Vasopressin Excess and Hyponatremia

Phuong-Chi T. Pham, MD, Phuong-Mai T. Pham, MD, and Phuong-Thu T. Pham, MD

● Hyponatremia is a common electrolyte disorder that frequently is overlooked and undertreated. Although the
pathophysiological process of hyponatremia is complex, arginine vasopressin (AVP) is a common etiologic factor.
Excess AVP release by osmotic or nonosmotic stimuli or both can lead to sodium and water imbalance. Conventional
treatment options for hyponatremia, including water restriction and administration of sodium chloride with or without
loop diuretics, do not directly address the underlying water retention induced by excess AVP in many cases.
Clinical trials showed that AVP-receptor antagonists, including lixivaptan, tolvaptan, and conivaptan, produce
aquaresis, the electrolyte-sparing excretion of free water, to correct serum sodium concentration. We review results
from recent clinical trials involving AVP-receptor antagonists in the treatment of hyponatremia associated with AVP
excess. Am J Kidney Dis 47:727-737.
© 2006 by the National Kidney Foundation, Inc.

INDEX WORDS: Hyponatremia; arginine vasopressin–receptor antagonist; syndrome of inappropriate secretion of

antidiuretic hormone; cirrhosis; congestive heart failure.

H YPONATREMIA, USUALLY defined as a

serum sodium concentration less than 136
mEq/L (⬍136 mmol/L), is a common, yet fre-
quently overlooked and undertreated, condi-
tion.1,2 Depending on the definition used, the
prevalence of hyponatremia in hospitalized pa-
tients was reported to range from 3% to 15%.3-5
Hyponatremia per se has been well documented as
a potentially life-threatening condition, as well as
an independent predictor of death in intensive care
unit and geriatric patients and patients with heart
failure, acute ST elevation myocardial infarction,
and cirrhosis.6-12
Despite the high prevalence of hyponatremia
in hospitalized patients and its association with
adverse overall outcomes, many clinicians fail to
address this condition at its early stage because
of its nonspecific symptoms and often complex
management options.
For many years, sodium replacement, rela-
tively arbitrary free-water restriction, or both,
with or without the use of loop diuretics, com-
prised the major therapeutic options for hypona-
tremia. The management of hyponatremia is a
multistep process that demands great focus from
the clinician because he or she must determine the
appropriate rate of correction according to the
chronicity of the disorder, select the best therapeu-
tic option based on the cause of hyponatremia,
predict dynamic changes in salt and water bal-
ance according to the underlying cause and ongo-
ing acute illnesses, closely monitor changes in
serum sodium levels, and adjust the patient’s
therapy or rate of sodium infusion accordingly.
To further challenge the clinician, currently avail-
able therapeutic options may be unpredictable
and prone to complications. The use of loop
diuretics and water restriction, for example, may
lead to volume depletion–induced renal failure
and unpleasant lifestyle changes, respectively.
In the treatment of significant or life-threaten-
ing hyponatremia in patients with edematous
states, another challenge arises when free-water
restriction cannot provide a timely improvement.
In such cases, a loop diuretic may be adminis-
tered, but this approach can induce profound
hypotension, hypokalemia, potentially worsen-
ing hyponatremia, and renal failure. In cases of
severe hyponatremia, sodium infusion may be
considered at the expense of exacerbating the
preexisting hypervolemic state.
Until recently, clinicians had not been able to
more directly treat one of the most common
causes of hyponatremia, namely, excessive secre-
tion of antidiuretic hormone, otherwise known as
arginine vasopressin (AVP).13,14 AVP-receptor
From the Nephrology Division, Olive View-UCLA Medi-
cal Center, Sylmar; Department of Medicine, Kidney and
Pancreas Transplantation, David Geffen School of Medicine
at UCLA, Los Angeles, CA; and Central Maine Medical
Center, Lewiston, ME.
Received September 13, 2005; accepted in revised form
January 24, 2006.
Originally published online as doi:10.1053/j.ajkd.2006.01.020
on March 23, 2006.
Support: None. Potential conflicts of interest: None.
Address reprint requests to Phuong-Chi T. Pham, MD,
Olive View-UCLA Medical Center, Department of Medicine,
Nephrology Division, 14445 Olive View Dr, 2B-182 Sylmar,
CA 91342. E-mail: pctp@ucla.edu
© 2006 by the National Kidney Foundation, Inc.
0272-6386/06/4705-0002$32.00/0
doi:10.1053/j.ajkd.2006.01.020

American Journal of Kidney Diseases, Vol 47, No 5 (May), 2006: pp 727-737 727
728
antagonists are a new class of drugs designed
specifically to promote aquaresis, the electrolyte-
sparing excretion of free water, and subsequently
increase serum sodium levels.
AVP IN WATER AND ELECTROLYTE BALANCE
Overview of AVP Release
AVP is produced predominantly in magnocel-
lular neurons in the paraventricular and supraop-
tic nuclei in the hypothalamus, subsequently
transported down axon terminals through the
supraoptic hypophyseal tract, and eventually
stored in the posterior pituitary as inactive com-
plexes with neurophysins.15,16 AVP is released
quantally by exocytosis from secretory granules
in response to osmotic and nonosmotic stimuli.15
An increase in serum osmolality leads to extra-
cellular water shift in the hypothalamus osmore-
ceptor cells. The resultant cell-volume shrinkage
or increased intracellular osmolality in osmore-
ceptor cells initiates a cascade of events leading
to enhanced AVP synthesis and release.17 Os-
motic changes that stimulate AVP release also
enhance its production. In humans, the osmotic
threshold for AVP release is approximately 280
to 290 mOsm/kg (280 to 290 mmol/kg).18 With
serum osmolality greater than the osmotic thresh-
old, AVP release is increased linearly. A 2- to
4-fold increase in AVP level may be observed
with each 1% increase in serum osmolality.19
The exact threshold for AVP release decreases
with age and during pregnancy.20,21 The slope of
the AVP response to plasma osmolality tends to
vary among individuals and may be genetically
determined; however, the slope of AVP response
within each individual may alter in response to
blood volume and pressure.22 Renal water han-
dling also is linear in response to AVP. An
increasing systemic AVP level results in a propor-
tional decrease in urine flow and increase in
urine osmolality (Fig 1).23
In patients with hyponatremia associated with
the syndrome of inappropriate antidiuretic hor-
mone release (SIADH), AVP release may follow
1 of 4 distinct patterns and not necessarily reflect
osmotic or volume changes (Fig 2).13,24 Type A,
found in 24% of patients from a small study
cohort involving 25 patients with SIADH, is
characterized by erratic fluctuations in AVP re-
lease that are independent of serum osmolality.
