanted electromagnetic flow probes on the ascending aorta. Regional blood flow
velocity was measured with pulsed Doppler flow probes on the superior mesenteric (n=7), left
renal (n=7), and right iliac (n=7) arteries. Doppler flow probes were calibrated in situ in each
rat to determine regional blood flow values. Neurohumoral reflex control of pressure was
removed pharmacologically, and blood pressure and cardiac output were returned to resting
control values with intravenous norepinephrine infusion, which was maintained at that
constant level throughout the study. Hemodynamic changes were measured in response to blood
volume expansion with infusion of 0.9 ml blood over 6 minutes. This small change in blood
volume resulted in significant increases in vascular resistance of 15% in the whole body, 8% in
the intestine, 18% in the kidney, and 15% in the hind limb. The pressure-flow slope, used as an
index of autoregulation (slope=0, perfect autoregulation; slope=l, rigid vasculature), averaged
034 in the whole body, 0.52 in the intestine, 0.19 in the kidney, and 039 in the hind limb. When
compared with the whole body, blood flow autoregulation was less in the intestine, greater in the
kidney, and the same in the hind limb. (Hypertension 1991;17:1078-1084)
T
he whole body autoregulation response has
been demonstrated recently and quantified
in unanesthetized areflexic rats.1-2 These
studies revealed that in the absence of the rapidacting reflex controllers of blood pressure, small
increases in blood volume (5%) caused significant
increases in total peripheral resistance (TPR) (22%).
Whole body autoregulation has been defined to be a
result of the summation of all the regional autoregulatory responses. These responses have been proposed to be responsible for the rise of TPR in
volume-dependent forms of hypertension.3-7 The
contribution of the regional autoregulatory responses
in major flow regions to TPR in volume-dependent
hypertension has remained uncertain. The three major flow regions evaluated in this study, which represent at least 75% of the cardiac output (CO), are the
skeletal muscle, intestinal, and renal circulations.
Given the potential importance of the responses of
From the Department of Physiology, Medical College of Wisconsin, Milwaukee, Wis.
Supported by program project grant HL-25987-5 from the
National Institutes of Health and by grant-in-aid #89-GA-08 from
the American Heart Association, Wisconsin Affiliate.
Address for correspondence: Allen W. Cowley, Jr., PhD, Department of Physiology, Medical College of Wisconsin, 8701
Watertown Plank Road, Milwaukee, WI 53226.
these regional circulations during changes of blood
volume and CO in normal and hypertensive states,
the present studies were designed 1) to characterize
the autoregulation response to an increase in blood
volume in the skeletal muscle, intestinal, and renal
circulations in conscious rats, and 2) to compare the
relative contributions of the mesenteric, renal, or
hind limb circulations to the whole body autoregulation response in the same animal.
Methods
Surgical Instrumentation
Three surgical procedures were performed to instrument the rats with regional Doppler flow probes,
an aortic electromagnetic flow probe, and arterial
and venous catheters. In the first operation, male
Sprague-Dawley rats weighing 300-350 g were anesthetized with a mixture of acepromazine (5 mg/kg
i.m.) and ketamine (50 mg/kg i.m.). Doppler flow
probes with various lumen sizes were constructed in
our lab according to the method of Haywood et al8
using 20-MHz piezoelectric crystals (DBF-120A,
Crystal Biotech Inc, Holliston, Mass.) and insulated
silver-plated copper wire leads (Cooner Wire,
Chatsworth, Calif.). The probes were selected to
provide a proper fit around the vessel and were
Hinojosa-Laborde et al
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implanted on either the superior mesenteric artery,
the left renal artery, or the right iliac artery via a
midline incision. The wire leads were tunneled subcutaneously and secured to the back of the neck. The
animals were allowed 5-7 days to recover and to
ensure fibrosis of the flow probes on the vessels.
