CIRCULATORY HOMEOSTASIS
CHF: Circulatory Homeostasis Gone Awry
The role of the renin-angiotensin-aldosterone system
(RAAS) is integral to salt and water retention, particularly
by the kidneys. Over time, positive sodium balance leads first
to intra- and then to extravascular volume expansion, with
subsequent symptomatic heart failure. This report examines
the role of the RAAS in regulating a less well recognized
component essential to circulatory homeostasis—central
blood volume. The regulation of central blood volume draws
on integrative cardiorenal physiology and a key role played
by the RAAS in its regulation. In presenting insights into
the role of the RAAS in regulating central blood volume,
this review also addresses other sodium-retaining states with
a predisposition to edema formation, such as cirrhosis and
nephrosis.(CHF. 2002;8:37–48) ©2002 CHF, Inc
Karl T. Weber, MD;1 Brad S. Burlew, MD;1
Richard C. Davis, MD, PhD;1 Kevin P. Newman, MD;1
Ivan A. D’Cruz, MD;1 Ralph G. Hawkins, MD;1
Barry M. Wall, MD;1 Robert B. Parker, PharmD2
From the Divisions of Cardiovascular Diseases and
Nephrology, Department of Medicine;1 and the College
of Pharmacy,2 University of Tennessee Health Science
Center, Memphis, TN
Address for correspondence/reprint requests:
Karl T. Weber, MD, Division of Cardiovascular
Diseases,University of Tennessee Health Science Center,
Room 353 Dobbs Research Institute, 951 Court Avenue,
Memphis, TN 38163
E-mail: KTWeber@utmem.edu
CHF JANUARY/FEBRUARY 2002 37
Heart failure is a worldwide health problem of ever-in-
creasing proportions, particularly among the elderly.
Both systolic and diastolic left ventricular dysfunction
can eventuate in a clinical syndrome having character-
istic signs and symptoms, known as congestive heart
failure (CHF). The presence of ventricular dysfunction,
however, does not mandate a diagnosis of CHF. The
appearance of CHF is dependent on salt and water re-
tention mediated by an activation of neurohormonal
systems that include the renin-angiotensin-aldos-
terone system (RAAS). This is underscored by the
more than 6000 patients enrolled in the SOLVD trial
(Studies of Left Ventricular Dysfunction), based on
their meeting the entrance criterion of reduced left
ventricular ejection fraction (<35%).1,2 Symptomatic
patients were enrolled into the treatment arm of
SOLVD, and asymptomatic patients into its preven-
tion arm. The level of resting plasma renin activity
(PRA) distinguished these two study populations.3
Those with elevated PRA, a marker of RAAS activation
and indicator of sodium retention mediated by its ef-
fector hormones, angiotensin (Ang) II and aldos-
terone, had symptomatic failure. On the other hand,
PRA was normal in asymptomatic enrollees, with the
exception of those receiving a diuretic, in whom it was
elevated and suggestive of reduced intravascular vol-
ume as the cause of RAAS activation.4,5 In both symp-
tomatic and asymptomatic patients, the SOLVD trial
demonstrated the efficacy of an angiotensin-convert-
ing enzyme (ACE) inhibitor in reducing morbid and
mortal events.
These findings underscore the importance of the
RAAS in promoting, and the role of the kidney in me-
diating, sodium retention. Over time, positive sodium
balance leads first to intra- and then extravascular
volume expansion with subsequent symptomatic
heart failure. Several questions arise regarding the
RAAS in patients with heart failure. Is it confined to
an advanced stage when cardiac output and renal
perfusion, in particular, are markedly impaired? Can
elevations in plasma Ang II and aldosterone appear
intermittently, even during the course of a day, to ac-
count for periods of sodium retention that then beget
symptomatic heart failure (or decompensation) in pa-
tients previously compensated (asymptomatic) on an
apparently effective regimen of ACE inhibitor and
loop diuretic? If so, why? Are such periods of positive
sodium balance, which may require hospitalization if
38 CIRCULATORY HOMEOSTASIS
sustained and marked, indicative of “refractory”
heart failure? Are they reversible, and if so, how?
In this report, we endeavor to address these ques-
tions by examining the role of RAAS in regulating a
less well recognized, yet nonetheless important com-
ponent essential to circulatory homeostasis: central
blood volume (CBV). CBV regulation draws on inte-
grative cardiorenal physiology and a key role played
by the RAAS in its regulation. We will also address
other sodium-retaining states with a predisposition to
edema (e.g., cirrhosis and nephrosis) to further draw
insights into the role of the RAAS in regulating CBV.
CBV and Circulatory
Homeostasis
Posture and CBV: An Overview. CBV refers to the
volume of blood contained within the thorax; it in-
cludes blood within the heart and pulmonary circula-
tion (i.e., between the right atrium and aortic valve).
This “effective” plasma volume of the thorax is influ-
enced by venous return, pleural pressure, competent
atrioventricular and semilunar heart valves, the size
and distensibility of atrial and ventricular chambers,
intravascular volume, and posture. Sensors and ef-
fectors of CBV function as major determinants of cir-
culatory homeostasis.