Type B, also known as “reset osmostat,” is a
PHAM, PHAM, AND PHAM
Fig 1. Physiological relations between plasma os-
molality, plasma AVP concentrations, urine volume,
and urine osmolality in healthy humans. To convert
AVP in pg/mL to pmol/L, multiply by 0.923; osmolality
in mOsm/kg to mmol/kg, multiply by 1. (Adapted from
Best Pract Res Clin Endocrinol Metab 17; Verbalis JG,
Disorders of body water homeostasis, pp 471-503,
200314; and Clin Endocrinol Metab 14, Robinson AG,
Disorders of antidiuretic hormone secretion, pp 55-88,
1985,23 with permission from Elsevier.)
pattern observed in approximately 36% of pa-
tients in whom a normal linear AVP response is
preserved, but is initiated at a lower osmotic
threshold than that observed in most of the popu-
lation. Type C, observed in 32% of patients, is
characterized by normal AVP release when se-
rum osmolality is normal or elevated, but AVP
release is not inhibited when serum osmolality is
low. Type D, a pattern observed in 8% of pa-
tients, is associated with normal osmoregulated
AVP release, but with an inability to dilute urine
or excrete a normal water load. This condition
could be caused by enhanced AVP sensitivity or
the presence of other antidiuretic factors.24
Nonosmotic stimuli of AVP release include
hypovolemia, a decrease in arterial blood pres-
sure, neural regulation by various neurotransmit-
ters and neuropeptides in the hypothalamus, and
various pharmacological agents. Decreases in
plasma volume exceeding 8% may exponentially
stimulate the release of AVP, presumably in part
VASOPRESSIN EXCESS AND HYPONATREMIA
A hypoglycemia.27,28
20
Plasma AVP (pmol/L)
10 B
C
LD
D
260 280 300
Plasma Osmolality (mmol/kg)
Fig 2. Four patterns of induced AVP release in
patients with SIADH. Erratic AVP release unrelated to
(A) plasma osmolality, (B) regulation of water excre-
tion around a lower “reset osmostat” value, (C) AVP
release when it cannot be “switched off” at low plasma
osmolality, and (D) normal AVP release in patients
with SIADH. The shaded area represents normal re-
sponses.13,24 To convert AVP in pg/mL to pmol/L,
multiply by 0.923; osmolality in mOsm/kg to mmol/kg,
multiply by 1. (Reprinted from Int J Biochem Cell Biol
35; Baylis PH, The syndrome of inappropriate antidi-
uretic hormone secretion, pp 1495-1499, 2003,13 with
permission from Elsevier. Copyright 1985, The Endo-
crine Society.24)
by decreasing tonic inhibitory impulses from the
left atrial and possibly pulmonary vein stretch
receptors to the hypothalamus.19 Hypotension,
particularly secondary to blood loss, serves as a
potent stimulus for AVP release through activa-
tion of carotid and aortic baroreceptors.25 In
addition, the decrease in arterial blood pressure
also may induce AVP release through activation
of the sympathetic nervous system and renin-
angiotensin-aldosterone system.26 Many neuro-
transmitters and neuropeptides in the hypothala-
mus, including acetylcholine, angiotensin II,
histamine, bradykinin, and neuropeptide Y, also
have been implicated in the stimulation of AVP
release.27,28 Other nonosmotic stimuli also may
have a role, including various pharmacological
agents, such as morphine, nicotine, chemothera-
729
peutic agents, tricyclic anticonvulsants, antide-
pressants, clofibrate, and chlorpropamide, and
such conditions as nausea, vomiting, pain, and
AVP Receptors
The neurohypophyseal hormone AVP exerts
its actions through G-protein–coupled mem-
brane receptors pharmacologically subtyped as
V1A (vascular), V2 (renal), and V3 (pituitary),
also denoted as V1B in the literature.
V1A receptors are found on vascular smooth
muscle, liver, kidneys, reproductive organs, spleen,
adrenal cortex, and platelets. The vasoconstrictive,
mitogenic, and possibly platelet aggregative and
hypercoagulable actions of AVP through V1A theo-
retically may contribute to the pathogenesis and
progression of arterial hypertension, heart fail-
ure, and atherosclerosis.29
V2 receptors are expressed primarily in baso-
lateral membranes of renal cortical and medul-
lary collecting ducts and, to a lesser extent, distal
tubules, where the antidiuretic effect of AVP is
mediated. Binding of circulating AVP to the
G-protein–coupled V2 receptor on basolateral
membranes of the principal cells in collecting
ducts induces the activation of adenylyl cyclase,
production of cyclic adenosine monophosphate,
and activation of protein kinase A. The result is
enhanced production and trafficking of the water
channel aquaporin-2 to the luminal membranes,
where water reabsorption through osmotic equili-
bration with the hypertonic medullary intersti-
tium occurs. Physiological actions of AVP through
V2 receptors have a major role in plasma tonic-
ity, volume regulation, and blood pressure main-
tenance.29,30
V3 (or V1B) receptors are found predomi-
nantly in the anterior pituitary corticotroph cells
and, to a lesser extent, the brain, kidney, pan-
creas, and adrenal medulla. Physiologically, acti-
vation of V3 receptors is associated with adreno-
corticotropic hormone and ␤-endorphin release.29
AVP and Water Homeostasis
Total-body water content in healthy individu-
als is estimated to be between 55% to 65% of
total-body weight and is dependent on various
factors, including age, sex, and fat content.22
Two thirds of the total-body water volume is
distributed in the intracellular fluid, and one
730
third, in the extracellular fluid. Two thirds of the
extracellular fluid volume is in interstitial tis-
sues, and one third is in the intravascular space,
of which 85% occupies the venous circulation
and 15% occupies the arterial circulation.22
Maintenance of these intricate water partitions
involves the movement of osmotically active
solutes and passive water diffusion between the
intracellular and extracellular fluid. In normal
human physiological states, sodium, potassium,
and glucose are the major osmotically active or
effective solutes. Intercompartmental movement
of any of these osmotically effective solutes
necessitates either an active/facilitated reverse-
transport process or the obligatory parallel diffu-
sion of water across the 2 compartments to main-
tain equivalent osmotic pressures.31 Solutes, such
as urea, are considered ineffective because they
can move freely across cell membranes bidirec-
tionally without necessitating any other process
to maintain the osmolality of either compart-
ment.
