Vasopressin antagonism: a future treatment option in heart failure

Pramod Sanghi, Barry F. Uretsky and Ernst R. Schwarz*

Divison of Cardiology, Department of Internal Medicine, The University of Texas Medical Branch, School of Medicine, 5.106 John Sealy Annex, 301 University Blvd, Galveston, TX 77555-0553, USA

Received 11 June 2004; revised 23 November 2004; accepted 16 December 2004; online publish-ahead-of-print 4 February 2005.

* Corresponding author. Tel: +1 409 772 9835; fax: +1 409 772 4982. E-mail address: erschwar{at}utmb.edu


    Abstract
 Top
 Abstract
 Introduction
 Vasopressin physiology
 Vasopressin in heart failure
 Vasopressin antagonists
 Current trials
 References
 
Arginine vasopressin plays an important role in volume homeostasis. Patients with heart failure have chronically elevated plasma vasopressin concentrations which may contribute to their clinical syndrome of fluid retention. Recently, a number of agents have been developed to antagonize the effects of vasopressin by targeting its V1a and V2 receptors, which are involved in vascular tone and free water regulation, respectively. Two vasopressin antagonists, in particular, tolvaptan and conivaptan, have shown promise in animal studies and small-scale human trials. The following is a review of current experimental and clinical studies using vasopressin antagonists and their potential role in the treatment of heart failure.

Key Words: Vasopressin • Antidiuretic hormone • Heart failure


    Introduction
 Top
 Abstract
 Introduction
 Vasopressin physiology
 Vasopressin in heart failure
 Vasopressin antagonists
 Current trials
 References
 
Heart failure commonly manifests as a syndrome of salt and water retention. Essential to this process is the activation of the sympathetic nervous system, the renin–angiotensin–aldosterone axis, and arginine vasopressin (AVP).1 Strategies for treating chronic heart failure have employed beta-adrenergic receptor blockers, angiotensin converting enzyme inhibitors, and aldosterone antagonists. The possible benefits of blocking vasopressin in patients with heart failure remains unclear. We review the potential role for vasopressin antagonists as therapeutic agents in patients with chronic heart failure.


    Vasopressin physiology
 Top
 Abstract
 Introduction
 Vasopressin physiology
 Vasopressin in heart failure
 Vasopressin antagonists
 Current trials
 References
 
The primary function of AVP, or antidiuretic hormone, is to regulate the body's water content and blood pressure by influencing the rate of water excretion by the kidney.2 Vasopressin is produced in the hypothalamus in response to two stimuli: low blood volume and hypernatraemia. Baroreceptors located in the carotid artery, aortic arch, and left atrium sense falls in blood pressure and directly stimulate neurones located in the supraoptic nuclei (SON) and paraventricular nuclei (PVN) of the hypothalamus to produce vasopressin (Figure 1). In addition, osmoreceptors located in the hypothalamus sense small changes in serum osmolality, which either stimulate or inhibit vasopressin release from the hypothalamus. These neurones project into the posterior pituitary where vasopressin is initially stored and then released into the circulation. Vasopressin receptors (V2) located in the renal collecting duct respond to elevated vasopressin levels by increasing free water re-absorption. Vasopressin receptors (V1a) located primarily in vascular smooth muscle cells respond to vasopressin with vasoconstriction.3 V1a receptors have also been identified in rat myocardium and may play a role in contractility by mobilizing endoplasmic reticulum calcium stores and generating inositol 3 phosphate.4,5



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Figure 1 Regulation of water balance by AVP. Osmoreceptors residing in the anteroventral third ventricle region of the hypothalamus detect decreases in serum osmolality thereby stimulating the production of AVP. Baroreceptors located in the left atrium, carotid sinus, and aortic arch detect arterial underfilling which stimulate neurons in the SON and PVN to produce AVP (the atrial receptors are mediated by the vagus nerve rather than blood pressure). The neurons of the SON and PVN project into the posterior pituitary gland where AVP is initially stored and then released into the circulation. V1a receptors located in the vascular smooth muscle sense increased levels of AVP and cause vasoconstriction. AVP also stimulates V2 receptors located in the collecting duct of the kidney which cause free water absorption.

