547
Brief Review
Abnormal Pressure Natriuresis
A Cause or a Consequence of Hypertension?
John E. Hall, H. Leland Mizelle, Drew A. Hildebrandt, and Michael W. Brands
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
In all forms of chronic hypertension, the renal-pressure natriuresis mechanism is abnormal
because sodium excretion is the same as in normotension despite the increased blood pressure.
However, the importance of this resetting of pressure natriuresis as a cause of hypertension is
controversial. Theoretically, a resetting of pressure natriuresis could necessitate increased
blood pressure to maintain sodium balance or it could occur secondarily to hypertension.
Recent studies indicate that, in several models of experimental hypertension (including
angiotensin II, aldosterone, adrenocorticotrophic hormone, and norepinephrine hypertension),
a primary shift of renal-pressure natriuresis necessitates increased arterial pressure to
maintain sodium and water balance. In genetic animal models of hypertension, there also
appears to be a resetting of pressure natriuresis before the development of hypertension.
Likewise, essential hypertensive patients exhibit abnormal pressure natriuresis, although the
precise cause of this defect is not clear. It is likely that multiple renal defects contribute to
resetting of pressure natriuresis in essential hypertensive patients. With long-standing hypertension, pathological changes that occur secondary to hypertension must also be considered. By
analyzing the characteristics of pressure natriuresis in hypertensive patients and by comparing
these curves to those observed in various forms of experimental hypertension of known origin,
it is possible to gain insight into the etiology of this disease. (Hypertension 1990;15:547-559)
I
n many patients with hypertension, there are no
obvious renal defects. Most of the common
indexes used to evaluate renal function, such as
glomerular filtration rate (GFR) or renal plasma
flow, are often within the normal range, which leads
many investigators to believe that hypertension can
develop in the absence of kidney abnormalities. Yet,
there is one aspect of kidney function, the relation
between renal sodium and water excretion and arterial pressure, that is abnormal in all types of experimental and clinical hypertension. Normally, an
increase in arterial pressure would elevate sodium
excretion, a phenomenon often referred to as pressure natriuresis.1-3 The fact that hypertensive
patients are in sodium balance and have normal
sodium excretion (equal to intake) despite increased
blood pressure indicates that pressure natriuresis is
reset. The mechanisms responsible for this resetting
and its role in hypertension have been the subject of
considerable controversy. The goal of this paper is to
From the Department of Physiology and Biophysics, University
of Mississippi Medical Center, Jackson, Mississippi.
Supported by grants HL-23502, HL-39399, and HL-11678 from
the National Institutes of Health. D.A.H. and M.W.B. were
supported by National Research Service awards F32 HL-07931
and F32 HL-08171.
Address for correspondence: John E. Hall, PhD, Department of
Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505.
briefly review the function of pressure natriuresis in
normal regulation of arterial pressure and body fluid
volumes, the evidence that abnormalities of pressure
natriuresis play a causal role in hypertension, and
some potential mechanisms by which pressure natriuresis may be reset in hypertension.
Renal-Body Fluid Feedback Control
of Arterial Pressure
The renal-pressure natriuresis mechanism has been
postulated to be a primary component of a feedback
system for long-term regulation of arterial pressure
and body fluid volumes.14 Under most conditions,
this mechanism acts to stabilize arterial pressure as
well as body fluid volumes. For example, disturbances that elevate arterial pressure without impairing renal excretory capability also tend to increase
sodium and water excretion through pressure natriuresis and diuresis, thereby reducing extracellular
fluid volume and returning blood pressure toward
normal (Figure 1). Hypertension caused by increases
in cardiac output or total peripheral resistance cannot be sustained if pressure natriuresis is unaltered
because sodium excretion would remain above
sodium intake until arterial pressure returned completely to the original set point. Similarly, reductions
in blood pressure tend to lower sodium excretion and
increase extracellular fluid volume until blood pressure returns to normal. An important aspect of this
548
Hypertension
Vol 15, No 6, Part 1, June 1990
1
PERIPHERAL VASOCONUDUdlOIf
NO REKAL ACTION
CONTROL (N-6)
' 30-14225 (N-6)
' AH (N-6)
500
^400
UBUIART
SODIUM
I 300
( x NORMAL)
Normal
KnUte
BO
100
ISO
300
MEAN ARTERIAL PRESSURE (mmHtf
STIMULUS
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
MEAN
ARTERIAL
PRESSURE
a
200
t
100
twr
70
80
90
100 110
120
130
UAM UTFJUU. PtKSOK |naMt]
140
150
FIGURE 2. Line graph showing relations between arterial
pressure and sodium excretion in control dogs and in dogs
infused with converting enzyme inhibitor SQ-14,225 (captopril) or angiotensin II (All) (5 ng/kg/min). Data were
obtained by measuring arterial pressure at different levels of
sodium intake under steady-state conditions. Reprinted with
permission.6
tion to normal through pressure natriuresis. In the
steady state, renal excretion would be maintained
equal to intake but at the expense of hypertension.
URINART
SODIUM
OUTPUT
( z NORMAL)
Neurohumoral Modulation of Pressure Natriuresis
-
3
-
1 0 1 3
TIME (DATS)
3
4
FIGURE 1. Graphs showing predicted effects of a hypertensive stimulus, caused either by increased cardiac output or
increased total peripheral resistance, without a shift of the
renal-pressure natriuresis curve. Blood pressure is initially
elevated but cannot be sustained at that level because sodium
excretion exceeds intake, thereby reducing extracellular fluid
volume until blood pressure eventually returns to normal where
intake and output of sodium are balanced.
feedback system is that there are many neurohumoral systems that act to amplify its effectiveness.
For example, increases in blood pressure not only
tend to raise renal excretion directly through hydraulic effects on the kidney but also inhibit formation of
angiotensin II (Ang II) and aldosterone, which further elevates renal excretion and decreases extracellular fluid volume, promoting a more rapid recovery
of blood pressure.5
Although pressure natriuresis normally acts to
stabilize. blood pressure, abnormalities of renal
hemodynamics or tubular reabsorption can alter the
set point at which arterial pressure and sodium
excretion are controlled. For example, excessive formation of antinatriuretic hormones or diseases that
reduce renal excretory capability could shift the
pressure natriuresis curve to higher pressures and
tend to cause sodium retentio'n and increased extracellular fluid volume if intake remained constant.
Accumulation of fluid would continue until blood
pressure increased sufficiently to restore renal excre-
Any neurohumoral system capable of causing longterm changes in renal excretory function could influence blood pressure regulation by altering pressure
natriuresis. A reduction in renal excretory capability
would tend to shift the curve to high pressures,
whereas a chronic increase in renal excretory capability would be associated with a shift of pressure natriuresis toward lower blood pressures. Under steadystate conditions, no change in sodium excretion would
be observed because changes in blood pressure would
compensate for primary changes in renal excretory
function. In most instances, the various neurohumoral
systems act in concert with the basic pressure natriuresis mechanism to prevent chronic changes in blood
pressure, but there are certain pathophysiological
conditions associated with abnormal activity of these
neurohumoral systems that may alter the set point at
which blood pressure is regulated.
