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1-91
Relation Between Sodium Intake,
Renal Function, and the Regulation
of Arterial Pressure
Jeffrey L. Osborn
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The long-term regulation of arterial pressure requires the maintenance of a balance between
sodium and water intake and sodium and water excretion. Normal salt and water balance leads
to stable body fluid volumes and the maintenance of normal renal function is critical to
establishing extracellular fluid volume homeostasis. This review focuses on the role of the
kidney in the long-term control of salt and water balance with particular emphasis on the
relations between sodium intake, the renin-angiotensin-aldosterone system, renal sympathetic
nerve activity, and the regulation of arterial pressure via renal sodium and water excretion. The
accumulation of evidence in recent years demonstrates that low level elevation of renin release,
circulating angiotensin II or aldosterone, or activation of renal sympathetic outflow may alter
renal function such that normal natriuretic and diuretic responses to arterial pressure are
significantly impeded. Under these circumstances, the maintenance of normal sodium and
water excretion requires a significant elevation of arterial pressure. Thus, compromised renal
function leads to elevation of arterial pressure to maintain adequate sodium and water balance
during periods of increased sodium intake. The resultant chronic elevation of arterial pressure
then becomes a compromise that is used by the kidneys to maintain normal extracellular body
fluid volumes. (Hypertension 1991;17[suppl I]:I-91-I-96)
T
he regulation of the extracellular fluid volume
encompasses the continuous, ongoing maintenance of normal sodium and water balance
as a relation between sodium intake and excretion.
As humans, we exist as intermittent sodium and
water consumers, leaving the bulk of the task of
regulating our constant expansion of extracellular
fluid volumes to the renal excretory processes. There
are many factors that influence renal sodium excretion and thereby participate in this regulatory process. These factors can be subdivided into extrinsic
and intrinsic mechanisms. Extrinsic mechanisms include the production of angiotensin II (Ang II) and
aldosterone, the release of atrial natriuretic factor,
and the alterations of renal sympathetic outflow;
some intrinsic mechanisms are the regulation of
glomerular filtration rate, renal hemodynamics, intrarenal physical forces controlling tubular reabsorp-
From the Department of Physiology, Medical College of Wisconsin, Milwaukee, Wis.
Supported by an American Heart Association Established Investigator Award, by an American Heart Association Grant-inAid, and by National Heart, Lung, and Blood Institute grants
HL-40137 and HL-29587.
Address for correspondence: Jeffrey L. Osborn, PhD, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI
53226.
tion, and intrarenal hormonal systems such as kinins,
Ang n, and prostaglandins.
Renal Function and Arterial Pressure
A close correlation between normal kidney function and blood pressure control has been demonstrated in several experimental forms of hypertension
including the spontaneously hypertensive rat (SHR)1
and the Dahl salt-sensitive (DS) rat.2 The spontaneously hypertensive strain of rats develops elevated
arterial pressure spontaneously with age, and in some
strains this hypertension is exacerbated with elevated
sodium chloride intake. Kawabe et al3 have shown
that in this strain, replacement at an early age of the
SHR kidneys by transplantation with kidneys from
age-matched normotensive control rats results in a
substantial diminution of the blood pressure. This
same response has been shown in other genetic
models of hypertension including the Milan hypertensive strain4 and the DS rat.5 Thus, a direct correlation has been documented between renal function
and arterial pressure in several genetic models of
hypertension, and in some strains a critical interaction exists between sodium intake and the magnitude
of the hypertension.
The complex relations between the natriuretic
responses to increased arterial pressure in the SHR
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RENAL PCRFUSKW PRESSURE
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FIGURE 1. Line graph showing urinary sodium excretion
responses to step changes in arterial pressure in anesthetized
Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats
(SHR). Rats were studied at 3-5, 6-9, and 12 weeks of age.