Whereas intracellular water homeostasis is
dependent on osmotically active solutes, total-
body water balance is determined and main-
tained predominantly by the thirst center and
renal water excretion.14 Thirst, a physiological
response to increase free-water uptake, may be
stimulated by hyperosmolality, profound volume
contraction, and gastric salt loading.32 With expo-
sure to hyperosmolality, osmoreceptor cells in
the subfornical organ and organum vasculosum
laminae terminalis activate neurons projecting to
the paraventricular and supraoptic nuclei in the
hypothalamus to stimulate thirst. In addition,
profound volume contraction caused by a signifi-
cant decrease in arterial blood pressure or vol-
ume depletion may induce an increase in levels
of intracerebroventricular angiotensin II, a strong
dipsogenic factor.33 Finally, thirst may be stimu-
lated by gastric sodium loading, presumably
through sodium receptors in the abdominal vis-
cera (such as hepatic portal osmoreceptors), inde-
pendent of any increase in systemic plasma osmo-
lality.34
Renal free-water excretion is dependent on the
integrity of nephron-diluting segments, mainte-
nance of a hypertonic medullary interstitium,
and intact AVP activity at the collecting ducts.
For renal water excretion to occur, free water
first is produced in the nephron-diluting seg-
PHAM, PHAM, AND PHAM
ment, the thick ascending loop of Henle, by salt
extractions from the lumen through the sodium-
potassium-2 chloride cotransporter. Intraluminal
free water is produced with this process because
water cannot diffuse across the luminal surface
in parallel with salt uptake due to the unique
water-impermeable characteristic of this diluting
segment. Reabsorption of salt without water con-
tinues to occur in the distal convoluted tubule,
where dilution of urine is maximized. While free
water is produced within the lumen, salt uptake
simultaneously enhances and maintains the greater
tonicity of the medullary interstitium. Subse-
quently, the free water formed may be either reab-
sorbed or excreted into urine at the collecting ducts,
as dictated by AVP. In the presence of AVP and
an intact hypertonic medullary interstitium, AVP,
through V2 receptors, upregulates the expression
and trafficking of aquaporin-2 to the luminal side
of the collecting tubules and allows water to be
reabsorbed efficiently down a more tonic medul-
lary milieu. AVP-facilitated free-water reabsorp-
tion decreases urine volume and increases urine
concentration.14 In the absence of AVP, the free
water produced from the diluting segment is
excreted and is reflected clinically as high urine
output with low osmolality.
AVP Excess and Hyponatremia
Although AVP is the major regulatory factor in
the maintenance of total-body water, its exces-
sive production and release can result in pro-
found water retention and hyponatremia.13 In
hypovolemia, volume loss or decrease in arterial
blood pressure promotes AVP release appropri-
ately to enhance both thirst and renal water
retention. Hyponatremia occurs when free water
is replaced in excess of salt.
In hypervolemia caused by congestive heart
failure (CHF), blood volume is expanded, but
cannot be translocated effectively from the ve-
nous to arterial circulation to support adequate
cardiac output. As a result, effective arterial
volume, pressure, or both are decreased in a
manner similar to that in a hypovolemic state. To
expand the effective arterial volume, AVP release
is enhanced to increase thirst, water intake, and
renal water retention.35 With normal renal perfu-
sion, as much as 70% of glomerular filtrate is
reabsorbed proximally, leaving the remaining
volume to reach the loop of Henle, where the
VASOPRESSIN EXCESS AND HYPONATREMIA
upper limit on urine flow and output is deter-
mined. As renal perfusion decreases in associa-
tion with low cardiac output, glomerular filtrate
volume decreases, increased proximal filtrate re-
absorption occurs, and thus a smaller remaining
filtrate volume is delivered to the diluting seg-
ment for free-water production and subsequent
excretion. Any free water that can be produced in
the subsequent diluting segment will be reab-
sorbed avidly in the collecting ducts through the
action of AVP on V2 receptors. The severe de-
crease in urine volume (salt and water retention)
and free-water clearance (FWC; water retention)
induced by the decreased glomerular filtrate vol-
ume and secondary excessive AVP release per-
petuate the edematous state, while exacerbating
hyponatremia. In addition to volume expansion
and hyponatremia, the elevated AVP levels in
patients with CHF secondarily may increase sys-
temic vascular resistance through V1A vasocon-
strictive activity and decrease cardiac output.30
Accordingly, the excess AVP-induced V1A vaso-
constrictive effect theoretically may be harmful
to some patients with CHF.
As in patients with CHF, those with cirrhosis
or nephrosis who have poor arterial pressure
because of peripheral vasodilation, low intravas-
cular oncotic pressure, or both may present with
decreased urine output, enhanced free-water re-
absorption, and significant hyponatremia caused
by poor renal perfusion and enhanced AVP re-
lease.21,36 Of interest, prostaglandin synthesis
inhibitors, such as nonsteroidal anti-inflamma-
tory drugs, were observed to potentiate the anti-
diuretic effect of AVP, presumably through stimu-
lation of AVP-induced generation of cyclic
adenosine monophosphate, and thereby may ex-
acerbate free-water retention and hyponatremia
in patients with preexisting hypervolemia and
low intravascular effective volume or pres-
sure.37-39
Euvolemic hyponatremia accounts for 60%
of all forms of chronic hyponatremia, of which
SIADH, a disorder in which AVP release is
independent of volume, blood pressure, and os-
motic control, predominates.13,40 SIADH is de-
fined by 5 major criteria: (1) hypotonic hypona-
tremia; (2) euvolemia; (3) inappropriately high
urine osmolality (ie, ⬎70 to 100 mOsm/kg [⬎70
to 100 mmol/kg]) in the presence of hyponatre-
mia; (4) normal renal, thyroid, and adrenal func-
731
tion; and (5) high renal sodium excretion (ie,
⬎40 mEq/L [⬎40 mmol/L]).41
The major categories of illnesses associated
with SIADH include neoplasm, neurological dis-
ease or trauma, pulmonary disorders, and various
stress states, such as nausea, vomiting, pain, and
anxiety. In addition, SIADH may be caused by a
number of medications, particularly tricyclic an-
tidepressants and anticonvulsants.1,13,40,42
Impact of Age on AVP
The pathophysiological processes of age-
related disturbances in water homeostasis and
the resultant hyponatremia are complex and most
likely multifactorial. In older individuals, total-
body water content is as much as 20% less than
that in younger individuals.43 A change in salt
and water balance therefore may result in a more
pronounced effect on body fluid osmolality and
various salt concentrations. The development of
hyponatremia specifically may be attributed to
the decreased capacity for free-water handling
because of various factors, including a decrease
in glomerular filtration rate, decrease in solute
load caused by poor nutritional intake, and en-
hanced osmotic and nonosmotic AVP sensitiv-
ity.20,44 In addition, a blunted aldosterone re-
sponse was observed in healthy elderly
individuals.45 In patients in whom water balance
is simultaneously altered, hyponatremia may oc-
cur.
