487
Autoregulatory Responses of Superficial Nephrons
and Their Association with Sodium Excretion
during Arterial Pressure Alterations in the Dog
L. GABRIEL NAVAR, P. DARWIN BELL, AND THOMAS J. BURKE
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SUMMARY Micropuncture experiments were conducted to assess autoregulatory behavior of superficial nephrons
and to evaluate the possible contribution of alterations in tubular and peritubular capillary pressures to the mechanism
responsible for the arterial pressure effects on urine flow and sodium excretion. In response to decreases in renal
arterial pressure (RAP), autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR) was highly
efficient to blood pressures as low as 80 mm Hg. Proximal tubule pressure (PTP), peritubular capillary pressure
(PCP), distal tubule pressure, and single nephron GFR (SNGFR) remained within 5% of control values with
reductions in RAP to 90 mm Hg. Further decreases in RAP to the lower autoregulatory range caused significant
decreases in PTP and PCP; the slight decreases in SNGFR were not significant. Within the autoregulatory range,
GFR and filtered sodium load were not altered, and urine flow and sodium excretion responses were due to changes in
net fractional sodium and water reabsorption. No quantitative relationships could be established between the
magnitude of the changes in urine flow or sodium excretion and PTP, PCP, or proximal tubule fractional reabsorption. These experiments demonstrate that superficial nephrons autoregulate in association with the total nephron
population except for a proportionately greater reduction when RAP is reduced to the lower autoregulatory range.
Furthermore, the urinary responses to reduced arterial pressure occur even in the absence of quantitatively associated
alterations in proximal tubule function or PCP.
THE EFFECTS of changes in arterial pressure on renal
hemodynamics and on urine flow and sodium excretion
have been of interest to many investigators. At the whole
kidney level, the phenomenon of renal autoregulation has
been explored by evaluating the responses to changes in
renal perfusion pressure and it has been demonstrated that
both renal blood flow (RBF) and glomerular filtration rate
(GFR) can exhibit a remarkable stability over a wide
range of perfusion pressure.1"1 In spite of this autoregulatory efficiency, many studies have demonstrated consistent relationships between arterial pressure and both urine
flow and sodium excretion rate.1"9 The existence of these
relationships has provided the basis for the suggestion that
there exists a physiologically significant interaction between the mechanisms that control water and electrolyte
excretion and those responsible for the control of arterial
blood pressure;10"14 however, the specific intrarenal mechanisms have not been delineated clearly.
A number of micropuncture studies have focused on the
evaluation of the responses of individual superficial nephrons to changes in arterial pressure. Many of these studies
have evaluated primarily the alterations in tubular pressures and function that may be associated with the arterial
From the Departments of Physiology and Biophysics and of Medicine
(Division of Nephrology), University of Alabama in Birmingham Medical
Center, Birmingham, Alabama, and Department of Physiology and Biophysics, University of Colorado Medical Center, Denver, Colorado.
Supported by grants from the National Heart and Lung Institute (HL
18426, 7K04 HL00143), from the National Institute of Arthritis and
Metabolic Disease (AM 17646), and from the American, Alabama, and
Colorado Heart Associations.
Address for reprints: Dr. Luis Gabriel Navar, Department of Physiology and Biophysics, University of Alabama Medical Center, University
Station, Birmingham, Alabama 35294.
Original manuscript received March 29, 1976; accepted for publication
February 16, 1977.
pressure-induced changes in sodium excretion and urine
flow.15"22 These latter observations are of interest in that
they have explored one possible means to explain the
intrarenal mediation of the observed changes in urine
output. Specifically, it has been suggested that the changes
in sodium excretion and urine flow associated with
changes in arterial pressure are mediated primarily by
alterations in peritubular factors and associated changes in
proximal tubule pressure and reabsorption.15"20 However,
in many of these studies, clear evidence of autoregulatory
capability has not been present. This makes it difficult to
determine how the coexisting presence of this phenomenon would interact with the observed changes in intrarenal
function. In fact, agreement has not been reached concerning the degree of autoregulatory ability of the superficial nephrons with respect to the total nephron population.
For example, the pressure responses in the tubular and
peritubular capillary structures to changes in arterial pressure have been variable, with some studies showing good
autoregulatory behavior of proximal tubule pressure and
peritubular capillary pressure,23"26 whereas other studies
have suggested that these values can be altered substantially in response to blood pressure even in the absence of
significant changes in renal blood flow or GFR.15"20 With
respect to distal tubule pressure, there is little information
even as to its normal value in the dog, although autoregulation of distal tubule pressure in the rat has been reported.26
The responses of single nephron GFR (SNGFR) of the
outer cortical nephrons to changes in renal arterial pressure are even more controversial, since interpretation of
SNGFR data is complicated by the current controversy
regarding the role of the distal tubular feedback media-
488
CIRCULATION RESEARCH
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nism in mediating the autoregulatory responses.25'27 This
problem notwithstanding, some investigators have reported highly efficient autoregulation of SNGFR in response to decreases in renal arterial pressure down to
about 100 mm Hg.20-26> "• 28 However, the results of Robertson et al.24 indicated that SNGFR autoregulation was
less complete than autoregulation of glomerular and proximal tubule pressures, whereas Kallskog et al.29 suggested
that the outer cortical nephrons do not exhibit autoregulation following reductions in arterial pressure.
Because of the degree of controversy that exists concerning the response of the superficial nephrons to
changes in arterial pressure and the uncertainty concerning the interaction of the autoregulatory process with the
process responsible for the arterial pressure induced
changes in urine output and sodium excretion, we were
prompted to evaluate this problem in a setting in which we
could determine the effects of arterial pressure on both the
autoregulatory process and the urinary excretion responses.
Methods
Experiments were performed on 43 mongrel dogs of
both sexes, weighing 13 to 21 kg and anesthetized with
sodium pentobarbital (30 mg/kg, iv).They were prepared
for micropuncture and clearance studies as previously described.25-27 A tracheotomy was performed to maintain a
patent airway, and a jugular vein was catheterized for the
infusion of inulin. Following the priming dose, an infusion
of 5% inulin was administered to maintain a plasma concentration of either 0.2 or 0.8 mg/ml, depending on
whether or not tubular fluid samples were to be taken. The
carotid arteries were isolated from the carotid sheath and
ligatures were placed loosely around each vessel. A catheter was advanced into a foreleg vein for the administration
of additional anesthetic as necessary, and of isotonic saline
at a rate no greater than 1 ml/min. Systemic blood pressure was monitored continuously through a catheter
placed in the femoral artery with a Statham pressure
transducer (Statham Laboratories). This catheter also was
used for collection of arterial blood samples.