Renin-Angiotensin System
One of the most powerful modulators of pressure
natriuresis, and consequently of long-term blood
pressure control, is the renin-angiotensin system
(RAS). Figure 2 shows an analysis of the steady-state
interrelations between Ang II, arterial pressure, and
sodium excretion during chronic changes in sodium
intake in three groups of dogs with different levels of
activity of the RAS.6 In these experiments, sodium
intake was raised progressively in steps from 5 to
approximately 500 meq/day and maintained at each
level until balance between intake and output of
sodium was achieved. In normal dogs with an intact
RAS, sodium balance was maintained with only
Hall et al Pressure Natriuresis in Hypertension
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
minor changes in blood pressure (5-10 mm Hg) over
the entire range of sodium intake, indicating a very
effective pressure natriuresis mechanism. In fact, the
steepness of the chronic curve relating arterial pressure to sodium excretion is due in large part to
changes in Ang II formation in response to changes
in sodium intake or arterial pressure. When Ang II
was infused at a low rate (5 ng/kg/min) throughout
the experiment so that circulating levels could not
decrease, very large increases in blood pressure
(40-50 mm Hg) were needed to maintain sodium
balance when intake was raised. This observation
indicates that the inability to suppress Ang II formation greatly reduces the effectiveness of pressure
natriuresis. In a third group of dogs, Ang II formation was blocked throughout the experiment with the
converting enzyme inhibitor captopril (SQ-14,225).
After blockade of Ang II formation, renal excretory
capability was markedly increased because sodium
balance was maintained at lower than normal blood
pressures.
Thus, appropriate changes in activity of the RAS
play a key role in allowing the normal individual to
adapt to a wide range of sodium intakes with
minimal changes in blood pressure. However,
abnormalities of the RAS, such as the inability to
decrease Ang II formation appropriately in
response to high sodium intake, can also cause
pronounced effects on pressure natriuresis and
therefore long-term blood pressure regulation.
Atrial Natriuretic Factor
Another hormone that may play a role in modulating pressure natriuresis is atrial natriuretic factor
(ANF). Numerous studies have demonstrated that
ANF has powerful acute effects on sodium excretion
(See References 7 and 8 for reviews) and that this
hormone shifts the acute pressure natriuresis curve
to lower blood pressures.9'10 Recently, ANF has been
demonstrated to have powerful chronic effects on
renal excretory function. To assess the long-term
direct actions of ANF on the kidney while controlling
for various neurohumoral changes that might override its natriuretic effects, Mizelle et al11 used a split
bladder technique and infused ANF into one renal
artery for several days while infusing vehicle into the
contralateral kidney; thus, measurements of separate
renal function could be made in ANF- and vehicleinfused kidneys. This is a powerful method for studying the long-term direct effects of ANF on renal
function because both the infused and contralateral
kidneys are exposed to the same blood pressure and
neural influences and the same circulating hormones
and other constituents of the blood except for ANF.
Therefore, any differences in renal function can be
attributed to differences in ANF concentrations. In
these experiments, ANF infusion at low physiological
rates caused pronounced increases in renal excretion
that persisted as long as ANF was infused. Sodium
excretion in the contralateral kidney decreased by
almost an identical amount so that the total sodium
549
balance was maintained relatively constant. These
findings indicate that ANF, at physiological concentrations, is capable of increasing renal excretory
function chronically and provides the basis for a
possible role of ANF in long-term regulation of body
fluid volumes and blood pressure.
To further examine the importance of intrarenal
versus systemic actions of ANF in long-term regulation of blood pressure, Hildebrandt et al12 recently
compared the chronic blood pressure effects of ANF
infused at very low rates directly into the kidney with
the effects produced by intravenous infusions at the
same rates. The results from these studies demonstrated that intrarenal infusions of ANF at rates too
low to have any major systemic actions caused pronounced decreases in blood pressure over a period of
several days. These findings demonstrate that physiological increases in intrarenal levels of ANF can
reduce blood pressure chronically while increasing
renal excretory capability, indicating a shift of renalpressure natriuresis. However, the importance of this
effect in different physiological and pathophysiological conditions has not been fully elucidated.
The precise mechanisms by which ANF alters
long-term pressure natriuresis are not well understood. Part of the natriuretic effect of ANF may be
mediated through interactions with the RAS.9 For
example, ANF reduces renin secretion and may
antagonize the renal tubular and vascular actions of
Ang II.13-15 Further studies are needed, however, to
quantify the importance of interactions between
ANF and the RAS and the exact mechanisms by
which ANF influences chronic pressure natriuresis
and blood pressure regulation.
In addition to the RAS and ANF, other neurohumoral systems may also influence blood pressure
by altering renal-pressure natriuresis. For example,
DiBona16 recently reviewed evidence that the renal
nerves may influence renal excretory capability and
blood pressure regulation in several models of experimental hypertension. Other hormone systems, such
as the kallikrein-kinin system, the renal prostaglandins, and other natriuretic factors besides ANF, have
also been postulated to be important in regulating
renal excretory function and arterial pressure.17"21
Unfortunately, there are few data concerning the
quantitative importance of these systems in longterm regulation of pressure natriuresis, and it is not
always prudent to extrapolate from the results of
acute experiments.
Abnormal Renal-Pressure Natriuresis
in Hypertension
As discussed above, renal-pressure natriuresis is
abnormal in all forms of chronic hypertension
because average sodium excretion is approximately
the same as in normotension, assuming that sodium
intake is normal. Figure 3 illustrates the approximate
steady-state relations between blood pressure and
sodium excretion in several types of hypertension. In
each example, the pressure natriuresis curve is
550
Hypertension
Vol 15, No 6, Part 1, June 1990
5,
FIGURE 3. Schematic drawing showing steady-state relations between arterial pressure and sodium excretion and
sodium intake in various forms of
hypertension. K^, glomerular capillary
filtration coefficient; SHR, spontaneously hypertensive rats; Goldblatt, onekidney, one clip Goldblatt hypertensive
rats.
SODIUM INTAKE
AND OUTPUT
(X Normal)
2.
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
-o-50
100
200
150
ARTERIAL PRESSURE
(mmHg)
shifted so that sodium balance occurs at elevated
blood pressures. Obviously, a shift of this curve to
higher pressures must occur in all forms of chronic
hypertension, otherwise sodium excretion would
remain above intake until it caused severe volume
depletion and circulatory collapse. However, note
that the characteristics of pressure natriuresis differ
in various forms of hypertension. As discussed below,
the differing slopes and intercepts of the pressure
natriuresis curves in various forms of hypertension
may provide clues about the etiology of hypertension.
Although it is clear that there are abnormalities of
pressure natriuresis in hypertension, the importance
of these abnormalities as a cause of hypertension has
been debated. According to the renal-body fluid
feedback concept,1 a primary reduction of renal
excretory capability, caused by decreased GFR or
increased tubular reabsorption, initiates a compensatory increase in blood pressure that serves to
maintain fluid balance. Reductions in renal excretory
capability can be due to various intrinsic functional
or pathological changes in the kidney or to neurohumoral factors that influence renal excretion. In the
steady state, normal sodium excretion would be
maintained and the initial change in GFR or tubular
reabsorption would be masked by the elevated blood
pressure.
An opposing view of abnormal pressure natriuresis
in hypertension is that it occurs secondarily to
increased arterial pressure.22-24 This concept predicts that hypertension is initiated by abnormalities
of the heart or peripheral vasculature that tend to
elevate cardiac output or total peripheral vascular
resistance and that the kidneys secondarily adapt to
increased blood pressure to maintain sodium balance. Obviously, if the kidneys could completely reset
their pressure natriuresis mechanism and maintain
normal sodium excretion independently of changes in
blood pressure initiated by nonrenal abnormalities,
renal-pressure natriuresis would not play a significant
role in long-term blood pressure regulation. Therefore, one of the most important and controversial
issues concerning the role of the kidneys in the
pathogenesis of hypertension is whether arterial
pressure has a long-term effect on sodium and water
excretion, or alternatively, whether the kidneys can
regulate sodium excretion independently of blood
pressure. Unfortunately, this has been a difficult
question to answer experimentally because attempts
to produce long-term changes in renal perfusion
pressure (e.g., renal artery stenosis) are usually
accompanied by compensatory changes in systemic
arterial pressure or neurohumoral changes that also
influence renal excretion. However, recent studies
have addressed this problem by examining the role of
pressure natriuresis in various models of experimental hypertension in which the direct effects of
increased blood pressure were separated from other
factors that influence renal excretion.