 
The cascade of intracellular signalling events that allows vasopressin to perform its various functions has been elucidated within the last decade. The V1a receptor couples to specific G proteins that activate phospholipase C-beta, which leads to the release of intracellular calcium.6,7 The V2 receptor, on the other hand, couples to a Gs protein which, via a cAMP (cyclic adenosine 3',5'-monophosphate) dependent mechanism, allows for the active transport of water molecules.8 An important component in this cascade is the aquaporin-2 (AQP-2) water channel, which allows water molecules to be transported in a single file manner from the apical to the basolateral side of the principal cells of the collecting duct, allowing free water re-absorption back into the circulation (Figure 2).



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Figure 2 AVP signal transduction pathway in the collecting duct. Vasopressin binds to the V2 receptor on the basolateral surface of the principal cells of the collecting duct of the kidney. The receptor couples to Gs, a heterotrimeric GTP binding protein, which then binds to adenylate cyclase thereby increasing cAMP production. PKA is a multimeric protein which, when activated by cAMP, phosphorylates the AQP-2 molecule where it is delivered via cytoplasmic vesicles to the apical surface of the collecting duct. The water channels then allow a single file of water molecules to traverse the apical membrane in response to the osmotic gradient where they are returned back to the circulation.

 
As one would expect, circulating vasopressin plasma levels correlate directly with AQP-2 expression. It has been shown that exogenous administration of vasopressin in normal rats markedly increases AQP-2 trafficking on the apical membrane of collecting duct cells.9 In fact, an increase in AQP-2 protein levels has been noted in rats with heart failure and other diseases of impaired water excretion where the circulating vasopressin level are high.10 Interestingly, AQP-2 can be detected in the urine during upregulation of AQP-2 gene expression in the kidney corresponding with high serum vasopressin levels.11 Radioimmunoassay, allowing quantitative analysis of urinary AQP-2, may prove to be a useful marker of heart failure status much like that of brain naturetic peptide.


    Vasopressin in heart failure
 Top
 Abstract
 Introduction
 Vasopressin physiology
 Vasopressin in heart failure
 Vasopressin antagonists
 Current trials
 References
 
Serum vasopressin levels have been shown to be chronically elevated in several animal models of low-output and high-output cardiac failure as well as in humans with congestive heart failure.12,13 Data from the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment studies showed that patients with heart failure had significantly higher levels of vasopressin compared with control groups.14 This elevation occurred even in patients who were asymptomatic or at a mildly symptomatic stage of left ventricular dysfunction. The Survival and Ventricular Enlargement (SAVE) trial also demonstrated that high vasopressin levels were associated with worsened 1 year cardiovascular mortality.15 Therefore, it has been hypothesized that chronically high levels of circulating vasopressin may play an important role not only in the pathophysiology of the heart failure syndrome but also contribute to its disease progression.

The increased levels of circulating vasopressin seen in heart failure are paradoxical and inappropriate. In the presence of low cardiac output, baroreceptors in the carotid artery sense arterial underfilling and perceive the body as being volume depleted.1 Vasopressin is then released, allowing free water to be reabsorbed by the kidney despite an already oedematous state. This carotid baroreceptor response appears to override not only left atrial stretch receptors but also the osmoreceptors' attempts to suppress vasopressin levels. In fact, chronic heart failure appears to cause a resetting of the osmostat, which leads to persistent hypernatraemia.16 The reasons for this are not entirely clear; however, Uretsky et al.17 showed that heart failure patients had an exaggerated rise in plasma vasopressin levels in response to an osmotic contrast load, suggesting that ineffective circulating blood volume and not osmolality is the likely cause for this shifting of the osmotic threshold.

In addition to the body fluid effects, significant haemodynamic alterations have also been observed with high levels of circulating vasopressin.18 Intravenous infusions of vasopressin hormone in heart failure patients have been shown to increase systemic vascular resistance significantly and pulmonary capillary wedge pressure acutely. Vasopressin likely causes these detrimental changes in heart failure patients by stimulating arterial vasoconstriction and subsequently increasing afterload via V1a receptor activation. These effects are presumably exaggerated in the failed heart due to its inability to tolerate small changes in volume and afterload.

