Neurohormonal Activation in Congestive

Heart Failure and the Role

of Vasopressin
Kanu Chatterjee,

MB

Vasoactive neurohormonal systems (eg, sympathetic

nervous system [SNS], renin-angiotensin-aldosterone
system, and arginine vasopressin [AVP]) are defense
mechanisms designed to preserve arterial volume and
circulatory homeostasis during periods of low cardiac
output. Neurohormonal systems, which are normally
stimulated under conditions of acute volume depletion,
are activated by the low cardiac output and arterial
pressure. However, sustained and chronic activation of
these systems, as occurs in congestive heart failure
(CHF), can cause progressive ventricular remodeling and

worsening heart failure. Vasoconstriction, water retention, and increased blood volume are results of the
activation of the SNS, the renin-angiotensin pathway,
and AVP secretion. These effects can accelerate progression of CHF, contributing to increased morbidity and
mortality. AVP regulates vascular tone and free-water
reabsorption, respectively, through the vasopressin V1a
and V2 receptor subtypes and therefore is a potential
neurohormonal target in the treatment of CHF. 2005
by Excerpta Medica Inc.
Am J Cardiol 2005;95(suppl):8B13B

ongestive heart failure (CHF) is a complex clinical

disorder resulting from any structural insult causC
ing cardiac dysfunction associated with hemodynamic

rect systemic vasoconstriction and activates other

systems (eg, AVP, aldosterone) that contribute to
maintaining adequate intravascular volume. AVP increases free-water reabsorption in the renal collecting
duct, thereby decreasing excretion of water and electrolytes and increasing blood volume.2 However,
chronic activation of these systems (eg, due to CHF)
can have deleterious effects on cardiac function and
contributes to the progression of CHF (Figure 1).35
The increased vasoconstriction resulting from SNS
activation results in increased left ventricular afterload. This, in turn, increases myocardial demand, left
ventricular end-diastolic pressure, pulmonary capillary wedge pressure, and pulmonary congestion while
decreasing cardiac output. An activated adrenergic
system also produces myocyte necrosis directly. The
increased intravascular volume induced by AVP-mediated reabsorption of free water results in elevated
intracardiac pressure as well as pulmonary congestion
and edema. Systemic vasoconstriction mediated by
angiotensin II increases left ventricular afterload and
can also directly induce cardiac myocyte necrosis and
alter the myocardial matrix structure.1 Angiotensin
also potentiates the SNS and AVP.
Counterregulatory vasodilatory mechanisms are
also activated in CHF, including the natriuretic peptide system, nitric oxide, and prostaglandins.6 However, these mechanisms are generally not adequate to
maintain cardiac function, systemic perfusion, or sodium balance. The end result of neurohormonal activation in CHF is clinical deterioration and progressive
left ventricular dysfunction.2
Neurohormonal activation manifests as increases
in plasma levels of AVP, renin, aldosterone, atrial
natriuretic factor, and norepinephrine. It is well documented that the degree of neurohormonal activation
is correlated with severity of heart failure. In a substudy of Studies of Left Ventricular Dysfunction
(SOLVD), baseline levels of plasma norepinephrine,

abnormalities, such as inadequate cardiac output, abnormal vascular resistance, and ventricular filling
pressures. In patients with severe CHF, low cardiac
output, decreased end-organ perfusion, and low blood
pressure lead to activation of various interrelated neurohormonal systems that contribute to progressive
ventricular remodeling and CHF. These systems include the sympathetic nervous system (SNS), natriuretic peptides, the renin-angiotensin-aldosterone system (RAAS), endothelin-1, adenosine, tumor necrosis
factor and interleukin-6, and arginine vasopressin
(AVP).1 Activation of these neurohormonal systems
occurs in patients with left ventricular dysfunction
without overt CHF. In the past 20 years, increased
understanding of the role of the neurohormonal systems activated by myocardial injury has resulted in the
development of new therapeutic targets in the treatment of CHF. This article discusses the neurohormonal systems that are activated in CHF, with a focus
on the role of AVP.