In the second surgical procedure, the rats were
anesthetized with pentobarbital (65 mg/kg) and also
treated with atropine sulfate (0.4 mg/kg) to depress
respiratory tract secretions. The rats were intubated
and respired with room air using a rodent respirator
(model 680, Harvard Apparatus, South Natick,
Mass.). A left thoracotomy through the third intercostal space exposed the ascending aorta, and an
electromagnetic flow probe was implanted (series
EP100, Carolina Medical Electronics, Inc, King,
N.C.). The flow probe cable was secured subcutaneously across the lateral thoracic area, and the connector end of the flow probe was exteriorized dorsally. The rats were allowed 3-5 days to recover.
A third brief surgical procedure then was used to
instrument the rats with an arterial catheter for the
measurement of arterial pressure and three venous
catheters for separate infusions of norepinephrine,
blocking drugs, and donor blood. This was performed during light inhalation anesthesia (methoxyflurane), and catheters were placed in the left
femoral artery, left femoral vein, right femoral vein,
and right jugular vein. The catheters were tunneled
and exteriorized at the back of the neck. The
animals were subjected to the experimental protocol 1-2 days after catheter placement.
Experimental Protocol
Three groups of rats were used in this study to
evaluate mesenteric flow (n=7), renal flow (n=7), or
iliacflow(n=7) in the unanesthetized state. The rats
were not fasted before the experiment. During the
experimental protocol, the rats were placed in a
Plexiglas restrainer contained within a quiet environmental chamber. Mean arterial pressure (MAP) was
measured from the arterial catheter with a pressure
transducer (Statham P23Dd, Gould Instruments, Oxnard, Calif.); CO was measured by an electromagnetic flowmeter (model 501D, Carolina Medical);
and Doppler flow velocities were measured by a
multichannel pulsed Doppler flowmeter (ValpeyFisher, Hopkinton, Mass.).
The rats were allowed to acclimate to the restrainer while hemodynamic variables were recorded
for 1 hour. After this equilibration period, pharmacological blockade was performed of the major neurohumoral systems involved in arterial pressure regulation. Chlorisondamine chloride (10 mg/kg) and
methscopolamine bromide (0.5 mg/kg) were given to
block ganglionic transmission of the autonomic nervous system. Captopril (1 mg/kg) was used to inhibit
angiotensin II synthesis. A specific vascular vasopressin receptor antagonist, d(CH2)jTyr(Me)AVP (10
Mg/kg), prevented the vasoconstrictor effects of circulating vasopressin. These drugs were administered
Regional Autoregulation in Rats
1079
intravenously as a bolus injection and then infused
continuously (0.015 ml/min) as a mixture throughout
the protocol. The effectiveness of these blocking
agents was tested in our laboratory as described
previously.1 Immediately after neurohumoral blockade, MAP and CO were restored and maintained at
normal control levels with a constant infusion of
norepinephrine (0.5-1.0 ^.g/kg/min). Although the
neurohumoral blocking agents and norepinephrine
were administered intravenously in saline, a special
effort was made to minimize the volume of saline
introduced into the circulation. We calculate that,
during an hour of infusion of blocking drugs and
norepinephrine, the animal received approximately
1.2 ml saline. Assuming the rats had normal renal
function, this amount of saline will not affect the
volume status of the rat.
After a 30-minute hemodynamic stabilization period, the animals were subjected to an acute blood
volume expansion by infusion of 0.9 ml donor blood
into a venous catheter at a rate of 0.15 ml/min for 6
minutes. This infusion was estimated to cause a 5%
increase in blood volume. The volume expansion was
sustained for 5 minutes after the infusion. Then 0.9
ml of blood was removed to return blood volume to
normal levels. The preparation of donor blood has
been described previously and consisted of red blood
cells that were obtained from a donor animal and
were washed and resuspended in physiological saline
solution containing 9% albumin.1
Flow Probe Calibration
At the end of each experiment, each Doppler flow
probe was calibrated in situ to determine absolute
flow values. Blood was infused at various rates (0-15
ml/min) through the artery proximal to the probe
while Doppler shifts were recorded. We found the
calibrations to be reproducible for each probe. However, there was variability between probes, and the
relation between Doppler shift and blood flow often
was not linear at high flow rates.9 The regional flow
data presented in this study therefore are expressed
as absolute flow (milliliters per minute) based on the
calibration of each flow probe used in these studies.
