Debate
Atrial Natriuretic Factor Plays a Significant
Role in Body Fluid Homeostasis
Edward H. Blaine
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Atrial natriuretic factor (ANF) is a hormone with the physiological characteristics of a
regulator of body fluid volume. It is potent, has a short duration of action, and responds to a
physiologically relevant stimulus in a negative feedback-controlled system. It can act directly
or indirectly (via inhibition of aldosterone biosynthesis) on the kidney to alter sodium transport
and may regulate fluid distribution within the extracellular space. The peptide circulates at low
(nanomolar) levels, and recent studies with renal inner medullary cells document relevant
receptor binding and second messenger activation in this concentration range. In vivo data
support a direct action on the kidney to enhance natriuresis, and blockade of a primary
catabolic pathway for ANF within the kidney results in augmented natriuresis at concurrent
endogenous peptide concentrations. Long-term, low dose infusion directly into the renal artery
of conscious dogs supports a physiological action of ANF to promote urinary sodium excretion.
Nevertheless, under certain circumstances, natriuresis does not occur even at high circulating
levels of ANF. Apparently other factors such as renal perfusion pressure, volume status, and
renal nerve activity are important in determining the natriuretic response to a given level of
peptide. We hypothesize that the role played by ANF in volume regulation is highly complex,
and the kidney responds with increased sodium excretion only when a constellation of variables
is appropriately arrayed. That is, ANF is a necessary, but not sufficient, condition to induce
natriuresis. {Hypertension 1990;15:2-8)
W
hen the first cell wrapped itself in a membrane, volume regulation became a key to
survival. The factors controlling body fluid
volume (e.g., the balance between intake and output
of salt and water) are many and complex. Intake is
mediated through thirst and salt appetite, whereas
output is a complex interplay of variables that primarily affect renal function. Historically, the factors considered important for regulation of the renal output of
salt and water are glomerular filtration and the facilitated reabsorption of sodium by aldosterone.
The actions of aldosterone in regulating sodium
reabsorption from the nephron and changes in glomerular filtration have not proven adequate to explain
all of the experimental findings related to extracellular volume control. Based on the compelling experiments of DeWardener et al,1 in which it was shown
that the natriuresis associated with saline volume
expansion was not prevented by controlling filtration
and aldosterone levels, the concept of a salt-excreting
reflex pathway was established. Presumably, there
Address for correspondence: Edward H. Blaine, PhD, Department of Pharmacology, Box 8103, Washington University School of
Medicine, 660 South Euclid Avenue, St. Louis, MO 63110.
The text of these debates was presented at the 1989 meeting of
the Federations of American Societies for Experimental Biology in
New Orleans, Louisiana, March 20, 1989.
are receptors able to distinguish increases in body
fluid volume and relay that information to the kidney
to increase salt and water excretion.
It has been known from antiquity that water immersion enhances urine formation, and a common treatment for dropsy before discovery of modern drugs
was water immersion in therapeutic baths. Such
observations suggest that displacement of blood to
the cardiothoracic region results in natriuresis.
Given the low pressure and high compliance of the
venous side of the circulation compared with the high
pressure and low compliance of the arterial tree, it
would seem likely that volume sensors are located
within the low pressure system. A cogent argument
that such receptors are located in the cardiac atria
was presented by Gauer and Henry.2 More recent
data from Epstein's laboratory,3 among others, has
shown clearly that water immersion results in a large
increase in urinary sodium excretion. Presumably,
the cardiac atria detect the "fullness" of the system
and signal the kidneys to increase salt and water
excretion. Volume-sensitive receptors regulating vasopressin release4 and water intake5 were known to
exist in the cardiac atria, but receptors capable of
increasing urinary sodium excretion were less well
defined.6 Clearly the system worked, but the mediator was unknown.