NEUROHORMONAL ACTIVATION IN
CONGESTIVE HEART FAILURE
Activation of vasoactive neurohormonal systems
(eg, SNS, RAAS, AVP) initially can maintain circulatory homeostasis.2 Activation of the SNS increases
cardiac contractility, heart rate, and systemic vasoconstriction, which provides an immediate means of increasing blood pressure. RAAS activation induces diFrom the Chatterjee Center for Cardiac Research, Division of Cardiology, University of California, San Francisco, San Francisco, California, USA.
Address for reprints: Kanu Chatterjee, MB, Chatterjee Center for
Cardiac Research, Division of Cardiology, University of California,
San Francisco, San Francisco, California. E-mail: chatteri@
medicine.ucsf.edu.

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2005 by Excerpta Medica Inc.

All rights reserved.

0002-9149/05/$ see front matter

doi:10.1016/j.amjcard.2005.03.003

FIGURE 1. Neurohormonal activation in congestive heart failure. (Adapted from Braunwald Atlas of Heart Diseases Online.4)

FIGURE 2. Relation between neurohormonal activation and mortality in patients with congestive heart failure. ANP atrial natriuretic
peptide. (Reprinted with permission from Circulation.8)

plasma renin activity, plasma atrial natriuretic peptide,

and AVP were compared in control subjects, patients
with left ventricular dysfunction but no overt symptoms of CHF, and patients with overt CHF.7 Patients
with left ventricular dysfunction had significantly
higher levels of neurohormonal activation than control
subjects, and those with overt CHF had the highest
levels. These data suggest that neurohormonal activation occurs in the early stages of CHF when symptoms
may not be apparent and that this activation increases
as patients progress from mildly symptomatic left
ventricular dysfunction to overt CHF.
The level of neuroendocrine activation also appears to be related to prognosis. In the Cooperative
North Scandinavian Enalapril Survival Study (CONSENSUS), levels of angiotensin, atrial natriuretic peptide, norepinephrine, and epinephrine were significantly higher among patients who died than those who
survived, regardless of whether they were randomized
to the enalapril or placebo group (Figure 2).8 In that
study, patients with CHF who had plasma norepinephrine concentrations above the median had a 6-month

survival rate of only 32% compared with a rate of

50% among patients with plasma norepinephrine
levels above the median. Similarly, baseline serum
sodium concentration, a correlate of plasma renin activity, has been found to be a significant predictor of
cardiovascular mortality in patients with CHF.7 The
link between neurohormonal activation and long-term
prognosis is also supported by studies that show
improvement in cardiac function after administration of inhibitors of neurohormonal activation in
patients with severe CHF. In -blocker trials in
chronic CHF,9 a significant reduction in morbidity
and mortality after treatment with -blockers has
been documented. -Blockade can suppress most of
the adverse hemodynamic, electrophysiologic, and
metabolic effects of the SNS in patients with CHF
and may also suppress the RAAS.2 Similarly, angiotensin-converting enzyme (ACE) inhibitors as
well as angiotensin II receptor blockers, which suppress the activity of angiotensin II, have been
shown to improve indices of left ventricular function and survival in patients with CHF.10

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FIGURE 3. Stimulation and production of arginine vasopressin. (Adapted from Braunwald Atlas of Heart Diseases Online4 and J Am
Coll Cardiol.15)