The electromagnetic flow probes used in this study
also were calibrated to determine absolute flow values. Theseflowprobes were calibrated on an isolated
blood vessel infused with whole blood.
Statistical Analysis
One-way analysis of variance with repeated measures was used to evaluate the hemodynamic changes
in response to volume expansion, followed by a
Duncan's multiple range test to determine significant
differences in these hemodynamic changes when
compared with control values. Linear regression
analysis was used to determine the slopes of the
pressure-flow relation for whole body and regional
responses. To evaluate differences between whole
body and regional pressure-flow relations, the slopes
of the lines were compared using a two-slope com-
1080
Hypertension
Vol 17, No 6, Part 2 June 1991
TABLE 1. Resting Hemodynamic Values in Conscious Rats During Intact and Areflexic Conditions
Intact
Areflenc
Mean arterial pressure (mm Hg)
123±2
114±2*
Cardiac output (ml/min)
112±3
107±4*
Mesentenc flow (ml/min)
13±2
10±2
Renal flow (ml/min)
11±2
10±2
Hind limb flow (ml/min)
9±2
9±1
Total peripheral resistance
(mm Hg-min/ml)
l.ll±0.04 1.08±0.05
Mesentenc resistance (mm Hg-min/ml) 12.2±3.1
13 1±2 0
Renal resistance (mm Hg-min/ml)
14 1±3.1
14 7±3 3
Hind limb resistance (mm Hg-min/ml) 15.5±1.9
13.2±1.3
Values are mean±SEM. Hemodynamic values during areflenc
conditions were obtained while rats were infused with norepinephrine.
'Significant difference between intact and areflexic.
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parison test that is defined as a t test for differences
between two regression lines.10 All data are expressed as mean±SEM; a value of p< 0.05 was considered statistically significant.
Results
Baseline Hemodynamics
Table 1 shows resting hemodynamic values before and after neurohumoral blockade. MAP was 9
mm Hg less (p<0.05) and CO was 5 ml/min less
(p<0.05) in the areflexic state. These were small
differences, and the calculated TPR values were not
different between intact and areflexic states. The
flows and resistances of the three regions were all
similar between intact and areflexic conditions,
indicating that redistribution of blood flow in the
mesenteric, renal, and hind limb circulations did
not occur after restoration of MAP, CO, and TPR
to nearly normal levels with norepinephrine after
neurohumoral blockade.
Hemodynamic Responses to Volume Expansion
Figure 1 represents the average whole body hemodynamic values observed before and during the
6-minute infusion of blood (n=21). Volume expansion caused small but significant increases in CO
after 1 minute of blood infusion. After 2 minutes of
infusion, MAP and TPR increased significantly and
continued to increase throughout the infusion period. At the end of the 6-minute volume expansion,
CO had increased 8%, MAP had increased 23%, and
TPR had increased 15%.
Figure 2 shows the regional hemodynamic responses to volume expansion. In the intestinal circulation (n=7), blood volume expansion caused a significant increase in mesenteric blood flow, from
10.4+1.6 to 11.5±1.4 ml/min after 6 minutes. This
represents a 13% increase in blood flow, which was
associated with a 21% increase in MAP and an 8%
increase in mesenteric resistance. In the renal circulation (n=7), blood volume expansion caused a very
small increase in renal blood flow, from 9.9 ±1.7 to
TIME (min)
FIGURE 1. Line graphs showing mean arterial pressure
(MAP), cardiac output (CO), total peripheral resistance
(TPR), and changes in blood volume (A BLD. VOL) before
and during 6-nunute infusion of blood in conscious areflexic
rats (n=21). 'Significant difference from 0 minutes, shown as
the shaded area (p<0.05).
Data are expressed as
mean±SEM.
10.5 ±1.8 ml/min, which was statistically different
from control only during the last minute of blood
infusion. This 6% increase in renal blood flow was
associated with a 24% increase in MAP and an 18%
increase in renal resistance. The hemodynamic response of the hind limb circulation after blood volume expansion was a small but significant increase in
iliac blood flow, from 9.2±0.9 to 10.0±1.0 ml/min.