As shown in Figure 1, CBV regulates the stretch
(and size) of atria and ventricles. This serves to: 1)
Figure 1. Central blood volume (CBV) is an important determi-
nant of atrial and ventricular stretch. As such, CBV is involved
in the regulation of cardiac output, the release of natriuretic
peptides and the activation of the renin-angiotensin-aldos-
terone system (RAAS) and adrenergic nervous system (ANS),
each of which influences salt and water homeostasis.
CHF JANUARY/FEBRUARY 2002
influence cardiac output and stroke volume through
length-dependent properties of cardiac muscle
(Frank-Starling mechanism); and 2) determine atrial
and ventricular release of a family of natriuretic
peptides (atrial [ANP] and brain [BNP]). Low-pres-
sure cardiopulmonary receptors serve as CBV sen-
sors. They regulate effectors that maintain the
balance between the sympathetic and parasympa-
thetic nervous systems, including renal adrenergic
nerves, activation of the circulating RAAS, and ex-
tracellular fluid volume.6
Upright posture normally is associated with gravi-
ty-based displacement of a portion of CBV from the
thorax into the capacitance venous circulation of the
abdomen and lower extremities (Figure 2). There ad-
ditionally exists an efflux of plasma volume into the
interstitial space of dependent arms and legs with
upright posture. The influence of upright posture on
circulatory homeostasis has been examined by plac-
ing an individual in a semi-erect position on a tilt
table and applying lower-body negative pressure or
inflatable cuffs around the lower extremities, or by
having a person assume a sitting (with legs dangling)
or standing position. Upright posture elicits a rapid
(within minutes) activation of both the RAAS and
adrenergic nervous system. Activation of these neu-
rohormonal systems with upright posture serves to
promote arteriolar vasoconstriction that preserves ar-
terial pressure. This occurs at the expense of renal
and hepatic perfusion. Additionally, Ang II, aldos-
terone, and norepinephrine all serve to promote salt
and water retention within proximal and distal seg-
ments of the nephron. These responses are prevent-
ed when upright tilt is combined with inflation of an
antigravity suit placed around both lower extremi-
ties. They are inhibited when an individual is in an
antiorthostatic position (head-down tilt), where ex-
pansion of CBV and cardiac stretch raise cardiac out-
put and promote the release of ANP and BNP.
Figure 2. Central (CBV) and peripheral (PBV) blood vol-
umes respectively include those found within and outside
of the thorax. In normal individuals or those with early
heart failure, assumption of upright posture is accompa-
nied by a fall in CBV. In more advanced heart failure with
cardiomegaly this decline in CBV is attenuated or lost. See
text for further discussion
CIRCULATORY HOMEOSTASIS
When upright posture is accompanied by ambula-
tion (isotonic exercise), vasodilatation of working
skeletal muscle redistributes systemic blood flow in
their direction. This further compromises renal and
hepatic perfusion and is an additional stimulus to
RAAS activation. Reduced hepatic blood flow attenu-
ates the normally rapid clearance of aldosterone by
the liver. This contributes to elevations in its plasma
concentration and enhances renal sodium avidity
within the distal nephron. As a consequence of these
responses to physical activity, sodium excretion, al-
ready compromised by upright posture alone, is fur-
ther reduced.
CBV and Posture in Normal Man. Few studies
have measured CBV in man and its response to shifts
in posture. Radiologic estimates of cardiac size have
demonstrated the decline in heart volume that occurs
with upright posture.7,8 Using this approach, Nylin9
estimated supine and upright heart volumes to be
843 mL and 574 mL, respectively. London et al.10 de-
fined cardiopulmonary blood volume as the volume
contained between the right atrium and aortic valve.
They calculated it as the product of cardiac output
(mL/sec) and mean transit time(s) for indocyanine
green to traverse this distance. Using this approach,
they calculated normal man to have a supine central
volume of 795 mL/m2. For an average-sized individ-
ual (1.75 m2), this would amount to a volume of 1391
mL. Using a similar technique, others have estimated
cardiopulmonary blood in normal man to be 1554
mL and 1938 mL.11,12 The average of these estimates,
1624 mL, represents approximately 15%–20% of nor-
mal total blood volume.12 In normal volunteers tilted
upright to 25° for 10 minutes, a 27% reduction in
echocardiographic left ventricular end-diastolic vol-
ume is observed.13 In patients without heart disease,
60° upright tilt is accompanied by a 17% reduction in
right ventricular end-diastolic volume.14 To simulate
the effect of upright posture on cardiopulmonary blood
volume, blood pressure cuffs were placed around the
thighs of a supine man and inflated to a pressure 5 mm
Hg below arterial diastolic pressure.11 Thirty minutes
after inflation, central volume fell by 219 mL, and
this was accompanied by a fall in right atrial pressure
and cardiac output and a rise in PRA.
RAAS activation with assumption of upright posture
alone (without ambulation) has been examined with the
use of a tilt table.15,16 When normal individuals are tilt-
ed to 60° or 80° for 30–40 minutes (Figure 3), PRA in
peripheral and renal venous blood rises within minutes
and continues to rise during the period of observation.
A prompt recovery of PRA is observed over the course
of 30 minutes (Figure 3, left panel). After a 60 mm Hg
inflation of an antigravity suit around the lower extrem-
CHF JANUARY/FEBRUARY 2002 39
ities, repeat tilting is not associated with a rise in PRA
(Figure 3, right panel). Stimulation of juxtaglomerular
cells located within afferent renal arterioles and their
release of renin during upright posture or lower body
negative pressure are related to stimulation of low-pres-
sure cardiopulmonary receptors and reflexive vasocon-
striction by sympathoadrenergic activation.17–21 Plasma
norepinephrine rises within minutes of tilting and it,
too, is attenuated by the antigravity suit.