ACTIVATION OF THE RENINANGIOTENSIN-ALDOSTERONE SYSTEM

The activity of the RAAS is central to the maintenance of water and electrolyte balance and blood
volume.11 The enzyme renin is released primarily by
the juxtaglomerular cells of the kidney in response to
activity of the SNS, changes in renal perfusion pressure, reduced sodium absorption by the distal renal
tubules, or AVP release.12 Renin converts a precursor
molecule (angiotensinogen) to angiotensin I, which is
then converted by ACE to angiotensin II. Angiotensinogen II produces several physiologic effects that
are important in fluid regulation,12,13 including vasoconstriction and the stimulation of aldosterone from
the adrenal cortex, which increases sodium ion resorption by the distal renal tubules.14 Angiotensin II also
modulates the thirst center. The production of angiotensin II by renin and ACE takes place systemically in
plasma and also within specific tissues, including the
brain, heart, and blood vessels. In acute CHF, the
decrease in renal blood flow caused by progressive
CHF activates the RAAS. This increase in RAAS
activity contributes to systemic vascular resistance.15
Activity of the RAAS is blocked by ACE inhibitors,
angiotensin II receptor blockers, and aldosterone antagonists (eg, spironolactone, eplerenone) of the mineralocorticoid receptor.16

ROLE OF ARGININE VASOPRESSIN

IN CIRCULATORY HOMEOSTASIS
AVP is an antidiuretic hormone that regulates freewater absorption, body osmolality, blood volume,
blood pressure, cell contraction and proliferation, and
adrenocorticotropin secretion.3 AVP is a vasoactive
hormone that acts on the kidney to stimulate the
conservation of solute-free water. It is also a potent
vasoconstrictor. The hormone is synthesized in the
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neurosecretory cells of the paraventricular and supraoptic nuclei of the hypothalamus and is excreted by
the posterior pituitary gland (Figure 3).4,15 AVP release is stimulated by sensory cells known as osmoreceptors, which are located in the supraoptic and
paraventricular nuclei of the hypothalamus and which
respond to small changes in the osmolality of the
extracellular fluid compartment. A change in osmolality of as little as 1% stimulates the release of AVP
from the posterior pituitary gland.17 AVP is also stimulated by a decrease in circulating blood volume of
approximately 10%. A decrease in blood volume
causes unloading of pressure-sensitive baroreceptors located in the left ventricle, aortic arch, carotid
artery, and renal afferent arterioles, which triggers
AVP release. Several other stimuli for AVP release
have been identified, including norepinephrine and
angiotensin II.18
The actions of AVP are mediated by 3 types of
vasopressin receptor subtypes: V1a, V1b (also referred
to as V3 receptors), and V2 receptors.19 V1a receptor
mediated actions include vasoconstriction and myocardial hypertrophy, whereas V2-mediated actions are
related to water and sodium regulation. AVP activation of the V1b receptors regulates, in part, the release
of adrenocorticotropin hormone from the pituitary
gland (Table 1).1,20
The V1a receptor subtypes are found in the vascular
smooth muscle cells, platelets, lymphocytes and
monocytes, adrenal cortex, and myocardium.1 AVP
modulates vascular tone via V1a receptors on vascular
smooth muscle cells. Any acute reduction in arterial,
venous, or intracardiac pressure (eg, as occurs during
dehydration, severe hypotension, or shock) is sensed
by cardiopulmonary and sinoaortic baroreceptors,
which then stimulate AVP release by the pituitary

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TABLE 1 Sites of Expression and Physiologic Actions of the Vasopressin Receptor Subtypes
Vasopressin Receptor Subtype

Site of Expression

Physiologic Actions

V1a (V1-vascular)

Liver, vascular smooth muscle, platelets,

adrenal cortex, kidney, spleen, adipocytes,
reproductive organs, brain
Corticotropin cells, possibly kidney,
pancreas, adrenal medulla
Renal collecting ducts

Vasoconstriction, human platelet aggregation,

mitogenesis in vascular smooth muscle cells

V1b (V3-pituitary)
V2 (V2-renal)

Release of ACTH and -endorphin

Antidiuresis

ACTH adrenocorticotrophic hormone (corticotropin).