Hypertension Caused by Antinatriuretic Hormones
Excessive secretion of mineralocorticoids or other
antinatriuretic hormones such as Ang II typically
causes transient sodium retention and gradual elevation of blood pressure.1819-25-26 Sodium retention lasts
for only a few days and is followed by an "escape" in
which sodium excretion returns to normal. The mechanisms responsible for this escape have been the
subject of considerable research, and various concepts
have been proposed to explain this phenomenon.18"19
According to the renal-body fluid feedback concept,
mineralocorticoids or Ang II reduce renal excretory
Hall et al
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
capability and initiate a sequence of events that elevate arterial pressure. Increased blood pressure then
restores sodium excretion to normal through pressure
natriuresis. However, because mineralocorticoids and
Ang II almost invariably raise total peripheral vascular
resistance, the high blood pressure has also been
postulated to be caused by direct or indirect effects of
these agents to constrict the peripheral vasculature.27-30 For example, mineralocorticoids have been
postulated to activate the sympathetic nervous system
or to stimulate the release of a ouabain-like circulating
inhibitor of sodium-potassium adenosine triphosphatase secondary to volume expansion,31'32 changes that
are believed to cause peripheral vasoconstriction and
hypertension. The escape from sodium retention has
also been postulated to be independent of increased
arterial pressure and to be mediated by increased
formation of various natriuretic factors, such as a
ouabain-like natriuretic hormone, ANF, kinins, prostaglandins, or reduced renal sympathetic nerve
activity.17-21
To resolve these issues and to directly test the
importance of pressure natriuresis in regulating
sodium balance in hypertension, we compared the
chronic blood pressure and renal effects of aldosterone or Ang II infusion in dogs in which renal
perfusion pressure was either permitted to increase
or servo-controlled at the normal level.25-26 In normal
dogs, aldosterone or Ang II infusion caused relatively
mild hypertension, with sodium excretion decreasing
transiently and then returning toward control on the
second day of infusion, and after 7 days cumulative
sodium balance was only slightly elevated. In contrast, when renal perfusion pressure was servocontrolled during aldosterone (Figure 4) or Ang II
infusion (Figure 5), sodium excretion remained considerably below intake throughout the experiment.
Therefore, cumulative sodium balance continued to
increase, which caused pronounced edema in several
dogs. The systemic arterial hypertension was also
much more severe when renal artery pressure was
prevented from increasing, and some dogs developed
severe ascites or pulmonary edema within a few days.
When the servo-controller was stopped and renal
perfusion pressure was allowed to increase to hypertensive levels while Ang II or aldosterone infusions
were continued, there was a prompt escape from
sodium retention and cumulative sodium balance,
and arterial pressure returned to about the same
levels measured in normal dogs during aldosterone
or Ang II infusion.
The results from these studies indicate that pressure natriuresis plays an essential role in maintaining
sodium balance in mineralocorticoid and Ang II
hypertension. When this mechanism was prevented
from operating, severe fluid retention occurred,
which would eventually lead to complete circulatory
collapse. Although these observations emphasize the
importance of pressure natriuresis, they do not rule
out the possibility that other factors may also be
important in maintaining sodium balance in response
Pressure Natriuresis in Hypertension
551
•—• Control
• - -• Serro-Control
RENAL
ARTERT
PRESSURE
(mmHg)
MEAN SYSTEMIC
ARTERIAL
PRESSURE
(mmHf)
URINARY
SODIUM
EXCRETION
ooo
CUMULATIVE
SODIUM
BALANCE
(mEq/day)
too
TIMEfdajm)
FIGURE 4. Line graphs showing effects of aldosterone infusion when renal perfusion pressure was servo-controlled at the
normal level (servo-control) or allowed to increase (control) in
dogs maintained on high sodium intake. Adapted from Reference 25.
to Ang II or mineralocorticoid excess. It is possible
that various natriuretic hormones, especially ANF,
could play a role in minimizing the rise in blood
pressure needed to maintain sodium balance.
The intrarenal mechanisms by which increased arterial pressure allows escape from the antinatriuretic
effects of aldosterone or Ang II appear to be related to
small increases in GFR and renal plasma flow and
decreases in fractional sodium reabsorption2526 (see
References 18 and 19 for further review). With prolonged hypertension, lasting for months or years,
pathological changes in the glomerular capillaries may
cause reductions in GFR that necessitate further
elevations in arterial pressure and inhibition of tubular reabsorption to maintain sodium balance. However, the observation that GFR and renal plasma flow
are elevated as mineralocorticoid hypertension develops, even though renal excretory capability is reduced,
illustrates an important point: evaluation of renal
excretory capability cannot be based on steady-state
measurements of renal hemodynamics, tubular reabsorption, or even sodium excretion as each of these
variables is influenced by various compensatory mechanisms that are set into motion as hypertension develops. In the case of mineralocorticoid hypertension,
increased GFR and renal plasma flow, along with a
reduction in proximal fractional reabsorption, appear
552
Hypertension
Vol 15, No 6, Part 1, June 1990
HS - 7
170
150
AiTOtlAl
ntESSBK
130
[MH||
110
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
-4
-2
12
FIGURE 5. Line graphs showing effects of angiotensin II
infusion in a dog in which renal perfusion pressure was
servo-controlled at the normal level After 4 days, severe
hypertension arid sodium and water retention resulted in
pulmonary edema. Reprinted with permission.26
to be important compensations for a primary increase
in distal tubular sodium reabsorption. In the steady
state, distal tubular delivery of sodium is increased to
offset increased distal reabsorption, and a decrease in
renal excretory capability is apparent only when the
arterial pressure that is needed to maintain sodium
excretion equal to intake is considered.
Hypertension Caused by "Vasoconstrictors"
An abnormality of renal-pressure natriuresis has
also been found in several forms of hypertension that
are usually considered to be caused by peripheral
vasoconstriction. For example, both norepinephrine
and vasopressin are among the most potent peripheral
vasoconstrictors of the body. In fact, vasopressin is
more powerful as a vasoconstrictor than Ang II.33 Yet,
with chronic infusions of vasopressin or norepinephrine, only small increases in blood pressure are
observed as long as kidney function is not impaired.33"36 The fact that these powerful vasoconstrictors do not usually cause pronounced chronic hypertension, even though they elicit large acute increases
in vascular resistance and blood pressure, is difficult to
explain if one considers changes in peripheral vascular
resistance to be a primary cause of hypertension.
However, the failure of vasopressin or norepinephrine
to cause severe sustained hypertension is explainable
if one considers their modest antinatriuretic actions.
Although vasopressin is a potent antidiuretic hormone, it does not have a major antinatriuretic action.
Therefore, increases in arterial pressure that result
from peripheral vasoconstriction tend to cause natriuresis, which offsets the fluid retention initiated by
vasopressin.33-35'36 When vasopressin was infused
chronically in normal dogs at a rate that produced
maximal antidiuresis, there was initially a modest
increase in blood pressure associated with transient
increases in urine osmolality and decreased urine
volume. However, after 3-4 days urine volume and
osmolality returned toward normal and arterial pressure began to decrease, averaging only a few millimeters of mercury above control after 1-2 weeks of
infusion.35 This decline of blood pressure was associated with increased sodium excretion and a negative sodium balance. In contrast, when pressure
natriuresis was prevented by servo-controlling renal
arterial pressure, vasopressin infusion caused pronounced and sustained decreases in urine volume,
increased urine osmolality, a slight retention of
sodium, and severe hypertension.35
Thus, the pressure natriuresis and diuresis mechanisms play an essential role in offsetting the antidiuretic effect of vasopressin, thereby minimizing volume expansion and hypertension even though
vasopressin is one of the most powerful vasoconstrictors known. The modest transient hypertension that
occurs when renal function is normal depends primarily on increased volume rather than the peripheral vasoconstriction. Cowley et al37 found that, when
total body weight was held constant by decreasing
fluid intake during vasopressin infusion in dogs, there
was no significant increase in blood pressure. However,
when fluid retention is severe because of impaired
pressure natriuresis, vasopressin may cause large
increases in blood pressure. In our experiments,35 when
renal artery pressure was servo-controlled during
chronic vasopressin infusion, continuous retention of
fluid occurred and blood pressure increased markedly.