Sitting with legs dangling for 60 minutes (see con-
trols, Figure 4) is accompanied by a modest, albeit
significant, rise in PRA and plasma aldosterone and
norepinephrine.22 Each of these responses seen with
sitting is less extensive than those observed with up-
right tilt.15,16 Plasma aldosterone concentrations rise
several-fold above supine values (50–100 ng/dL) when
normal individuals are upright for 3 hours perform-
ing physical activities of daily living. This response is
exaggerated when there is pre-existing RAAS activa-
tion secondary to dietary sodium restriction or diuret-
ic-induced reduction in intravascular volume.23–25
Shifts in plasma volume that occur with 60 min-
utes of standing have been examined in healthy male
volunteers via measurements of hematocrit, hemo-
globin, and plasma proteins.26 The major efflux of
plasma volume seen with standing occurs within 20
minutes and continues at a lesser rate over the
course of 60 minutes. The resultant hemoconcentra-
tion is reflected in a 10% rise in hematocrit and 20%
elevation in plasma proteins. It is estimated that a
580 mL efflux in plasma volume occurs during
standing (vis-à-vis hemodilution and influx of 440
mL in the supine position).
In normal man, a 10° head-down tilt increases car-
diopulmonary blood volume from a supine value of
795 mL/m2 to 878 mL/m2. For an average-sized per-
son (1.75 m2), this amounts to an increase in central
volume of 145 mL (1536–1391 mL).10 Central venous
Figure 3. Left panel: During upright tilt in normal volun-
teers, the decline in central blood volume is accompanied
by a rapid increase in plasma renin activity (PRA) and a
rapid recovery during the recumbency. Reprinted with
permission from Circulation. 1970;41:89–95. 15 Right
panel: The rise in PRA with tilt is abrogated by inflation
of an antigravity suit (+G) around the lower extremities.
Reprinted with permission from Scand J Clin Lab Invest.
1978;38:163–169.16
40 CIRCULATORY HOMEOSTASIS
pressure rises from a supine value of 1.65 to 2.70 mm
Hg in response to this central hypervolemia.
In healthy volunteers, 8 hours in an antiorthostatic
position (20° head-down tilt) is accompanied by di-
uresis and saluresis significantly greater than are seen
when such individuals are maintained in a supine
posture for a comparable period of time.27 The an-
tiorthostatic response in salt and water excretion is
comparable to that seen when furosemide is given to
these men under usual ambulatory conditions. The
diuresis and saluresis seen when furosemide is com-
Figure 4. In cirrhotic patients with ascites, sitting (with legs
dangling) is accompanied by a rapid rise in plasma aldos-
terone (PAC), renin activity (PRA) and norepinephrine
(PNC) concentrations. This response is more marked than
that observed in normal volunteers in the sitting position.
Note that patients with cirrhosis and ascites have an eleva-
tion in these neurohormones under basal (B) conditions.
Reprinted with permission from Gut. 1985;26:629–635.22
CHF JANUARY/FEBRUARY 2002
bined with the antiorthostatic posture are in excess of
that seen with head-down tilt alone.
In control patients having normal hemodynamic
findings at the time of diagnostic cardiac catheteriza-
tion, a shift in posture from 45° upright to 15° head-
down tilt is accompanied by a rise in right atrial and
wedge pressures and a 30% increase in plasma ANP.
CBV and Posture in Disease States Associated With
Sodium Retention. Preascitic Cirrhosis. Neurohormonal
responses that accompany 2 hours of standing (with
ambulation) followed by 2 hours of bedrest were exam-
ined and compared in cirrhotic and healthy male vol-
unteers.28 When they were upright, glomerular
filtration and plasma ANP and norepinephrine levels
did not differ between groups. Sodium excretion in the
upright posture, however, was lower in cirrhotic pa-
tients. This correlated inversely with plasma aldos-
terone, which rose to levels greater than predicted by
PRA, implicating reduced hepatic clearance of aldos-
terone. On return to supine posture, plasma aldos-
terone and sodium excretion were normalized. With
bedrest, the plasma concentration of ANP rose to a
level greater than that in controls. This would implicate
greater atrial stretch and enhanced venous return with
recumbency in these patients, which was a result of in-
travascular volume expansion that occurred during up-
right posture. As a result of these neurohormonal
responses, sodium excretion in recumbent cirrhotics
rose to levels greater than those of controls.
Thus, in patients with preascitic cirrhosis, basal
(supine) PRA is normal. Activation of the RAAS occurs
with ambulation and leads to salt and water retention
and expansion of intravascular volume. Such a re-
sponse may be relevant to patients with compensated
heart failure who experience bouts of symptomatic
failure after physical activity. Bedrest serves to coun-
terbalance salt retention in preascitic cirrhosis and is
accompanied by a reduction in plasma aldosterone
and an elevation of ANP. When RAAS activation is
sustained, positive sodium balance eventuates in ex-
pansion of both intra- and extravascular volumes (e.g.,
ascites). Aldosterone is the primary mediator of stand-
ing-induced sodium retention. The observed dissocia-
tion between its plasma concentration and PRA raises
the likely prospect that reduced hepatic perfusion and
aldosterone clearance are present and contributory to
sodium retention during upright posture.