Reprinted with permission from Roman.6
have recently been carefully examined by Roman.6
Anesthetized SHR and Wistar-Kyoto (WKY) rats
were studied between 3 and 12 weeks of age, and the
urinary sodium excretion responses were measured
after arterial pressure was increased and decreased
by mechanical aortic constriction above and below
the kidneys. Circulating factors that may influence
urinary sodium excretion (i.e., Ang II, norepinephrine, aldosterone, arginine vasopressin, and atrial
natriuretic factor) were held constant by intravenous
infusion at low physiological doses. Normotensive
WKY rats exhibited a steep natriuretic response to
step increases in arterial pressure, and this pressure
natriuresis occurred regardless of the age of the rat
studied (Figure 1). In contrast, SHR at 3-5 and 6-9
weeks of age exhibited a diminished natriuresis in
response to the same step increases in arterial pressure. Furthermore, by 12 weeks of age when the
hypertension in these animals was well established,
the slope of the pressure natriuresis curve was even
further reduced (Figure 1). These results indicated
that in the Okamoto strain of SHR, a reduced ability
to excrete sodium in response to elevated arterial
pressure occurs at very early ages before the onset of
the hypertension. At older ages, when the hypertension is well established, the reduction in pressure
natriuresis becomes even more pronounced. Thus, a
reduced renal capacity to increase sodium excretion
in response to an increase in arterial pressure may be
responsible in part for the chronic elevation of arterial pressure. As previously described, this notion is
further documented by the fact that replacement of
the SHR kidney with that of a normotensive WKY
rat results in a substantial reduction in the level of
the hypertension.3-4
Angiotensin n and Renal Function in
Blood Pressure Control
One of the factors that may be responsible for
limiting the ability of the kidney to respond normally
to arterial pressure is the renin-angiotensin-aldosterone axis. In conscious dogs with normal renal function, elevation of sodium intake results in little or no
change in arterial pressure because urinary sodium
excretion is rapidly elevated to maintain normal
sodium and extracellular fluid volume balance and
thereby prevent further volume-mediated elevations
of arterial pressure.7 Hall et al8 have demonstrated
that Ang II blockade with converting enzyme inhibition (SQ 14,225) markedly shifts the pressure-natriuresis relation toward lower arterial pressures. This
leftward shift in the pressure-natriuresis curve is
particularly pronounced during states of low sodium
intake due to the large activation of renin release and
subsequent Ang II production in response to sodium
depletion. Conversely, low level infusion of Ang II
(5.0 ng/kg/min i.v.), which does not alter arterial
pressure alone, shifts the renal pressure-natriuresis
and -diuresis curves toward higher perfusion pressures necessary to achieve similar rates of urinary
sodium excretion.7
The shift in the renal pressure-natriuresis and
-diuresis curves toward higher pressures may result
from direct tubular antinatriuretic effects of Ang II.
Antinatriuresis during chronic Ang II infusion may
be a result of activation of aldosterone release from
the adrenal glomerulosa. Distal tubular elevation of
sodium reabsorption would then result in a net
decrease in overall sodium excretion for any given
step change in systemic arterial pressure. In addition,
pressure natriuresis may be blunted by Ang II at
more proximal nephron sites. Specific Ang II receptors have been identified on proximal tubular cells9
and intrarenal Ang II has been shown to increase
sodium reabsorption at this site by specific activation
of sodium-hydrogen exchange.1011 Intrarenal Ang II
then may directly decrease net sodium excretion by
increasing total sodium chloride/bicarbonate reabsorption. Thus, the overall influence of Ang II on
urinary sodium excretion during step increases in
arterial pressure is to limit the natriuretic capacity of
the kidney by elevating tubular sodium reabsorption
at proximal and distal nephron sites.
Normal renal natriuretic and diuretic responses to
elevated arterial pressure are essential to the maintenance of body fluid volumes and consequently of
arterial pressure homeostasis during low level infusion of circulating hormones such as Ang II, aldosterone, and arginine vasopressin. When renal excretory function is allowed to respond normally to
changes in arterial pressure, low level infusions of
Ang II or aldosterone do not markedly alter arterial
pressure. In contrast, when renal perfusion pressure
is held constant at a normal arterial pressure of
approximately 100 mm Hg, low level infusion of
either Ang II8 or aldosterone12 produces overt and, in
some cases, malignant hypertension. This hypertension is associated with continual sodium and water
retention and expansion of the extracellular fluid
volume. Thus, small alterations in extrinsic circulating hormonal factors do not produce hypertension
Osbom
under normal conditions; however, in the presence of
compromised renal function, such that the kidneys
do not respond normally to transient elevations of
arterial pressure, low level activation of the reninangiotensin-aldosterone axis produces sodium and
water retention and the development of severe arterial hypertension.