The chronic elevation of vasopressin levels seen in heart failure patients may ultimately have detrimental myocardial effects. In rats, vasopressin has been shown to stimulate myocardial cell hypertrophy.1921 In these studies, vasopressin administration was found to have a direct protein synthetic effect on cultured rat cardiomyocytes with concomitant increases in calcium concentration and activation of mitogen-activated protein kinase. Although it is not known whether vasopressin contributes to myocyte hypertrophy in humans, these mechanisms of cellular hypertrophy share many of the features seen in the typical hypertrophic response of the adult heart that is associated with other agonists such as angiotensin II and endothelin-1.19


    Vasopressin antagonists
 Top
 Abstract
 Introduction
 Vasopressin physiology
 Vasopressin in heart failure
 Vasopressin antagonists
 Current trials
 References
 
Initial investigations of vasopressin antagonists evaluated peptide analogues and were effective at increasing water excretion in rats. In humans, however, they had poor bioavailability, lacked a persistent effect, and even had partial agonistic effects.22 In 1991, Yamamura et al.23 introduced the first orally effective non-peptide selective AVP V2 receptor antagonist. Since that time, a number of selective antagonists have been tested for their safety and efficacy. Conivaptan is a well-studied compound that has a 10 : 1 selectivity for the V1a receptor which is found on vascular smooth muscle cells and cardiomyocytes.3 Intravenous conivaptan has been shown to inhibit dose dependently the pressor response of exogenous vasopressin given to dogs.24 In addition, conivaptan was found to inhibit AVP-induced protein synthesis of cardiomyoctyes,25 suggesting a potential role in preventing cardiac hypertrophy. In these animal studies, a substantial aquaretic effect was also demonstrated. Intravenous and oral forms were shown to increase urine flow without significant electrolyte changes.24 Dogs with pacing-induced heart failure also had marked diuresis with concomitant haemodynamic improvements in cardiac ouput, wedge pressure, and peripheral vascular resistance.26

One small human study looking at the pharmacokinetics of conivaptan administration in six normotensive subjects found a significant dual response as well. Not only did conivaptan inhibit vasopressin-induced skin vasoconstriction, but it also increased urine flow seven-fold and reduced urine osmolality from 600 mOsm/L to <100 mOsm/L.27 This open label study gave a single oral dose of 60 mg and a single intravenous dose of 50 mg at 1 week intervals. Its peak vasoconstrictor and aquaretic effects were observed at ~2 h after drug intake in both the oral and the intravenous forms.

A larger study of 142 patients with advanced heart failure (NYHA class III and IV) was conducted to determine whether conivaptan could show favourable haemodynamic changes in this population.28 This was a double blind randomized placebo controlled trial that used a single dose of 10, 20, or 40 mg intravenous conivaptan. There were significant reductions in right atrial and pulmonary capillary wedge pressures with the 20 and 40 mg intravenous doses of conivaptan compared with placebo. These acute haemodynamic improvements were accompanied by substantial increases in urine output without causing hyponatraemia or worsening the serum creatinine.

Tolvaptan is another AVP antagonist that has been extensively studied in animals. It is selective for the V2 receptor (29 : 1) found in the principal cells of the renal collecting duct. Animal studies have demonstrated efficacy. Oral administration to rats has shown increased urine volumes and decreased urine osmolality in a dose dependent manner.29,30 Tolvaptan also increases sodium excretion. As there is a proportionately greater amount of free water excretion, overall urine osmolality is reduced. In one study, this aquaretic effect persisted for the duration of the study of 4 weeks, although the greatest effect was seen on the first day.29 When direct comparisons with furosemide are made, no differences are appreciated with regards to urine volume at low and high doses.30 However, the excretion of sodium and overall electrolytes into the urine is less with tolvaptan compared with furosemide. Combination therapy is also promising as it has shown additive effects on urinary volume, free water excretion, and osmolality.

Two major human trials looking at tolvaptan in heart failure patients have been published.31,32 The first studied 254 patients with NYHA class I–III heart failure and compared the effects of three different oral doses of tolvaptan added to standard congestive heart failure (CHF) therapy.31 This randomized, double blind, placebo controlled trial in patients showing clinical evidence of volume overload gave oral tolvaptan for a duration of 25 days. Demographic and baseline characteristics were similar in the four groups, although a larger percentage of patients in the placebo group (81%) were taking an ACE inhibitor/angiotensin receptor blocker (ARB) compared with 67–69% in the tolvaptan treated groups. The average furosemide dose was 85 mg/day. The majority of patients were taking digoxin and either an ACE inhibitor or an ARB, but only 26% were taking a beta-blocker.