This 10% increase in iliac blood flow was associated
with a 25% increase in MAP and a 15% increase in
hind limb resistance.
Pressure-Flow Relations
Figure 3 shows the pressure-flow relations for the
whole body and the three regional circulations. The
data are plotted as the fractional change in pressure
(AP/P) and the fractional change in flow (AF/F)
during each minute of blood infusion. AP represents
the difference between the MAP at 1-minute time
intervals and MAP at zero time (P). AF represents
the difference between CO or regional flow at the
same 1-minute time intervals and flow at zero time
Hinojosa-Laborde et al
0.8
Regional Autoregulation in Rats
1081
n
04-
NO AUTOBIGUt-mON
03-
0J3-
0.1 _
*
.
-
-
•
0.0
* COUPLET! AUTOBKULATION
-0.1
-0.1
0.0
0.1
0.2
0.3
0.4
0.8
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AP/P
FIGURE 3. Plot showing normalized pressure (P) -flow (F)
relations during volume expansion in the whole-body (solid
line; n=21), intestinal (circles; n=7), renal (triangles; n=7),
and hind limb (squares; n=7) circulations. Shaded lines indicate
theoretical pressure-flow relations for a system that shows no
autoregulation and a system that shows complete autoregulation.
The slope of the pressure-flow relation was 0.34±0.02 (T=0.58)
in the whole body, 0.52±0 09 (r=0.61) in the intestinal circulation, 0.19±005 (r=0.42) in the renal circulation, and0.39±0.06
(r=0 48) in the hind limb circulation.
TIME (min)
FIGURE 2. Line graphs showing mean arterial pressure
(MAP), regional flow, and regional resistance before and
during 6-minute infusion of blood in the intestinal (circles;
n=7), renal (triangles; n—7), and hind limb (squares; n=7)
circulations. Asterisk indicates significant difference from 0
minutes, shown as the shaded area (p<0.05). In the upper
panel, there were significant increases in MAP in all three
groups after the second minute of infusion. In the middle
panel, asterisks above the symbols correspond to mesentenc
flow, whereas those below the symbols correspond to iliac flow.
Renal flow was significantly increased only during the last
minute of volume expansion. In the lower panel, asterisks are
located adjacent to the corresponding data points. Data are
expressed as mean±SEM.
(F). The ratios AP/P and AF/F were determined
before volume expansion (time=0) and at l-minute
intervals during the 6-minute protocol. The regression lines for the pressure-flow relations were determined by seven points in each rat with the use of a
linear regression analysis. The data points plotted in
Figure 3 represent the averaged pressure-flow relations in each group. The slopes of the regression lines
can be used to represent the autoregulatory capacity
of the regional circulations such that a nonautoregulating system would have a slope of 1, and a
perfectly autoregulating system would have a slope of
0. The slope of the pressure-flow relation in the
whole body was 0.34±0.02. In the regional circulations, the pressure-flow relations had slopes of
0.52 ±0.09 in the intestinal circulation, 0.19 ±0.05 in
the renal circulation, and 0.39 ±0.06 in the hind limb
circulation. The average slope of the three circulations was 0.35 ±0.04, which was not significantly
different from the slope for the whole body. Statistical analysis of these data revealed that the autoregulatory capacity of the mesenteric circulation was
significantly less than that of the whole body, whereas
the renal circulation demonstrated significantly
greater autoregulation than the whole body. The
autoregulation observed in the hind limb was not
different from that of the whole body.
Discussion
Blood flow autoregulation has been defined classically as the ability of an organ to change its vascular
resistance in an effort to maintain a relatively constant flow in response to a change in perfusion
pressure. In 1963, a concept called "whole body
autoregulation" was proposed as a mechanism for
the onset of volume-dependent hypertension.3-4 The
whole body autoregulation theory proposes that an
expansion of body fluid volume with an accompanying increase in CO results in tissue overperfusion and
initiates a local tissue response to increase vascular
resistance. The resultant increase in TPR diminishes
the overperfusion of tissue and causes a reduction in
venous return and CO. Thus, whole body autoregulation is a possible mechanism by which an initial,
transient increase in CO resulting from volume expansion can lead to a sustained increase in TPR.