Thus, the chronic hypertensive effects of vasopressin,
although modest in animals with normal renal function,
may be more severe when renal function is impaired.
Similar results have also been observed with other
vasoconstrictors, such as norepinephrine, and with
adrenocorticotrophic hormone, which potentiates
the hypertension produced by vasoconstrictors such
as norepinephrine.34-38-40 Each of these forms of
hypertension begins with an increase, rather than a
decrease, in sodium excretion. The finding that
sodium excretion increases transiently could be interpreted as evidence that the hypertensive action of
these hormones is unrelated to any impairment of
renal excretory capability. However, it appears that
the transient natriuresis occurs secondarily to
increased blood pressure caused by peripheral vasoconstriction or increased cardiac output and that
norepinephrine and adrenocorticotrophic hormone
both have a slight antinatriuretic effect on the kidney
Hall et al Pressure Natriuresis in Hypertension
PERIPHERAL VABOCON8TRICTKMC
WEAK RENAL ACTION
UJUHAHT
80OICM
(xHOBMAL)
Konul
BO
100
1BO
200
MEAN ARTXRIAL PBISSDBS (mmBO
ISO
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
MSAlf
ARTERIAL
PRBSSUKK
100
UKUtAKT
SODIUM
OUTPUT
( I NORMAL)
-
2
-
1
0
1
2
TTMI(DATB)
3
553
transient natriuresis would be expected because
extracellular fluid volume would decrease and arterial pressure would eventually stabilize at a level
(point C) at which sodium intake and output are
balanced. This explanation fits with our finding that
the natriuretic effects of vasoconstrictors such as
norepinephrine and vasopressin are abolished when
renal perfusion pressure is prevented from increasing. In fact, there is a slight sodium retention when
renal perfusion pressure is servo-controlled in these
models of hypertension.38
Thus, there is strong experimental support for the
basic premise of the renal-body fluid feedback concept, that increases in blood pressure have a major
long-term effect on sodium excretion. In all forms of
experimental hypertension studied thus far, there is a
shift of the pressure natriuresis mechanism to a
higher blood pressure, which initiates and sustains
the hypertension. In some cases, the renal actions of
these hypertensive stimuli may be obscured by other
effects, such as peripheral vasoconstriction or
changes in vascular capacity, that increase blood
pressure above the renal set point at which sodium
balance is maintained. In these circumstances,
sodium excretion may actually increase as hypertension develops. However, the maintenance of elevated
blood pressure chronically depends on the changes in
renal function that contribute to the shift of renalpressure natriuresis.
4
FIGURE 6. Graphs showing probable long-term relation
between arterial pressure and sodium excretion and sodium
intake before and during infusion of a powerful peripheral
vasoconstrictor that has a relatively weak effect on renalpressure natriuresis. The normal curve (solid line) is compared
with the vasoconstrictor curve (dashed line). Initially, the
vasoconstrictor would cause natriuresis, because arterial pressure is elevated (to point B) above the set point for balance
between intake and output of sodium (point C).
that is responsible for the mild hypertension that these
hormones produce chronically.34-39 If pressure natriuresis is prevented by servo-controlling renal artery
pressure, both of these hormones can cause severe
hypertension that parallels sodium retention.34-39
Figure 6 shows the probable relation between
blood pressure and sodium excretion after infusion of
a powerful peripheral vasoconstrictor that has a
relatively weak antinatriuretic effect on the kidney
(e.g., norepinephrine). The antinatriuretic effect of
the vasoconstrictor would shift the renal-pressure
natriuresis mechanism to higher blood pressures,
thereby necessitating a small increase in blood pressure to maintain sodium balance. However, if the
antinatriuretic action of the vasoconstrictor is weak,
compared with its peripheral vascular actions, blood
pressure would be elevated above the renal set point
for regulation of sodium balance (to point B rather
than point C where intake and output are balanced)
and would cause a transient natriuresis. Only a
Can Abnormal Pressure Natriuresis Mechanism
Occur Secondarily to Chronic Increases
in Blood Pressure?
In the experimental models of hypertension discussed above, primary changes in renal-pressure
natriuresis resulted in adaptations of blood pressure
(i.e., hypertension occurred as a compensatory
response to maintain sodium and water balance).
These experiments also illustrate another important
point: if pressure natriuresis is impaired and imbalances between fluid intake and output are maintained, severe edema and complete circulatory collapse occur within a few days. Rapid adaptations of
blood pressure to primary alterations in renal function are essential for survival in these forms of
hypertension.
Although high blood pressure may satisfy the
immediate need to maintain sodium balance, it may
also lead to additional changes in renal excretory
function that can exacerbate the hypertensive process over long periods of time. A good example is the
hypertension that develops after placing a Goldblatt
clip on one renal artery while leaving the contralateral kidney intact (two-kidney, one clip Goldblatt
hypertension). Initially, the hypertension is caused by
impaired function of the clipped kidney, while the
contralateral intact kidney undergoes natriuresis,
which partly ameliorates the hypertension.41 Full
compensation for impaired function of the clipped
kidney is not achieved by the contralateral kidney
because its excretory function is also partly attenu-
554
Hypertension
Vol 15, No 6, Part 1, June 1990
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
ated by various functional changes, such as increased
circulating Ang II. 142 Therefore, increased blood
pressure is necessary to maintain sodium excretion
and intake in balance.
In the early stages of hypertension, removal of the
clipped kidney restores blood pressure to normal,
whereas removal of the contralateral kidney exacerbates the hypertension.43 However, with prolonged
hypertension pathological changes in the vasculature
of the contralateral kidney begin to appear and add
to the impairment of renal function.44 At this stage,
removal of the clipped kidney or unclipping only
partially restores blood pressure.44'45 However,
removal of the contralateral "normal" kidney and
unclipping together usually normalizes blood pressure.46 This observation indicates that chronic exposure to high blood pressure in the untouched kidney
may cause structural changes that alter its pressure
natriuresis mechanism and contribute to progression
of hypertension. Thus, the two-kidney, one clip Goldblatt model of hypertension, although initiated by
increased preglomerular resistance in part of the renal
tissue, is characterized by functional or pathological
changes in the remaining normal renal tissue that
contribute to the maintenance of hypertension. A
similar situation could occur when there are patchy
areas of renal ischemia due to a variety of causes,
including renal infarcts, nonhomogeneous constriction
of the renal vasculature, or nonhomogeneous
nephrosclerosis.1-47 In fact, any abnormality of renal
function that causes underperfusion in one area of the
kidney is likely to cause impairment of the remaining
nephrons via the renin released from underperfused
nephrons.1'47
Conceivably, any initial disturbance of renal function that leads to compensatory increases in intrarenal pressures due to increased systemic arterial pressure or preglomerular vasodilation could cause
pathological changes that would eventually result in
glomerular membrane or arteriolar damage,48 thereby gradually shifting pressure natriuresis to higher
and higher blood pressures. In this way, renalpressure natriuresis could gradually adapt to chronic
increases in blood pressure. This adaptation, however, would not act as a physiological mechanism to
maintain sodium balance; instead, these changes
could be a pathological cause of further increases in
blood pressure that would in turn be important in
maintaining sodium balance.