Cirrhosis With Ascites. Basal (supine) RAAS activation
and urinary sodium retention are characteristic of
these patients.22 Placing them in a sitting position
(with legs dangling) for 60 minutes leads to further
elevation in PRA, evident at 10 and 30 minutes and
sustained at 60 minutes (see cirrhotics, Figure 4).
CIRCULATORY HOMEOSTASIS
The rise in PRA is comparable to a 60° or 80° tilt in
normal man despite a presumptive lesser shift in
CBV imposed by sitting. This suggests that the re-
duction in renal perfusion and impairment in renal
hemodynamics are marked when patients with cir-
rhosis and ascites are sitting. Accompanying the rise
in PRA are elevations in plasma aldosterone and nor-
epinephrine. Urinary sodium excretion is inversely
related to the integral of the aldosterone response
(i.e., the duration and rise in plasma aldosterone).
Thus, impaired renal perfusion, RAAS activation,
and expansion of intra- and extravascular volumes are
present in patients with cirrhosis and ascites. Eleva-
tions in plasma aldosterone are present when these
patients are supine. Upright ambulation provides an
additional stimulus for RAAS activation with an addi-
tional rise in plasma aldosterone, leading to exagger-
ated sodium retention. These patients need a
“physiologic diuretic” to counteract their continuous
retention of salt and water. Such “diuresis” is achieved
with the central hypervolemia that accompanies sub-
mersion of these individuals in a pool of water to the
clavicles, known as head-out water immersion; expan-
sion of CBV induces negative sodium balance in these
patients29 and those with nephrosis.30,31 This response
is not observed with antishock trousers.32
Hypoalbuminemia. Urine output and renal sodium ex-
cretion were examined in response to sequential
variations in posture in patients with hypoalbumine-
mia-related fluid retention.33 Results were compared
to those of healthy volunteers. The regimen included
initial sitting followed by bedrest, bedrest with legs
elevated to 10°, and finally 10° head-down tilt. Pa-
tients studied had cirrhosis, nephrosis, poor nutri-
tion, or protein-losing enteropathy. Urinary sodium
excretion, especially with sitting (but other positions
as well), was lower in the patients with edema and as-
cites. It rose progressively from sitting through head-
down tilt, with the latter inducing greater sodium
excretion than bedrest (with or without legs elevat-
ed). In each position, the percent increase in sodium
excretion seen in these patients was greater than that
in normal controls.
Thus, CBV expansion in patients with hypoalbu-
minemia simulates physiologic diuresis. The
reductions in effective CBV that occur when these
individuals are upright are accentuated by hypoal-
buminemia, where reduced colloidal osmotic pres-
sure serves a permissive role in augmenting loss of
plasma volume during upright posture. Manipula-
tions of CBV, induced by either head-down tilt or
head-out water immersion, could be used to
counter-regulate sodium retention in patients with
hypoalbuminemia.
CHF JANUARY/FEBRUARY 2002 41
Chronic Heart Failure. Urinary sodium excretion is
greater in the supine position than with 4 or 6 hours
of upright posture combined with activities of daily
living.34,35 PRA and plasma aldosterone become ele-
vated with upright posture and ambulation. The abil-
ity of these patients to carry out such a long period
of continuous activity suggests that their heart failure
was mild. Limiting symptoms of exertional dyspnea
and fatigue were not reported.
In patients with ventricular dysfunction and nor-
mal filling pressures (wedge pressure, ≤15 mm Hg;
right atrial pressure, ≤ 5 mm Hg) and a mild to mod-
erate reduction in the resting (supine) cardiac index
(≥ 2.0 L/min/m2), 60° tilt for 10–15 minutes is accom-
panied by venous pooling and significant elevations
in PRA and plasma norepinephrine, to higher than
normal recumbency levels.5,36,37 However, when the
hemodynamic status of patients with heart failure is
more impaired (wedge pressure, ≥15; right atrial
pressure, ≥5 mm Hg; cardiac index, ≤2.0 L/min/m2),
upright tilt is not associated with a further rise in
PRA (elevated at supine rest), despite a fall in right
atrial and left heart filling pressures and cardiac out-
put.36–38 Why this should be the case is uncertain at
present. Several possibilities are considered below.
Radiologic measurements of heart volume in supine
and erect postures have been obtained in patients with
various forms of acquired or congenital heart disease.7,8
The greater the volume of the diseased and enlarged
heart, the less marked are postural changes in cardiac
volume. This attenuated difference in cardiac volume
between supine and erect posture in these patients is
abrogated by such valvular lesions as pulmonic or mi-
tral stenosis. The difference in heart volume between
these positions is related most closely to heart rate in
the standing position (greatest reduction in cardiac vol-
ume with higher heart rates). Responses to tilt in
echocardiographic left ventricular end-diastolic volume
have been examined in patients with New York Heart
Association class III or IV decompensated failure with
ventricular dilatation. In contrast to normal volunteers
or patients with compensated heart failure, upright pos-
ture is not accompanied by a measurable reduction in
the left ventricular filling volume.13 Likewise, 60° up-
right tilt is not accompanied by a reduction in right ven-
tricular end-diastolic volume in patients with CHF and
cardiomegaly.14
A shift from 45° upright posture to 15° head-down
tilt in patients with New York Heart Association class
III or IV failure was accompanied by a rise in wedge
and right atrial pressures from 17 to 25 mm Hg and
5 to 10 mm Hg, respectively. Despite this stimulus,
elevated basal levels of plasma ANP did not rise fur-
ther.39 In the presence of chronic atrial distention,
this blunted response of ANP may further contribute
42 CIRCULATORY HOMEOSTASIS CHF JANUARY/FEBRUARY 2002

to the sodium retention seen with upright posture in
such patients, and contrasts with the normal eleva-
tion in ANP that occurs with recumbency, which re-
verses the salt-avid state induced by ambulation.