PHARMACOLOGICAL OPTIONS
FOR HYPONATREMIA
Current treatment options for patients with
hyponatremia, including sodium supplementa-
tion, water restriction, and concomitant diuretic
therapy, usually are effective, but not without
limitations. Although sodium supplementation
through saline infusion is effective in patients
with hypovolemic hyponatremia, its use may
be problematic in patients with hypervolemic
hyponatremia because of the acute volume
expansion. Water restriction with or without
concomitant diuretic administration in patients
with euvolemic and hypervolemic hyponatremia
may lead to a slow response, less predictable
outcomes, and, sometimes, serious complica-
tions. For example, water restriction in patients
with underlying malignancy or various other
SIADH-associated conditions may lead to anxi-
732 PHAM, PHAM, AND PHAM

Table 1. Overview of AVP-Receptor Antagonists ics are associated with neurohormonal activation
involving the renin-angiotensin-aldosterone sys-
Receptor Disorders Studied in Clinical
Agent Target Trials tem and sympathetic nervous system and may
be particularly harmful to elderly and cardiac
Lixivaptan V2 CHF,49 SIADH,49 patients.31
cirrhosis48,49
Tolvaptan V2 CHF (NYHA class I-IV),50
(LVEF ⬍ 40%)51 Overview of AVP-Receptor Antagonists
Conivaptan V1A/V2 CHF NYHA class III and IV35 The role of AVP-receptor antagonists in the
Euvolemic or hypervolemic
treatment of patients with hyponatremia was
hyponatremia52,54,55
evaluated in clinical trials. This novel class of
Abbreviations: NYHA, New York Heart Association; agents was shown to promote aquaresis, the
LVEF, left ventricular ejection fraction. electrolyte-sparing excretion of free water.47 Cur-
rently, AVP-receptor antagonists directed at V2 re-
ety, malnourishment, and symptomatic volume ceptors (lixivaptan and tolvaptan) are in develop-
depletion. ment for clinical use in patients with euvolemic and
In cases of prolonged hyponatremia in which hypervolemic hyponatremia. Conivaptan, a V1A/V2-
fluid restriction is not tolerated, demeclocycline, receptor antagonist, recently was approved in the
a tetracycline antibiotic, may be an option. Nev- United States for use in hospitalized patients
ertheless, the use of demeclocycline is limited by with euvolemic hyponatremia (Tables 1 and 2).
poor results; troublesome adverse events, includ- Lixivaptan. The efficacy and tolerability of
ing azotemia, photosensitivity, and nausea; and lixivaptan (VPA-985), an oral V2-receptor antag-
contraindications in patients with cirrhosis or onist, was evaluated in patients with hyponatre-
renal failure.22,46 Conventional diuretics are ef- mia secondary to CHF, SIADH, and cirrhosis
fective in decreasing volume overload, but may with ascites. In a randomized, double-blind, mul-
lead to excessive salt and water excretion and ticenter trial, 60 patients with dilutional hypona-
result in or worsen effective arterial volume tremia (serum sodium levels between 115 and
depletion and hyponatremia. In addition, diuret- 132 mEq/L [115 and 132 mmol/L]) secondary to

Table 2. Effects of AVP-Receptor Antagonists in Patients With AVP Excess

Agent/Study No. of Urine Urine Serum Body Blood Heart Renal

Duration Reference Patients Output* FWC† Osmolality Sodium Weight Pressure Rate Thirst Function

Lixivaptan
7d Gerbes et al48‡ 60 1 1 2 1 2 NC NC 1 ND
Wong et al49§ 44 1 1 2 1 2 NC NC 1 NC
Tolvaptan
25 d Gheorghiade et al50储 254 1 NA 2 1 2 NC NC 1 NC
60 d Gheorghiade et al51¶ 319 1 NA NA 1 2 NC NC 1 NC
Conivaptan
1d Udelson et al35# 142 1 NA 2 1 NA NC NC NA NA
4d Verbalis et al52¶ 84 NA 1 NA 1 NA NA NA NA NA
5d Ghali et al54¶ 74 NA 1 NA 1 NA NA NA NA NA
Gross et al55¶ 83 NA 1 NA 1 NA NA NA NA NA

Abbreviations: 1, increase; 2, decrease (see text for actual statistical significance); NC, no change from baseline in all
groups; ND, no difference— glomerular filtration rate decreased approximately 10% from baseline in all active-treatment
groups and the placebo group, but the change was similar in all groups; NA, data not available.
*Urine output or net fluid balance (defined as urine output ⫺ fluid intake).
†In the 4- and 5-day conivaptan studies, effective water clearance was measured instead of FWC.
‡One liter per day fluid restriction.
§Fluid restriction of 1.5 L/d, but may be higher for those with high urine output (⬎3 L/d).
储No fluid restriction.
¶Freedom of fluid access not stated by investigators.
#Fluid restriction of 250 mL/2 h from time of insertion of pulmonary artery catheter throughout the treatment period.
VASOPRESSIN EXCESS AND HYPONATREMIA
cirrhosis were randomly assigned to administra-
tion of placebo (n ⫽ 20); lixivaptan, 100 mg/d
(n ⫽ 22); or lixivaptan, 200 mg/d (n ⫽ 18).48
Treatment was continued for as long as 7 days or
until the primary end point of normalization of
serum sodium levels (ⱖ136 mEq/L [ⱖ136 mmol/
L]) was reached. All patients continued to take
their usual medications throughout the study
period. Normalization of serum sodium levels
was achieved in 27% and 50% of patients admin-
istered lixivaptan, 100 and 200 mg/d, but in no
patient in the placebo group, respectively. Accord-
ingly, lixivaptan increased serum sodium levels
from baseline more than placebo at study end
(128.3 ⫾ 4.1 to 130.4 ⫾ 6.5 mEq/L [128.3 ⫾ 4.1
to 130.4 ⫾ 6.5 mmol/L] in patients administered
100 mg/d [P ⫽ 0.053], 126.4 ⫾ 4.4 to 132.3 ⫾
6.9 mEq/L [126.4 ⫾ 4.4 to 132.3 ⫾ 6.9 mmol/L]
in those administered 200 mg/d [P ⬍ 0.001], and
127.3 ⫾ 3.0 to 127.7 ⫾ 4.0 mEq/L [127.3 ⫾ 3.0
to 127.7 ⫾ 4.0 mmol/L] in those administered
placebo). Mean changes in serum sodium levels
per day were 0.8 ⫾ 0.4/L/d, 1.8 ⫾ 0.5/L/d, and
0.1 ⫾ 0.2/L/d in the 100-mg/d, 200-mg/d, and
placebo groups, respectively. The maximum in-
crease in serum sodium levels with either dose of
lixivaptan was 7/L/d. Both doses of lixivaptan
increased FWC significantly more than placebo
(lixivaptan, 100 mg/d, 0.3 ⫾ 0.3 mL/min [P ⬍
0.01]; lixivaptan, 200 mg/d, 1.2 ⫾ 0.4 mL/min
[P ⬍ 0.001]; and placebo, ⫺0.7 ⫾ 0.2 mL/min).