Renal Sympathetic Nerves, Renal Function, and
Arterial Pressure
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From the previous discussion, a large body of
evidence indicates that alteration of renal function by
some intrinsic or extrinsic mechanism is required for
the chronic elevation of arterial pressure. There are
multiple routes by which elevation of renal sympathetic nerve activity may function as the mediator of
this alteration in renal function, including stimulation of renin release, elevation of intrarenal or circulating Ang II, redistribution of intrarenal blood flow
or glomerular filtration rate, and activation of renal
tubular sodium reabsorption. Ultimately, the kidney
must function to maintain extracellular fluid volume
constant via regulation of urinary sodium excretion.
Thus, important interactions must exist between the
relative rates of sodium intake, sodium excretion,
level of renal sympathetic nerve activity, and arterial
pressure.
Renal sympathetic nerve activity may alter urinary
sodium and water excretion by activating sodium
reabsorption by at least two specific mechanisms.
First, release of neuroadrenergic transmitter at the
juxtaglomerular granular cells increases the release
of renin via /3i-adrenergic receptor activation.13-15
This adrenergic stimulation of renin release will
consequently increase circulating Ang II and aldosterone and subsequently decrease urinary sodium
excretion by the mechanisms previously discussed.
Second, renal sympathetic outflow also directly stimulates renal tubular sodium reabsorption at the proximal convoluted tubule16"18 or at the thick ascending
limb of the loop of Henle.16 Direct sympathetic
innervation of these tubular structures has been
identified,19 and the adrenergic receptor mediating
these responses has been described by several investigators as a.16-18 Recent evidence indicates that
a-adrenergic receptor activation of renal tubular
structures increases sodium reabsorption by activation of sodium-hydrogen exchange, eliciting net increases in renal sodium bicarbonate reabsorption.20
It is important to note that direct neurogenic activation of tubular sodium reabsorption will concomitantly decrease the distal delivery of sodium chloride,
leading to further activation of renin release via the
macula densa. Thus, renal sympathetic nerve activity
may have an important influence on the net renal
excretion of sodium and water. Under these conditions of elevated renal sympathetic nerve activity, the
renal pressure-natriuresis relation can be significantly shifted toward higher pressures, thereby requiring elevated arterial pressure to achieve adequate sodium excretion.
Renal Function and Blood Pressure
1-93
Important interactions likely exist between renal
sympathetic outflow, renal function, and the ability of
the kidney to excrete salt and water. We have evaluated the influence of increasing and decreasing
sodium intake on the renal hemodynamic and renin
secretion responses to direct electrical stimulation of
the renal nerves.21 In that study, sodium depletion
enhanced and sodium loading suppressed the renin
secretion responses to 0.5,1.0, and 2.0 Hz renal nerve
stimulation. These changes in the responses to neural
activation of renin secretion likely resulted from an
interaction between direct neurotransmitter stimulation of ft-adrenergic receptors and alterations in
tubular sodium chloride delivery out of the proximal
nephrons to the distal macula densa mechanism for
renin release. These results indicated that important
interactions exist between sodium chloride intake
and the neural control of renin secretion; however,
the data also suggested that these responses in
normal kidneys would be protective against expansion of the extracellular fluid volume (i.e., sodiumdepleted states lead to exacerbated renin responses
and the reverse is also true).
In contrast, renal hemodynamic responses to renal
nerve stimulation demonstrated markedly different
results. Figure 2 documents that elevation of sodium
intake rendered the renal vasculature more responsive to renal nerve stimulation. In sodium-depleted
anesthetized dogs, renal nerve stimulation did not
elicit renal vasoconstriction at 0.5 or 1.0 Hz, whereas
dogs placed on a high sodium intake significantly
decreased renal bloodfloweven at 0.5 Hz renal nerve
stimulation. These data demonstrated that elevation
of sodium intake enhanced the renal vascular responses to renal sympathetic outflow either by increasing the release of sympathetic neurotransmitter
in the kidney or by increasing the renal vascular
responsiveness to intrarenal norepinephrine. Recent
evidence also suggests that elevation of renal perfusion pressure interacts with vascular smooth muscle
to enhance the renal vascular responsiveness to norepinephrine.22 Thus, important interactions between
sodium chloride intake, renal perfusion pressure, and
the level of renal sympathetic outflow may result in
subtle alterations in renal function, which lead to
expansion of the extracellular fluid volume and consequently to elevation of arterial pressure.