Abnormal Pressure Natriuresis in
Essential Hypertension
In most patients with hypertension, no specific renal
dysfunction can be identified in the early stages of the
disease, and there is little evidence for increased levels
of antinatriuretic hormones such as Ang II or aldosterone. Thus, the hypertension of these patients is
usually referred to as "idiopathic" or "essential."
However, it is clear that renal excretory function is not
normal in these patients because the renal-pressure
natriuresis mechanism is reset so that normal sodium
excretion is maintained only at elevated blood pressures. Omvik et al23 demonstrated that when arterial
pressure was acutely reduced by nitroprusside infusion in patients with essential hypertension, sodium
excretion decreased below normal indicating that
pressure natriuresis was reset in these patients. Similar abnormalities of renal-pressure natriuresis have
been found in all animal models of genetic hypertension studied thus far.2-41'49"53
The observation of abnormal pressure natriuresis
in essential hypertension is not direct evidence that
such an abnormality plays a causal role in elevating
blood pressure. However, in genetic models of spontaneous hypertension that have many similarities to
human essential hypertension, there is evidence that
abnormalities of pressure natriuresis occur before
the development of hypertension and are not merely
secondary to increased blood pressure. For example,
in prehypertensive Dahl salt-sensitive (DS) rats the
slope of the relation between urine flow and renal
perfusion pressure measured in acute experiments is
considerably less than that seen in Dahl salt-resistant
(DR) rats53 (Figure 7). The fact that this occurs
before the rats develop hypertension suggests that
abnormal pressure natriuresis in the DS rat is not
caused by renal damage secondary to hypertension
but represents an intrinsic difference between the
kidneys of DS and DR rats. The mechanisms that
underlie the shift of pressure natriuresis in DS rats
are not entirely clear but may be related in part to
abnormalities of renal hemodynamics. Roman53
demonstrated that a shift of GFR autoregulation to
higher pressures occurred in prehypertensive DS rats
fed a low sodium diet. Recently, Tobian et al54 also
demonstrated that there is a glomerular defect in
prehypertensive DS rats that limits their capacity to
increase GFR in response to amino acid infusion.
Cross transplantation studies between DS and DR
rats indicate that the hypertension of these rats
follows abnormal kidney function.55-56
In Okamoto spontaneously hypertensive rats (SHR),
abnormalities of renal function also appear to play a
role in causing hypertension. Transplantation of kidneys from SHR to Wistar-Kyoto (WKY) rats produces hypertension in the previously normotensive
recipient.57-59 Moreover, this alteration in renal function is not merely the result of damage secondary to
hypertension because transplantation of kidneys
from SHR even before they develop hypertension
eventually causes hypertension in the WKY rat
recipient.57 Acute studies in SHR suggest that multiple abnormalities of renal function may occur at
different stages of hypertension. Renal blood flow
autoregulation has been reported to be shifted to
higher blood pressures in young 10-week-old SHR
compared with WKY control rats.60 When differences in neural and endocrine influences in the
kidneys are minimized by renal denervation and by
maintaining plasma levels of vasopressin, aldosterone, cortisol, and norepinephrine constant by intravenous infusion, the slope of the renal-pressure
Hall et al
555
Curtis et al,66 who reported that transplantation of
kidneys from normotensive donors to patients with
essential hypertension and renal failure led to complete normalization of blood pressure. If the high
blood pressure in these patients was caused by some
factor extrinsic to the kidneys, hypertension should
have eventually reappeared after transplantation.
However, blood pressure remained normal in all
patients for an average follow-up period of 4.5 years.
Parfrey67 also reported that, in children born to
parents who were both hypertensive, the pressure
natriuresis curve was shifted when compared with
that of children with normotensive parents, even
before the onset of hypertension. These observations
provide further support for the view that abnormal
pressure natriuresis in essential hypertensive patients
may be a cause and not merely a consequence of
increased blood pressure. However, as discussed
above, once the hypertensive process begins pathological changes can occur in the kidneys that can add
to the shift of the pressure natriuresis curve and
further elevate blood pressure.
120
80
URINE FLOW
ul/mln
40
20
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
15
SO CHUM
EXCRETION
uEq/mtn
Pressure Natriuresis in Hypertension
ID-
Possible Mechanisms of Shift in Pressure Natriuresis
in Essential Hypertension
100
12S
150
175
200
RENAL ARTERIAL PRESSURE
inm HQ
FIGURE 7. Line graphs showing effect of changes in renal
perfusion pressure on urine flow and sodium excretion in Dahl
salt-resistant rats, in hypertensive Dahl salt-sensitive rats, and
in prehypertensive Dahl salt-sensitive rats fed a low salt diet.
Adapted from Reference 53.
natriuresis curve of SHR is reduced compared with
that of WKY rats.52 This finding suggests that there
may be intrinsic changes in renal function that contribute to resetting of pressure natriuresis in SHR.
However, chronic studies in intact SHR suggest that
increased renal nerve activity and immunological
abnormalities may also contribute in part to a parallel shift of pressure natriuresis.61-62
In the Milan strain of SHR, cross transplantation
studies between normotensive and hypertensive rats
also indicate that the hypertension follows the
kidney.63-64 Several lines of evidence recently
reviewed by Bianchi et al65 suggest that hypertension
in Milan rats may be initiated by a primary increase
in renal tubular reabsorption. However, the exact
intrarenal mechanisms responsible for abnormal
pressure natriuresis in each of these models of
genetic hypertension have not been fully elucidated.
The possibility that these observations in animals
may be relevant to the pathogenesis of human essential hypertension is supported by the findings of
A single renal defect responsible for shifting pressure natriuresis and elevating blood pressure in
human essential hypertension has not been found. It
seems likely that essential hypertension is a heterogeneous disease beginning with different abnormalities of renal hemodynamics or tubular reabsorption
in different patients. Unfortunately, measurements
of various indexes of kidney function after hypertension is established or even during the slow insidious
development of hypertension may not provide a great
deal of insight into the pathophysiological processes
that initiate hypertension because these measurements represent a summation of compensatory
mechanisms and abnormalities involved in causing
hypertension. For example, renal vascular resistance
is almost invariably increased in patients with essential hypertension.41-6869 Yet, high renal vascular resistance could be an autoregulatory response to
increased blood pressure in some cases or it could
play a causal role in others if it is increased sufficiently to lower renal blood flow and GFR.
In some instances, reduced renal excretory capability may be associated with a compensatory
increase in renal blood flow and GFR, as occurs
when there is a primary increase in tubular reabsorption (i.e., early stages of mineralocorticoid hypertension). In an attempt to document abnormalities of
renal hemodynamics in essential hypertension, various workers have reported increased, decreased, or
no change in renal blood flow at various stages of
hypertension.68'69
Such variability is expected with different insults to
the kidney and when factors known to influence renal
blood flow and GFR, such as sodium and protein
intake, are uncontrolled. Also, episodic measurements made during resting conditions may not accu-
556
Hypertension
Vol 15, No 6, Part 1, June 1990
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
rately reflect the average values for renal hemodynamics existing throughout the day during periods of
stress and activity as well as inactivity. For patients
with hypertension who have greater responses to
vasoconstrictors, reductions in renal blood flow and
GFR may not be present during resting conditions
but could occur during periods of activity and could
play a role in the pathogenesis of hypertension.
Perhaps even more important, it is usually not possible to sequentially analyze the changes in renal
function that occur during the onset of hypertension
in humans or to conduct detailed and invasive experiments that allow separation of those abnormalities
that could cause hypertension from those that merely
occur as part of an overall compensatory response.