Adapted with permission from Am J Cardiovasc Drugs1 and Am Heart J.20

gland.20 The binding of AVP to V1a receptors results

in potent arteriolar vasoconstriction and a resultant
increase in systemic vascular resistance. In healthy
individuals, the increase in AVP does not produce
significant increases in blood pressure because AVP,
through stimulation of V2 receptors, also helps lower
heart rate and cardiac output, thereby reducing blood
pressure.20 Supraphysiologic levels of AVP also reduce cardiac contractility and coronary blood flow
through V1a-mediated coronary vasoconstriction,
whereas AVP levels in the normal physiologic range
have the opposite effect, causing small transient increases in cardiac contractility.20
The V2 receptor subtypes are found primarily in
the cells of the renal collecting duct. Binding of AVP
to V2 receptors on the cells of the renal collecting duct
results in stimulation of aquaporin-2, which is among
several water-channel renal proteins that increase the
permeability of vascular membranes to water. Insertion of these water channels into the membranes of
cells in the collecting duct of the kidney results in
increased free-water reabsorption and a decrease in
plasma osmolality.21 In healthy individuals, when the
plasma is hypertonic (ie, serum sodium exceeds 142
mmol/L [140 mEq/L]), plasma AVP concentrations
increase and urine becomes maximally concentrated
in the collecting duct of the nephron. When plasma is
hypotonic (eg, serum sodium 135 mmol/L), plasma
AVP concentrations are normally undetectable and the
urine is maximally diluted.22
V1b receptors are found in the anterior pituitary.
AVP action at V1b receptors modulates the release of
adrenocorticotropin hormone and -endorphin.22 Adrenocorticotropin hormonemediated release of aldosterone may result in increased sodium and water
reabsorption.3

ROLE OF ARGININE VASOPRESSIN

IN CONGESTIVE HEART FAILURE
Circulating AVP levels have been found to be
significantly elevated in patients with CHF compared
with healthy controls, with higher levels found in CHF
patients with significant cardiac decompensation and
hyponatremia.7,23,24 Study findings showed AVP levels in patients with advanced CHF were 9.5 pg/mL
compared with 4.7 pg/mL in healthy age-matched
controls.23 In a baseline evaluation of patients in
SOLVD, plasma AVP concentrations increased with

the severity of cardiac impairment, with the highest

levels in those with overt symptoms of CHF.7 Increases in AVP secretion occur in response to nonosmotic stimuli, such as the low arterial pressure and
effective arterial volume characteristic of CHF.3
Therefore, AVP secretion may be elevated, despite
low plasma osmolality and hypotonicity. Excess AVP
activity has several adverse effects on free-water reabsorption, cardiac contractility, and vascular tone.
The increased AVP activity in CHF may lead to an
increase in the number of aquaporin-2 channels in the
renal collecting duct.21 Increased expression of aquaporin-2 messenger RNA has been observed in rat
models of severe CHF. Rats with an elevated left
ventricular end-diastolic pressure and reduced plasma
sodium concentrations had a significant increase in
aquaporin-2 expression compared with rats with
mildly compensated CHF without elevated left ventricular end-diastolic pressure or reduced plasma sodium concentrations.25 The increased expression of
aquaporin-2 and the resultant increase in free-water
reabsorption, even under conditions of low plasma
sodium concentrations, illustrate how excess AVP activity contributes to the development of hyponatremia
and edema in CHF.
Elevations in circulating AVP levels are also associated with hemodynamic abnormalities in patients
with CHF. Intravenous infusions of AVP significantly
increased systemic vascular resistance and pulmonary
capillary wedge pressure while decreasing cardiac
output and stroke volume in CHF patients.26 The
increase in venous blood volume that results from V2
receptormediated water retention can increase preload, leading to increases in pulmonary capillary
wedge pressure and left ventricular filling pressure.
Increases in afterload as a result of V1a activation and
the subsequent arterial vasoconstriction may also contribute to the hemodynamic changes associated with
AVP release.20 These mechanisms suggest that excess
AVP activity at both V1a and V2 receptors is responsible for the adverse hemodynamic changes that occur
in CHF. Therefore, dual AVP receptor antagonists
have the potential to attenuate these adverse effects.
In addition, AVP exerts potent mitogenic and hypertrophic effects on vascular smooth muscle cells
primarily through activation of the V1a receptors,27
although there is some evidence that AVP activity at
V1b receptors can also induce cell proliferation.28 In

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vitro, AVP has been found to induce a time-dependent

and concentration-dependent increase in the secretion
of vascular endothelial growth factor in vascular
smooth muscle cells.27 Thus, the V1 receptormediated actions of AVP may contribute to the cardiac
remodeling that occurs after cardiac injury.