Thus, the severity, chronicity, and nature of heart
failure are determinants of the neurohormonal re-
sponse to upright posture. When right and left heart
filling pressures are normal or mildly elevated, PRA
rises during tilt. On the other hand, PRA does not
rise when atrial pressures are markedly elevated in
the presence of chamber dilatation. Additionally,
ANP responses to posture from distended atria may
be blunted. A number of issues need to be addressed
to adequately understand the influence of chronic
heart failure on neurohormonal responses associated
with variations in CBV that accompany changes in
posture (see below). These responses are integral to
understanding sodium balance and its relationships
to posture and to counteracting sodium retention.
The decline in CBV seen with upright posture is
attenuated in chronic heart failure when there is as-
sociated cardiomegaly. This reserve in CBV is due
to several factors that influence atrial and ventricu-
lar volumes: 1) atrial and ventricular dilatation in-
volving both the right and left heart in the absence
of valvular stenosis; 2) a marked increase in disten-
sibility of enlarged atrial and ventricular chambers,
and therefore, with any fall in chamber pressure,
the accompanying decline in chamber volume is
small; 3) the presence of mitral and/or tricuspid
valvular incompetence; 4) expansion of intravascu-
lar volume secondary to sodium retention; and 5)
venoconstriction and lower extremity edema, op-
posing the loss of plasma volume into the intersti-
tial space and the overall decline in CBV (see
below). Collectively, these factors create a reserve in
CBV during upright posture.
This reserve in CBV accounts for the abnormal
response to the Valsalva maneuver seen in patients
with cardiomegaly, irrespective of its etiologic basis,
with the exception of stenotic valvular disease.40,41
The increased intrathoracic pressure that accompa-
nies this maneuver is associated with a reduction in
venous return and cardiac output. Reduced right
atrial stretch leads to the reflexive changes noted
earlier that promote arteriolar vasoconstriction. De-
spite the elevation in vascular resistance, arterial
pressure normally falls because of reduced venous
return and thereby reduced cardiac output (Figure
5, left panel). Release of the closed glottis and
restoration of venous return in the face of arteriolar
constriction is accompanied by increased cardiac
output and a rise in arterial pressure above baseline.
In heart failure with cardiomegaly, the response
of arterial pressure to Valsalva is quite different
(Figure 5, right panel). Instead of the expected fall
in arterial pressure, there is an immediate and per-
sistent rise throughout the maneuver (described as
a “square wave” response). This is based on the
preservation of cardiac output in the setting of vaso-
constriction induced by reduced venous return and
stimulation of low-pressure receptors of the car-
diopulmonary unit. The CBV reserve present in is-
chemic or dilated (idiopathic) cardiomyopathy
preserves cardiac output during the Valsalva maneu-
ver. This square wave response of arterial pressure
to the Valsalva maneuver is not seen in patients with
mitral stenosis or pericardial disease, which counter-
act the reserve in cardiac volume.42 Measurements
of CBV, cardiac volume (including enlarged atrial

Figure 5. Left panel: The Valsalva maneuver is normally accompanied by a fall in arterial pressure. Release of the closed glottis is
followed by an overshoot in pressure above baseline. Reprinted with permission from Diseases of the Heart. 3rd ed. W. B. Saunders;
1966.40 Right panel: In patients with cardiomegaly, and in the absence of valvular stenosis or left to right shunt, the Valsalva maneu-
ver is accompanied by a prompt rise in arterial pressure which remains throughout the procedure. This “square wave” response in
arterial pressure is related to the reserve in central blood volume described in Figure 2. See text for further discussion
BA=brachial artery; ECG=electrocardiogram; RA= right atrium
Reprinted with permission from Cardiac Diagnosis and Treatment. 2nd ed. Harper & Row; 1976.41
CIRCULATORY HOMEOSTASIS
and ventricular chamber volumes), plasma volume,
and valvular regurgitation have not been examined
in studies that addressed neurohormonal activation
in response to tilt in patients with chronic heart fail-
ure and cardiomegaly.
In chronic heart failure with chamber dilatation, a
marked increase in distensibility of dilated atria at-
tenuates the decline in atrial volume that accompa-
nies the fall in chamber pressure with upright
posture. In dogs with chronic right and left heart di-
latation due to abdominal aorta-to-inferior vena cava
fistula, Zucker et al.43 found further left atrial disten-
tion by saline infusion to be accompanied by de-
pressed discharge of left atrial receptors. The
increase in atrial chamber distensibility and observed
structural alterations in receptor endings were held
responsible for the depressed atrial sensitivity.