Recent evidence from this laboratory indicates
that the renal sympathetic nerves also have an important influence on the regulation of sodium balance by precisely regulating the rate of decreasing
urinary sodium excretion after a step decrease in
sodium intake. In six conscious dogs, renal sympathetic efferent nerve activity was continuously monitored, and urinary sodium excretion was simultaneously measured at hourly intervals. Dogs were placed
on a high sodium intake by intravenous infusion (5.0
meq/hr) for 7 days. Renal nerve recording electrodes
then were implanted, and after recovery, control high
sodium intake measurements were made, at which
time dogs were switched to a low sodium intake (0.2
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Supplement I
Hypertension
Vol 17, No 1, January 1991
0.5 Hz
LOW NORM HIOH
-10
FIGURE 2. Bar graph showing
changes in renal blood flow (RBF)
in response to renal efferent nerve
stimulation (15 V, 1.0 msec) at 0.5,
1.0, and 2.0 Hz. Renal hemodynamic responses were studied in dogs
on low, normal, and high sodium
intakes. Reprinted with permission
from Osborn and Kinstetter.21
-20
"30
ARBF
(ml/mln)
* =Dilf«r«nt from 0
• = Dlllarant Iron High N»+ OUt
-40
-50
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-80
-70 _
meq/hr). Measurements were then continued for an
additional 30 hours during low sodium intake. As
shown in Figure 3, urinary sodium excretion decreased by approximately 3 meq/hr within 12 hours
(from a total intake of 5 meq/hr) after sodium intake
was decreased. This reduction in sodium excretion
was associated with a significant increase in renal
sympathetic nerve activity over the same time interval
(Figure 3). Subsequent bilateral renal denervation
markedly increased the time interval over which dogs
achieved sodium balance such that similar decreases
in urinary sodium excretion did not occur until 20
hours after reduction of sodium intake. Plasma renin
activity and plasma aldosterone concentrations were
not significantly altered at 6 and 24 hours after the
step decrease in sodium intake.23 These results have
been interpreted to suggest that the renal nerves may
A
A ARSNA
«AUN«V
Sodium and Water Retention as a
Function of Hypertension
400
300
5
en
35
>
-2
too
-3
0
2
4
8
8
function as an important rapid controller of sodium
excretion when sodium intake is altered. Clearly,
there exist numerous mechanisms for the maintenance of normal sodium balance when sodium intake changes. The rate at which sodium balance is
achieved, however, may primarily be controlled by
the renal nerves by induction of rapid alterations in
tubular sodium transport. Thus, functional aberrations in the regulation of efferent renal sympathetic
outflow could potentially cause transient but significant expansion of the extracellular fluid volume
after step changes in sodium intake. These continual expansions and contractions of body fluid volumes could potentially result in a chronic resetting
of the renal pressure-natriuresis and -diuresis
curves and thereby produce prolonged elevation of
arterial pressure.
10 12 14 16 18 20 22 24 28 28 30 32
HOURS AFTER DECREASING Na INTAKE
FIGURE 3. Graph showing changes in urinary sodium excretion (UNtV) and renal sympathetic nerve activity (RSNA) of
conscious dogs for 30 consecutive hours after sodium intake
was decreased. Sodium intake was delivered intravenously at
5.0 meqihr in control (120 meq/day) and decreased to 0.2
meqihr (5.0 meq/day).