By the end of the study, glomerular filtration
rate decreased by approximately 10% in both
lixivaptan groups and the placebo group. Treat-
ment with lixivaptan did not have an additional
negative impact on renal function. Use of either
dose of lixivaptan was associated with increased
thirst compared with placebo.48
In another multicenter, randomized, placebo-
controlled trial, lixivaptan was evaluated for its
efficacy and safety in the correction of hyponatre-
mia. The study involved 44 patients with hypona-
tremia (serum sodium ⬍130 mEq/L [⬍130 mmol/
L]) secondary to CHF (n ⫽ 6), SIADH (n ⫽ 5),
and cirrhosis with ascites (n ⫽ 33).49 Patients
were randomly assigned to administration of
placebo (n ⫽ 11) or oral lixivaptan at 25 mg
twice daily (n ⫽ 12), 125 mg twice daily (n ⫽ 11),
or 250 mg twice daily (n ⫽ 10) during a 7-day
period. All patients continued to take their usual
medications, including diuretics, and followed
733
dietary sodium restriction determined by each
investigator and fluid restriction (1.5 L/d). The
last condition was not strictly enforced because
patients with urine output greater than 3 L/d were
allowed to have greater fluid intake. The actual
amount of fluid intake in each group was not
reported in the study. Nevertheless, lixivaptan
increased net fluid volume (urine output ⫺ fluid
intake) and FWC significantly more than placebo
(P ⬍ 0.05), in accordance with the dosage admin-
istered. At the end of the 7-day study, FWC was
⫺0.3 ⫾ 0.2 mL/min in patients administered
lixivaptan, 25 mg (P ⫽ not significant), 0.5 ⫾
0.2 mL/min in those administered 125 mg (P ⬍
0.01), 0.3 ⫾ 0.3 mL/min in those administered
250 mg (P ⬍ 0.01), and ⫺0.7 ⫾ 0.3 mL/min in
patients administered placebo.
In a separate analysis of patients who had
cirrhosis, serum sodium levels increased signifi-
cantly more between day 1 and the end of the
study in patients administered lixivaptan, 25 mg
(126 ⫾ 1 mEq/L on day 1 versus 129 ⫾ 2 mEq/L
on day 7 [126 ⫾ 1 versus 129 ⫾ 2 mmol/L]; P ⬍
0.05), 125 mg (122 ⫾ 2 versus 127 ⫾ 3 mEq/L,
respectively; P ⬍ 0.05), or 250 mg (125 ⫾ 1
versus 132 ⫾ 1 mEq/L; P ⬍ 0.003) than in those
administered placebo (127 ⫾ 1 versus 126 ⫾ 1
mEq/L; P ⬍ 0.05). Accordingly, there was a
significant decrease in urine osmolality in pa-
tients administered lixivaptan.
Serum creatinine levels did not change signifi-
cantly in any of the patient groups throughout the
study period. However, the group administered
the highest dose of lixivaptan (250 mg twice
daily) consistently reported increased thirst and
had significantly increased thirst scores. With
respect to the vasoactive hormonal profile, includ-
ing vasopressin, norepinephrine, plasma renin
activity, and aldosterone, lixivaptan only in-
creased AVP levels significantly by study end.49
Tolvaptan. The efficacy and tolerability of
tolvaptan (OPC-41061), an oral V2-receptor an-
tagonist, were evaluated in patients with CHF. In
a randomized double-blind trial designed to inves-
tigate the effects of 3 doses of tolvaptan, 254
patients with a “diagnosis of CHF” were ran-
domly assigned to administration of tolvaptan,
30 mg/d (n ⫽ 64), 45 mg/d (n ⫽ 64), and 60
mg/d (n ⫽ 63) or placebo (n ⫽ 63) in combina-
tion with standard furosemide therapy for 25
days.50 Tolvaptan was effective in increasing
734
urine output, decreasing total-body weight, and
improving edema despite no fluid restriction.
Although fluid intake increased in patients admin-
istered tolvaptan, 30, 45, or 60 mg, mean net
fluid loss (urine output ⫺ fluid intake) was signifi-
cantly greater with each of these tolvaptan doses
(1,337, 988, and 1,286 mL/d, respectively) than
with placebo (98 mL/d; P ⬍ 0.05). Mean change
in urine osmolality from baseline to end of study
also was significantly less with each tolvaptan
dose (30 mg, 7.13 ⫾ 164.49 mOsm/kg [7.13 ⫾
164.49 mmol/kg]; 45 mg, ⫺19.38 ⫾ 157.03
mOsm/kg; and 60 mg, ⫺49.51 ⫾ 152.98 mOsm/
kg) than with placebo (168.55 ⫾ 204.2 mOsm/
kg; P ⬍ 0.05).
Of 254 patients, 28% had hyponatremia (se-
rum sodium ⬍136 mEq/L [⬍136 mmol/L]) at
baseline. In this subset, significantly more pa-
tients showed normalized serum sodium levels at
day 1 in the tolvaptan-treated group compared
with placebo (80% versus 40%, respectively;
P ⬍ 0.05). Correction of hyponatremia was
maintained throughout the study period (82%
versus 40%; P ⬍ 0.05).