The kidney was exposed via a left flank incision, and the
renal artery, vein, and ureter were freed of the surrounding tissue. An electromagnetic flow probe was placed
around the renal artery near its base and connected to a
square wave flowmeter (Carolina Medical Electronics). A
22-gauge curved needle was inserted into the renal artery
to measure renal arterial pressure (RAP). The line was
kept patent by a continuous infusion of heparinized saline
solution at a rate of 0.2 ml/min, with a Harvard infusion
pump (Harvard Apparatus). This system was mechanically
zeroed before each experiment to assure that there was no
overestimation of true renal arterial pressure. An adjustable plastic clamp was placed around the renal artery between the flow probe and the pressure-measuring needle
in order to constrict the renal artery and cause a direct
reduction in RAP. A catheter was inserted into the left
ureter to allow collections of timed urine volumes. The
kidney was placed on a Lucite holder, and a square section
of renal capsule of approximately 2 cm2 was removed. This
area was continuously bathed with either a heparinized
VOL. 41, No. 4, OCTOBER
1977
saline solution warmed to 37°C or mineral oil dripped
through a Lucite rod, also used to illuminate the surface of
the kidney. The experiments were conducted either as
"pressure experiments" or "collection experiments." Because the saline bathing the micropuncture surface is necessary for proper operation of the micropressure unit,
pressure measurements were not taken in the collection
experiments, in which the kidney was bathed with mineral
oil to optimize tubular fluid collections.
PRESSURE EXPERIMENTS
Pressures in proximal tubules, peritubular capillaries,
and distal tubules were measured by a micropressure servo
null system (Instrumentation for Physiology and Medicine). To localize distal tubules and to measure tubular
transit times, 0.5 ml of a 10% fast green dye solution (pH
adjusted to 7.0) was injected directly into the renal artery
through the renal arterial catheter. Upon injecting the
dye, there was an initial green flush of the proximal tubules with a homogenous disappearance occurring within
20-30 seconds. Twenty to 40 seconds later, the dye would
appear in the surface distal tubules. Superficial segments
of distal tubules were selected for pressure measurements.
After each distal tubule pressure measurement, the puncture site was checked for leaks by turning off the micropressure unit and injecting a small quantity of the stained
solution from within the pressure-measuring pipette. First
order peritubular capillaries were used for the measurement of peritubular capillary pressure, and proximal tubules were chosen at random. The time between the green
flush on the surface of the kidney and its disappearance
from the visible proximal tubule segments was designated
as the proximal transit time, and the appearance of dye in
the visible distal tubule segments was used to assess distal
tubule transit times. These criteria were selected primarily
because they allowed maximum consistency in the measurements.
After the inulin infusion was initiated, a period of 50
minutes was allowed for stabilization of the preparation.
Two to three timed volumes of urine (10-20 minutes)
were collected and a plasma sample was taken at the midpoint of each urine collection. Systemic blood pressure,
renal arterial pressure, and renal blood flow were continuously monitored throughout the experiment. Pressures in
five to eight proximal tubules and three to four peritubular
capillaries were measured. In seven experiments, the carotid arteries were constricted to elicit a baroreceptor
response and allow the assessment of autoregulatory behavior in response to an elevation of arterial pressure.
Renal arterial pressure was reduced in 16 experiments in
steps of approximately 25 mm Hg by constriction of the
renal artery clamp. After arterial pressure reduction, urine
collections and pressure measurements were repeated.
The renal arterial pressure was reduced to at least one
level in 16 dogs, to two levels in 11 dogs, and to three
levels in three dogs. Measurements were taken at renal
arterial pressures down to and slightly below the lower
limit for RBF autoregulation. The renal artery clamp was
then released, allowing renal arterial pressure to return to
control values. In 11 dogs, clearance measurements as
previously described were repeated and, in addition, the
NEPHRON AUTOREGULATION AND PRESSURE DIVRESIS/Navar et al.
fast green dye was injected into the renal artery to evaluate transit times and localize distal tubules. Transit times
were measured and pressures determined in two to three
distal tubules. Renal arterial pressure was reduced again,
as explained, and measurements of transit times and distal
tubular pressures repeated. Distal tubule pressures at reduced pressure were obtained in seven experiments. In
three experiments, the two phases of the experimental
protocol were combined.
COLLECTION EXPERIMENTS
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In 22 other experiments, a similar protocol was followed, except that the kidney surface was bathed with
mineral oil and tubular fluid samples were collected. In 15
experiments, the SNGFR responses to variable decreases
in RAP were assessed. Because of our previous experience
that SNGFR based on proximal tubule fluid collections
may not adequately reflect autoregulatory responsiveness,27 these SNGFR data were based only on distal tubule
fluid collections. Distal tubules were identified, using intra-arterial injections of dye as described, and marked by
the injection of a small quantity of nigrosin dye. Tubule
fluid collections were made at control arterial pressure and
after reduction of renal arterial pressure. In five of these
experiments and seven additional experiments, the effects
of decreases in arterial pressure on proximal fractional
volume reabsorption were determined. To avoid obstruction of tubular fluid flow, samples were collected and
recollected under free flow conditions without injection of
an oil block. Individual tubule segments were identified
with nigrosin dye as previously explained. The plasma
inulin concentration in all the collection experiments was
maintained between 0.7 and 0.9 mg/ml to allow a level of
inulin in the tubule fluid samples that could be readily
assessed by the microfluorometric method30 (Aminco).
At the end of each experiment, the electromagnetic flow
probe was calibrated in situ by catheterizing the renal
artery and collecting timed blood samples in a graduated
cylinder. The kidney was removed, stripped of all surrounding tissue, blotted dry, and weighed. This allowed
RBF and GFR values to be expressed per gram of kidney
weight. Microhematocrit measurements were performed
on all arterial blood samples. The anthrone colorimetric
technique was used to determine inulin concentrations in
both plasma and urine samples and glomerular filtration
rate was calculated by the standard clearance formula.
Routine measurements of plasma and urine composition
were made. Sodium and potassium concentrations in
plasma and urine samples were determined by flame photometry (Instrumentation Labs.) and osmolality was determined with an osmometer (Fiske Instruments). Protein
concentration in each plasma sample was measured with a
protein refractometer (American Optical Corp.), and
plasma colloid osmotic pressure was measured directly
with a membrane osmometer mounted on a pressure
transducer (Statham).
