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Neurohormonal Activation in CongestiveHeart Failure and the Role

of Vasopressin

Kanu Chatterjee, MB

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asoactive neurohormonal systems (eg, sympatheticervous system [SNS], renin-angiotensin-aldosteroneystem, and arginine vasopressin [AVP]) are defenseechanisms designed to preserve arterial volume and

irculatory homeostasis during periods of low cardiacutput. Neurohormonal systems, which are normallytimulated under conditions of acute volume depletion,re activated by the low cardiac output and arterialressure. However, sustained and chronic activation of

hese systems, as occurs in congestive heart failure

CHF), can cause progressive ventricular remodeling and

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orsening heart failure. Vasoconstriction, water reten-ion, and increased blood volume are results of thectivation of the SNS, the renin-angiotensin pathway,nd AVP secretion. These effects can accelerate progres-ion of CHF, contributing to increased morbidity andortality. AVP regulates vascular tone and free-water

eabsorption, respectively, through the vasopressin V1a

nd V2 receptor subtypes and therefore is a potentialeurohormonal target in the treatment of CHF. �2005y Excerpta Medica Inc.

Am J Cardiol 2005;95(suppl):8B–13B

ongestive heart failure (CHF) is a complex clinicaldisorder resulting from any structural insult caus-

ng cardiac dysfunction associated with hemodynamicbnormalities, such as inadequate cardiac output, ab-ormal vascular resistance, and ventricular fillingressures. In patients with severe CHF, low cardiacutput, decreased end-organ perfusion, and low bloodressure lead to activation of various interrelated neu-ohormonal systems that contribute to progressiveentricular remodeling and CHF. These systems in-lude the sympathetic nervous system (SNS), natri-retic peptides, the renin-angiotensin-aldosterone sys-em (RAAS), endothelin-1, adenosine, tumor necrosisactor–� and interleukin-6, and arginine vasopressinAVP).1 Activation of these neurohormonal systemsccurs in patients with left ventricular dysfunctionithout overt CHF. In the past 20 years, increasednderstanding of the role of the neurohormonal sys-ems activated by myocardial injury has resulted in theevelopment of new therapeutic targets in the treat-ent of CHF. This article discusses the neurohor-onal systems that are activated in CHF, with a focus

n the role of AVP.

EUROHORMONAL ACTIVATION INONGESTIVE HEART FAILURE

Activation of vasoactive neurohormonal systemseg, SNS, RAAS, AVP) initially can maintain circu-atory homeostasis.2 Activation of the SNS increasesardiac contractility, heart rate, and systemic vasocon-triction, which provides an immediate means of in-reasing blood pressure. RAAS activation induces di-

rom the Chatterjee Center for Cardiac Research, Division of Cardi-logy, University of California, San Francisco, San Francisco, Califor-ia, USA.

Address for reprints: Kanu Chatterjee, MB, Chatterjee Center forardiac Research, Division of Cardiology, University of California,an Francisco, San Francisco, California. E-mail: chatteri@

ect systemic vasoconstriction and activates otherystems (eg, AVP, aldosterone) that contribute toaintaining adequate intravascular volume. AVP in-

reases free-water reabsorption in the renal collectinguct, thereby decreasing excretion of water and elec-rolytes and increasing blood volume.2 However,hronic activation of these systems (eg, due to CHF)an have deleterious effects on cardiac function andontributes to the progression of CHF (Figure 1).3–5

he increased vasoconstriction resulting from SNSctivation results in increased left ventricular after-oad. This, in turn, increases myocardial demand, leftentricular end-diastolic pressure, pulmonary capil-ary wedge pressure, and pulmonary congestion whileecreasing cardiac output. An activated adrenergicystem also produces myocyte necrosis directly. Thencreased intravascular volume induced by AVP-me-iated reabsorption of free water results in elevatedntracardiac pressure as well as pulmonary congestionnd edema. Systemic vasoconstriction mediated byngiotensin II increases left ventricular afterload andan also directly induce cardiac myocyte necrosis andlter the myocardial matrix structure.1 Angiotensinlso potentiates the SNS and AVP.