Serum creatinine levels did not change in any
group by the end of the study. Thirst was re-
ported at a significantly greater frequency in
tolvaptan-treated groups compared with placebo
(31.3%, 40.3%, and 24.6% in the 30-, 45-, and
60-mg groups compared with 4.8% in the pla-
cebo group). Nevertheless, only 2 patients from
the 60-mg group were reported to discontinue
the medication because of polyuria. No signifi-
cant changes in heart rate, blood pressure, serum
potassium level, or renal function were ob-
served.50
In the phase 2 clinical trial Acute and Chronic
Therapeutic Impact of a Vasopressin Antagonist
in Congestive Heart Failure, 319 patients hospi-
talized with CHF and a left ventricular ejection
fraction less than 40% were assigned to placebo
(n ⫽ 80) or tolvaptan, 30 mg/d (n ⫽ 78), 60 mg/d
(n ⫽ 84), or 90 mg/d (n ⫽ 77), plus routine
therapy, including diuretics, for as long as 60
days.51 Median body-weight decrease from base-
line associated with placebo (⫺1.90 kg; range,
⫺4.20 to ⫺0.50 kg) was significantly smaller
than that with tolvaptan, 30 mg (⫺3.30 kg;
range,⫺7.30 to ⫺1.35; P ⫽ 0.006), 60 mg (⫺2.80
kg; range, ⫺5.90 to ⫺1.80; P ⫽ 0.002), and
90 mg (⫺3.20 kg; range, ⫺5.80 to ⫺1.60; P ⫽ 0.06).
PHAM, PHAM, AND PHAM
Mean urine output at 24 hours also was less with
placebo (2,296.5 ⫾ 1,134.1 mL) than with each
dose of tolvaptan (30 mg, 4,056.2 ⫾ 2,310.2 mL;
P ⫽ 0.02; 60 mg, 4,175.2 ⫾ 2,695.4 mL; P ⬍
0.001; and 90 mg, 4,127.3 ⫾ 2,050.8 mL; P ⬍
0.001). This effect was maintained throughout
the hospitalization period.
Patients recruited into the study had only mild
hyponatremia (average serum sodium level,
138.65 mEq/L [138.65 mmol/L]). Nonetheless,
at 1 day after randomization, there was a trend
for a slight increase in mean serum sodium levels
from baseline in patients administered tolvaptan,
30 mg (2.77 ⫾ 3.56 mEq/L), 60 mg (3.38 ⫾ 4.84
mEq/L), and 90 mg (3.50 ⫾ 3.63 mEq/L), but
a decrease in patients administered placebo
(⫺0.20 ⫾ 3.12 mEq/L). In addition, the 68 patients
with hyponatremia (serum sodium level ⬍136
mEq/L) at baseline were reported to have a rapid
improvement and often normalization of serum
sodium levels. The improvement in serum so-
dium levels was maintained throughout the study
in all treated groups.
As in the previous clinical trial, no significant
changes in heart rate, blood pressure, serum
potassium level, or renal function were observed.
Thirst was a common adverse event, observed in
11.9% of patients administered tolvaptan versus
1.3% of the placebo group. Although there was
no difference between the tolvaptan and placebo
groups in the rate of worsening heart failure at 60
days, post hoc analysis showed lower mortality
for patients with renal dysfunction or severe
systemic congestion (defined as dyspnea, jugular
venous distension, and edema) administered
tolvaptan.51
Conivaptan. The acute efficacy of intrave-
nous conivaptan, the first AVP-receptor antago-
nist with activity at both the V1A and V2 recep-
tors, was evaluated in patients with New York
Heart Association classes III and IV heart failure.
In this randomized double-blind study, 142 pa-
tients were assigned to administration of a single
intravenous dose of conivaptan, 10 mg (n ⫽ 37),
20 mg (n ⫽ 32), or 40 mg (n ⫽ 35), or placebo
(n ⫽ 38).35 During the 4-hour period immedi-
ately after drug infusion, urine output was signifi-
cantly greater in patients administered conivaptan
(10 mg, 68.9 ⫾ 17.4 mL/h; 20 mg, 152.2 ⫾ 19.2
mL/h; 40 mg, 176.2 ⫾ 17.8 mL/h) than those
administered placebo (11.2 ⫾ 17.3 mL/h; P ⬍
VASOPRESSIN EXCESS AND HYPONATREMIA
0.001 versus all conivaptan doses). The in-
crease in urine output was associated with a
decrease in urine osmolality: ⫺249.8 ⫾ 26.9
mOsm/kg (⫺249.8 ⫾ 26.9 mmol/kg) with
conivaptan, 10 mg; ⫺279.6 ⫾ 31.7 mOsm/kg
with conivaptan, 20 mg; ⫺319.3 ⫾ 25.8
mOsm/kg with conivaptan, 40 mg; and ⫺2.2 ⫾
27.9 mOsm/kg with placebo (P ⫽ 0.0001 versus
all conivaptan doses). Serum sodium concentra-
tions were not significantly different from pla-
cebo at 4 hours. Nevertheless, there was a trend
for greater serum sodium level increases in the
conivaptan groups (10 mg, 0.5 ⫾ 0.5 mEq/L
[0.5 ⫾ 0.5 mmol/L]; 20 mg, 0.8 ⫾ 0.7 mEq/L;
and 40 mg, 1.5 ⫾ 0.4 mEq/L) compared with the
placebo group (0.4 ⫾ 0.7 mEq/L).
In a randomized, double-blind, multicenter,
placebo-controlled, parallel-group study, intrave-
nous conivaptan (a 20-mg loading dose followed
by continuous infusion of 40 [n ⫽ 29] or 80 mg/d
[n ⫽ 26] for 4 days) was compared with placebo
(n ⫽ 29) in patients with euvolemic or hypervo-
lemic hyponatremia (serum sodium level, 115 to
⬍130 mEq/L [115 to ⬍130 mmol/L]).52 The
primary efficacy measure was change in serum
sodium level from baseline to end of study,
measured by the area under the sodium level–
time curve. Secondary measures included
change in serum sodium level from baseline at
day 4, time from first dose to achieve a 4-mEq/L
or greater change in serum sodium level, num-
ber of patients achieving a 6-mEq/L or greater
change in sodium level or normal sodium
level, and effective water clearance (defined as
electrolyte-free water clearance as opposed to
solute-free water clearance for FWC—the
former was suggested to more accurately ex-
plain the “physiology of the renal role in the
variations in natremia”).53 Changes in serum
sodium levels from baseline to end of study,
measured by the area under the sodium level–
time curve, were significantly greater in pa-
tients administered conivaptan than those ad-
ministered placebo. Serum sodium levels
increased significantly more with both
conivaptan doses (6.8 and 9.0 mEq/L, respec-
tively; P ⬍ 0.001) than placebo (2.0 mEq/L).