Therefore, rather than listing the various alterations
in kidney function that have been reported, it may be
more useful to briefly consider the types of renal
abnormalities that have been shown experimentally
to cause hypertension and the characteristic changes
in pressure natriuresis in these models compared
with those found in essential hypertension.
Effects of Increased Preglomendar Resistance
The observation that many patients with essential
hypertension demonstrate a parallel shift of the renalpressure natriuresis curve, similar to that found in
experimental models of hypertension caused by
increased preglomerular resistance (e.g., Goldblatt
hypertension), is consistent with the possibility that
hypertension in these patients may be caused by
increased preglomerular resistance. Widespread constriction of preglomerular vessels, due to extrinsic
neurohumoral influences or intrinsic abnormalities
such as resetting of the macula densa feedback mechanism, would be predicted to cause essentially the
same renal and circulatory changes as observed in the
one-kidney, one clip Goldblatt model of hypertension.
After compensatory increases in blood pressure, one
might expect to find nearly normal renal blood flow,
GFR, and plasma renin activity that are in fact
observed in many essential hypertensive patients.
Effects of Reduced Glomendar Capillary
Filtration Coefficient
Another abnormality of renal function that could
lead to hypertension by altering pressure natriuresis
is a reduction in the glomerular capillary filtration
coefficient (K{). The chronic hypertensive effect of a
decrease in Kt would, of course, depend on the
sensitivity of GFR to changes in Kt. In some rat
strains in which filtration pressure equilibrium exists,
GFR is relatively insensitive to changes in Kt and is
highly dependent on renal plasma flow.70 However,
in many rat strains and in other species, such as the
dog, as well as humans, filtration pressure equilibrium
probably does not occur in most circumstances.71
Therefore, reducing Kt would be expected to initially
lower GFR and sodium excretion while increasing
renin secretion via the macula densa mechanism.
However, as arterial pressure increased, GFR and
renin release could be restored toward normal so that
the only persistent abnormality of renal function
would be reduced filtration fraction, increased glomerular hydrostatic pressure, and perhaps small
increases in renal blood flow. Increases in renal blood
flow and restoration of GFR could occur in part
through a macula densa feedback72 as well as through
increases in blood pressure. Unfortunately, a compensatory increase in glomerular hydrostatic pressure,
needed to offset a decrease in Kt, could lead to
additional renal dysfunction over a period of years by
causing glomerulosclerosis,48 thereby reducing Kf even
further and requiring additional increases in arterial
pressure and glomerular hydrostatic pressure to maintain GFR constant. Obviously, such a sequence could
initiate a vicious cycle leading to progressive renal
damage and eventually kidney failure.48 The clinical
counterpart to this sequence may be found in hypertension caused by glomerulonephritis or possibly
essential hypertension with more subtle dysfunction of
the glomerular capillary membrane. In contrast to
hypertension caused by increased preglomerular resistance, hypertension due to reduced K{ is associated
with a decreased slope of the pressure natriuresis
curve (Figure 2). The significance of this reduced
slope is that it causes arterial pressure to be very salt
sensitive; increases in sodium intake exacerbate the
hypertension, whereas low sodium intake ameliorates
the high blood pressure.1
Effects of Increased Tubular Reabsorption
Some essential hypertensive patients show pressure
natriuresis characteristics that cannot be explained
entirely by preglomerular constriction or decreased Kt.
For example, renal-pressure natriuresis may have a
decreased slope in some individuals indicating that
they are salt-sensitive, whereas hypertension caused
primarily by preglomerular constriction is usually not
salt-sensitive.1 Also, many patients with essential
hypertension have decreased plasma renin activity.
Both abnormalities, the low plasma renin activity and
the salt-sensitivity of blood pressure, could be
explained by increased tubular reabsorption or by a
combination of changes leading to increased fractional
reabsorption and renal vasoconstriction.
In general, those forms of experimental hypertension that are initiated by increased tubular reabsorption (e.g., mineralocorticoid hypertension) are saltsensitive.1'58 In these types of hypertension, the
pressure natriuresis curve has a reduced slope rather
than a parallel shift as occurs with increased preglomerular resistance. Another feature of hypertension
caused by primary increases in tubular reabsorption in
distal parts of the nephron beyond the macula densa is
that it is often associated with secondary suppression
of plasma renin activity and a tendency toward extracellular volume expansion (e.g., mineralocorticoid
hypertension). However, when increased tubular
reabsorption is coupled with peripheral vasoconstriction (e.g., Ang II hypertension), the degree of volume
expansion depends on the relative severity of renal
Hall et al Pressure Natriuresis in Hypertension
and peripheral vasoconstriction. With severe peripheral vasoconstriction and decreased vascular capacitance, much less volume is needed to raise blood
pressure sufficiently to offset the increase in tubular
reabsorption and to maintain fluid balance. If vascular
capacitance is markedly reduced, a much smaller
volume is needed to raise blood pressure, and extracellular fluid volume may actually be reduced despite
an increase in tubular reabsorption.
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
Effects of Reduced Nephron Number
Another factor that could increase salt-sensitivity
of blood pressure and decrease plasma renin activity
in essential hypertensive patients is a gradual loss of
nephrons due to aging or to periodic mild insults to
the kidney occurring over a long period of time.
Reduction in kidney mass, in the absence of other
abnormalities, usually does not cause hypertension.1'58 Experimental studies have demonstrated
that surgical removal of large portions of the kidney,
to the point that uremia occurs, rarely causes severe
hypertension as long as sodium intake is normal.73'74
When entire nephrons are lost without ischemia
occurring in the remaining nephrons, overall glomerular filtration and tubular reabsorption capability are
simultaneously reduced so that balance between filtration and reabsorption can be maintained without
major adaptive changes in arterial pressure. However, kidneys with reduced numbers of nephrons are
very susceptible to additional insults that impair
renal excretory function. Thus, hypertension associated with mineralocorticoid excess is much more
severe after renal mass is reduced.58 Also, the ability
to increase sodium excretion in response to the
additional challenge of high sodium intake requires a
greater arterial pressure after decreasing kidney
mass73'74 (i.e., blood pressure becomes very saltsensitive).
Loss of nephrons could also lead to decreased
plasma renin activity. Although total renal blood flow
and GFR would tend to be reduced with nephron
loss, functional and morphological compensations in
the remaining nephrons would tend to cause vasodilation and increased single nephron GFR as well as
increased distal delivery of sodium chloride. An
increase in single nephron GFR and distal tubular
sodium chloride delivery in the surviving nephrons
would be expected to inhibit renin synthesis and
secretion via a macula densa mechanism.75-76 In
support of this possibility, there is usually a gradual
decline in the number of functioning glomeruli after
the fourth decade of life.77 Also, the observation that
urine concentrating ability decreases with age, even
though levels of antidiuretic hormone are normal or
elevated,78 supports the possibility of a gradual
decrease in medullary tonicity with age that in turn
could be the result of high solute delivery or
increased medullary blood flow in the remaining
nephrons.
Although it is clear that essential hypertensive
patients have abnormal pressure natriuresis, the pre-
557
cise causes of this defect are unclear. It is probably
unwise to ascribe a single cause for all essential
hypertensive patients. It may be more useful to analyze the renal and circulatory abnormalities of these
individuals and then compare them to various known
causes of experimental hypertension. In this way, it
may be possible to determine whether the hypertension is initiated by increased preglomerular resistance,
increased tubular reabsorption, decreased numbers of
functioning nephrons, reduced glomerular capillary
filtration coefficient, or some combination of these
abnormalities. With long-standing hypertension,
pathological changes that occur secondary to hypertension must also be considered. By analyzing the
characteristics of pressure natriuresis in hypertensive
patients and by comparing these curves to those
observed in various forms of experimental hypertension of known origin, it is often possible to gain insight
into the etiology of this disease.