Data were analyzed by standard statistical techniques
including paired analysis, linear regression analysis, and
co-variance analysis. Unless noted otherwise, data are
presented as the mean ± standard deviation (SD). When
the standard error of the mean (SE) is used, this is designated.
Results
HEMODYNAMIC RESPONSES
Renal autoregulatory capability was assessed at the
whole kidney level from the responses of RBF and GFR to
change in renal arterial pressure. Table 1 compares the
results obtained in the pressure and collection experiments. Renal blood flow was efficiently autoregulated
over the entire range of arterial pressures studied and
showed only a small decrease (less than 10%) over this
pressure range in both groups. For the most part, GFR
responses also showed a similar pattern of high efficiency
autoregulation, with the exception that GFR at the lowest
arterial pressure in the pressure group was decreased to a
greater extent than RBF. This could be due to the inherent
limitations of the clearance technique with low urine flows
at lower arterial pressures. Overall, the experimental
preparations set up for either the pressure or collection
experiments exhibited whole kidney autoregulatory behavior down to renal arterial pressure levels similar to
TABLE 1 Renal Blood Flow and Glomerular Filtration Rate (GFR) Responses to Changes in
Renal Arterial Pressure for both "Pressure" (P) and "Collection" (C) Experiments
Renal arterial pressure
Renal blood flow
(ml/min g)
(mm Hg)
GFR
(ml/min g)
P
C
P
148 ± 10
n = 11
118 ± 6
n = 16
101 ± 4
n = 14
82 ± 5
n = 12
69 ± 5
n =7
142 ± 12
n = 12
117 ± 5
n = 13
102 ± 4
n = 10
83 ± 6
n = 9
4.05 ± 0.75
4.05 ± 1.,15
0.71 ± 0.17
0.67 ± 0. 16
4.2 ± 1.0
3.93 ± 1 .13
0.75 ± 0.19
0.64 ± 0 .15
3.93 ± 0.89
3.9 ± 0 .95
0.73 ± 0.23
0.69 ± 0 .18
3.75 ± 0.92
3.83 ± 1 .01
0.67 ± 0.2
0.64 ± 0 .22
3.7 ± 0.9
489
C
P
C
0.40 ± 0.23
Results are presented as the mean values ± SD. The individual values were grouped intofivearterial pressure ranges:
above 130 mm Hg, 110-129 mm Hg, 90-109 mm Hg, 75-89 mm Hg, and below 75 mm Hg (last level reached only in
the pressure dogs). The number of experimental values contributing to the average value at each arterial pressure
category is designated by n.
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CIRCULATION RESEARCH
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those previously obtained.2'3> 31~33 The close association of
RBF and GFR was reflected in the measured values for
filtration fraction. At the control arterial pressure range,
filtration fraction was 0.31 ± 0.07 and was not significantly different from this value at any of the other pressure
ranges studied except the lowest arterial pressure category
in the "pressure" dogs. Plasma protein concentration averaged 5.9 ± .61 g/dl and colloid osmotic pressure was
15.2 ± 2 mm Hg.
In some previous studies, overall intrarenal resistance
(IRR) has been calculated by using either intrarenal venous pressure32'33 as an estimate of overall peritubular
capillary pressure (PCP) or by using measurements of
proximal tubule pressure to estimate PCP.'9 To compare
the results of the present experiments with those reported
by Kaloyanides et al.19 for the isolated kidney, direct
measurements of peritubular capillary pressure were used
to estimate overall IRR. The assumption that measurements of superficial PCP reflect overall PCP values seems
valid in view of the similarity between intrarenal venous
pressure measurements and micropressure measurements
of pep. 32 - 33 - 34 Figure 1 shows the average responses of
PCP and IRR to changes in renal arterial pressure. PCP
was maintained reasonably constant over the arterial pressure range studied; it decreased slightly from 14 ± 5 mm
Hg at a mean RAP of 147 mm Hg, and to 10 ± 2 mm Hg
at a RAP of 70 mm Hg. This relative constancy of PCP
was reflected in the calculated values for IRR which was
35 ± 7 units at the highest arterial pressure and approached a minimal intrarenal resistance of 17 ± 5 units at
70 mm Hg.32'33 Thus, the major changes in intrarenal
resistance in response to changes in RAP appeared to be
localized to segments proximal to the peritubular capillaries. A crude estimate of venous resistance could also be
obtained from the quotient of PCP and RBF. With these
calculations, it appeared that the changes in venous resistance with changes in RAP were very slight and we found
no consistent or significant trend in venous resistance as a
function of arterial pressure. At the highest arterial pressure, venous resistance was 3.5 resistance units and was
not altered significantly at reduced arterial pressures.
TUBULAR PRESSURES AND TRANSIT TIMES
Measurements of proximal tubular pressures (PTP)
were made in 17 of the experiments, whereas distal tubule
pressures (DTP) were obtained in only 12 of the dogs and
were more limited. Thus for Figure 2 the proximal tubule
pressures were grouped into five arterial pressure ranges
as for Figure 1, but the distal tubule pressures were
grouped into only three arterial pressure ranges. At the
highest arterial pressures, proximal tubule pressure was 24
± 5 mm Hg and distal tubule pressure averaged 13 ± 2
mm Hg. Both exhibited high efficiency autoregulation
down to a RAP of 100 mm Hg, with PTP decreasing very
slightly to 22.5 and DTP remaining unchanged. With
further decreases in renal arterial pressure, the decreases
in PTP were greater; PTP fell to 18 mm Hg at an average
RAP of 70 mm Hg. These decreases in PTP were consistent and statistically significant. The limited number of
DTP measurements at these lower pressures was not suffi-
VOL. 41, No. 4, OCTOBER
1977
40 _ 30 -
> E
I20
RBF
10
4
60
100
120
140 160
80
Renal Arterial Pressure (mm Hg)
FIGURE 1 The average relationships obtained in 14 dogs between
renal arterial pressure (RAP) and peritubular capillary pressure
(PCP) (lower curve) and calculated intrarenal vascular resistance
(IRR) (upper curve). The individual values obtained at the various
arterial pressures were grouped into five arterial pressure ranges
[above 130 mm Hg (n = 9), 110-130 mm Hg (n = 11), 90-109
mm Hg (n = 14), 75- 89 mm Hg (n = 11), and below 75 mm Hg
(n = 7)]. The average values ± one standard deviation are demarcated. This technique for grouping the data is used in order to
reflect any nonlinearities in the relationships. RBF = renal blood
flow.
cient to establish any significant changes as a function of
RAP.