Another example where chamber distensibility is
important relates to left ventricular diastolic dysfunc-
tion due to increased tissue stiffness. This would ac-
count for a marked fall in cardiac output and wedge
pressure during tilt. If not associated with a marked
elevation in vascular resistance, the fall in arterial
pressure would resemble orthostatic hypotension.
This would aggravate sodium retention, particularly
in the presence of pharmacologic agents with va-
sodilator properties.
The presence of lower-extremity edema and/or as-
cites reduces the capacitance and compliance of the
peripheral and splanchnic venous circulations. Ac-
cordingly, the shift in CBV into these vessels with as-
sumption of upright posture is reduced. Edema
therefore resembles attenuated responses in CBV
when upright posture is combined with an antigravi-
ty suit or head-out water immersion. Moreover,
edema and ascites reduce peripheral blood volume
and thereby increase CBV. In the recumbent posi-
tion, this is associated with elevations in right and
left atrial pressures, which may equalize as the re-
straining limit posed by the parietal pericardium is
reached. Elevations in CBV and atrial pressure rep-
resent the pathophysiologic setting that contributes
to the appearance of dyspnea with recumbency (or
orthopnea), paroxysmal episodes of dyspnea with re-
clining (e.g., paroxysmal nocturnal dyspnea), and
nocturia in patients with heart failure. Diuretic treat-
ment, which resolves these manifestations of expand-
ed extravascular volume and which accounts for
extramural compression of these vessels, serves to re-
store the expected shift in central volume to capaci-
tance vessels during upright posture.
Magrini and Niarchos44 examined the influence
of lower extremity edema on cardiopulmonary blood
volume and right atrial pressure during recumbency
and 80° head-up tilt in patients with edema due to
CHF JANUARY/FEBRUARY 2002 43
cirrhosis, nephrosis, or hypoalbuminemia. Supine
central volume averaged 1506 mL, or 27% of total
blood volume (normal values up to 22%), with right
atrial pressure of 17 mm Hg. Following resolution of
the edema after 2 weeks of oral furosemide and
spironolactone, supine central volume was reduced
to 1219 mL (22% of total blood volume) and right
atrial pressure declined to 7 mm Hg. With upright
tilt before diuretic treatment, central volume was
only slightly decreased, to 1452 mL (26% of total
blood volume), and right atrial pressure declined
from 17 to 13 mm Hg. Following diuresis, central
volume declined with tilt, from 1219 mL supine to
957 mL upright, and right atrial pressure fell from 7
mm Hg supine to 1 mm Hg upright. These findings
led these investigators to conclude that edema was
primarily responsible for the abnormalities in central
volume and atrial pressure observed in supine and
upright postures. In the supine posture, edema and
decreased venous capacitance lead to a translocation
of peripheral blood volume to the central compart-
ment. In the upright position, edema reduces the
shift in central volume to the peripheral compart-
ment. Additionally, and similarly to the square-wave
response in arterial pressure noted with the Valsalva
maneuver in patients with heart failure and car-
diomegaly, systolic and diastolic arterial pressures
rose with head-up tilt in the presence of edema, and
these responses were normalized after diuretic treat-
ment. These investigators further demonstrated that
when acute heart failure (i.e., following myocardial
infarction) occurred in the presence of massive
lower-extremity edema, sublingual nitroglycerin did
not reduce right and left atrial pressures. 45 This
proved to be the case after resolution of the edema
with diuretics and accompanying improvement in ve-
nous compliance (and capacitance).
Response to Loop Diuretics
Posture and Response to Loop Diuretics in Normal
Man and Disease States Associated With Sodium
Retention. Normal Volunteers. Upright posture is
accompanied by attenuated diuretic and saluretic re-
sponses to intravenous furosemide.46 This is attrib-
uted to pharmacodynamic mechanisms, including
altered tubular sodium handling attendant to RAAS
and adrenergic system activation.
Cirrhosis (and Ascites). The diuresis and natriuresis seen
in response to intravenous bumetanide are always
greater in the supine position than with 6 hours of up-
right activity.35 Glomerular filtration is significantly
higher when these patients are supine. Plasma concen-
trations of renin, aldosterone, and norepinephrine are
44 CIRCULATORY HOMEOSTASIS CHF JANUARY/FEBRUARY 2002

each elevated with upright posture. Elevations in plas-
ma aldosterone reach 600–800 ng/dL, an exaggerated
response far greater than observed in normal man with
either upright posture, sodium deprivation, or follow-
ing loop diuretic administration.23
activity.35 Similar posture-dependent responses of
salt and water excretion are observed in patients with
heart failure treated with furosemide, whereas the
rise in PRA and Ang II seen with 4 hours of upright
activity is attenuated by ACE inhibitor treatment.34

Nephrosis. The influence of posture and responsiveness Loop Diuretic Pharmacokinetics/Pharmacodynamics in

to loop diuretics has likewise been assessed in patients
with nephrotic syndrome that included impaired renal
function and proteinuria (>3 g/day), lower-extremity
edema, and hypoalbuminemia (<2.5 g/dL).47 Diuretic
and saluretic responses to intravenous furosemide are
greater with 6 hours of bedrest than with a compara-
ble period of physical activity. Positive sodium bal-
ance, which appeared during upright posture alone
(without a diuretic), became negative with bedrest and
even more negative when bedrest was combined with a
diuretic (left panel, Figure 6). Baseline elevation in
plasma aldosterone rose to 500 pg/mL or more with
upright posture. An inverse, linear correlation be-
tween urinary sodium excretion and plasma aldos-
terone levels was observed (right panel, Figure 6).