The hypothesis that sodium and water retention
precedes the onset of arterial hypertension has been
extensively investigated. For the purposes of the
present discussion, recent studies will be presented,
which indicate that minimal changes in blood volume
are required to elicit significant changes in arterial
pressure. In conscious areflexic rats, Hinojosa-Laborde et al24 recently reported that elevation of blood
volume by as little as 5% can significantly increase
arterial pressure. This significant finding suggested
that a very low level elevation of body fluid volume
can indeed elevate arterial pressure by increasing
cardiac output. It is critical to note, however, that for
blood volume increases to lead to chronic elevation
of arterial pressure, baroreceptor reflex control of
arterial pressure must either be completely reset or
impairment of low or high pressure baroreceptor
Osbom
Na
Intake
Renal Function
Extrinsic
Mechanism
Intrlnmtc
Mechanism
Rand Merve /kottvltu
taolotenslan II
AtTtal Ifatrlu-eflc Factor
Aldosterone
Ptyslcttl Factors
Anglotenslon n
Prostaglondlns
KtnM
CFR
Extracellular
Fluid
Volume
Na'
Balance
Cardiac
Output
Urinary
Na+ Excretion
Arterial
Pressure
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FIGURE 4. Schematic diagram of relations between sodium
intake and sodium excretion in regulation of extracellular fluid
volume and arterial pressure. Intrinsic and extrinsic mechanisms controlling renal function exist in parallel with arterial
pressure to regulate urinary sodium excretion and extracellular
fluid volume. GFR, glomerular filtration rate.
reflexes must exist. Krieger et al25 have similarly
shown in normal conscious dogs that low dose Ang II
infusion (5 ng/kg/min i.v.) in combination with a high
sodium chloride intake (120 meq/day) elicits arterial
hypertension that is preceded by sodium and water
retention and elevation of cardiac output. The calculated elevation of blood volume from this sodium and
water retention was approximately 5% of that in the
normotensive state. This arterial hypertension was
prevented under conditions in which sodium and
water retention was prevented by fixing total body
water constant by a servocontrol system. Thus, recent
evidence in both conscious rats and dogs indicates that
small changes in blood volume may significantly elevate cardiac output and arterial pressure. For this
elevation of arterial pressure to result in chronic
hypertension, some alteration in baroreceptor reflex
control of sympathetic outflow would be required.
However, alterations in renal sympathetic outflow may
also contribute to the increase in arterial pressure by
further facilitating renal sodium and water retention.
Renal Function, Sodium Balance, and
Control of Arterial Pressure
The regulation of extracellular fluid volume and
cardiac output are known to be important controllers
of arterial pressure.26 The relations between extracellular fluid volume, sodium intake, sodium excretion, and arterial pressure are depicted in Figure 4.
Compensation for changes in sodium intake, and
consequently control of extracellular fluid volume,
must be achieved by increasing and decreasing urinary sodium excretion. Previous studies have shown
the steep relation between arterial pressure and the
excretion of sodium by the kidneys. However, this
relation is dependent on normal renal function and
the proper balance between both the intrinsic and
extrinsic mechanisms that continually influence renal
function.
Renal Function and Blood Pressure
1-95
Renal function and ultimately the renal responses
to arterial pressure can be markedly influenced by
the extrinsic and intrinsic factors. Activation of the
renin-angiotensin-aldosterone axis and alteration of
renal sympathetic outflow may directly affect intrarenal handling of sodium and water, which may interrupt the normal maintenance of extracellular fluid
volume homeostasis. These factors also do not function in a fashion that is mutually exclusive. In this
regard, elevation of circulating Ang II or activation of
renal sympathetic outflow may also cause major
changes in intrarenal physical factors, Ang II, prostaglandins, kinins, glomerular filtration rate, or intrarenal hemodynamics. Any one or a combination of
these factors may sufficiently alter renal function in
such a way that the renal ability to rapidly elevate
urinary sodium excretion in response to a challenge
of increased sodium intake is reduced. Under these
circumstances, the resultant expansion of extracellular fluid volume elevates arterial pressure to overcome this excretory deficit and thereby return body
fluid volumes to a normal state. Thus, the kidney
functions in a vital capacity in the long-term control
of arterial pressure by regulation of extracellular
fluid volume. Subtle alterations in renal excretory
function during periods of elevated sodium intake
result in the maintenance of normal bodyfluidvolumes at the expense of chronically elevating arterial
pressure and thus producing the onset of arterial
hypertension.