Blaine
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The cardiac atria were known to contain specific,
secretory-like granules. That the abundance of these
granules changes in association with changes in salt
and water status was first observed by Marie and
colleagues.7 It fell to DeBold and his coworkers8 to
make the seminal observation that simple saline
extracts of atria, when injected into normal test rats,
produced a pronounced increase in urinary sodium
excretion. Thus, the body appears to harbor its own
diuretic, and although not as efficacious as furosemide, atrial natriuretic factor (ANF) is a thousand
times more potent.9
ANF satisfies all of the conditions to be an endogenous volume-regulating hormone. It is a powerful
natriuretic agent as was originally demonstrated with
atrial extracts and repeatedly confirmed with synthetic peptides. The peptidic nature of the mediator
allows for rapid control because of the short inherent
half-life. Release of ANF from the cardiac atria is
controlled by a volume-related variable, stretch of
the atrial myocytes. Expansion of the extracellular
fluid or water immersion is associated with increased
circulating levels of ANF in both animals and humans.
(See Reference 10 for a recent review to support
these contentions.) Blockade of this response with
monoclonal antibodies suggests a key role for ANF.11
Finally, natriuresis occurs at plasma levels of the
peptide that are physiologically feasible.12-13
So what is the question of the debate? There seems
irrefutable evidence to support the natriuretic activity of ANF. The debate appears to hinge on the
observation that, under certain circumstances, there
is a dissociation of the natriuretic effects of ANF
from circulating levels.14 That is, natriuresis is not
tightly coupled to the concurrent level of ANF.
One of the most striking observations that we
made several years ago was that normal, euvolemic
monkeys, when infused with ANF, did not undergo a
natriuresis, but when these same animals were anesthetized or very slightly volume expanded, a pronounced increase in urinary sodium excretion was
observed with the same dose of ANF.9 This was the
first indication of the dissociation between circulating
ANF and natriuresis. These data suggested the lack
of a simple relation between plasma level of the
hormone and the natriuretic action. Rather, this was
a complex interaction and several jointly dependent
variables were important, changes in any of which
could determine the magnitude of the response.
Thus, we would say that for volume regulation, the
atrial peptide system is highly complex and the
kidney responds with increased sodium excretion
only when a constellation of variables is appropriately arrayed. These variables are several, including
receptor number, renal perfusion pressure, extracellular volume, renal sympathetic nerve activity, and
quite possibly others. It is simplistic to view this
system as responding only to changes in plasma levels
of ANF.
There are other excellent examples of volume
regulatory systems where the mediator and the renal
ANF and Body Fluid Homeostasis
1.2 1.0
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^
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r
1
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1
-11 -10 -9 -8 -7
Log [Peptidel M
I
I
I
-5
FIGURE 1. Line graph showing competitive inhibition of
[125I]atrial natriuretic factor (ANF) binding by analogues.
Inner medullary collecting duct cells from rabbit kidney were
incubated with [mI]'ANF in presence of increasing concentrations of unlabeled ANFIanalogues (0-10~5 M). Inhibition is
expressed as ratio of amount of radioactivity bound in presence of competitor to that bound in its absence. Labels in
parentheses refer to amino acids of ANF; ANF-(l-28) is the
full length peptide. Reprinted with permission from American
Journal of Physiology (1988;255:F324-F330); see original
report for technical details.
responses are dissociated. A classic is the renal
escape from the sodium-retaining actions of mineralocorticoids. As is widely recognized, when mineralocorticoids are administered continuously, sodium
is retained for only a few days, after which the
individual comes back into balance with an expanded
extracellular fluid volume. Indeed, it couldn't be
otherwise. If volume-retaining or volume-excreting
systems were not feedback controlled, balance would
not be possible, nor would life. A similar analogy can
be drawn with diuretics. Treat patients with even the
most potent and efficacious diuretic and sodium
excretion will exceed intake for only a day or two,
after which balance is restored despite the continued
presence of the diuretic. Were it otherwise, diuretics
would be lethal.
One of the key elements to validate the role of
ANF as a renally effective hormone is the presence of
receptors for the hormone at locations that can result
in changes in sodium excretion. Our laboratory was
one of the first to identify ANF receptors on renal
membranes, but we did not localize these receptors
to a specific site in the kidney.15 Later, there was
abundant evidence of localization of ANF receptors
on the glomeruli16 but binding to renal tubules was
scant. Quite recently several papers have appeared
documenting a renal tubular receptor that is linked
through guanylate cyclase and mediates sodium transport. This receptor is responsive to ANF. Do these
receptors respond to ANF at levels that are physiologically feasible? If they do not, then it is immaterial
what other conditions must exist simultaneously to
support the natriuresis.