This is analogous to responses seen when patients
with cirrhosis are sitting. Plasma levels of ANP are not
altered by posture in patients with the nephrotic syn-
drome. Loop diuretic treatment is marginally effective
in upright, ambulatory patients with nephrosis. Nega-
tive sodium balance is restored with bedrest, and par-
ticularly when loop diuretic administration is
coincident with supine posture.
Chronic Heart Failure. As in patients with cirrhosis
(and ascites), the natriuresis and diuresis seen in re-
sponse to intravenous bumetanide are always greater
in the supine position than with 6 hours of upright
Patients With Sodium Retention. To counteract sodium
retention in patients with heart failure, loop diuretics,
such as furosemide, are frequently used. These agents
act at the luminal surface of the thick, ascending limb
of the loop of Henle; thus, their pharmacologic activi-
ty depends on achievement of an adequate concentra-
tion of the drug in the tubular lumen. However,
considerable intra- and interindividual variability ex-
ists in the diuretic response to these drugs. Sources of
this variability include alterations in both their phar-
macokinetics and pharmacodynamics.
Compared to the compensated state, the pharma-
cokinetics of oral furosemide are significantly altered
in patients with decompensated heart failure. In de-
compensated patients, both the absorption lag time
(up to 3 hours) and the rate of absorption are delayed,
resulting in lower peak plasma concentrations (≈30%)
and thus lower concentrations at the urinary site of ac-
tion (left panel, Figure 7).48 As a result of this alter-
ation in absorption, a reduction in diuresis with oral
furosemide occurs with decompensation, thus necessi-
tating intravenous drug administration to attain dry
weight. As euvolemia and clinical compensation are
re-established, the changes in furosemide absorption
return toward normal, but do not completely normal-
ize. Heart failure results in similar effects on bumeta-
nide, but not torsemide, absorption.49,50

Figure 6. Fluctuations in sodium balance are shown for upright and supine postures, before or after diuretic treatment, in
patients with the nephrotic syndrome (left panel). Positive sodium balance relates to sodium retention, negative balance to
sodium excretion. The saluretic response to diuretic is greatest in the supine position. Urinary sodium excretion (UNa V) is
inversely correlated with plasma aldosterone (ALDO) levels (right panel). Reprinted with permission from Am J Kidney
Dis. 2000;36:719–727.47
CIRCULATORY HOMEOSTASIS CHF JANUARY/FEBRUARY 2002 45

In addition to changes in oral pharmacokinetics,
heart failure reduces renal responsiveness to loop di-
uretics. When heart failure patients with normal renal
function are given intravenous loop diuretics, normal
amounts of the drug reach the urinary site of action,
indicating that the decreased diuretic response is not
related to altered pharmacokinetics.48 Therefore,
these findings suggest abnormal pharmacodynamics
as the mechanism of diuretic resistance in heart fail-
ure and other sodium-retaining states (e.g., cirrhosis).
As shown in the right panel of Figure 7, the furose-
mide concentration-response curve is shifted down-
ward and to the right in heart failure, compared to
that of patients without left ventricular dysfunction.
Thus, for any given amount of diuretic excreted in
urine, sodium excretion is reduced in heart failure
patients compared to controls. Mechanisms responsi-
ble for this reduced responsiveness in chronic heart
failure include increased Ang II-mediated proximal
tubular sodium resorption and aldosterone-associated
sodium retention in the collecting duct. Since concen-
trations of diuretic in the tubular lumen are normal,
the clinical implication of this diminished response is
that resistance cannot be overcome by administering
larger diuretic doses. Brater48 has suggested that this
circumstance might be counteracted by coadministra-
tion of either a thiazide-like diuretic or acetazolamide
with the loop diuretic. The large-volume diuresis and
kaluresis associated with this approach detracts from
its clinical utility in the long-term management of
heart failure. A more useful alternative, in our judg-
ment, is to attempt to reduce plasma levels of RAAS
effector hormones, thus minimizing the stimulus for
sodium and water retention, which, in turn, will im-
prove responsiveness to loop diuretics.
Summary and Conclusions
Activation of the RAAS is integral to circulatory home-
ostasis, including the regulation of CBV. Accordingly,
its activation normally occurs throughout the day, on
the basis of posture: it increases when man is upright,
with or without ambulation, to promote sodium reten-
tion; it is quiescent when the position is supine, allow-
ing less potent natriuretic peptides to restore sodium
balance. Effector hormones of the RAAS take on a crit-
ical role in patients with heart failure, cirrhosis, or
nephrosis, in which salt and water retention predis-
pose to edema formation.
Is RAAS activation confined to advanced stages of
heart failure? In symptomatic patients with chronic
heart failure, in whom the impairment in renal perfu-
sion is marked at all times, irrespective of posture, el-
evations in resting (supine) PRA and aldosterone are
to be expected. In such individuals, upright posture
(with or without ambulation) may further aggravate
sodium avidity through exaggerated RAAS activation.