Tolvaptan was found to significantly decrease body weight and its effect was observed primarily on the first day (Figure 3). Overall, patients treated with tolvaptan had greater urine volumes, greater net fluid losses, decreases in urine osmolality, and greater mean total 24 h urinary sodium excretions. Tolvaptan treated patients had small but significant improvements in serum sodium but this effect gradually decreased over 25 days. No significant differences were observed in heart rates, blood pressure, renal function, potassium concentration, or vasopressin levels. The side-effects seen more commonly in the tolvaptan treated patients were thirst, dry mouth, and polyuria, which resulted in a few patients withdrawing from the study. The authors concluded that in stable heart failure patients, once a day tolvaptan, when added to standard therapy, was safe, well tolerated, resulted in increased urine output/overall weight loss, and tended to normalize the serum sodium. It is not clear whether the correction of hyponatraemia had any beneficial CNS effects. Specific assessments concerning mental status were not made; however, quality of life assessments showed no differences between the groups.



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Figure 3 Significant (P<0.001, Fisher's exact test) decreases in body weight were observed primarily on the first day of treatment with all three doses of tolvaptan compared with placebo. These reductions persisted throughout the 25 days of the study. (Adapted from ref. Gheorghiade et al.3)

 
The other major trial regarding tolvaptan in heart failure patients is Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) in CHF.32 This study randomized 319 patients admitted for decompensated heart failure to placebo vs. tolvaptan (30, 60, or 90 mg/day) continued for up to 60 days. The main outcome measures were change in body weight at 24 h after randomization, as well as death, hospitalization, or unscheduled outpatient visits for heart failure at 60 days after randomization. Baseline characteristics between the groups were reasonably well matched. As expected, after 24 h, a significant reduction in body weight was observed in patients who were treated with tolvaptan compared with those who received placebo. This effect was not dose dependent. At discharge, which occurred at a mean of 4 days after randomization, fewer tolvaptan treated patients complained of dyspnoea.

After 60 days, no significant differences in the primary endpoints of death, hospitalization, and worsening heart failure were demonstrated; however, a trend towards decreased mortality was observed in the tolvaptan group (P=0.18). A post hoc analysis observed that total mortality was lower in the tolvaptan treated groups in patients who had higher blood urea nitrogen (BUN) levels (>29 mg/dL) and signs of severe systemic congestion at randomization. Although these results are encouraging, the mortality benefits seen in this subgroup must be interpreted with caution and can only serve as hypothesis generating. In addition, 130 patients in the study discontinued their therapy prematurely. The most frequent side effect observed in the tolvaptan groups was excessive thirst seen in 7.7–11.9% of patients.


    Current trials
 Top
 Abstract
 Introduction
 Vasopressin physiology
 Vasopressin in heart failure
 Vasopressin antagonists
 Current trials
 References
 
Currently, a number of large multi-centre trials are underway to examine any potential long-term benefits that these agents may have in heart failure patients. ADVANCE (A Dose evaluation of a Vasopressin ANtagonist in CHF patients undergoing Exercise) is a double blind placebo controlled randomized trial investigating the effects of conivaptan on functional capacity by examining the change in exercise time to reach 70% of peak oxygen consumption.33 The hypothesis for this study is that blocking the V1a receptor should produce beneficial haemodynamic effects. EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) is another ongoing multi-centre trial designed to evaluate the long-term efficacy and safety of oral tolvaptan (30 mg daily) in subjects hospitalized with decompensated heart failure.34 Endpoints in this study are time to all-cause mortality, CV mortality, hospitalizations, serum sodium, and oedema. Positive results from these and other human trials are necessary before proper consideration of adding vasopressin antagonists to the armamentarium of heart failure therapy is given.


    References
 Top
 Abstract
 Introduction
 Vasopressin physiology
 Vasopressin in heart failure
 Vasopressin antagonists
 Current trials
 References
 

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