Overall responses of the superficial nephrons were assessed from measurements of transit times of lissamine
green through visible segments of proximal and distal
tubules in 12 experiments. These data are limited due to
the fact that only a few injections of dye can be given
before accumulation of dye interferes with precise determination of end points. At a control RAP (122 ± 20 mm
Hg), proximal transit time averaged 26 ± 5.7 sec and
00
i
30
E
E
20 -
o- 10
•ih
60
80
100
120
140
Renal Arterial Pressure (mm Hg)
160
FIGURE 2 Responses of proximal tubule pressure (O) and distal
tubule pressure (0) to reductions in renal arterial pressure (RAP).
Proximal tubule pressures were obtained in 17 experiments and are
grouped in the five arterial pressure ranges as for Figure 1, with n
= 7 at RAP above 130, n = 12 at RAP of 110-129, n = 15 at
RAP of 90-109, n = 12 at RAP of 75-89, and n = 8 at RAP
below 75 mm Hg. Distal tubule pressures were obtained in 12 dogs
al control arterial pressures and in seven dogs at reduced arterial
pressure and therefore are grouped into only three arterial pressure
ranges [above 130 mm Hg (n = 4), 100-120 mm Hg (n = 10),
and below 100 mm Hg (n = 7)[.
NEPHRON AUTOREGULATION AND PRESSURE DIUKESIS/Navar et al.
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distal transit time was 56 ± 12 sec. When RAP was
reduced to 89 ± 12 mm Hg, proximal transit time was not
altered significantly [A = +2.4 ± 2.0 (SE) sec], although
the increase in distal transit time of +7.4 ± 2.6 (SE) sec
was statistically significant. Further reductions in RAP to
68 ± 5 mm Hg resulted in significant increases in both
proximal transit time [A +5.5 ± 2.0 (SE) sec] and distal
transit time [A = +15.8 ± 5.2 (SE) sec].
To assess the association between autoregulation of
pressure in the superficial nephrons and whole kidney
autoregulatory responses, the relative changes in RBF
were compared to the relative changes in PTP and PCP in
response to reduction in renal arterial pressure. Data obtained during RAP reduction were grouped into three
pressure ranges: control values, values during the first
constriction, and values during the second constriction.
The relative responses are shown in Figure 3. With the
first constriction, RAP decreased from 122 ± 22 mm Hg
to 94 ± 12 mm Hg. Average RBF remained within 1 % of
control. Average decreases in PTP and PCP were slight,
being 4.4% and 5.2%. The consistency of the PTP responses was greater than that of PCP responses and the
small decrease in PTP was statistically significant, although it amounts to a change of about 1 mm Hg. With the
second constriction, RAP was decreased to 73 ± 11 mm
Hg; there appeared to be small but inconsistent decreases
in RBF which did not achieve statistical significance. In
contrast, both PTP and PCP demonstrated substantial and
highly significant decreases of 18% and 23%.
In the seven experiments in which pressure measurements were obtained before and after carotid artery occlusion, arterial pressure was increased from an average of
113 ± 11 mm Hg to 141 ± 15 mm Hg. There were no
significant changes in RBF (-8%), GFR ( + 7%), PTP
(+11%), and PCP ( + 16%) in response to the carotid
occlusion, although the variability in these measurements
seemed substantially greater than could be explained on
the basis of just the elevated arterial pressure.
Constriction #1
491
Constriction #2
+5
0
RBF
-5
PTP
y
PCP
10 -
RBF
PTP
T
15
T
20
25
30
-0.7 -4.4 -5.2
±2.2 ±1.8 ±3.1
N.S.
N.S
PC
1
1
!
- 6 . 8 - 1 8 -22.9
±3.4 ±4.1 ±3.8
N.S.
FIGURE 3 Comparison of the percent changes in renal blood flow
(RBF), proximal tubular pressure (PTP), and peritubular capillary
pressure (PCP) after reduction in renal arterial pressure by constriction of the renal artery. The average control renal arterial
pressure was 122 ±22 mm Hg and was decreased to 94 ±12 mm
Hg during the first constriction. In 10 experiments, the renal
arterial pressure was reduced further to 73 ± 11 mm Hg, and the
data shown for the second constriction no. 2 are averaged from
these 10 experiments. The mean differences ± SEare shown and *
designates significance at the 5% level, whereas ** designates
significance at the 1 % level.
tionship obtained for SNGFR and distal volume flow rate
when plotted against arterial pressure. Average SNGFR at
the highest RAP was 45 nl/min and remained within 1 nl/
min of this value at the next two pressure levels. This
average value was decreased to 36 nl/min at the lowest
pressure level; however, this decrease did not achieve
statistical validity even when evaluated on a paired basis
with the values at control pressure. Because of this degree
of variability, one cannot be confident whether this decrease is real or only apparent. Nevertheless, essentially
complete autoregulation of SNGFR was observed down to
a RAP of 100 mm Hg. Likewise, distal tubular volume
flow rate was not altered significantly and the tubular
fluid-to-plasma inulin ratios were not modified to a significant extent. Because both SNGFR and whole kidney GFR
SNGFR RESPONSES
In a separate group of 15 dogs, we determined the
changes in SNGFR in response to decreases in arterial
pressure. As explained, the requisite total tubular fluid
collections require the interposition of an oil block in the
tubule and consequently interrupt volume flow to the
remaining part of the nephron. To avoid or at least minimize changes in volume flow past the macula densa segments of the distal tubule and thereby prevent interference
with the postulated mechanism thought to be involved in
feedback regulation of SNGFR,27 all estimates of SNGFR
were based on distal tubule fluid collections. The disadvantages of this approach, however, are the limited number of samples that can be obtained and the greater technical difficulty in these collections compared to proximal
collections. These factors probably contribute, at least
partially, to the observed degree of variation between
dogs. From these 15 experiments, a total of 56 collections
were made from 30 experimental periods. These experimental periods were divided into the four arterial pressure
ranges designated in Table 1. Figure 4 describes the rela-
•
•I
60-
50
S E c 40-
^ o §30
JS
•o
20
100 •/H-
70
90
110
Renal Arterial Pressure
130
mm Hg
150
FIGURE 4 Relationships between renal arterial pressure (RAP)
vs. single nephron glomerular filtration rate (SNGFR) (0) and
RAP vs. distal volume flow rate (M). Data are grouped as described for Table. 1 All values are expressed as the mean ± SD and
the numbers in parenthesis refer to the number of dogs per number
of tubules used to obtain the designated average point. No significant changes in TF/P inulin ratios could be demonstrated, the
values being 3.39 ± 0.79, 4.43 ± 1.85, 3.68 ± 0.77, and 4.01 ±
1.29 from the highest to the lowest pressure ranges.