Acknowledgment
We thank Mrs. Ivadelle Osberg Heidke for excellent secretarial assistance.
References
1. Guyton AC: Arterial Pressure and Hypertension. Philadelphia,
WB Saunders Co, 1980
2. Roman RJ: Pressure diuresis mechanism in the control of renal
function and arterial pressure. Fed Proc 1986;45:2878-2884
3. Hall JE, Guyton AC, Coleman TG, Mizelle HL, Woods LL:
Regulation of arterial pressure: Role of pressure natriuresis
and diuresis. Fed Proc 1986;45:2897-2903
4. Guyton AC, Cowley AW Jr, Young DB, Coleman TG, Hall JE,
DeClue JW: Integration and control of circulatory function, in
Guyton AC, Cowley AW (eds): International Review of Physiology, Cardiovascular Physiology II. Baltimore, University Park
Press, 1976, pp 341-385
5. Hall JE, Mizelle HL, Woods LL: The renin-angiotensin system
and long-term regulation of arterial pressure. / Hypertens
1986;4:387-397
6. Hall JE, Guyton AC, Smith MJ Jr, Coleman TG: Blood
pressure and renal function during chronic changes in sodium
intake: Role of angiotensin. Am J Physiol 1980;239:F271-F280
7. Laragh JH, Atlas SA: Atrial natriuretic hormone: A regulator
of blood pressure and volume homeostasis. Kid Int 1988;
34(suppl 25):564-571
8. Ballerman BJ, Brenner BM: Role of atrial peptides in body
fluid homeostasis. Ore Res 1986^8:619-630
9. Mizelle HL, Hall JE, Hildebrandt DA: Atrial natriuretic
peptide and pressure natriuresis: Interactions with the reninangiotensin system. Am J Physiol 1989;257:R1169-R1174
10. Takezawa K, Cowley AW Jr, Skelton M, Roman RJ: Atriopeptin in alters renal medullary hemodynamics and the pressurediuresis response in rats. Am J Physiol 1987;256:F992-F1002
11. MizeUe HL, Hall JE, Hildebrandt DA, Montani J-P: Does
atrial natriuretic peptide (ANP) cause chronic natriuresis?
Kidney Int 1989;35:285
12. Hildebrandt DA, Mizelle HL, Hall JE: Intrarenal infusion of
atrial natriuretic peptide (ANP) lowers blood pressure chronically (abstract). FASEB J 1989;3:A697
13. Harris PJ, Thomas D, Morgan TO: Atrial natriuretic peptide
inhibits angiotensin stimulated proximal tubular sodium and
water reabsorption. Nature 1987;326:697-698
14. Burnett JC Jr, Granger JP, Opgenorth TJ: Effects of synthetic
atrial natriuretic factor on renal function and renin release.
Am J Physiol 1984;247:F863-F866
558
Hypertension
Vol 15, No 6, Part 1, June 1990
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
15. Garcia R, Thibault G, Cantin M, Genest J: Effect of purified
38. Hall JE, Granger JP, Hester RL, Montani J-P: Mechanisms of
sodium balance in hypertension: Role of pressure natriuresis.
atria] natriuretic factor on rat and rabbit vascular strips and
J Hypertens 1986;4(suppl 4):S57-S65
vascular beds. Am J Physiol 1984;247:R34-R39
39. Woods LL, Mizelle HL, Hall JE: Control of sodium excretion
16. DiBona GF: Neural control of renal function: Cardiovascular
in NE-ACTH hypertension: Role of pressure natriuresis. Am
implications. Hypertension 1989;13:539-548
J Physiol 1988;255:R894-R900
17. Buckalew VM, Dimond KA: Effect of vasopressin on sodium
excretion and plasma antinatriferic activity in the dog. Am J
40. Lohmeier TE, Carroll RG: Chronic potentiation of vasoconstrictor hypertension by adrenocorticotrophic hormone.
Physiol 1976;231:28-33
Hypertension 1982;4(suppl II):II-138-II-148
18. Gonzalez-Campoy JM, Romero JC, Knox FG: Escape from
41. Coleman TG, Guyton AC, Young DB, DeClue JW, Norman
the sodium retaining effects of mineralocorticoids: Role of
RA, Manning RD Jr: The role of the kidney in essential
ANF and intrarenal hormone systems. Kidney Int 1989;
hypertension. Clin Exp Pharmacol Physiol 1975;2:571-581
35:767-777
42. Masaki Z, Ferrario CM, Bumpus FN: Effects of SQ-20,881 on
19. Knox FG, Burnett JC Jr, Kohan DE, Spielman WS, Strand JC:
the intact kidney of dogs with two-kidney, one clip hypertenEscape from the sodium-retaining effects of mineralocortision. Hypertension 1980;2:649-656
coids. Kidney Int 1980;17:263-276
43. Liard JF: Effet de Pablation partielle ou totale du tissu renal
20. DeWardener HE, Clarkson EM: Concept of natriuretic horsur l'hypertension renovasculaire chez le rat. Experientia 1969;
mone. Physiol Rev 1985;65:658-659
25:934-935
21. Marin-Grez M, Oza NB, Carretero OA: The involvement of
44. Wilson C, Byrom FB: Vicious cycle in chronic Bright's disease:
urinary kallikrein in the renal escape from the sodium retainExperimental evidence from the hypertensive rat. Q J Med
ing effect of mineralocorticoids. Henry Ford Hosp Med J
1941;10:65-93
1973;21:85-9O
45. Thurston H, Bing RF, Swales JP: Reversal of two-kidney one
22. Liard JF: Cardiogenic Hypertension, in Guyton AC, Young
clip renovascular hypertension in the rat. Hypertension 1980;
DB (eds): Cardiovascular Physiology III, International Review of
2:256-265
Physiology, vol 18. Baltimore, University Park Press, 1979, pp
46. Floyer MA: The effects of nephrectomy and adrenalectomy
317-355
upon the blood pressure in hypertensive and normotensive
rats. Clin Sci 1951;10:405-421
23. Omvik P, Tarazi RC, Bravo EL: Regulation of sodium balance
in hypertension. Hypertension 1980;2:515-523
47. Sealey JE, Blumenfeld JD, Bell GM, Pecker MS, Sommers SC,
Laragh JH: On the renal basis for essential hypertension:
24. Thompson JMA, Dickinson CJ: The relation between the
Nephron heterogeneity with discordant renin secretion and
excretion of sodium and water and the perfusion pressure in
sodium excretion causing a hypertensive vasoconstrictionthe isolated, blood-perfused, rabbit kidney, with special refervolume relationship. / Hypertens 1988;6:763-777
ence to changes occurring in clip-hypertension. Clin Sci Mol
48. Brenner BM: Hemodynamically mediated glomerular injury
Med 1976^0:223-236
and the progressive nature of kidney disease. Kidney Int
25. Hall JE, Granger JP, Smith MJ Jr, Premen AJ: Role of renal
1983;23:647-655
hemodynamics and arterial pressure in aldosterone "escape."