Figure 1, from a study by Gunning et al,17 illustrates
the binding of ANF to inner medullary collecting duct
cells for the dose range 10"13 M through 10"8 M with
Hypertension Vol 75, No 1, January 1990
A Control
{ iU
-
0
1
2
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0.5 pA |
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B ANP (10'11Af)
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A Control
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toiJl
1
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- 0
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2
4
TIME (min)
6
FIGURE 3. Line graph showing effect ofamiloride (0.1 mM)
and atrial natriuretic factor or peptide (ANP) (1 \xM) on 22Na
uptake in hyperpolarized inner medullary cells. Reprinted with
permission from Journal of Clinical Investigations
(1988;82:1067-1074); see original report for technical details.
- 1
- 3
2pA I
200 msec
B cGMP (0 .01 mM)
- o
- 1
- 2
FIGURE 2. Patch clamp records from rabbit kidney inner
medullary cells. Top panel (control) shows activity of up to six
channels. When 10'" M atrial natriuretic factor or peptide
(ANP) was added no more than three channels were open
simultaneously. Lower panel (control) shows spontaneous
opening of up to three channels simultaneously, and when 0.01
mM cyclic guanosine monophosphate (cGMP) was added
simultaneous openings were rare. Reprinted with permission
from Science (1989;243:383-385); see original report for
technical details.
the ED50 approximately 10 10 M, well within the
physiological range. The N-terminal truncated ANF(5-28) binds similarly but the N- and C-terminal
truncated peptides ANF-(5-25) and ANF-(13-28)
bind poorly or not at all. Also, these latter peptides
have little or no biological activity. To further illustrate that this binding is biologically relevant, guanylate cyclase activation was monitored by measurement
of the increase in intracellular cyclic guanosine monophosphate (cGMP) formation for these same cells.
The peptides have a similar activity to increase cGMP
as that observed for binding to the receptor. (Cyclic
GMP is the only second messenger that has been
identified for ANF, and the receptor and paniculate
guanylate cyclase are a single molecule.18 High affinity
binding occurs at another site that is not linked
through guanylate cyclase, and it is thought that this
second, biologically silent receptor may serve a storage
or clearance function.19) In another recent study,20
specific cation channels were identified in inner medullary collecting duct cells that were inhibited by ANF
at l(T n M. Cyclic GMP at 0.01 mM had a similar
inhibitory action on this cation channel (Figure 2).
These data are important in establishing a renal
tubular site of action for ANF and documenting that
a fundamental receptor-mediated mechanism exists
and can operate in the physiological range of ANF
concentrations.
Amiloride, an acylguanidine diuretic with potassiumsparing characteristics, inhibits sodium reabsorption
in the distal nephron including the inner medullary
collecting duct. Zeidel et al21 recently observed a
similarity between amiloride and ANF with regard to
inhibition of sodium transport. Although ANF exhibits similar action to amiloride (Figure 3) it is three to
four orders of magnitude more potent. Amiloride
blocks the sodium entry step into transporting epithelia that are generally described as tight (having
high resistance to paracellular shunt pathways). These
data would suggest that the action of ANF is similar
to amiloride and has its effect from the luminal side
of the nephron. If this interpretation is correct, it
would make even more remote the relation between
plasma levels of ANF and its renal action. An
interesting difference between amiloride and ANF is
that the latter is not potassium sparing,9 which suggests a fundamental difference between the two
compounds, particularly with reference to the tubular locus of their predominant influence.
Tubular receptors may not be the only way in
which ANF modifies renal sodium handling. There is
abundant data showing that ANF is a potent inhibitor of aldosterone biosynthesis (see Reference 10 for
recent review), and this mechanism may contribute
substantially to the renal actions of the peptide.
There may be yet other mechanisms by which ANF
plays a role in regulating renal function. The author's
personal bias is that there is an important vascular
action of ANF that is key to its natriuretic action. In
fact, the dependence of the natriuresis on renal
perfusion pressure, or some pressure-related variable
Elaine
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0
2 4
6 8 10 12 14
TIME (min)
FIGURE 4. Graphs showing time course of changes in urine
flow and papillary blood flow after infusion of atrial natriuretic
factor or peptide (ANP) (100 ng/kg/min) in Munich-Wistar
rats. Reprinted with permission from American Journal of
Physiology (1987;252:F992-F1002); see original report for
technical details.
supports this contention. An especially appealing
hypothesis is that ANF alters medullary resistance
and vasa recta flow. Recent data from Roman's
laboratory (Takezawa et al22) support this contention
(Figure 4). It is possible that changes in pressure or
concentration gradients play a role in ANF-induced
natriuresis.