References
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1983^:59-72
2. Tobian L, Lange J, Azar S, Iwai J, Koop D, Coffee K, Johnson
MA: Reduction of natriuretic capacity and renin release in
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rats. Ore Res 1978;43(suppl I):I-92-I-98
3. Kawabe K, Watanabe TX, Shiono K, Sokabe H: Influence on
blood pressure of renal isografts between spontaneously
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Heart J 1978;19:886-894
4. Fox U, Bianchi G: The primary role of the kidney in causing
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strain (MHS) and normotensive rats. Clin Exp Pharmacol
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spontaneously hypertensive rats. Hypertension 1987;9(suppl III):
m-130-m-136
7. 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
8. Hall JE, Granger JP, Hester RL, Coleman TG, Smith MJ Jr,
Cross RB: Mechanisms of escape from sodium retention
during angiotensin II hypertension. Am J Physiol 1984;246:
F627-F634
9. Douglas JG: Angiotensin II receptor subtypes of the kidney
cortex. Am J Physiol 1987;253:F1-F7
10. Liu FY, Cogan MG: Angiotensin II stimulation of hydrogen
ion secretion in the rat early proximal tubule: Modes of action,
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Vol 17, No 1, January 1991
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11. Liu FY, Cogan MG: Angiotensin II stimulates early proximal
bicarbonate absorption in the rat by decreasing cyclic adenosine monophosphate. / Clin Invest 1989;84:83-91
12. Hall JE, Granger JP, Smith MJ Jr, Premen AJ: Role of renal
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Hypertension 1984;6(suppl I):I-183-I-192
13. Osborn JL, DiBona GF, Thames MD: ft Receptor mediation
of renin secretion elicited by low frequency renal nerve
stimulation. / Pharmacol Exp Ther 1981;216:265-269
14. Johns EJ: An investigation into the type of 0-adrenoceptor
mediating sympathetically activated renin release in the cat Br
/Pharmacol 1981;73:749-754
15. Kopp UC, Aurell IM, Nilsson IG, Ablad B: The role of
/3-adrenoceptors in the renin release response to renal sympathetic nerve stimulation. PflugersArch 1980-387:107-113
16. DiBona GF: Neural control of renal function: Role of renal
o-adrenoceptors. / Cardiovasc Pharmacol 1985;8:S18-S23
17. Hesse IFA, Johns EJ: The role of o-adrenoceptors in the
regulation of renal tubular sodium reabsorption and renin
secretion in the rabbit. Br J Pharmacol 1985;84:715-724
18. Osborn JL, Holdaas H, Thames MD, DiBona GF: Renal
adrenoceptor mediation of antinatriuretic and renin secretion
responses to low frequency renal nerve stimulation in the dog.
Ore Res 1983^3:298-305
19. Barajas L, Powers L, Wang P: Innervation of the renal cortical
tubules: A quantitative study. Am J Physiol 1984;247:F50-F60
20. Osborn JL, Harland RW: arAdrenoceptor mediation of urinary bicarbonate excretion. Am J Physiol 1988;255:
F1116-F1121
21. Osborn JL, Kinstetter DD: Effects of altered N a d intake on
renal hemodynamic and renin release responses to RNS. Am
J Physiol 1987;253:F976-F981
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Enhanced norepinephrine sensitivity in renal arteries at elevated transmural pressure. Am J Physiol 1990-,259:H29-H33
23. Osborn JL: Neurogenic mediation of antinatriuresis following
reduction of sodium intake in conscious dogs. Kidney Int
1989;35:471
24. Hinojosa-Laborde C, Greene AS, Cowley AW Jr: Whole body
autoregulation in conscious areflexic rats during hypoxia and
byptroxiz.AmJ Physiol 1989;256:H1023-H1029
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blood volume in angiotensin II salt-dependent hypertension in
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Relationship between body fluid volumes and arterial pressure. Fed Proc 1986;45:2864-2870
KEY WORDS • renal function • sodium excretion • blood
pressure • kidney
Relation between sodium intake, renal function, and the regulation of arterial pressure.
J L Osborn
Hypertension. 1991;17:I91
doi: 10.1161/01.HYP.17.1_Suppl.I91
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