Counterregulatory vasodilatory mechanisms arelso activated in CHF, including the natriuretic pep-ide system, nitric oxide, and prostaglandins.6 How-ver, these mechanisms are generally not adequate toaintain cardiac function, systemic perfusion, or so-

ium balance. The end result of neurohormonal acti-ation in CHF is clinical deterioration and progressiveeft ventricular dysfunction.2

Neurohormonal activation manifests as increasesn plasma levels of AVP, renin, aldosterone, atrialatriuretic factor, and norepinephrine. It is well doc-mented that the degree of neurohormonal activations correlated with severity of heart failure. In a sub-tudy of Studies of Left Ventricular Dysfunction

SOLVD), baseline levels of plasma norepinephrine,

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lasma renin activity, plasma atrial natriuretic peptide,nd AVP were compared in control subjects, patientsith left ventricular dysfunction but no overt symp-

oms of CHF, and patients with overt CHF.7 Patientsith left ventricular dysfunction had significantlyigher levels of neurohormonal activation than controlubjects, and those with overt CHF had the highestevels. These data suggest that neurohormonal activa-ion occurs in the early stages of CHF when symptomsay not be apparent and that this activation increases

s patients progress from mildly symptomatic leftentricular dysfunction to overt CHF.

The level of neuroendocrine activation also ap-ears to be related to prognosis. In the Cooperativeorth Scandinavian Enalapril Survival Study (CON-ENSUS), levels of angiotensin, atrial natriuretic pep-

ide, norepinephrine, and epinephrine were signifi-antly higher among patients who died than those whourvived, regardless of whether they were randomizedo the enalapril or placebo group (Figure 2).8 In thattudy, patients with CHF who had plasma norepineph-

FIGURE 1. Neurohormonal activation in congestive heart failu

IGURE 2. Relation between neurohormonal activation and mortaeptide. (Reprinted with permission from Circulation.8)

ine concentrations above the median had a 6-month t

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urvival rate of only 32% compared with a rate of50% among patients with plasma norepinephrine

evels above the median. Similarly, baseline serumodium concentration, a correlate of plasma renin ac-ivity, has been found to be a significant predictor ofardiovascular mortality in patients with CHF.7 Theink between neurohormonal activation and long-termrognosis is also supported by studies that showmprovement in cardiac function after administra-ion of inhibitors of neurohormonal activation inatients with severe CHF. In �-blocker trials inhronic CHF,9 a significant reduction in morbiditynd mortality after treatment with �-blockers haseen documented. �-Blockade can suppress most ofhe adverse hemodynamic, electrophysiologic, andetabolic effects of the SNS in patients with CHF

nd may also suppress the RAAS.2 Similarly, an-iotensin-converting enzyme (ACE) inhibitors asell as angiotensin II receptor blockers, which sup-ress the activity of angiotensin II, have beenhown to improve indices of left ventricular func-

(Adapted from Braunwald Atlas of Heart Diseases Online.4)

in patients with congestive heart failure. ANP � atrial natriuretic

lity

ion and survival in patients with CHF.10

POSIUM: HYPONATREMIA IN CONGESTIVE HEART FAILURE 9B

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CTIVATION OF THE RENIN-NGIOTENSIN-ALDOSTERONE SYSTEMThe activity of the RAAS is central to the mainte-

ance of water and electrolyte balance and bloodolume.11 The enzyme renin is released primarily byhe juxtaglomerular cells of the kidney in response toctivity of the SNS, changes in renal perfusion pres-ure, reduced sodium absorption by the distal renalubules, or AVP release.12 Renin converts a precursor

olecule (angiotensinogen) to angiotensin I, which ishen converted by ACE to angiotensin II. Angio-ensinogen II produces several physiologic effects thatre important in fluid regulation,12,13 including vaso-onstriction and the stimulation of aldosterone fromhe adrenal cortex, which increases sodium ion resorp-ion by the distal renal tubules.14 Angiotensin II alsoodulates the thirst center. The production of angio-

ensin II by renin and ACE takes place systemically inlasma and also within specific tissues, including therain, heart, and blood vessels. In acute CHF, theecrease in renal blood flow caused by progressiveHF activates the RAAS. This increase in RAASctivity contributes to systemic vascular resistance.15

ctivity of the RAAS is blocked by ACE inhibitors,ngiotensin II receptor blockers, and aldosterone an-agonists (eg, spironolactone, eplerenone) of the min-ralocorticoid receptor.16

OLE OF ARGININE VASOPRESSINN CIRCULATORY HOMEOSTASIS

AVP is an antidiuretic hormone that regulates free-ater absorption, body osmolality, blood volume,lood pressure, cell contraction and proliferation, anddrenocorticotropin secretion.3 AVP is a vasoactiveormone that acts on the kidney to stimulate theonservation of solute-free water. It is also a potent