Early studies in anesthetized dogs with the central
nervous system ablated demonstrated the existence
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Vol 17, No 6, Part 2 June 1991
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of whole body autoregulation when the TPR was
reduced by blood withdrawal and reductions of
CO.11"13 Recent studies in our laboratory revealed
that whole body autoregulation could be demonstrated in unanesthetized areflexic rats in response to
small changes in blood volume.1-2 These studies were
the first to show how sensitive the systemic vasculature
could be, in that elevations in MAP of nearly 30%
could be achieved with a 5% increase in blood volume.
However, regional autoregulation responses have not
been quantified previously while simultaneously determining the gain of whole body autoregulation.
The baseline hemodynamic values in the areflexic
rats presented in the present study were well within
the physiological range. Although Doppler flow
probes are used routinely to evaluate regional blood
flows in conscious rats, the absolute values of blood
flow have not been determined previously by calibration of each flow transducer at the end of the
protocol. The regional blood flows we measured are
difficult to compare quantitatively to values obtained
in other studies, but our results are consistent with
blood flows that were determined with radioactive
microspheres and reported as percent of CO.14-16
In our areflexic model, norepinephrine infusion is
necessary to provide normal basal vascular tone
around which the vessel can autoregulate. The similarity of regional flows between intact and areflexic
states indicates that norepinephrine is not causing a
redistribution of blood flow in these major circulations. Low levels of systemic adrenergic stimulation
with phenylephrine have been shown to cause vasoconstriction due to autoregulation in the mesenteric
vasculature of conscious rats.17 This phenomenon
also may be occurring in our experiments during
norepinephrine infusion, such that basal vascular
tone in the mesenteric circulation may be maintained
by autoregulatory vasoconstriction rather than by the
direct effects of norepinephrine. However, it is unlikely that the autoregulatory efficiency in response
to volume expansion is affected, because it has been
shown that these low levels of adrenergic stimulation
do not affect the ability of the mesenteric circulation
to autoregulate.17
We observed significant autoregulation ability in
all three regions studied. The intestinal circulation
showed the least degree of autoregulation, which was
significantly less than the whole body response. Significant intestinal autoregulation also has been observed in anesthetized rats in response to vasoconstrictors.17 Previous studies in isolated mesenteric
preparations in the dog revealed that autoregulation
in this bed is affected by the presence of food18 and
the distribution of blood within the digestive tract.19
The present study was conducted in fed rats because
we considered this to be the normal physiological
state for rats. Thus, the autoregulation observed
under these conditions would reveal the normal
physiological responses.
The autoregulation phenomenon was described
first in the skeletal muscle,20 and autoregulation in
isolated hind limb preparations have been well documented.21 In our study, we demonstrated significant
autoregulation in the hind limb circulation that was
similar to that of the whole body.
The renal circulation elicited the highest degree of
autoregulation, which was significantly greater than
the whole body autoregulation response. Our results
are consistent with those of Conrad et al,22 which
demonstrated autoregulation of renal blood flow in
conscious rats during increases in arterial pressure
up to 139 mm Hg. A recent study by Hellebrekers et
al23 has demonstrated a strong degree of autoregulation in the renal circulation of unanesthetized dogs
in response to vasoconstrictor agents. They also
observed a moderate degree of autoregulation in the
intestinal circulation but no autoregulation in the
hind limb circulation, as was observed also by Metting et al24 in conscious dogs.