The in vitro data are certainly important to understanding the action of ANF, but in any physiological
discussion the overriding consideration is what happens in vivo.
The in vivo data are confusing for several reasons.
The relatively high doses of exogenous peptide that
have been administered have actions in addition to
enhancement of urinary sodium excretion. These
additional actions may greatly influence the net effect
that ANF has on urinary sodium excretion. The
effects of ANF on blood pressure have been particularly confounding to our understanding of the physiological action of the peptide. It would appear from
the published data that at least two conditions must
occur simultaneously. These two conditions are adequate renal perfusion pressure and adequate levels of
ANF. In other words, adequate plasma levels of ANF
are necessary but not sufficient to produce natriuresis; a jointly necessary condition, adequate renal
perfusion pressure, is also required.
This point is illustrated with some of our early data
from monkeys.9 Figure 5 shows the dose-response
relation for synthetic ANF and sodium excretion in
anesthetized monkeys. Note the bell shape of the
curve. This is quite unlike other diuretics where a
maximum response is reached and maintained at
higher doses (a dose-response curve for hydrochlo-
(mg/kg i.v.)
i
5
i
10
25
50 100 200 400 800
DOSE (pmoles/kg/min)
FIGURE 5. Line graph showing natriuretic response to increasing doses of atrial natriuretic factor or peptide (ANP) or
hydrochlorothiazide (HCTZ) in anesthetized
monkeys.
Reprinted with permission from Journal of Hypertension
(1986;4:17-24); see original report for technical details.
rothiazide is also shown on the figure). The complexity of the curve is likely related to the independent
effects of ANF on blood pressure and natriuresis.
The synthetic diuretics have little or no acute effects
on pressure. The fact that natriuresis decreases at
high doses of ANF renders renal responsiveness
difficult to assess.
140120-
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100-
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80-
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TIME (min)
300
360
FIGURE 6. Upper panel: Line graph shows natriuretic and
blood pressure response of four conscious euvolemic monkeys
to continuous infusion of 30 pmol/kg/min atrial natriuretic
factor or peptide (ANP). Bottom panel: Line graph shows
response of these same monkeys on different day to same dose
of ANP but after a modest volume expansion (1 ml/kg plus
0.25 ml/kg/min normal saline). Reprinted with permission
from Journal of Hypertension (1986;4:17-24); see original
report for technical details.
Hypertension
Vol 15, No 1, January 1990
AP24
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0.4
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FIGURE 7. Line graph showing potentiation of natriuretic
response to atrial natriuretic factor by vasopressin in intact and
renal denervated dogs. In innervated dogs ( • ) , vasopressin
potentiated the response, whereas in denervated dogs (A), the
response was maximal before vasopressin was added, and
vasopressin produced no additional response. Reprinted with
permission from Circulation Research (1989,64:370-375);
see original report for technical details.
In the upper panel of Figure 6 is illustrated the
effects of a 3-hour infusion of ANF on conscious
euvolemic monkeys. Surprising to us at that time was
the total lack of natriuresis in this physiologically
relevant setting (conscious, trained, euvolemic monkeys). Notice, however, that arterial blood pressure
fell and that the blood pressure reduction was maintained for the duration of the infusion. When these
same monkeys were tested in an identical setting,
except that they received a modest volume expansion
with isotonic saline (1 ml/kg as a bolus injection
followed by 0.25 ml/kg/min sustaining infusion), natriuresis was fully apparent (Figure 6, lower panel).