IGURE 3. Stimulation and production of arginine vasopressin. (Adoll Cardiol.15)

asoconstrictor. The hormone is synthesized in the w

0B THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 95 (9

eurosecretory cells of the paraventricular and su-raoptic nuclei of the hypothalamus and is excreted byhe posterior pituitary gland (Figure 3).4,15 AVP re-ease is stimulated by sensory cells known as osmo-eceptors, which are located in the supraoptic andaraventricular nuclei of the hypothalamus and whichespond to small changes in the osmolality of thextracellular fluid compartment. A change in osmola-ity of as little as 1% stimulates the release of AVProm the posterior pituitary gland.17 AVP is also stim-lated by a decrease in circulating blood volume ofpproximately 10%. A decrease in blood volumeauses “unloading” of pressure-sensitive barorecep-ors located in the left ventricle, aortic arch, carotidrtery, and renal afferent arterioles, which triggersVP release. Several other stimuli for AVP releaseave been identified, including norepinephrine andngiotensin II.18

The actions of AVP are mediated by 3 types ofasopressin receptor subtypes: V1a, V1b (also referredo as V3 receptors), and V2 receptors.19 V1a receptor–

ediated actions include vasoconstriction and myo-ardial hypertrophy, whereas V2-mediated actions areelated to water and sodium regulation. AVP activa-ion of the V1b receptors regulates, in part, the releasef adrenocorticotropin hormone from the pituitaryland (Table 1).1,20

The V1a receptor subtypes are found in the vascularmooth muscle cells, platelets, lymphocytes andonocytes, adrenal cortex, and myocardium.1 AVPodulates vascular tone via V1a receptors on vascular

mooth muscle cells. Any acute reduction in arterial,enous, or intracardiac pressure (eg, as occurs duringehydration, severe hypotension, or shock) is sensedy cardiopulmonary and sinoaortic baroreceptors,

ted from Braunwald Atlas of Heart Diseases Online4 and J Am

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hich then stimulate AVP release by the pituitary

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land.20 The binding of AVP to V1a receptors resultsn potent arteriolar vasoconstriction and a resultantncrease in systemic vascular resistance. In healthyndividuals, the increase in AVP does not produceignificant increases in blood pressure because AVP,hrough stimulation of V2 receptors, also helps lowereart rate and cardiac output, thereby reducing bloodressure.20 Supraphysiologic levels of AVP also re-uce cardiac contractility and coronary blood flowhrough V1a-mediated coronary vasoconstriction,hereas AVP levels in the normal physiologic rangeave the opposite effect, causing small transient in-reases in cardiac contractility.20

The V2 receptor subtypes are found primarily inhe cells of the renal collecting duct. Binding of AVPo V2 receptors on the cells of the renal collecting ductesults in stimulation of aquaporin-2, which is amongeveral water-channel renal proteins that increase theermeability of vascular membranes to water. Inser-ion of these water channels into the membranes ofells in the collecting duct of the kidney results inncreased free-water reabsorption and a decrease inlasma osmolality.21 In healthy individuals, when thelasma is hypertonic (ie, serum sodium exceeds 142mol/L [140 mEq/L]), plasma AVP concentrations

ncrease and urine becomes maximally concentratedn the collecting duct of the nephron. When plasma isypotonic (eg, serum sodium �135 mmol/L), plasmaVP concentrations are normally undetectable and therine is maximally diluted.22

V1b receptors are found in the anterior pituitary.VP action at V1b receptors modulates the release of

drenocorticotropin hormone and �-endorphin.22 Ad-enocorticotropin hormone–mediated release of aldo-terone may result in increased sodium and watereabsorption.3

OLE OF ARGININE VASOPRESSINN CONGESTIVE HEART FAILURE

Circulating AVP levels have been found to beignificantly elevated in patients with CHF comparedith healthy controls, with higher levels found in CHFatients with significant cardiac decompensation andyponatremia.7,23,24 Study findings showed AVP lev-ls in patients with advanced CHF were 9.5 pg/mLompared with 4.7 pg/mL in healthy age-matchedontrols.23 In a baseline evaluation of patients in

TABLE 1 Sites of Expression and Physiologic Actions of the Vaso

Vasopressin Receptor Subtype Site of Expression

V1a (V1-vascular) Liver, vascular smooth muscleadrenal cortex, kidney, splereproductive organs, brain

V1b (V3-pituitary) Corticotropin cells, possibly kpancreas, adrenal medulla

V2 (V2-renal) Renal collecting ducts

ACTH � adrenocorticotrophic hormone (corticotropin).Adapted with permission from Am J Cardiovasc Drugs1 and Am Heart J.20