The results of the present study, when considered
with pressure-flow studies of isolated kidneys and
hind limb and splanchnic regions, strongly suggest
that the overall rise in TPR with blood volume
expansion primarily was due to the summation of
regional autoregulatory responses. First, the measured total blood flow through the three regions was
only 29 mJ/min (27%) of the measured 107 ml/min for
CO in the areflexic state. Yet it can be assumed that
the contralateral unmeasured kidney and other three
remaining limbs were autoregulating as well as those
that were measured. In addition, the superior mesenteric artery supplies approximately 50% of the
blood flow to the intestinal circulation, which then
ultimately flows into the hepatic circulation. Because
at rest the kidneys receive approximately 25% of CO,
the skeletal muscle approximately 20%, and the
splanchnic circulation approximately 30%, the total
blood flow reflected by the three regions represents
at least 75% of the total CO. Thus, despite significant
regional differences, the average autoregulatory
strength of the three regions was nearly identical to
that of the whole body, which suggests that the
changes in TPR were predominantly a result of the
observed regional responses. Second, an extensive
literature7-21'25 indicates that the changes in regional
resistance seen in the present study are a result of
local autoregulation, because the pressure-flow relations are similar to those determined in isolated
blood-perfused kidneys and hind limbs. Third, when
a mathematical model of the circulation based on
data from isolated organs was used to predict the
whole-body autoregulatory response, the predicted
response was similar to that actually measured in the
present study.25
An alternative hypothesis for the rise in TPR with
blood volume expansion is the centrally mediated
release of a circulating digitalislike factor that
inhibits the Na+,K+-ATPase pump and increases
vascular tone.26 We recently have presented evidence that a centrally mediated mechanism was not
responsible for the rise in TPR during acute increases in blood volume.27 It remains possible that
Hinojosa-Laborde et al Regional Autoregulation in Rats
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this factor may be important during chronic volume
expansion and could be released independent of the
central nervous system.
A controversial issue regarding the autoregulation
phenomenon is whether the stimulus for the response is an increase in flow or an increase in
pressure. A recent study by Meininger et al28 has
shown that changes in transmural pressure without
changes in blood flow can elicit autoregulation responses in rat cremaster muscle. In addition, several
studies on the interaction between vasoconstrictor
agents and autoregulation have demonstrated pressure-dependent autoregulation.17-23-29 In the present
study, we are unable to speculate on the stimulus for
autoregulation, because volume expansion causes an
increase in both flow and pressure.
There is evidence that increased vascular resistance in certain regions is elevated in some forms of
hypertension by autoregulatory mechanisms. Studies
of blood flow autoregulation in the hind limb skeletal
muscle30 and in the intestine31 have shown that autoregulation in these regions contributes to the elevated
vascular resistance associated with the development of
renal hypertension. The renal circulation has been
studied extensively in models of hypertension because
of the popular theory that abnormal renal function is
a prerequisite for the development of hypertension. In
Dahl salt-sensitive rats, renal blood flow is autoregulated at significantly higher pressures than in Dahl
salt-resistant rats.32 In the spontaneously hypertensive
rat, it is believed that the elevated renal vascular
resistance is due to autoregulation in the kidney.33 In
light of the evidence for the role of intestinal, renal,
and hind limb autoregulation in the development of
hypertension, the results of the present studies provide important fundamental information about the
autoregulation in these regions relative to the autoregulatory capability of the entire systemic circulation
in the unanesthetized state.
In summary, the data support the view that the
rapid rise of TPR in response to blood volume
expansion in areflexic animals predominantly is due
to regionally controlled autoregulatory responses,
and the normal hemodynamic characteristics of these
regions are an important factor in understanding the
contributions of these vascular beds to the onset and
maintenance of hypertension.
Acknowledgments
The donations of chlorisondamine by CIBA Pharmaceutical Co. and captopril by the Squibb Institute
for Medical Research are gratefully acknowledged.
We thank Rosalie Zamiatowski and Meredith Skelton for their technical assistance and Terri Harrington for her secretarial assistance.
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Hypertension
Vol 17, No 6, Part 2 June 1991
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KEYWORDS • cardiac output • autoregulation • blood volume
• vascular resistance • blood pressure • renal circulation •
mesenteric arteries
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Contribution of regional vascular responses to whole body autoregulation in conscious
areflexic rats.
C Hinojosa-Laborde, B H Frohlich and A W Cowley, Jr
Hypertension. 1991;17:1078-1084
doi: 10.1161/01.HYP.17.6.1078
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