This was despite a fall in arterial blood pressure,
although it was not as large as when these monkeys
were tested during euvolemia. We also tested whether
increasing arterial pressure with intravenous angiotensin II would restore the natriuresis, and that, too,
was successful (data not shown). Likewise, if you
restore pressure with angiotensin II or methoxamine
in rats receiving an ANF infusion, there is a marked
potentiation of the natriuretic response.23
Renal perfusion pressure is not the only factor
determining the renal response to a given dose of
ANF, however. We have observed in rats and in dogs
that nonpressor doses of vasopressin greatly potentiate the natriuretic response when administered intravenously but not when administered into the renal
artery.24 Figure 7 shows the potentiation of the
natriuretic response to intravenous vasopressin in
dogs with innervated and denervated kidneys. In the
innervated kidney, vasopressin potentiates the natriuretic response, but after denervation, ANF alone
has a markedly greater effect that is not further
potentiated by vasopressin. Based on work from
Bishop's laboratory,25 these data suggested a major
O
o
51
C7
8
6
4
UJ
3.
2
20 40 60 80 100 120
TIME (min)
FIGURE 8. Line graphs showing mean arterial pressure
(MAP), urine flow (V), and urinary sodium excretion (UNaV)
from rats receiving SC46542 ( • ) (a ligand that binds exclusively to the nonguanylate cyclase-linked atrial natriuretic
factor (binding site), thirophan (A) (an inhibitor or endopeptidase 24.11), or the two treatments in combination ( • ) .
Reprinted with permission from Journal of Pharmacology
and Experimental Therapeutics (1989;243:172-176); see
original report for technical details.
role for the level of renal sympathetic nerve activity
in determining ANF natriuretic action.24
We have seen how renal perfusion pressure and
the renal nerves can dictate the level of natriuresis
induced by ANF, but other factors are also at work.
These factors, important particularly for altering
endogenous levels of ANF in the kidney to regulate
the level of activity, are the rate of hydrolysis by
endopeptidase 24.11,26 especially in the renal tubular
brush border, and binding of ANF to the nonguanylate cyclase-linked binding site.19 Blocking
endopeptidase alone with the inhibitor thiorphan has
no effect on the natriuretic actions of ANF. Likewise,
blocking the non-guanylate cyclase-linked site alone
with a specific inhibitor has no effect. But, blocking
both of these pathways reveals the capacity for a
pronounced natriuresis based on the endogenous
level of the peptide (Figure 8). These data strongly
support the idea that endogenous levels of ANF can
produce a marked natriuresis when other variables,
in this case those determining metabolic clearance,
are appropriately arrayed.
Despite these compelling arguments, physiologists
demand documentation that exogenous administration of the hormone, at physiologically relevant levels, produce the appropriate response. Such experiments are extraordinarily difficult. They require
studies in conscious animals in normal correspondence with their environment, and usually, continued
administration for days or weeks. Fortunately, such
Blaine ANF and Body Fluid Homeostasis
experiments have been conducted with ANF, and the
results support a role for ANF in regulating urinary
sodium excretion. Mizelle et al12 have shown recently
that ANF infused continuously into the renal artery
of conscious dogs at levels that produce physiologically relevant plasma concentrations induces a sustained natriuresis. In this study, when the effects of
the peptide were restricted to the kidney (e.g., blood
pressure remained constant) natriuresis was maintained for the duration of the 5 -day infusion. Undoubtedly, the natriuresis would wane in time as significant
volume reduction ensued and arterial pressure was
reduced. In fact, in a similar study where ANF was
infused at physiologically relevant levels intravenously, natriuresis was limited by the fall in arterial
blood pressure.27
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In a very general sense, the renal response to ANF
supports the body fluid-pressure feedback control
system originally described by Guyton et al28 as the
controller for arterial blood pressure. In that context,
ANF can be viewed as a substance that alters the
kidney's ability to excrete sodium and, in concert with
the other factors that alter renal excretory ability,
contributes to the overall conditions that determine
arterial blood pressure.
In conclusion, I have shown that 1) ANF has the
physiological characteristics to be a mediator of body
fluid regulation, 2) ANF satisfies the conditions to be
a component of a physiological feedback-controlled
system, 3) ANF is part of a highly complex and
integrated system and is one of several jointly necessary factors that must occur simultaneously to effect
natriuresis, and 4) ANF at physiologically relevant
plasma concentrations can elevate urinary sodium
excretion for long time periods. That natriuresis does
not always occur indicates that other limiting conditions dominate.