492
CIRCULATION RESEARCH
VOL. 41, No. 4, OCTOBER
1977
exhibited autoregulatory behavior, the ratio of these two
measurements (SNGFR/GFR) was not altered significantly by reductions in renal arterial pressure. The control
value was 68 ± 6 (nl/min)/ml/min • g) at the higher pressures and 76 ± 9 at the lower pressures.
URINARY OUTPUT AND FRACTIONAL
REABSORPTION RESPONSES TO REDUCED
ARTERIAL PRESSURE
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As already mentioned, there were no significant alterations in GFR in response to reductions in RAP down to
about 80 mm Hg. To evaluate possible trends in the
filtered sodium load, we analyzed the relationship between filtered sodium load (FNa) and RAP by linear
regression. This failed to provide any statistical evidence
supporting the possibility that FNa changed with RAP.
Average FNa was 101 /xEq/(min-g) and the regression
coefficient was 0.26 /u,Eq/(min • g) per mm Hg; this value is
not statistically different from zero. Analysis of data points
above a RAP of 80 mm Hg yielded a regression coefficient
almost equal to zero (—0.09). In contrast, the urinary
excretion responses showed consistent changes with RAP.
Figure 5 shows the urine flow responses to changes in
renal arterial pressure. The line representing the regression equation is also shown; a highly significant and consistent relationship is evident. The relationship obtained
between RAP and fractional water reabsorption is shown
in the top portion of Figure 5. The "hydropenic" status of
the dogs is evident and at pressures below the overall
mean of 110 mm Hg, almost all fractional reabsorption
values are greater than 99 %. Net fractional reabsorption
decreased progressively at the higher arterial pressures
and the variability also increased somewhat. Nevertheless,
the responses were sufficiently consistent to yield a regression coefficient of — 0.013%/mm Hg that was highly significant. Similar patterns were obtained when the relationships between RAP and urinary sodium excretion or fractional sodium reabsorption were evaluated. These are
shown in Figure 6. At the average RAP, sodium excretion
was 1.06 ^Eq/(min-g). The regression coefficient for this
relationship is 0.021 /xEq/(min • g) per mm Hg. Fractional
Na reabsorption averaged 98.8% with a regression coefficient of — 0.02%/mm Hg. Both regression coefficients
were highly significant at the 0.001 level.
To determine possible relationships between proximal
tubule or peritubular capillary pressures and the urinary
responses to changes in arterial pressure, a comparison of
the magnitude of the responses in these variables was
performed for each experiment. The data were grouped
into control data, responses during the first renal arterial
constriction, and responses during the second renal arterial constriction. The percent changes from control were
calculated for proximal tubular pressure, peritubular capillary pressure, sodium excretion, and urine flow during
the two constriction periods. Similar relative responses
were calculated for the seven dogs in which data were
obtained before and after elevation of systemic arterial
pressure by constriction of the carotids, although these
responses showed substantially greater variability. Presumably, this could be due to the nonspecific effects of the
baroreceptor reflex.15-16>18iZ3 The relative responses in
80
100
120
140
160~
RENAL ARTERIAL PRESSURE mm Hg
FIGURE 5 Alterations in urine flow (UF) and fractional water
reabsorption in response to changes in renal arterial pressure
(RAP). RAP vs. urine flow is plotted in the lower portion. Data
points from individual pressure experiments are connected and the
line of the regression equation is drawn. The regression equation is
UF = 0.09-(RAP) - 4.8. The standard error of the regression
coefficient (Sb) was 0.014, and the t value of 6.59 is highly
significant. In the upper portion of the figure, fractional water
reabsorption is plotted against RAP for all data points. The regression equation for these data is FRV = -0.013(RAP) + 100.7. Sb
was 0.0024 and the t value of 5.46 is also highly significant.
PTP and PCP were compared to the relative changes in
both urine flow and sodium excretion. During the first
constriction, RAP decreased from an average of 123 mm
Hg to 94 mm Hg. The decrease in PTP averaged 5.21 ±
1.77 (SE) %, and PCP decreased by 2.55 ± 3.16% compared to decreases in urine.flow and sodium excretion of
34 ± 5% and 44 ± 7%. During the second constriction,
RAP was decreased to 77 mm Hg; PTP decreased by
19.42 ± 4.4% and PCP decreased by 22 ± 4%. Urine
£ IOO jg
99
g |
98
O
W
*£
z
Q7
96
95
60
80
100
120
140
160
RENAL ARTERIAL PRESSURE mm Hg
FIGURE 6 Responses of sodium excretion C£,Vo and fractional
sodium reabsorption (FRXa) to changes in renal arterial pressure
(RAP). For lower graph, data points from individual dogs are
joined. The regression equations are EXa = 0.021 (RAP) - 1.2;
Sb = 0.0046, and FRSa = -0.020 • (RAP) + 101; Sb = 0.004.
The regression coefficients for both relationships are highly significant at the 0.001 level.
NEPHRON AUTOREGULATION AND PRESSURE DIVSRESIS/Navar et al.
493
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flow and sodium excretion decreased by 64 ± 6% and 78
± 7%. During carotid constriction, arterial pressure increased to 141 mm Hg. The PTP and PCP responses were
more variable and showed average increases of 11 ± 7 %
and 16 ± 16%. The urine flow and sodium excretion
responses were 89 ± 32% and 134 ± 52%. In Figure 7,
the individual PTP responses are compared to the respective urine flow changes for each experimental period.
Decreases in PTP during the first constriction were usually
quite small and, in a number of the experiments, PTP was
essentially unchanged. However, the responses in urine
flow and sodium excretion were of greater magnitude and
consistent. Analysis of covariance failed to establish evidence suggestive of a correlation between the magnitude
of the PTP changes and the magnitude of the urinary
excretion responses. The correlation coefficient was not
significantly different from zero regardless of whether all
data points were evaluated as one group or as subgroups
according to the experimental periods. Similarly, there
was no evidence of a significant correlation between the
PTP changes and the changes in sodium excretion.