OLVD, plasma AVP concentrations increased with V

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he severity of cardiac impairment, with the highestevels in those with overt symptoms of CHF.7 In-reases in AVP secretion occur in response to nonos-otic stimuli, such as the low arterial pressure and

ffective arterial volume characteristic of CHF.3herefore, AVP secretion may be elevated, despite

ow plasma osmolality and hypotonicity. Excess AVPctivity has several adverse effects on free-water re-bsorption, cardiac contractility, and vascular tone.he increased AVP activity in CHF may lead to an

ncrease in the number of aquaporin-2 channels in theenal collecting duct.21 Increased expression of aqua-orin-2 messenger RNA has been observed in ratodels of severe CHF. Rats with an elevated left

entricular end-diastolic pressure and reduced plasmaodium concentrations had a significant increase inquaporin-2 expression compared with rats withildly compensated CHF without elevated left ven-

ricular end-diastolic pressure or reduced plasma so-ium concentrations.25 The increased expression ofquaporin-2 and the resultant increase in free-watereabsorption, even under conditions of low plasmaodium concentrations, illustrate how excess AVP ac-ivity contributes to the development of hyponatremiand edema in CHF.

Elevations in circulating AVP levels are also asso-iated with hemodynamic abnormalities in patientsith CHF. Intravenous infusions of AVP significantly

ncreased systemic vascular resistance and pulmonaryapillary wedge pressure while decreasing cardiacutput and stroke volume in CHF patients.26 Thencrease in venous blood volume that results from V2eceptor–mediated water retention can increase pre-oad, leading to increases in pulmonary capillaryedge pressure and left ventricular filling pressure.

ncreases in afterload as a result of V1a activation andhe subsequent arterial vasoconstriction may also con-ribute to the hemodynamic changes associated withVP release.20 These mechanisms suggest that excessVP activity at both V1a and V2 receptors is respon-

ible for the adverse hemodynamic changes that occurn CHF. Therefore, dual AVP receptor antagonistsave the potential to attenuate these adverse effects.

In addition, AVP exerts potent mitogenic and hy-ertrophic effects on vascular smooth muscle cellsrimarily through activation of the V1a receptors,27

lthough there is some evidence that AVP activity at

ssin Receptor Subtypes

Physiologic Actions

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Vasoconstriction, human platelet aggregation,mitogenesis in vascular smooth muscle cells

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SIUM: HYPONATREMIA IN CONGESTIVE HEART FAILURE 11B

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itro, AVP has been found to induce a time-dependentnd concentration-dependent increase in the secretionf vascular endothelial growth factor in vascularmooth muscle cells.27 Thus, the V1 receptor–medi-ted actions of AVP may contribute to the cardiacemodeling that occurs after cardiac injury.

ASOPRESSIN BLOCKADE IN THEREATMENT OF CONGESTIVE HEARTAILURE

The integral role of AVP in regulating sodium andater reabsorption, cardiac contractility, and vascular

one, as well as the importance of AVP activation inhe progression of CHF, make it a potential neurohor-onal target in the treatment of CHF. Inhibition ofVP activity at the V2 and/or the V1a receptors maye useful in the treatment of patients with CHF whoave symptoms of volume overload (eg, pulmonarydema, congestion) with hyponatremia. Several V2-elective AVP antagonists and 1 V1a/V2-selectivegent have been studied in patients with CHF.

AVP antagonism at the V2 receptors appears toroduce effective and sustained reductions in conges-ion without worsening renal function or electrolytebnormalities.29 However, the clinical efficacy of V2eceptor antagonism may be offset by the activation of

1a receptors secondary to increased plasma AVPoncentrations.30 Inhibition of V1a receptors concur-ently has been shown to reduce AVP-induced proteinynthesis of cardiomyocytes in animal models,31

hich may help relieve cardiomyocytic hypertrophy.1a receptor blockade also reduces plasma norepi-ephrine and angiotensin II levels as a result of im-roved systemic hemodynamics.10

The SNS, angiotensin II, and endothelin-1, whichre potent vasoconstrictors, also stimulate the releasef AVP independent of changes in plasma osmolalitynd may contribute to the adverse effects on cardiacunction in CHF.20 In turn, AVP potentiates the he-odynamic and renal effects of angiotensin II and

orepinephrine.A study by Clair and colleagues10 showed that

lthough both V1a receptor blockade and angiotensinI receptor blockade reduced left ventricular loadingonditions, only combination blockade of both recep-or types resulted in improved left ventricular functions well as myocyte contractility. A second study byaitoh and associates32 was designed to evaluate the

ffects of blocking both V1a and V2 receptor–medi-ted AVP activity as well as angiotensin II activity.lso studied were the effects of conivaptan, a dualVP receptor antagonist, with or without addition of

he ACE inhibitor captopril in a rat model of CHF.32

he researchers found that conivaptan treatment alonenduced free-water excretion (by blocking V2-medi-ted AVP activity) as measured by decreases in bodyeight, whereas combination treatment also signifi-

antly lowered blood pressure and decreased plasmaatriuretic peptide, left and right ventricular mass, andung mass. Thus, simultaneous blockade of V and