Mean time required for serum sodium level to
reach 4 mEq/L or greater was not “estimable” in
the placebo group, but was 23.7 hours in the
group administered conivaptan, 40 mg/d, and
735
23.4 hours in the group administered 80 mg/d. In
addition, a greater percentage of patients admin-
istered conivaptan, 40 mg/d (69%) or 80 mg/d
(88%), than those administered placebo (21%;
P ⬍ 0.01 and P ⬍ 0.001, respectively) showed
an increase in serum sodium levels to 6 mEq/L or
greater or normalized serum sodium level at
study end. At day 1, effective water clearance
also was significantly greater in patients adminis-
tered conivaptan, 40 mg/d (1,984 ⫾ 1,559 mL)
or 80 mg/d (1,759 ⫾ 1,748 mL), than in those
administered placebo (⫺332 ⫾ 434 mL; P ⬍
0.05 versus both doses).52
In 2 similar studies, 83 patients with eu-
volemic hyponatremia and 74 patients with hyper-
volemic hyponatremia were administered oral
conivaptan, 40 or 80 mg/d, or placebo for 5 days.
As in the other studies, conivaptan increased
serum sodium levels and effective water clear-
ance significantly more than placebo.54,55
Because in vivo and in vitro studies indicated
that conivaptan is a substrate and potent inhibitor
of cytochrome P-450 3A4, the liver and small-
intestine isoenzyme responsible for drug metab-
olism, only the intravenous formulation of
conivaptan was developed and approved in the
United States for the treatment of patients with
euvolemic hyponatremia.