Analysis of the degree of correlation between the percent changes in PCP and the percent changes in either
urine flow or sodium excretion also failed to indicate a
significant degree of correlation. Therefore, while PTP
and PCP, as well as urine flow and sodium excretion, were
coincidently related to changes in renal arterial pressure,
these pressure responses could not be associated quantitatively with the alterations in urine flow and sodium excretion.
To evaluate the possibility that the changes in renal
arterial pressure were altering fractional reabsorption at
the level of the proximal tubule, 12 dogs were subjected to
a similar procedure of renal arterial constriction during
which free flow collections from proximal tubules were
taken at control and reduced RAP. RAP was reduced
from a control of 125 ± 16 (SD) to 94 ± 13 (SD) mm Hg.
Both RBF and GFR exhibited satisfactory autoregulation,
and values at reduced RAP were not significantly different
from control values (ARBF = - 7 ± 4% and AGFR = - 6
± 4 % ) . Urine flow and sodium excretion decreased to
about the same levels as in the other series of experiments,
the urine flow decreasing by 44 ± 6% and the sodium
excretion by 70 ± 5%. The average TF/P(inulin) ratio
based on 53 tubules was 1.69 ± 0.08 (SE) at control
pressure and 1.53 ± 0.08 at reduced arterial pressure.
Paired analysis of data failed to reveal a significant difference in these values; furthermore, it should be noted that
the direction of the change, even though not significant
statistically, is opposite to that expected for a proximal
contribution to the increased net fractional reabsorption.
For control purposes, collections and recollections were
taken from 12 tubules with the arterial pressure maintained at control levels. Control TF/PIn averaged 1.69 ±
0.09 and recollections TF/PIn was 1.68 ± 0.18.
% A urine flow = 0.12; and % A peritubular capillary pressure vs.
% A sodium excretion = 0.05. All of these values were below that
necessary to establish significance at 5% level (0.396).
There are numerous differences between the present
results and those of previous studies. In particular, Kallskog et al.29 suggested that the outer cortical nephrons did
Discussion
The results of the present investigation extend previous
findings concerning single nephron autoregulatory behavior in the dog19-20'23>" by evaluating autoregulatory behavior at the lower arterial pressures. The measurements
of proximal and distal tubule pressures, peritubular capillary pressures, tubular transit times, and SNGFR indicate
80
that, for the most part, the autoregulatory behavior of the
60
entire kidney is closely reflected by the behavior of the
40
superficial nephrons. Only at renal arterial pressures in the
lower range for autoregulation was there an indication of
•20
% CHANGE IN PTP
10 20 A30
proportionately greater decreases in superficial nephron
-50
-30
-10
function. As blood pressure was reduced to the lower limit
-20
of the autoregulatory range, there was a small decrease in
RBF which was not significant; yet both proximal tubule
and peritubular capillary pressures decreased substan• Constriction # 1
-60
o Constriction #2
tially. There was also an indication of a decrease in
-80
• Carotid occlusion
SNGFR at the lowest RAP although the decrease failed to
% CHANGE
achieve statistical significance. The proportionately
IN UF
greater decreases in single nephron function compared to
FIGURE 7 Analysis of the association between proximal tubular
whole kidney RBF and GFR at the lower pressures still
pressure (PTP) and urine flow (UF) responses to changes in renal
arterial pressure. Data are expressed as percent change from con- within the autoregulatory range suggest that the lower
limit of the autoregulatory range of the superficial cortical
trol values; • = responses observed during thefirstconstriction
with reduction in renal arterial pressure (RAP) to a mean of 94 mm nephrons is higher than for the total nephron population,
and that, in the dog, decreases in superficial nephron
Hg; O = those obtained during the second constriction to a mean
function occur as the renal arterial pressure is reduced
RAP of 77 mm Hg; A = the responses obtained in the seven
experiments in which measurements were taken before and after
below approximately 90 mm Hg. Although no estimates of
occlusion of the carotid arteries. Thefigureshows only the results outer cortical nephron plasma flow were made, the results
for PTP vs. UF, but similar analyses were performed for PTP vs.
of the present study are consistent with the previously
E a and for PCP versus both UF and E o . The following correlareported changes in the distribution of intrarenal blood
tion coefficients were obtained: % A proximal tubule pressure vs. flow with decreases in renal arterial pressure below 100
% A urine flow = 0.107; % A proximal tubule pressure vs. % A
mm Hg reported by Abe35 and McNay and Abe.38
sodium excretion = 0.188; % A peritubular capillary pressure vs.
494
CIRCULATION RESEARCH
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not exhibit autoregulation. However, these conclusions
were based in large part on estimates of glomerular pressure as determined by the stop-flow pressure technique
which may actually interfere with autoregulatory behavior.25 Also, their SNGFR data are based on indirect estimates and were evaluated only at two pressure levels with
the lower one possibly below the autoregulatory limits for
the outer cortical nephrons in the rat. The present results
also differ from those reported by Kaloyanides et al.19 for
the isolated perfused dog kidney, since it was suggested
that as much as one-third of the total resistance adjustments in response to changes in arterial pressure may
occur at venular sites distal to the peritubular capillary
network. In our study, calculations of intrarenal resistance
indicated that most of the autoregulatory adjustments in
renal vascular resistance occurred proximal to the peritubular capillary network. In this regard, it is clear that the
autoregulatory responses of the kidney, when prepared as
in the present study, are distinct from those obtained in
the isolated kidney preparation. The reasons for these
differences are not clear, but the findings of the present
study are consistent with results of similar micropuncture
studies tested over a more limited pressure range.23'26 In
addition, the SNGFR responses observed in this study are
somewhat different from those reported by Robertson et
al.24 in that they suggested a small decrease in SNGFR
even though there was little change in proximal tubule
pressure and peritubular capillary pressure. One possible
means to explain this apparent difference is that the
SNGFR data of Robertson et al. are based only on proximal tubule fluid collections which may not adequately
reflect autoregulatory behavior.25'27 However, it is fully
recognized that this interpretation is not shared by all
investigators.26
To our knowledge, this is the first report of distal tubule
pressure in the dog. Average DTP at control arterial
pressure was 13 ± 1.4 mm Hg compared to 21.7 ± 3.1
mm Hg for proximal tubule pressure in the same 12 dogs.