As a final comment, it is interesting to note the
many parallels that have been drawn between the
atrial peptide system and the renin-angiotensin system. It is informative to recall also that the same
arguments regarding the relevance of the reninangiotensin system to blood pressure homeostasis
were raised. It was only when effective chemical
inhibitors of the renin-angiotensin system were discovered, in that case the angiotensin converting enzyme
inhibitors, that the true nature of the reninangiotensin system was appreciated. I suggest a similar
circumstance for the ANF system. Until there is an
effective inhibitor of the system that allows for clear
definition of the actions of ANF, we will not be able to
conclude what the "real" function of ANF may be.
Acknowledgments
I thank my many colleagues who have contributed
to this work. At Merck, Sharp & Dohme Research
Laboratories: Steve Brady, Anne Haley, Elizabeth
Marsh-Liedy, Mary A. Napier, Ruth Nutt, Terry
Schorn, and Margaret Whinnery. At G.D. Searle
Research and Development/Monsanto Co: Steven
Adams, Philippe Bovy, Dale Hartupee, John Koepke,
Gillian Olins, Kerry Spear, and Angelo Trapani.
References
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of the efferent mechanism of the sodium diuresis which
follows the administration of intravenous saline in the dog.
Clin Sci 1961;21:249-258
2. Gauer O, Henry JP: Circulatory basis of fluid volume control.
Physiol Rev 1963;43:423-481
3. Epstein M: Renal effects of head-out water immersion in man:
Implications for an understanding of volume homeostasis.
Physiol Rev 1978;58:529-581
4. Johnson JA, Moore WW, Segar WE: Small changes in left
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5. Zimmerman MB, Blaine EH, Strieker EM: Water intake in
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11. Hirth C, Stasch JP, Kazda S, John A, Morich F, Neuser D,
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hemodynamics and electrolyte excretion during chronic intrarenal infusion of atrial natriuretic peptide (ANP). FASEB J
1989;3:A697
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GM, Blaine EH: Interaction of non-guanylate cyclase-linked
atriopeptin receptor ligand and endopeptidase inhibitor in
conscious rats. / Pharmacol Exp Ther 1989;243:172-176
14. Goetz KL, Wang BC, Geer PG, Leadley RJ Jr, Reinhardt
HW: Atrial stretch increases sodium excretion independently
of release of atrial peptides. Am J Physiol 1986;250:R946-R950
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Brady S, Lyle T, Winquist R, Faison EP, Heinel LA, Blaine
EH: Specific membrane receptors for atrial natriuretic factor
in renal and vascular tissues. Proc Natl Acad Sci USA 1984;
81:5946-5950
16. Murphy KMW, McLaughlin LL, Michener ML, Needleman P:
Autoradiographic localization of atriopeptin II receptors in rat
kidney. Eur J Pharmacol 1985;111:291-292
17. Gunning ME, Ballerman BJ, Silva P, Brenner BM, Zeidel ML:
Characterization of ANP receptors in rabbit inner medullary
collecting duct cells. Am J Physiol 1988;255:F324-F330
18. Chinkers M, Garbers DL, Chang M-S, Lowe DG, Chin H,
Goeddel DV, Schulz S: A membrane form of guanylate cyclase
is an atrial natriuretic peptide receptor. Nature 1989;
. 338:78-83
19. Maack T, Suzuki M, Almeida FA, Nusseuzveig D, Scarborough RM, McEnroe G, Lewicki JA: Physiological role of silent
receptors of atrial natriuretic factor. Science 1987;239:675-678
20. Light DB, Schwiebert EM, Karlson KH, Stanton BA: Atrial
natriuretic peptide inhibits a cation channel in renal inner
medullary collecting duct cells. Science 1989;243:383-385
21. Zeidel ML, Kikeri D, Silva P, Burrowes M, Brenner BM:
Atrial natriuretic peptides inhibit conductive sodium uptake
by rabbit inner medullary collecting duct cells. J Clin Invest
1988;82:1067-1074
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Hypertension
Vol 15, No 1, January 1990
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KEY WORDS • atrial natriuretic factor
sodium excretion • water balance
• renal function
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Atrial natriuretic factor plays a significant role in body fluid homeostasis.
E H Blaine
Hypertension. 1990;15:2-8
doi: 10.1161/01.HYP.15.1.2
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