CONCLUSION
Hyponatremia is a common and potentially
serious condition most often caused by excessive
AVP secretion. With the exception of hypovole-
mic hyponatremia, for which saline infusion is
appropriate and the outcome generally is easily
predictable, current therapeutic options for pa-
tients with euvolemic and hypervolemic hypona-
tremia may result in unpredictable or undesirable
outcomes. Because excessive AVP release is the
key etiologic factor in perpetuating the hypona-
tremia observed in patients with such common
clinical conditions as CHF, cirrhosis, nephrosis,
and SIADH, therapy that directly antagonizes
AVP receptors potentially may offer better out-
comes. Current AVP-receptor antagonists were
shown to increase serum sodium levels effec-
tively at a safe dose-dependent rate and may
become a promising therapeutic option in the
treatment of patients with euvolemic and hyper-
volemic hyponatremia.47
736
REFERENCES
1. Adrogué HJ, Madias NE: Hyponatremia. N Engl J Med
342:1581-1589, 2000
2. Saeed BO, Beaumont D, Handley GH, Weaver JU:
Severe hyponatraemia: Investigation and management in a
district general hospital. J Clin Pathol 55:893-896, 2002
3. Gill G, Leese G: Hyponatremia: Biochemical and
clinical perspectives. Postgrad Med J 74:516-523, 1998
4. Tierney WM, Martin DK, Greenlee MC, Zerbe RL,
McDonald CJ: The prognosis of hyponatremia at hospital
admission. J Gen Intern Med 1:380-385, 1986
5. Anderson RJ, Chung HM, Kluge R, Schrier RW:
Hyponatremia: A prospective analysis of its epidemiology
and the pathogenetic role of vasopressin. Ann Intern Med
102:164-168, 1985
6. Lee CT, Guo HR, Chen JB: Hyponatremia in the
emergency department. Am J Emerg Med 18:264-268, 2000
7. Bennani SL, Abouqal R, Zeggwagh AA, et al: [Inci-
dence, causes and prognostic factors of hyponatremia in
intensive care]. Rev Med Interne 24:224-229, 2003
8. Terzian C, Frye EB, Piotrowski ZH: Admission hypo-
natremia in the elderly: Factors influencing prognosis. J Gen
Intern Med 9:89-91, 1994
9. Arieff AI, Llach F, Massry SG: Neurological manifes-
tations and morbidity of hyponatremia: Correlation with
brain water and electrolytes. Medicine (Baltimore) 55:121-
129, 1976
10. Goldberg A, Hammerman H, Petcherski S, et al:
Prognostic importance of hyponatremia in acute ST-eleva-
tion myocardial infarction. Am J Med 117:242-248, 2004
11. Ruf AE, Kremers WK, Chavez LL, Descalzi VI,
Podesta LG, Villamil FG: Addition of serum sodium into the
MELD score predicts waiting list mortality better than
MELD alone. Liver Transpl 11:336-343, 2005
12. Borroni G, Maggi A, Sangiovanni A, Cazzaniga M,
Salerno F: Clinical relevance of hyponatraemia for the
hospital outcome of cirrhotic patients. Dig Liver Dis 32:605-
610, 2000
13. Baylis PH: The syndrome of inappropriate antidi-
uretic hormone secretion. Int J Biochem Cell Biol 35:1495-
1499, 2003
14. Verbalis JG: Disorders of body water homeostasis.
Best Pract Res Clin Endocrinol Metab 17:471-503, 2003
15. Davison JM, Vallotton MB, Lindheimer MD: Plasma
osmolality and urinary concentration and dilution during
and after pregnancy: Evidence that lateral recumbency inhib-
its maximal urinary concentrating ability. Br J Obstet Gynae-
col 88:472-479, 1981
16. Ishikawa SE, Schrier RW: Pathophysiological roles
of arginine vasopressin and aquaporin-2 in impaired water
excretion. Clin Endocrinol 58:1-17, 2003
17. Robinson AG, Roberts MM, Evron WA, Verbalis JG,
Sherman TG: Hyponatremia in rats induces downregulation
of vasopressin synthesis. J Clin Invest 86:1023-1029, 1990
18. Robertson GL: Physiology of ADH secretion. Kidney
Int Suppl 21:S20-S26, 1987
19. Dunn FL, Brennan TJ, Nelson AE, Robertson GL:
The role of blood osmolality and volume in regulating
vasopressin secretion in the rat. J Clin Invest 52:3212-3219,
1973
PHAM, PHAM, AND PHAM
20. Luckey AE, Parsa CJ: Fluid and electrolytes in the
aged. Arch Surg 138:1055-1060, 2003
21. Andreoli TE: Water: Normal balance, hyponatremia,
and hypernatremia. Ren Fail 22:711-735, 2000
22. Fried LF, Palevsky PM: Hyponatremia and hypernatre-
mia. Med Clin North Am 81:585-609, 1997
23. Robinson AG: Disorders of antidiuretic hormone se-
cretion. Clin Endocrinol Metab 14:55-88, 1985
24. Robertson GL, Shelton RL, Athar S: The osmoregula-
tion of vasopressin. Kidney Int 10:25-37, 1976
25. Baylis PH: Osmoregulation and control of vasopres-
sin secretion in healthy humans. Am J Physiol 253:R671-
R678, 1987
26. Goldsmith SR, Francis GS, Cowley AW Jr, Golden-
berg IF, Cohn JN: Hemodynamic effects of infused arginine
vasopressin in congestive heart failure. J Am Coll Cardiol
8:779-783, 1986
27. Baylis PH: Regulation of vasopressin secretion. Bail-
lieres Clin Endocrinol Metab 3:313-330, 1989
28. Sladek CD: Regulation of vasopressin release by
neurotransmitters, neuropeptides and osmotic stimuli. Prog
Brain Res 60:71-90, 1983
29. Thibonnier M, Coles P, Thibonnier A, Shoham M:
The basic and clinical pharmacology of nonpeptide vasopres-
sin receptor antagonists. Annu Rev Pharmacol Toxicol 41:
175-202, 2001
30. Lee CR, Watkins ML, Patterson JH, et al: Vasopres-
sin: A new target for the treatment of heart failure. Am
Heart J 146:9-18, 2003
31. Costello-Boerrigter LC, Boerrigter G, Burnett JC Jr:
Revisiting salt and water retention: New diuretics, aquaret-
ics, and natriuretics. Med Clin North Am 87:475-491, 2003
32. Skott O: Body sodium and volume homeostasis. Am J
Physiol Regul Integr Comp Physiol 285:R14-R18, 2003
33. Thunhorst RL, Johnson AK: Effects of hypotension
and fluid depletion on central angiotensin-induced thirst and
salt appetite. Am J Physiol Regul Integr Comp Physiol
281:R1726-R1733, 2001
34. Striker EM, Callahan JB, Huang W, Sved AF: Early
osmoregulatory stimulation of neurohypophysial hormone
secretion and thirst after gastric NaCl loads. Am J Physiol
Regul Integr Comp Physiol 282:R1710-R1717, 2002
35. Udelson JE, Smith WB, Hendrix GH, et al: Acute
hemodynamic effects of conivaptan, a dual V1A and V2 vaso-
pressin receptor antagonist, in patients with advanced heart
failure. Circulation 104:2417-2423, 2001
36. Cardenas A, Arroyo V: Mechanisms of water and
sodium retention in cirrhosis and the pathogenesis of ascites.
Best Pract Res Clin Endocrinol Metab 17:607-622, 2003
37. Gines P, Berl T, Bernardi M, et al: Hyponatremia in
cirrhosis: From pathogenesis to treatment. Hepatology 28:
851-864, 1998
38. Anderson RJ, Berl T, McDonald KD, Schrier RW:
Evidence for an in vivo antagonism between vasopressin
and prostaglandin in the mammalian kidney. J Clin Invest
56:420-426, 1975
39. Breyer MD, Jacobson HR, Hebert RL: Cellular mecha-
nisms of prostaglandin E2 and vasopressin interactions in
the collecting duct. Kidney Int 38:618-624, 1990
VASOPRESSIN EXCESS AND HYPONATREMIA
40. Zerbe R, Stropes L, Robertson G: Vasopressin func-
tion in the syndrome of inappropriate antidiuresis. Annu Rev
Med 31:315-327, 1980
41. Bartter FC, Schwartz WB: The syndrome of inappro-
priate secretion of antidiuretic hormone. Am J Med 42:790-
806, 1967
42. Fraser CL, Arieff AI: Epidemiology, pathophysiol-
ogy, and management of hyponatremic encephalopathy. Am J
Med 102:67-77, 1997
43. Beck LH: The aging kidney. Defending a delicate
balance of fluid and electrolytes. Geriatrics 55:26-28, 31-22,
2000
44. Phillips PA, Rolls BJ, Ledingham JGG, et al: Re-
duced thirst after water deprivation in healthy elderly men.
N Engl J Med 311:753-759, 1984
45. Mulkerrin E, Epstein FH, Clark BA: Aldosterone
responses to hyperkalemia in healthy elderly humans. J Am
Soc Nephrol 6:1459-1462, 1995
46. Miller PD, Linas SL, Schrier RW: Plasma demeclocy-
cline levels and nephrotoxicity. Correlation in hyponatremic
cirrhotic patients. JAMA 243:2513-2515, 1980
47. Serradeil-Le Gal C, Wagnon J, Valette G, et al: Nonpep-
tide vasopressin receptor antagonists: Development of selective
and orally active V1A, V2 and V1B receptor ligands. Prog Brain
Res 139:197-210, 2002
48. Gerbes AL, Gulberg V, Gines P, et al: Therapy of
hyponatremia in cirrhosis with a vasopressin receptor antag-
onist: A randomized double-blind multicenter trial. Gastroen-
terology 124:933-939, 2003
737
49. Wong F, Blei AT, Blendis LM, Thuluvath PJ: A
vasopressin receptor antagonist (VPA-985) improves serum
sodium concentration in patients with hyponatremia: A mul-
ticenter, randomized, placebo-controlled trial. Hepatology
37:182-191, 2003
50. Gheorghiade M, Niazi I, Ouyang J, et al: Vasopressin
V2-receptor blockade with tolvaptan in patients with chronic
heart failure: Results from a double-blind, randomized trial.
Circulation 107:2690-2696, 2003
51. Gheorghiade M, Gattis WA, O’Connor CM, et al:
Effects of tolvaptan, a vasopressin antagonist, in patients
hospitalized with worsening heart failure: A randomized
controlled trial. JAMA 291:1963-1971, 2004
52. Verbalis JG, Bisaha JG, Smith N: Novel vasopressin
V1A and V2 antagonist conivaptan increases serum sodium
concentration and effective water clearance in hyponatre-
mia. J Am Soc Nephrol 15:356A, 2004 (abstr SA-P0254)
53. Mallie JP, Bichet DG, Halperin ML: Effective water
clearance and tonicity balance: The excretion of water revis-
ited. Clin Invest Med 20:16-24, 1997
54. Ghali JK, Bisaha JG, Smith N: Efficacy of the vaso-
pressin V1A/V2 antagonist conivaptan in patients with euv-
olemic or hypervolemic hyponatremia. J Am Soc Nephrol
15:355A, 2004 (abstr SA-P0251)
55. Gross P, Bisaha JG, Smith N: Conivaptan, a novel
V1A and V2 antagonist, increased serum sodium and effec-
tive water clearance in patients with euvolemic or hypervo-
lemic hyponatremia. J Am Soc Nephrol 15:355A, 2004
(abstr SA-P0243)