The average proximal to distal tubule pressure gradient
was 8.6 ± 2.9 mm Hg. Thus the absolute levels of DTP in
the hydropenic dog seem to be higher than those reported
for the hydropenic rat,37' 38 but because of the correspondingly greater proximal tubule pressures, the proximal to
distal tubule pressure gradient is similar or perhaps slightly
greater in the dog than in the rat.
In recent years, a substantial degree of emphasis has
been given to the potentially important role of the relationship between blood pressure and sodium excretion in
the control of blood pressure and in the pathogenesis of
various forms of hypertension."^13 Paramount to a further
understanding of the subtle means by which this relationship is altered in various types of hypertensive conditions,
is the need for a more complete understanding of the
intrarenal mechanism or mechanisms that mediate this
interaction between blood pressure and urinary excretion
of sodium and water. One conclusion appears to be evident from the present study. The effects of arterial pressure on urinary excretion rates are still present under
conditions in which there is no evidence of significant
alterations in renal blood flow or GFR. Coincident with
VOL. 41, No. 4, OCTOBER
1977
this high efficiency autoregulation, proximal tubule pressure and peritubular capillary pressure as well as SNGFR
are also autoregulated with a high degree of efficiency, at
least at blood pressures above 90 mm Hg. Although alterations in hemodynamics or SNGFR of deep nephrons
could explain the responses to RAP, studies using other
techniques to estimate renal function in deep nephrons
and medullary areas seem to suggest that the deep nephrons also exhibit autoregulation that is at least as good as
that of the superficial nephrons.28'29' 3S-36' 39 Thus, the
effect of blood pressure in a setting where GFR and
various indices of intrarenal function are autoregulated
with a high degree of efficiency, poses a dilemma. On the
one hand, there is the consistent effect of RAP on urine
flow and sodium excretion. On the other, there is a highly
efficient autoregulatory mechanism that prevents the
transmission of altered pressure to the intrarenal elements.
While a number of potential solutions to this dilemma
exist, most of these appear to have questionable validity
for conditions in which high autoregulatory efficiency is
present. The most obvious possible explanation is that
small, perhaps unmeasurable, changes in glomerular function lead to slight changes in glomerular filtration rate that
are accompanied by a slight degree of incomplete glomerular tubular balance and this leads to proportionately
larger changes in urine flow and sodium excretion.6'7> l4
Although this mechanism may be a satisfactory explanation when there is some evidence that changes in glomerular filtration rate do occur in response to changes in arterial pressure, one should be hesitant to use this explanation when there is no statistical evidence indicative of a
real change in GFR in response to changes in RAP, as was
true for the present study over the arterial pressure range
of approximately 90-140 mm Hg. In addition, no significant alteration in filtered sodium load occurred in response to changes in RAP. However, one cannot completely exclude the possibility that physiologically significant changes occur but are not within our capability for
measurement.
Because urine osmolality is decreased when RAP is
increased, it has also been suggested that the effects of
RAP on urine flow could be mediated by a type of medullary washout phenomenon dependent on the arterial pressure level.3'5'40 It was suggested that as arterial blood
pressure is altered, the blood flow to the medullary areas is
changed proportionately such that the hypertonicity of the
medullary environment is reciprocally related to the arterial pressure.3 To a large extent, this hypothesis was based
on data indicating that medullary renal blood flow was not
autoregulated with the same degree of efficiency as whole
kidney renal blood flow.5 More recent studies have indicated that this is not the case and that medullary blood
flow is autoregulated at least as well as cortical blood
flow.39 In addition, it is doubtful that the medullary washout phenomenon could also explain the concomitant
changes in sodium excretion that occur in response to
changes in arterial pressure. Furthermore, it has been
demonstrated that arterial pressure-mediated effects on
urine flow and sodium excretion continue to occur in
NEPHRON AUTOREGULATION AND PRESSURE DIURESIS/Navar et al.
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diabetes insipidus dogs in which the changes in urine
osmolality in response to changes in arterial pressure are
very slight.7 Therefore, while medullary washout may account, in part, for changes in urine flow and urine osmolality that occur with changes in blood pressure, it is unlikely
that it serves as a major mediator of the phenomenon of
pressure diuresis and natriuresis.
Finally, the observation that changes in the net fractional reabsorption of sodium and water occur in response
to changes in arterial pressure even in the absence of
changes in filtered loads, could be interpreted as showing
that this is mediated by changes in peritubular physical
forces2'9> "•19> 41 or "tubular driving force."42 This hypothesis has been suggested to explain the results of several
previous studies in which there were substantial alterations
in proximal tubule pressure or peritubule capillary pressure or both in response to changes in RAP.15"20 This
hypothesis may be of questionable validity in explaining
the alterations in fractional reabsorption of sodium and
water that occurred in the present study. There was no
significant quantitative association that could be established between the pressure responses in the proximal
tubules and peritubular capillaries and the excretory responses. However, these studies cannot rule out the possibility that very minute alterations in PCP, not within the
limits of our measurement capability, could be the significant factor responsible for altering the net tubular fractional reabsorption in response to alterations in renal arterial pressure. Admittedly, this is a difficult and controversial area and definitive conclusions could be made only
with knowledge of factors such as the interstitial fluid
hydrostatic and oncotic pressures as well as the oncotic
pressure profile within the peritubular capillaries. In the
absence of such information that could allow a complete
analysis, one can only say that these studies fail to provide
evidence that changes in either proximal tubule pressure
or peritubular capillary pressure are quantitatively associated with the urinary excretion responses. In addition,
decreases in renal arterial pressure did not cause significant alterations in fractional reabsorption from the accessible portion of the proximal tubule, at least over the
pressure range evaluated. Collectively, these data suggest
that the decreased urinary sodium and water excretion
observed during reduction in renal arterial pressure most
likely reflects an increase in reabsorption of filtrate in
some portion of the distal nephron through a mechanism
that remains unknown.43
Acknowledgments
We acknowledge the excellent technical assistance of Jan Ranellone and
Charles Thomas, the secretarial assistance of Allwyn Brown, and the
graphical assistance of Lynne Cohen. Assistance in statistical evaluation of
the data was provided by K. Kirk of the Department of Biostatistics,
University of Alabama.
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2. Shipley RE, Study RS: Changes in renal blood flow, extraction of
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renal artery blood pressure. Am J Physiol 167: 676-688, 1951
3. Thurau K: Renal Hemodynamics. Am J Med 36: 698-719, 1964
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7. Navar LG, Uther JB, Baer PG: Pressure diuresis in dogs with diabetes
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9. Aperia AC, Broberger CG, Soderlund S: Relationship between renal
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the Body Fluids, edited by AC Guyton, AE Taylor, HJ Granger.