1a

2 receptors and the renin-angiotensin pathway mayMH

2B THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 95 (9

e an effective approach to manage the vasoconstric-ion and water retention characteristic of CHF.

ONCLUSIONThe low cardiac output and arterial pressure char-

cteristic of CHF result in an abnormal and chronicctivation of neurohormonal systems. Activation ofhe SNS, the renin-angiotensin pathway, and AVPecretion results in vasoconstriction, edema, and in-reased blood volume. In the long term, these effectsan exacerbate left ventricular dysfunction and accel-rate progression of CHF, contributing to increasedorbidity and mortality. Antagonism of AVP activityith V1a-selective and V1a/V2-selective receptor an-

agonists has been shown to inhibit free-water reab-orption and improve hemodynamic parameters in pa-ients with CHF. Other neurohormones, such as atrialatriuretic peptide, brain natriuretic peptide, and en-othelin-1, have also been evaluated as possible tar-ets in the management of CHF.

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opic275.htm. Accessed November 16, 2004.5. Creager MA, Faxon DP, Cutler SS, Kohlmann O, Ryan TJ, Gavras H.ontribution of vasopressin to vasoconstriction in patients with congestive heart

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, Adams KF Jr. Vasopressin: a new target for the treatment of heart failure. Ameart J 2003;146:9–18.

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1. Nielsen S, Kwon TH, Christensen BM, Promeneur D, Frokiaer J, Marples D.hysiology and pathophysiology of renal aquaporins. J Am Soc Nephrol 1999;0:647–663.2. Guyton AC. The kidneys and body fluids. In: Guyton AC, Hall JE, eds.extbook of Medical Physiology. Philadelphia: WB Saunders, 1996:308–372.3. Goldsmith SR, Francis GS, Cowley AW Jr, Levine TB, Cohn JN. Increasedlasma arginine vasopressin levels in patients with congestive heart failure. J Amoll Cardiol 1983:1:1385–1390.4. Szatalowicz VL, Arnold PE, Chaimovitz C, Bichet D, Berl T, Schrier RW.adioimmunoassay of plasma arginine vasopressin in hyponatremic patients withongestive heart failure. N Engl J Med 1981:305:263–266.5. Xu DL, Martin PY, Ohara M, St John J, Pattison T, Meng X, Morris K, KimK, Schrier RW. Upregulation of aquaporin-2 water channel expression inhronic heart failure rat. J Clin Invest 1997:99:1500–1505.6. Goldsmith SR, Francis GS, Cowley AW Jr, Goldenberg IF, Cohn JN.emodynamic effects of infused arginine vasopressin in congestive heart failure.Am Coll Cardiol 1986;8:779–783.

7. Tahara A, Saito M, Tsukada J, Ishii N, Tomura Y, Wada K, Kusayama T,atsu T, Uchida W, Tanaka A. Vasopressin increases vascular endothelial growth

ab

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actor secretion from human vascular smooth muscle cells. Eur J Pharmacol999;368:89–94.8. Tahara A, Saito M, Sugimoto T, Tomura Y, Wada K, Kusayama T, Tsukada, Ishii N, Yatsu T, Uchida W, Tanaka A. AVP-induced mitogenic responses ofhinese hamster ovary cells expressing human V1A or V1B receptors. Pflugersrch 1999;437:219–226.9. Ohnishi A, Orita Y, Takagi N, Fujita T, Toyoki T, Ihara Y, Yamamura Y,noue T, Tanaka T. Aquaretic effect of a potent, orally active, nonpeptide V2ntagonist in men. J Pharmacol Exp Ther 1995;272:546–551.0. Burrell LM, Risvanis J, Johnston CI, Naitoh M, Balding LC. Vasopressineceptor antagonism: a therapeutic option in heart failure and hypertension. Exphysiol 2000;85S:259S–265S.1. Tahara A, Tsukada J, Tomura Y, Wada K, Kusayama T, Ishii N, Yatsu T,chida W, Taniguchi N, Tanaka A. Effect of YM471, a nonpeptide AVP receptor

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