Such individuals require interventions that favorably
alter renal hemodynamics and tubular sodium han-
dling, which includes counteracting Ang II and
aldosterone and enhancing salt and water excretion.
In pharmacologic terms, this relates, respectively, to
use of an ACE inhibitor to reduce the formation of
these effector hormones and antagonists of Ang II
type 1 (AT1) and aldosterone receptors to attenuate
their biologic activity, and a loop diuretic that pro-

Figure 7. Pharmacodynamics of furosemide are altered in patients with heart failure. When such a patient is decompensated, de-
layed gastric absorption and reduced peak serum concentrations are observed (left panel). They are reversed after compensation is
restored. In heart failure, urinary sodium excretion (UNa V) is attenuated for any given urinary concentration of furosemide (right
panel). Adapted with permission from Br Heart J. 1994;72(suppl):S40–S43.48
46 CIRCULATORY HOMEOSTASIS
motes salt and water excretion. Nonpharmacologic
interventions would include periods of recumbency,
with or without diuretic administration. RAAS activa-
tion, however, can also occur in asymptomatic pa-
tients with compensated heart failure. This occurs
with upright posture and is accentuated further dur-
ing ambulation. Impaired renal functional reserve
that appears in early heart failure is counteracted by
an ACE inhibitor or AT1 receptor antagonist.51–54
Can elevations in plasma Ang II and aldsosterone
appear intermittently, even during the course of a day,
to account for periods of sodium retention that then
beget symptomatic heart failure in patients previously
compensated? In asymptomatic patients with either
systolic or diastolic ventricular dysfunction, as in pa-
tients with preascitic cirrhosis, PRA is normal at rest
but rises with upright posture and rises even further
with ambulation. Hence, renal sodium avidity depends
on a patient’s daily schedule of upright posture and ac-
tivities. Patients with compensated heart failure, there-
fore, are subject to periods of sodium retention. If
sustained and marked, despite ACE inhibitor and/or
loop diuretic therapy, a net positive sodium balance
can eventuate in symptomatic heart failure. Such inter-
mittent periods of RAAS activation may account for the
inability of these patients to adequately eliminate di-
etary sodium. Volpe et al.51–53 and Magri et al.54 have
elegantly characterized impaired renal functional re-
serve that exists even in compensated patients with
early heart failure and which is expressed in their in-
ability to adequately respond to sodium loading pro-
vided by either dietary intake or intravenous infusion.
Enhanced proximal tubular sodium resorption, medi-
ated by Ang II, is held responsible, and ACE inhibition
or AT1 receptor antagonism attenuate this impairment
in functional reserve. This notwithstanding, sustained
upright posture- and activity-related periods of sodium
retention can evoke symptomatic heart failure, despite
an apparently effective regimen of these agents and
loop diuretics, during periods of inactivity.
Are such periods of positive sodium balance,
which may require hospitalization if sustained and
marked, indicative of refractory heart failure? Are
they reversible? Clinical experience in many patients
would suggest that this is not a refractory state.
Bedrest alone, with reduced dietary sodium intake
(e.g., a 3 g sodium diet) will often restore negative
sodium balance and eliminate symptoms. Such a reg-
imen is likely integral to the responsiveness seen
during hospitalization. It also can be realized with
home management. Impaired pharmacodynamics
relative to loop diuretics mandate larger-unit oral
doses and more frequent daily dosing to overcome
variable gastrointestinal absorption. This often
proves effective, together with bedrest, in the outpa-
CHF JANUARY/FEBRUARY 2002
tient management of symptomatic patients. Alterna-
tively, hospitalization with enforced bedrest, together
with intravenous administration of a loop diuretic,
may be necessary.
In more advanced cases of symptomatic heart
failure, where sodium retention is intense, with
marked expansion of intra- and extravascular vol-
umes, expressed as lower-extremity and sacral
edema (anasarca) with or without ascites, it may
prove necessary to utilize a timed infusion of a posi-
tive inotropic agent. Agents such as dobutamine or
milrinone augment cardiac output and thereby
renal perfusion and enhance diuretic delivery to the
nephron. Such agents alone may raise urinary sodi-
um excretion and more certainly, in most cases,
when combined with a loop diuretic. A phosphodi-
esterase inhibitor, such as milrinone, may offer
other advantages. These agents inhibit cytokine pro-
duction55; they prolong cyclic guanosine monophos-
phate, the intracellular mediator of natriuretic
peptides, which is normally inactivated by this en-
zyme. Additionally, natriuretic peptides inhibit se-
cretion of aldosterone and renin.
In closing, the syndrome of CHF appears as a re-
sult of salt-avid kidneys whose behavior is governed
by effector hormones of the RAAS. Activation of the
RAAS is integral to overall circulatory homeostasis,
including CBV regulation. Indeed, the RAAS can
prove lifesaving during periods of sodium depriva-
tion or in response to the loss of intravascular vol-
ume, such as accompanies hemorrhage, diarrheal
illness, or vomiting. In compensated heart failure,
where intravascular volume is normal and dietary
sodium restriction is not excessive, RAAS activation
during prolonged upright posture (with or without
ambulation) can lead to periods of salt retention
that, if sustained, lead to decompensation with
symptomatic failure. In heart failure, RAAS activa-
tion proves pathologic. It represents circulatory
homeostasis gone awry.
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