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15. Koch KM, Aynedjian HS, Bank N: Effect of acute hypertension on
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16. Bank N, Aynedjian HS, Bansal VK, Goldman DM: Effect of acute
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17. Bank N: The renal regulation of sodium transport. Bull NY Acad Med
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18. Dresser TP, Lynch RE, Schneider EG, Knox FG: Effect of increases
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19. Kaloyanides GJ, DiBona GF, Raskin P: Pressure natriuresis in the
isolated kidney. Am J Physiol 220: 1660-1666, 1971
20. DiBona GF, Kaloyanides GJ, Bastron RD: Effect of increased perfusion pressure on proximal tubular reabsorption in the isolated kidney.
Proc Soc Exp Biol Med 143: 830-834, 1973
21. Landwehr DM, Schnermann J, Klose RM, Giebisch G: The effect of
acute reductions in glomerular filtration rate on renal tubular sodium
and water reabsorption. Am J Physiol 215: 687-697, 1968
22. Stumpe KO, Lowitz HD, Ochwadt B: Fluid reabsorption in Henle's
loop and urinary excretion of sodium and water in normal rats and rats
with chronic hypertension. J Clin Invest 49: 1200-1212, 1970
23. Liebau G, Levine DZ, Thurau K: Micropuncture studies on the dog
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24. Robertson CR, Deen WM, Troy JL, Brenner BM: Dynamics of
glomerular ullrafiltration in the rat. III. Hemodynamics and autoregulation. Am J Physiol 223: 1191-1200, 1972
25. Navar LG, Chomdej B, Bell PD: Absence of estimated glomerular
capillary pressure autoregulation during interrupted distal delivery.
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26. Knox FG, Ott C, Cuche JL, Gasser J, Hass J: Autoregulation of single
nephron filtration rate in the presence and absence of flow to the
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27. Navar LG, Burke TJ, Robinson RR, Clapp JR: Distal tubular feedback in the autoregulation of single nephron glomerular filtration rate.
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28. Bonvalet JP, Bencsath P, De Rouffignac C: Glomerular filtration rate
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VOL. 41, No. 4, OCTOBER
1977
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Anomalous Responses of Tumor Vasculature to
Norepinephrine and Prostaglandin E2 in the Rabbit
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JOHN H. G.
RANKIN, RANDY JIRTLE, AND TERRANCE M.
PHERNETTON
SUMMARY We used 25-/im microspheres to compare blood flow to the V-2 carcinoma in the awake, unanesthetized rabbit with blood flow to other organs. Injection of norepinephrine (50 /ig) into the left ventricle caused a 41fold [95% confidence interval = (25-69)] increase in tumor vascular resistance (P < 0.01). This was more than one
order of magnitude greater than the increase in resistance in any other organ. Prostaglandin E2 (50 /ig) injected into
the left ventricle caused a 7-fold (4-13) increase in tumor vascular resistance (P < 0.01) and no significant increase of
the vascular resistance of other organs. The change in tumor vascular resistance was not completely due to an
increased level of circulating catecholamines because a 2-fold (1.6-3.4) increase in the resistance (P < 0.01) was seen
when prostaglandin E, was injected into the left ventricle of animals pretreated with phenoxybenzamine. The
prostaglandin E2-induced tumor vasoconstriction was not due to an increased level of circulating angiotensin II
because in animals in which a and angiotensin receptors were blocked, prostaglandin E 2 increased the tumor vascular
resistance by a factor of 3 (2.3-5.5) (P < 0.01). The tumor vasculature appears to be hypersensitive to a-receptor
activation and responds to prostaglandin E2 with vasoconstriction which cannot be accounted for by an increased level
of circulating catecholamines or angiotensin II. In these experiments, the vasculature of the tumor responded to
pharmacological agents in a manner that was not displayed by the vasculature of other organs. It may be possible to
selectively control tumor blood flow without adversely affecting the blood flow to other organs of the host.
MOST CANCERS are found as solid tumors, and much
research in the field of cancer is concerned with a description of the basic causes of tumor growth at the cellular
level. A unique approach has been taken by Folkman1
who has described the concept of angiogenesis in which
the tumor forces the host to develop a new vasculature in
order to supply nutrients to the tumor. Folkman has
pointed out that solid tumors cannot grow unless the
angiogenic responses are elicited.
In view of the great interest in cancer it is curious that
fundamental information regarding the cardiovascular
mechanisms responsible for the regulation of the tumor
From the Departments of Physiology and Gynecology-Obstetrics, University of Wisconsin Medical School, and Wisconsin Perinatal Center,
Madison General Hospital. Madison, Wisconsin.
Supported by Grant CA18756, awarded by the National Cancer Institute, Department of Health, Education and Welfare.
Address for reprints: John Rankin. Ph.D.. Madison General Hospital,
722E. 202 South Park Street, Madison, Wisconsin 53715.
Abstract presented at Spring meeting of American Physiological Society, 1977.
Received November 19. 1976; accepted for publication March 23,
1977.
blood flow has not been obtained .In 1975, Gullino2 stated
that "Control of circulation in tumors is an open question,
at present." There is undoubtedly a practical reason for
this neglect. The vasculature of the tumor is ever changing
and does not lend itself to precise anatomical description.
The traditional methods used to measure blood flow to an
organ are difficult to apply to tissues such as tumors which
have a variable size and location. In recent years the
microsphere method for the determination of regional
blood flows has been validated in many laboratories.3'4
We have performed a series of experiments designed to
explore the use of radioactive microspheres to measure
tumor blood flow, and we have used this technique to test
the hypothesis that the regulation of the tumor blood flow
does not differ from that of normal tissue. This hypothesis
was tested by observing the responses of the vasculature of
the tumor and other organs of the rabbit to norepinephrine which is known to cause vasoconstriction. Prostaglandin E2 also was used because it is known to have vasodilator activity in many organs5 and to modify the vasoconstrictor actions of norepinephrine.6
Autoregulatory responses of superficial nephrons and their association with sodium
excretion during arterial pressure alterations in the dog.
L G Navar, P D Bell and T J Burke
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Circ Res. 1977;41:487-496
doi: 10.1161/01.RES.41.4.487
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Copyright © 1977 American Heart Association, Inc. All rights reserved.
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