VASOPRESSIN BLOCKADE IN THE

TREATMENT OF CONGESTIVE HEART
FAILURE
The integral role of AVP in regulating sodium and
water reabsorption, cardiac contractility, and vascular
tone, as well as the importance of AVP activation in
the progression of CHF, make it a potential neurohormonal target in the treatment of CHF. Inhibition of
AVP activity at the V2 and/or the V1a receptors may
be useful in the treatment of patients with CHF who
have symptoms of volume overload (eg, pulmonary
edema, congestion) with hyponatremia. Several V2selective AVP antagonists and 1 V1a/V2-selective
agent have been studied in patients with CHF.
AVP antagonism at the V2 receptors appears to
produce effective and sustained reductions in congestion without worsening renal function or electrolyte
abnormalities.29 However, the clinical efficacy of V2
receptor antagonism may be offset by the activation of
V1a receptors secondary to increased plasma AVP
concentrations.30 Inhibition of V1a receptors concurrently has been shown to reduce AVP-induced protein
synthesis of cardiomyocytes in animal models,31
which may help relieve cardiomyocytic hypertrophy.
V1a receptor blockade also reduces plasma norepinephrine and angiotensin II levels as a result of improved systemic hemodynamics.10
The SNS, angiotensin II, and endothelin-1, which
are potent vasoconstrictors, also stimulate the release
of AVP independent of changes in plasma osmolality
and may contribute to the adverse effects on cardiac
function in CHF.20 In turn, AVP potentiates the hemodynamic and renal effects of angiotensin II and
norepinephrine.
A study by Clair and colleagues10 showed that
although both V1a receptor blockade and angiotensin
II receptor blockade reduced left ventricular loading
conditions, only combination blockade of both receptor types resulted in improved left ventricular function
as well as myocyte contractility. A second study by
Naitoh and associates32 was designed to evaluate the
effects of blocking both V1a and V2 receptormediated AVP activity as well as angiotensin II activity.
Also studied were the effects of conivaptan, a dual
AVP receptor antagonist, with or without addition of
the ACE inhibitor captopril in a rat model of CHF.32
The researchers found that conivaptan treatment alone
induced free-water excretion (by blocking V2-mediated AVP activity) as measured by decreases in body
weight, whereas combination treatment also significantly lowered blood pressure and decreased plasma
natriuretic peptide, left and right ventricular mass, and
lung mass. Thus, simultaneous blockade of V1a and
V2 receptors and the renin-angiotensin pathway may
12B THE AMERICAN JOURNAL OF CARDIOLOGY

be an effective approach to manage the vasoconstriction and water retention characteristic of CHF.

CONCLUSION
The low cardiac output and arterial pressure characteristic of CHF result in an abnormal and chronic
activation of neurohormonal systems. Activation of
the SNS, the renin-angiotensin pathway, and AVP
secretion results in vasoconstriction, edema, and increased blood volume. In the long term, these effects
can exacerbate left ventricular dysfunction and accelerate progression of CHF, contributing to increased
morbidity and mortality. Antagonism of AVP activity
with V1a-selective and V1a/V2-selective receptor antagonists has been shown to inhibit free-water reabsorption and improve hemodynamic parameters in patients with CHF. Other neurohormones, such as atrial
natriuretic peptide, brain natriuretic peptide, and endothelin-1, have also been evaluated as possible targets in the management of CHF.
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