49. Coleman TG, Manning RD Jr, Norman RA Jr, DeClue JW:
Hypertension 1984;6(suppl I):I-183-I-192
The role of the kidney in spontaneous hypertension. Am Heart
26. Hall JE, Granger JP, Hester RL, Coleman TG, Smith MJ Jr,
J 1975;89:94-98
Cross RB: Mechanisms of escape from sodium retention
50. Norman RA Jr, Enobakhare JA, DeClue JW, Douglas BH,
during angiotensin II hypertension. Am J Physiol 1984;
Guyton AC: Arterial pressure-urinary output relationships in
246:F627-F634
hypertensive rats. Am J Physiol 1978;234:R98-R103
27. Berecek KH, Bohr DF: Whole body vascular reactivity during
51. Tobian L, Lange J, Azar S, Iwai J, Koop D, Coffee K, Johnson
the development of deoxycorticosterone acetate hypertension
MA: Reduction of natriuretic capacity and renin release in
in the pig. Ore Res 1978;42:764-771
isolated, blood perfused kidneys of Dahl hypertension-prone
28. Miller AW, Bohr DF, Schork AM, Terris JM: Hemodynamic
rats. Ore Res 1978;43(suppl I):92-98
responses to DOCA in young pigs. Hypertension 1979;
52. Roman RJ, Cowley AW Jr: Abnormal pressure-diuresis1:591-597
natriuresis response in spontaneously hypertensive rats. Am J
Physiol 1985;248:F199-F2O5
29. Jones AW, Hart RG: Altered ion transport in aortic smooth
53. Roman RJ: Abnormal renal hemodynamics and pressuremuscle during DOCA hypertension in the rat. Ore Res 1975;
natriuresis relationship in Dahl salt-sensitive rats. Am J Physiol
37:333-342
1986;251:F57-F65
30. Takeda K, Bunag RD: Augmented sympathetic nerve activity
54. Tobian L, Johnson MA, Hanlon S, Bartemes K: A glomerular
and pressor responsiveness in DOCA hypertensive rats. Hyperdefect in prehypertensive Dahl S rats, which limits their
tension 1980;2:97-101
capacity to increase GFR. Am J Hypertens 1989;2:557-559
31. Haddy FJ: Abnormalities of membrane transport in hyperten55. Dahl LK, Heine M, Thompson K: Genetic influences of the
sion. Hypertension 1983;5(suppl V):V-66-V-72
kidneys on blood pressure. Ore Res 1974;34:94-101
32. Haddy FJ, Pamani MB: The vascular Na+-K+ pump in low
56. Dahl LK, Heine M: Primary role of renal homographs in
renin hypertension. / Cardiovasc Pharmacol 1984;6:S61-S74
setting chronic blood pressure level in rats. Ore Res 1975;
33. Cowley AW Jr: Vasopressin and cardiovascular regulation, in
36:692-696
Guyton AC, Hall JE (eds): International Review of Physiology,
57. Kawabe K, Watanbe TX, Shiono K, Sokabe H: Influences on
Cardiovascular Physiology IV. Baltimore, University Park Press,
blood pressure of renal isographs between spontaneously
1982, pp 189-242
hypertensive and normotensive rats. Jpn Heart J 1978;
34. Hall JE, Mizelle HL, Woods LL, Montani J-P: Pressure
19:886-899
natriuresis and control of arterial pressure during chronic
58. Coleman TG: Blood Pressure Control, Vol I. St. Albans, Vernorepinephrine infusion. / Hypertens 1988;6:723-731
mont, Eden Press, Inc, 1980
35. Hall JE, Montani J-P, Woods LL, Mizelle HL: Renal escape
59. Rettig R, Stauss H, Folberth C, Gauten D, Waldherr R, Unger
from vasopressin: Role of pressure natriuresis. Am J Physiol
T: Hypertension transmitted from stroke-prone spontaneously
1986;250:F907-F916
hypertensive rats. Am J Physiol 1989;257:F197-F203
36. Smith MJ Jr, Cowley AW Jr, Guyton AC, Manning RD Jr: Acute
60. Iverson BM, Sekse I, Ofstad J: Resetting of renal blood flow
and chronic effects of vasopressin on blood pressure, electrolytes,
autoregulation in spontaneously hypertensive rats. Am J Physand fluid volumes. Am J Physiol 1979-,237:F232-F240
iol 1987;252:F480-F486
37. Cowley AW Jr, Merril DC, Quillen E Jr, Skelton MM:
61. Norman R, Dzielak DJ: Role of renal nerves in onset and
Long-term blood pressure and metabolic effects of vasopressin
maintenance of spontaneous hypertension. Am J Physiol 1982;
243:H284-H288
with servo-controlled fluid volume. Am J Physiol 1984;
247:R537-R545
Hall et al
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
62. Norman R, Dzielak DJ, Bost KL, Khraibi AA, Galloway PG:
Immune system dysfunction contributes to the aetiology of
spontaneous hypertension. Hypertension 1985;3:261-268
63. Bianchi G, Fox U, DiFrancesco GF, Bardi U, Radice M: The
hypertensive role of the kidney in spontaneously hypertensive
rats. Clin Sci Mol Med 1973;45(suppl):135s-139s
64. Bianchi G, Fox U, Di Francesco GF, Giovanetti PM, Pagetti
D: Blood pressure changes produced by kidney cross transplantation between spontaneously hypertensive rats and normotensive rats. Clin Sci Mol Med 1978;47:435-448
65. Bianchi G, Cusi D, Ferrari P, Barlassina C, Pati P, Salardi S,
Torielli L, Ferrandi M, Salvati P, Colombo R, Alberghini E:
Renal abnormalities at the prehypertensive stage of essential
hypertension. / Cardiovasc Pharmacol 1988;12(suppl 3):
S43-S48
66. Curtis JJ, Luke RG, Dustan HP, Kashgarian M, Whelchel JD,
Jones P, Diethelm A: Remission of hypertension after renal
transplantation. N EnglJ Med 1983;3O9:10O9-1015
67. Parfrey PS: Salt and Hypertension, in Sleight P, Freis ED
(eds): Hypertension. London, Butterworth, 1982, pp 322-339
68. DeLeew PW, Birkenhager WH: The renal circulation in
essential hypertension. / Hypertens 1983;1:321-331
69. Hollenberg NK, Adams DF: The renal circulation in hypertensive disease. Am I Med 1976;60:773-784
70. Oken D: Does the ultrafiltration coefficient play a key role in
regulating glomerular filtration in the rat? Am J Physiol
1989;256:F505-F515
Pressure Natriuresis in Hypertension
559
71. Knox F, Cuche J-L, Ott CE, Diaz-Buxo JA, Marchand G:
Regulation of glomerular filtration and proximal tubular reabsorption. Ore Res 1975;36(suppl I):I-107-I-118
72. Schnermann J, Briggs J: Function of the juxtaglomerular
apparatus: Local control of glomerular hemodynamics, in
Seldin DW, Giebisch G (eds): The Kidney. New York, Raven
Press, 1985, pp 669-697
73. Coleman TG, Guyton AC: Hypertension caused by salt loading in the dog. III. Onset transients of cardiac output and
other circulatory variables. Ore Res 1969;25:153-160
74. Langston JB, Guyton AC, Douglas BH, Dorsett PE: Effect of
changes in salt intake on arterial pressure and renal function
in partially nephrectomized dogs. Ore Res 1963;12:508-513
75. Davis JO, Freemen RH: Mechanisms regulating renin release.
Physiol Rev 1976;56:l-56
76. Kotchen TA, Welch WJ, Ott CE: The renal tubular signal for
renin release. / Hypertens 1984;l(suppl 1):35
77. Dunnill MS, Halley W: Some observations on the quantitative
anatomy of the kidney. / Pathol 1973;110:113-161
78. Epstein M: Effects of aging on the kidney. Fed Proc 1979;
38:168-172
KEY WORDS • blood pressure • sodium excretion • angiotensin
• renin • atrial natriuretic factor • essential hypertension •
kidney
Abnormal pressure natriuresis. A cause or a consequence of hypertension?
J E Hall, H L Mizelle, D A Hildebrandt and M W Brands
Hypertension. 1990;15:547-559
doi: 10.1161/01.HYP.15.6.547
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1990 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://hyper.ahajournals.org/content/15/6_Pt_1/547
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally
published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not
the Editorial Office. Once the online version of the published article for which permission is being requested
is located, click Request Permissions in the middle column of the Web page under Services. Further
information about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/